Supplement to Podiatry Today® March 2015
Supported by
PRESENTERS
William W. Li, MD, is President, Medical Director, and
Vickie R. Driver, DPM, MS, FACFAS, is a Professor of Or-
Co-Founder of the Angiogenesis Foundation. He has been
thopedic Surgery (Clinical) at the Brown University School of
actively engaged in angiogenesis research and clinical devel-
Medicine, the Division Chief of Podiatric Surgery for the New
opment for three decades . He has held appointments on the
England VA Healthcare Medical Center in Providence, R.I., and
clinical faculties of Harvard Medical School, Tufts University,
the Director of Research for Hyperbarics and the Wound Care
and, Dartmouth Medical School. Dr. Li is a Founding Director of the American College
Center at Rhode Island Hospital. She is also the President of the Board of Directors for
of Wound Healing and Tissue Repair, an Honorary Fellow of the American College
the Association for the Advancement of Wound Care (AAWC), and has served on the
of Wound Care Specialists, and has served as advisor and consultant to leading
AAWC Board of Directors for seven years. and a Fellow of the American Board of Foot
global public and private companies. Dr. Li is involved in national and international
and Ankle Surgery. A well-known national and international educator, researcher
efforts to advance the applications of angiogenesis-based therapeutics across di-
and surgeon in the fields of limb preservation and wound healing, Dr. Driver has
verse medical fields, including oncology/hematology, cardiology, ophthalmology,
published over 100 peer-reviewed journal articles and abstracts, and participated
vascular surgery, dermatology, and wound care. Dr. Li has been published in many
as an investigator in over 60 clinical research trials. She has directed post-doctoral
leading peer-reviewed medical journals. Dr. Li has disclosed that he is a consultant
fellowship training in both wound healing and limb preservation for 15 years. Dr.
to MiMedx, Novadaq and Smith & Nephew.
Driver has disclosed that she is a scientific advisor to MiMedx.
Lisa J. Gould, MD, PhD, FACS, is an Affiliate Professor in
Gary Gibbons, MD, is the Medical Director of the South
the Department of Molecular Pharmacology and Physiolo-
Shore Hospital Center for Wound Healing in Weymouth, Mas-
gy at the University of South Florida. She has served on the
sachusetts, and a vascular surgeon by training. Dr. Gibbons
executive board of the Wound Healing Society for more than
was the first director of the Deaconess/Joslin Diabetic Wound
10 years and is an active participant in multiple academic
Center, dedicating his career to diabetic patients with wounds
societies. She is also the Director of the Wound Recovery and Hyperbaric Medicine
complicated by peripheral arterial disease who are in need of revascularizarion. Dr.
Center at Kent Hospital, Warwick, Rhode Island. Dr. Gould is board certified by the
Gibbons is a Professor of Surgery at the Boston University School of Medicine, and
American Board of Plastic Surgery, achieved a Certificate of Added Qualifications in
has been in practice for over 40 years. Dr. Gibbons has disclosed that he is a clinical
Hand Surgery, and is a Fellow of the American College of Surgeons. She has been
consultant to MiMedx, Spiracur, Celleration and Osiris Therapeutics.
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 Vet-
Paul Glat, MD, is the Director of the Division of Plastic Sur-
erans Hospital (2007-2012), where she provided wound and surgical care for our
gery, Director of the Burn Unit, and Director of Cleft Palate
nation’s wounded warriors, including treatment of pressure sores in the 100-bed
and Craniofacial programs at St. Christopher’s Hospital for
spinal cord unit. Dr. Gould has disclosed that she is a consultant to MiMedx.
Children in Philadelphia. Dr. Glat is consistently in demand as
a guest lecturer at plastic and reconstructive surgery meetings 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.
2
INTRODUCTION
wounds in the United States; the evolu-
people with diabetes will develop a di-
A multidisciplinary expert advisory
tion and emergence of amniotic mem-
abetic foot ulcer,2 while venous ulcers
panel of five leading physicians was
brane tissues in wound care; different
account for 70%-90% of ulcers found
convened in October, 2014, in Boston,
processing techniques and their effects
on the lower leg.3
Massachusetts to determine the appro-
on amniotic membrane grafts in facili-
priate use of amniotic tissue products
tating healing; the unique structure
for the treatment of acute and chron-
of EpiFix®; and functional differences
ic wounds. Primary objectives of the
between EpiFix® and other amniotic
expert advisory panel were to discuss
membrane tissue products.
how preserved cytokines and chemokines are helping define the multifaceted roles of EpiFix®, a dehydrated
human amnion/chorion membrane
(dHACM) allograft (MiMedx Group Inc.,
THE PROBLEM OF CHRONIC
WOUNDS AND AMNIOTIC
MEMBRANE AS A TREATMENT
OPTION
“The chorion
membrane from the
amniotic sac is not
directly associated
with maternal tissue
and therefore would
not promote an
immune response if
transplanted.”
Marietta, GA), in the treatment of dia-
Acute and chronic wounds are prev-
betic foot ulcers and venous leg ulcers;
alent and burdensome to patients and
to review the growing body of scien-
the U.S. health care system. It has been
Amniotic membrane tissue is a treat-
tific and clinical evidence associated
estimated that 1 to 2% of the popula-
ment option that has been shown
with EpiFix®; and to exchange practical
tion will experience a chronic wound
to facilitate healing of these difficult
information regarding the use of Epi-
during their lifetime. In the U.S. alone,
wounds. However, to make good clin-
Fix® in addressing challenges in plastic,
chronic wounds affect 6.5 million pa-
ical decisions regarding the use of am-
cosmetic and reconstructive surgery.
tients.1 Effective treatments for chron-
niotic membrane tissue, it is important
This supplement was created to pro-
ic wounds such as diabetic foot ulcers
to understand the nature of the tissue,
vide an overview of the discussions
(DFUs) and venous leg ulcers (VLUs) are
the characterization of different tissue
and emerging data supporting the
urgently needed to help reduce time
layers as well as the different process-
clinical use of EpiFix®. Topics of this
to healing, associated treatment costs,
ing techniques for various amniotic
supplement include current issues and
and the risk of further complications.
membrane products and the associat-
advances in treating acute and chronic
It is estimated that up to 25% of all
ed healing rates.
— Dr. Gould
3
EpiFix® Dehydrated Human Amnion/Chorion Membrane (dhacm) Therapy
AMNIOTIC TISSUE: ORIGIN OF
AMNION AND CHORION
plate is intertwined with the placenta
on within the first trimester of devel-
and is often confused with the chorion
opment to become the amniotic sac.
Amniotic membrane, or the amni-
membrane, which is part of the amni-
Amniotic membranes are composed
otic sac, is comprised of an inner layer
otic sac and does not come in contact
principally of three types of material:
called the amnion and an outer layer
with maternal tissue (Figure 1).
structural collagen and extracellular
called the chorion. The amniotic sac is
As the embryo continues to grow,
matrix, biologically active cells and a
formed after conception and during the
the amnion layer surrounding the fetus
large number of important regenera-
fetal maturation process.4 The chorionic
expands and conjoins with the chori-
tive molecules.
The use of amniotic membrane in
the clinical setting has a history spanning over 100 years. At present, amniotic products are delivered in multiple
configurations, including single and
Amniotic Sac
Chorion
multi-layer formats, and they are processed with varying techniques. Since
Amnion
all amniotic tissues are not processed
in the same way, the preserved tissues
Chorionic Plate
cannot be viewed as equal with respect
to their healing properties.
Umbilical Cord
Placenta
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.
PURION® PROCESSING OF
EPIFIX® — THE POWER OF
AMNION AND CHORION
When the amniotic sac is being processed 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 amnion and chorion layers and, due to the
proprietary PURION® Process utilized,
retains a substantial amount of growth
factors to enhance wound healing.
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.
4
The PURION® Process for EpiFix® includes gentle separation of the placen-
The New Standard in Bioactive Wound Healing
tal tissues, removal of the spongy layer
cells, blood, and soluble growth factors.
EPIFIX® AND SCIENTIFIC RIGOR
from between the amnion and chorion
In comparison, as described above, the
To further outline the unique ben-
layers (Figure 2), cleansing, reassem-
PURION® Processed EpiFix® uses a gen-
efits of the processing technique uti-
bling of the amnion and chorion layers,
tle cleansing wash that removes the
lized for EpiFix®, a series of published
and gentle tissue dehydration. The PU-
maternal blood while preserving the
scientific papers in collaboration with
RION® Process removes blood compo-
growth factors, cytokines, chemokines
the Georgia Institute of Technology
nents while protecting the intricate ex-
and extracellular matrix without dam-
and the Stanford University Medi-
tracellular matrix (ECM) of the amnion
aging the cells. The PURION® Process
cal School characterizing PURION®
and chorion membrane, leaving intact
retains the native cells and pericellular
Processed EpiFix® was discussed by
cells and the extracellular matrix. When
matter in the tissue after processing.
the panel members. They reviewed
dehydration is completed, the graft is
cut to multiple sizes, packaged, and
sterilized, yielding an EpiFix® allograft
that can be stored at ambient conditions for up to 5 years.
“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.”
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
— Dr. Glat
As mentioned earlier, different processing techniques yield varied quantities of preserved growth factors, cytokines, 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
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 products. (Adapted from Koob, et al.)5
5
EpiFix® Dehydrated Human Amnion/Chorion Membrane (dhacm) Therapy
proposed mechanisms of action re-
in preserving wound healing and in-
tors to help induce a patient’s healing
ported in each of the papers. The
flammatory regulators than other pro-
response. The cells act as simple de-
panelists also discussed published
cessed tissues tested.9
livery systems for introducing growth
scientific
papers
comparing
factors into the wound. It has been
pro-
cessed amnion-only grafts versus two
MiMedx® grafts, AmbioDry2™, a single
DIFFERENCES IN TYPES OF
SKIN SUBSTITUTES
reported, however, that the cells only
survive up to 72 hours in the wound
environment.10
layer amnion opthalmic graft, and Epi-
The effectiveness of cellular ver-
Fix®, an amnion and chorion layered
sus bio-preserved cellular materi-
graft for the preservation of wound
als in treating wounds was debated
healing and inflammatory regulators
between panel members. Amniotic
(Figures 3A and 3B).5-8 An additional
membrane tissues are ideal for trans-
EpiFix® is a bioactive tissue matrix
animal study demonstrated that the
plantation as they have been found to
that contains bio-preserved intact,
PURION® Process was more effective
be immunologically privileged and do
non-living cells (Figure 4). There are
not require decellularization. This dif-
a multitude of growth factors and cy-
ferentiates amniotic tissue from a xe-
tokines contained within the EpiFix®
nograft, which is derived from animal
allografts even though the cells are
tissues and needs to be decellularized
not viable. It has been demonstrat-
to reduce a patient’s immunological
ed that EpiFix® induces fibroblasts to
response to the implanted material.
proliferate, migrate, and upregulates
Cellular products can contain living or
basic fibroblast growth factor (bFGF),
non-living cells. Living cell grafts can
granulocyte stimulating factor (GCSF)
contain keratinocytes, fibroblasts and/
and placental growth factor (PlGF)
or other cells that secrete growth fac-
biosynthesis.7
“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.”
EPIFIX®: A BIOACTIVE TISSUE
MATRIX ALLOGRAFT
— Dr. Li
Figure 4. EpiFix® contains intact cells and
different amounts of various growth factors.
6
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
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 fibroblast and human microvascular
endothelial cell proliferation in vitro.5-8
The cellular signals contained in the
tissue upregulate the production of angiogenic factors, and they recruit and
promote engraftment of endogenous
progenitor cells, including hematopoietic cells, likely via stromal cell-derived
factor-1 (SDF-1) and other growth factors. This indicates that angiogenesis
and postnatal vasculogenesis could
be contributing modes of action for
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
EpiFix® activity, and that the bioactive
Growth Factor Content in EpiFix® vs.
Competitive Single Layer Grafts
nature causes the surrounding cells to
respond by upregulating biosynthesis
100
An important consideration is how
the growth factors interact with each
other. Amnion and chorion contain different amounts and types of the various growth factors. The chorion layer is
four to five times thicker and contains
more growth factors as a result (Figure 6). EpiFix® contains about 20 times
more chemokines and cytokines than
competitive products comprised of
amnion alone (Figure 7).5 In addition,
Percentage of Growth Factors
of growth factors to promote healing.9
80
PURION® Processed
80±6.6%
Growth Factors
60
Chorion
40
20
20±6.6%
Growth Factors
Amnion
5% Growth Factors
0
EpiFix®
Competitor Single Layer
Amnion Grafts
PURION® processed dHACM contains 20 times more growth
factors than competitor single layer amnion products
Figure 7. Growth factor content in EpiFix® vs. selected single layer grafts5
dermal fibroblasts have demonstrated an increase in production of bFGF,
GCSF, and PlGF when cultured in the
presence of 5 and 10 mg/mL EpiFix®
A DEEPER LOOK AT
ANGIOGENESIS AND WOUND
HEALING
crocirculation plays a significant role
in angiogenesis because the complex
branching patterns that occur are
extract. These are distinguishing fac-
When a wound is present, it is vi-
specialized depending on the tissue
tors that set EpiFix® apart from amni-
tal to be able to restore the perfusion
in which they reside. Endothelial cells
on-only grafts.
provided by the tissue capillaries. Mi-
form channels in various ways depend-
7
EpiFix® Dehydrated Human Amnion/Chorion Membrane (dhacm) Therapy
sis model in which one mouse genetiEpiFix® implanted in
normal mouse
EpiFix®
GFP +
mouse
Normal
mouse
Sham
Control ADM
TEI Primatrix®
BM-MSCs in GFP
mouse fluorescent
green
Surgically join skin so mice
share blood circulation”parabiosis”
cally engineered to have stem cells containing 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 donor to the wild type mouse when the latter was implanted with EpiFix®. Results
Figure 8. Parabiosis model to determine the amount of MSC migration and engraftment9
showed the EpiFix® induced, without
further manipulation, greater recruit-
ing on the tissue, and if the goal is to
ly realized that a single growth factor
ment of engrafted GFP cells inside the
restore capillaries, there must be an un-
has limitations. Since then, there have
implant when compared to the sham
derstanding of what control signals are
been incremental efforts to advance
implant, and an acellular bovine der-
required to rebuild blood vessels within
the science of wound care.
mis (PriMatrix®, TEI Biosciences, Boston,
the tissue in which they are growing.
“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
EpiFix® research has contributed to
MA) control (Figure 9). The investigation
this area. In a scientific study evaluat-
supported the hypothesis that EpiFix®
ing properties that support angiogen-
could serve as a stem cell magnet that,
esis, EpiFix® was shown to stimulate
when applied to a wound, could attract
increased angiogenesis compared to
endogenous stem cells to engraft into
control over a one-month observation,
the area of pathology. EpiFix® contains
when microvessels in the area of an im-
growth factors that provoke circulating
plant were counted.6 While it normally
progenitor cells to migrate and engraft
takes time for blood vessels to gener-
at the implant site, resulting in angio-
ate, quick initiation of the angiogene-
genesis restoring blood flow to the
sis process was observed when EpiFix®
damaged tissue (Figure 10).
was introduced. Authors of this study
proposed that the quick response may
GROWTH FACTORS IN EPIFIX®
INFLUENCE ANGIOGENESIS
With respect to wound angiogen-
result from the ability of EpiFix® to stim-
esis, there were many early efforts
ulate fibroblasts to secrete other import-
After appropriate sharp debridement
directed at applying a recombinant
ant growth factors that in turn stimulate
and moist wound care, EpiFix® modu-
growth factor to injured tissue. In
other cell types present in a wound to
lates the chronic wound environment,
1998, the wound community had its
release their own set of growth factors.6
resulting in normalization of many of
first recombinant growth factor with
In a separate study performed at
the dysfunctional cellular responses.
platelet-derived growth factor (beca-
Stanford University Medical School, Epi-
During this process, growth factors
plermin). While this was a major step
Fix® was shown to stimulate in vivo mes-
and cytokines from EpiFix® amplify
from a biotechnology perspective,
enchymal stem cell (MSC) migration.9
secretion of additional growth factors
wound care professionals also quick-
The investigators employed a parabio-
from endothelial cells to help acceler-
8
The New Standard in Bioactive Wound Healing
ate wound healing. Additional growth
**
factor signaling is important and not
30
limited to just a single growth factor,
compared with
but the multitude of growth factors
healthy skin and
**
25
sham implant.
that are contained in EpiFix® and may
††
be secreted by responding host cells at
be produced by endogenous platelets,
neutrophils, monocytes, macrophages,
and stem cells that are helping the
compared with
††
**
control ADM
15
(Primatrix®)
**
Intact Skin
10
Sham Implant
healing process.
Stem cell participation occurs fairly
5
Control ADM
early within the wound-healing cascade.11 When stem cells, a stem cell
magnet such as EpiFix®, or growth factors like SDF-1 are added into this process, the biology of wound healing is
presumably being boosted.12 The opti-
Indicates P ≤
0.05 for EpiFix®
20
GFP + Cells
the wound site. These same factors can
Indicates P ≤
0.05 for EpiFix®
EpiFix®
0
Day 3
Day 7
Day 14
Day 28
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
mal time to get stem cells into a wound
space is unclear.
When there is a stem cell magnet recruiting endogenous stem cells, these
native stem cells would migrate from
the surrounding tissue or through
the circulation to 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. Although inflammation is usually
considered destructive, in this case,
some inflammatory immune cells are
important to provide additional angiogenic 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 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
9
EpiFix® Dehydrated Human Amnion/Chorion Membrane (dhacm) Therapy
DIABETIC FOOT ULCERS – A
GROWING EPIDEMIC
Ulcers Surface Area Reduction (%)
Percent Surface Area Reduction of Ulcers Over Time
100
Amidst much new dialogue and
80
guidelines about treating diabetic
foot ulcers (DFUs), it is apparent that
60
DFUs are a growing epidemic. In 2005,
40
SOC
EpiFix
20
n=25
0
01 2345 6
-20
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
Time Point (Week)
51% after 5 years.14 In addition, it has
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
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
been reported that within 3 years of
surgery, there is an approximate 50%
mortality rate in these patients.15 Likewise, Armstrong showed that 50% of
patients receiving a diabetes-related
amputation will die within 5 years and
suggested that the impacts of diabetes-related wounds and amputation
are a greater burden on our healthcare
gin healing. In order for angiogenesis
tissue oxygenation. The expert panel
and regeneration to occur, adequate
was intrigued that the cytokine profile
wound bed preparation is imperative
in EpiFix® shows such multiplicity, and
to remove any infection, necrotic tis-
that the release kinetics are also differ-
sue, or pressure that may combat en-
ent. While more research is needed to
graftment of the patient’s stem cells.
determine how this fits into the physi-
Preventing amputations in patients
As a healing wound returns local
ological model, clearly when wounds
with diabetes should always begin
tissue to physiological perfusion, the
heal normally, they actually rely on this
with good ulcer care, including but
need for pro-angiogenic stimulus is
repertoire of coexisting inhibitors and
not limited to assessment of the pa-
profoundly reduced. The healing tissue
stimulators. Maturation at the very end
tient, his or her comorbidities and the
actively down-regulates the production
of angiogenesis to create good stable
wound, surgical debridement and con-
of growth factors, and inflammation
blood vessels involves recruitment of
trol of infection, vascular evaluation
also subsides. Healed tissues also up-
MSCs. In this case, MSCs are the precur-
and treatment, off-loading/pressure
regulate angiogenesis inhibitory factors
sors to pericytes and smooth muscle
relief, and appropriate dressings. While
that help prune the microcirculation
cells that support the newly formed ves-
some diabetic ulcers may be superficial
to baseline levels required for proper
sel and stabilize that circulation.
and can heal with conservative stan-
10
system than cancer. 16
GOOD STANDARD OF CARE
TECHNIQUES IMPERATIVE FOR
QUALITY HEALING
The New Standard in Bioactive Wound Healing
dard of care treatment, they are often
The initial RCT compared 4- and
notoriously slow to resolve, taking up
6-week healing rates of 13 patients with
to several months to heal. Indeed, one
13 wounds treated with EpiFix® versus
meta-analysis showed that less than
12 patients with 12 wounds treated
25% of DFUs heal with conservative
with moist wound healing (control).19
care within 3 months.17 Wound Healing
Wound treatment for both groups in-
Society guidelines recommend consid-
cluded surgical debridement, weekly
eration of advanced wound therapies if
moist wound healing dressing chang-
a diabetic ulcer does not reduce in size
es, and offloading. In addition, patients
by 50% or more after 4 weeks of stan-
in the EpiFix® arm of the study received
dard therapy.18
an EpiFix® graft applied every 2 weeks
under a nonadherent dressing. The re-
CLINICAL EVIDENCE SUPPORTS
EARLY INTERVENTION WITH
EPIFIX® FOR TREATING DFUS
sults showed 77% of EpiFix®-treated
9-12 Month Follow-up
Recording Percent of Ulcers
that Remained Healed vs.
Ulcers that Reopened (n=18)
100
80
94.4%
60
40
20
0
5.6%
Remained Healed
Reopened
Figure 13. Long-term follow-up showed 94.4% of
patients remained healed at 9-12 months. (Adapted from Zelen, et al.) 21
wounds healed in 4 weeks and 92%
EpiFix® treatment. The study patients
healed within 6 weeks compared to 0%
served as their own control based on
Results of four peer-reviewed clini-
and 8% of control wounds, respectively
data collected during the initial 6 weeks
cal studies of EpiFix® for the treatment
(P<0.001).19 The EpiFix® group received
of the RCT. Ninety-one percent of these
of Wagner grade I and II DFUs were
an average of 2.5 grafts to closure (Fig-
patients healed within 10 weeks. 20
reviewed by the panel. These studies
ures 11 and 12). This low rate of healing
A long-term follow-up study of DFUs
included a 25-patient randomized,
for control is similar to rates reported
healed with EpiFix® in the initial RCT
controlled clinical trial (RCT)19 as well
with standard of care in other studies of
and crossover studies was also con-
as a retrospective crossover20 and long-
advanced wound care products rang-
ducted with 18 of the 22 eligible pa-
term follow-up study for this patient
ing from 2-5% at 4 weeks and 4-10%
tients returning for follow-up at 9-12
population.21 A prospective 40-patient
after 6 weeks.24, 25 Based on published
randomized comparative study22 of
healing rates of other advanced wound
weekly versus biweekly application of
healing modalities, the initial protocol
EpiFix® for the treatment of DFUs was
for this EpiFix® RCT included enrollment
also reviewed. It is important to note
of 80 patients. However, once the data
that a fifth clinical trial was published
showed that 90% of patients treated
after the roundtable convened and has
with EpiFix® were healed at 6 weeks, it
been included in order to convey the
was recommended by independent ad-
growing clinical body of evidence for
judicators that the trial be concluded.
EpiFix®. This latest RCT is a 60-patient,
A follow-up DFU retrospective cross-
multicenter comparative effectiveness
over study20 included control patients
study of EpiFix® vs. Apligraf® (Organo-
from the initial RCT who did not achieve
genesis, Canton, MA) vs. the standard
greater than 50% closure after 6 weeks
“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.”
of care for the treatment of DFUs.23
and elected to crossover to receive the
— Dr. Driver
11
EpiFix® Dehydrated Human Amnion/Chorion Membrane (dhacm) Therapy
examinations
ing DFUs has also been investigated in
weekly versus weekly groups, respec-
showed 5.6% (1/18) of patients had a
a prospective, randomized single-cen-
tively. Complete healing occurred in
recurrent DFU and 94.4% remained ful-
ter clinical trial of 40 patients treat-
50% versus 90% by 4 weeks in the bi-
ly healed (Figure 13).21
ed with EpiFix®.22 The mean time to
weekly and weekly groups, respective-
Weekly versus biweekly application
complete healing was 4.1 ± 2.9 versus
ly (P = 0.014). The total percent healed
(every other week) of EpiFix® for treat-
2.4 ± 1.8 weeks (P = 0.039) in the bi-
was 92.5% within the 12-week study
months.21
Follow-up
period. All but one patient (39/40,
97.5%) had >50% reduction in wound
EpiFix® Rates of Healing (n=40)
P=0.091
P=0.014
P=0.047
size within 4 weeks and 37/40 pa-
P=0.231
tients (92.5%) treated with EpiFix® had
complete healing within 12 weeks.21
P=0.009
While a similar number of grafts were
used on each healed wound (biweekly 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 EpiFix® biweekly, despite a greater mean
HbA1c in the patients who received
weekly applications (Figure 14). The re-
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
sults of these studies validate the initial
RCT data showing that EpiFix® was ef-
Complete Healing at 4 Weeks
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
85%
P=0.001
35%
n=20
n=20
P=0.001
30%
n=20
Complete Healing at 6 Weeks
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
EpiFix®Apligraf® Control
fective in healing 90+% of DFUs.
Results of a landmark multicenter
95%
RTC of clinical and economic comP=0.0006
parative effectiveness of EpiFix® vs.
P=0.0001
Apligraf® vs. the standard of care for
45%
the treatment of DFUs were not yet
35%
available at the time of this roundtan=20
n=20
n=20
EpiFix®Apligraf® Control
Figure 15. Comparison of complete healing rates at weeks 4 and 6 (n=60). (Adapted from Zelen, et al.) 23
ble panel discussion, but are included
in this supplement.23 The RCT included
60 patients divided into 3 study arms.
Duration
EpiFix® (n=20)
Apligraf® (n=20)
Standard Care (n=20) EpiFix® Vs. Apligraf®
Median
Healing Time
13 Days
49 Days
49 Days
Figure 16. Comparison of speed of healing. (Adapted from Zelen, et al.)23
12
P=0.0001
EpiFix® Vs. Standard
Care
P=0.0001
The New Standard in Bioactive Wound Healing
All patients received weekly sharp de-
sults show the use of EpiFix® for Wag-
that EpiFix® use may well decrease
bridement and offloading with a re-
ner grade I and II DFUs healed twice as
the direct and indirect costs of DFU
movable cast walker. Twenty patients
many wounds, almost four times faster,
treatment, and prevent longer-term
in the control group received daily col-
at one-fifth the cost, and had far less
medical complications such as ampu-
lagen-alginate dressing changes with
graft wastage (one-sixtieth) compared
tation. Results from this trial not only
a moisture-retentive dressing. Twenty
to Apligraf®. The results also suggest
reconfirmed the 90% plus healing rates
patients in the EpiFix® arm received
weekly applications of EpiFix® and a
Average Patient Graft
Cost in Study
Total Cost of Grafts
Applied in Study
moisture-retentive dressing, and 20
patients received weekly applications
$200,000
of Apligraf®. The endpoints for this
$175,000
study were the percentage of patients
$150,000
who achieved complete healing, time
$125,000
to heal, and cost of treatment. Study
$100,000
ulcers achieving ≤20% healing with
$75,000
standard care treatment during the
$50,000
two-week run-in period remained in
$25,000
$10,000
$9,216
$184,315
$7,500
$5,000
$2,500
$33,379
$1,669
$0
the trial.
$0
EpiFix®
Apligraf®
EpiFix®
Apligraf®
The study results are presented in
Figures 15, 16, 17 and 18. These re-
Figure 17. Comparison of costs related to graft material used in study. (Adapted from Zelen, et al.) 23
Total Number of Grafts
Purchased in Study
Total cm2 of Grafts
Purchased
160
125
124
cm2
3,000
cm2
Number of Grafts Purchased
120
4,000
75
50
159
5,456
5,000
100
25
Total cm2 of Grafts
Applied in Study
80
68.2
2,000
43
Mean of
2.15 grafts
per study
patient
Mean of
6.2 grafts
per study
patient
40
1,000
0
0
EpiFix®
Apligraf®
154
EpiFix®
0
Apligraf®
EpiFix®
Apligraf®
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
13
EpiFix® Dehydrated Human Amnion/Chorion Membrane (dhacm) Therapy
year in the U.S.,26 costing up to $18 bil-
ry response with a resultant buildup
lion annually.27 Patients with VLUs have
of tissue breakdown products within
been shown to utilize more medical
these tissues. Activated white blood
resources with two times the cost for
cells enter the tissues and release their
private payers and 50% more for Medi-
chemicals, resulting in further tissue
care than patients without VLUs.27 The
damage, leading to auto-digestion
prevalence of VLUs increases with age
and increased buildup of degradation
and they are 2 to 3 times more com-
products. This impedes diffusion of ox-
mon in females.28 VLU recurrence rates
ygen and other nutrients into affected
range from 54%-78%29 and the many
areas. The result of this impediment
risk factors include venous insufficien-
can be death of the tissues surround-
cy, obesity, immobility, phlebitis, deep
ing the veins, which leads to a venous
vein thrombosis, and family history.30
ulcer. Venous ulcers typically occur on
VLUs have a major negative impact on
the lower leg near the ankle where vein
the quality of life in affected patients
pressures are highest and are typically
due to pain, physical impairments
surrounded by skin with a rusty brown
(immobility), social impairments, and
color from extravasated iron deposits.
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
Figure 19. Superficial and deep venous
drainage requires multiple systems throughout the leg, including the superficial system,
deep system, and connecting veins, or
perforators.
lost from work.32
When there is impaired venous return in any part of the system, which
can include deep, superficial, or mixed,
of EpiFix® in the treatment of Wag-
red and white blood cells stick to the
ner grade I and II DFUs, the trial also
vessel walls and red blood cells (RBCs)
demonstrated the superiority of EpiFix®
break down. This leaves iron depos-
over both Apligraf® and the standard
its in the walls, which leak out into
of care in complete healing, speed to
the tissues. Normally, venous return
healing, and cost of treatment.
brings blood back to the heart, but if
the valves become dysfunctional or
A LOOK AT VENOUS LEG
ULCERS
there is an obstruction, the blood flows
back down as far as it can, even into the
Venous leg ulcers (VLUs) develop in
feet. This dysfunctional process creates
an estimated 2.5 million patients per
a chemical response, an inflammato-
14
“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
The New Standard in Bioactive Wound Healing
PRINCIPLES OF STANDARD OF
CARE FOR VLUS
Standard therapy for venous disease incorporates leg compression to
reduce the diameter of the vein, increasing 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 reducing edema. Graduated compression
Figure 20. Primary study outcome measured the percentage of patients with ≥40% wound
reduction over 4 weeks. (Adapted from Serena, et al.)35
reduces reflux and improves venous
outflow for the calf muscle pump to
get blood back to the heart, decreasing 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 emotional therapy.34 Also, when addressing
Figure 21. Mean percent reduction in size of VLU during the study period. (Adapted from Serena, et al.)35
the hostile wound environment, sharp
surgical debridement includes de-
er compression alone was evaluated
significantly reduced in size compared
pendently draining pus and removing
in treating VLUs. EpiFix® was applied
to those treated with multilayer com-
devitalized tissue, bone, bacteria pro-
once or twice during a 4-week study
pression only (Figure 21). Based on the
teolytic enzymes and senescent cells.
period.35 Reduction in wound size
surrogate endpoint of ≥40% wound
of ≥40% occurred in a significantly
area reduction within 4 weeks as a
greater numbers of patients receiv-
predictor of overall healing,36,37,38 these
ing EpiFix® versus those receiving
data from the first controlled trial of
EpiFix® has demonstrated effective-
multilayer compression therapy only
EpiFix® VLU treatment indicate that
ness in treating VLUs. In a multicenter
(33/53 [62%] vs 10/31 [32%]; P = 0.005)
EpiFix® is effective in treating VLUs and
RCT, effectiveness of EpiFix® and mul-
(Figure 20). Over the 4-week study pe-
serves as a defining point for further
tilayer compression versus multilay-
riod, VLUs treated with EpiFix® were
clinical studies.
EPIFIX® FOR THE TREATMENT
OF VLUS
15
EpiFix® Dehydrated Human Amnion/Chorion Membrane (dhacm) Therapy
EPIFIX® DELIVERS NEW
CLINICAL OPTION IN PLASTIC
SURGERY
Figure 22. Case Report: A toddler presented
with a partial-thickness scald burn on the
face.
applied, and the patient’s pain resolved
quickly after covering the raw nerve
endings in the burn. The patient re-
The mechanisms behind the ben-
turned home the day after application
eficial effects of EpiFix® in treat-
and returned one week later for fol-
ing chronic extremity wounds may
low-up (Figure 23). The pain was man-
translate to the treatment of other
aged and the burn was healing well at
types of wounds, including burns,
that point. At 3 to 4 weeks after the ap-
radiation-induced wounds, surgical
plication, the patient was getting some
wounds, breast reconstruction, and
pigment back in the skin and showed
pressure ulcers. Other clinical indi-
no signs of future scarring (Figure 24).
cations for consideration include
The clinician found the membrane
Mohs surgery, laser resurfacing and
to be flexible and easy to work with
hair restoration. The potential advan-
during the treatment.
tages of using EpiFix® for burns and
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.
other plastic surgery cases versus
Case Report 2:
skin grafts include improved mobil-
Non-Healing Wound in a Cancer
ity with the applied membrane and
Patient
reduction in scarring in the healed
A patient with pancreatic cancer
area. EpiFix® helps heal a tissue de-
presented with a non-healing wound
fect while reducing inflammation. It
secondary to abdominal resection
reduces scarring and causes no clin-
(Figure 25). The wound had persisted
ical signs of rejection. While there are
for about one year despite multiple
no RCT data yet describing the use
applications of porcine small intesti-
of EpiFix® in acute wounds, multi-
nal submucosa. A new treatment plan
ple cases were presented during the
was initiated. The wound was curetted
panel meeting of effective EpiFix®
at the bedside and EpiFix® was applied
treatment of acute wounds in plastic
(Figure 26). At two weeks post initial
surgery. Two acute wound cases are
application, the wound was curetted
described below.
again and given a second application
(Figure 27). Four weeks following the
CASE REPORTS
first application, the wound was al-
Case Report 1:
most completely healed (Figure 28).
Pediatric Partial-Thickness Burn
A toddler presented with a parFigure 24. Case Report: At 2-4 weeks, the
patient was getting some pigment back in the
skin and showed no signs of future scarring.
16
CONCLUSION
tial-thickness, typical scald burn on the
Amniotic membrane is an import-
face and head (Figure 22). EpiFix® was
ant and complex tissue that is natu-
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 affects 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-
Figure 25. Case Report: A patient with pancreatic cancer presented with a non-healing
wound secondary to abdominal resection.
Figure 26. Case Report: The wound was curetted 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.
kines that improve the effectiveness
of the matrix and the overall product,
particularly when compared to amnion-only grafts.5-8 A controlled animal
study demonstrated that the PURION®
Process used with EpiFix® is more effective 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 numerous bioactive components that
continue to be present and released
BENEFITS OF EPIFIX® AMNIOTIC MEMBRANE TISSUE
over time to promote healing. Mech-
• EpiFix® is a dehydrated amniotic membrane tissue comprised of both amnion
and chorion membranes.
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 publications as have the effects of the growth
factors on various cell types from fibroblasts to endothelial cells to stem
cells. Investigators have demonstrated
the capability of EpiFix® to mobilize,
• 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 numerous bioactive components that are released over time to enhance healing.
• With in vivo studies, with the application of EpiFix®, native stem cells are attracted 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.
17
EpiFix® Dehydrated Human Amnion/Chorion Membrane (dhacm) Therapy
recruit and serve as a stem cell magnet
to make a difference in healing rates,
to enhance healing.
with weekly applications yielding su-
Initial EpiFix® RCTs have demon-
perior outcomes over biweekly applica-
strated significantly improved healing
tions.22 Health care providers and payers
rates over the standard of care in treat-
will continue to welcome data from ad-
ing DFUs.19,23 The results significantly
ditional EpiFix® studies involving dia-
demonstrated a 90% plus healing rate
betic and venous leg ulcers.
and with long-term follow-up, 94.4%
Finally, in addition to the manage-
remained healed at one year.21 Results
ment of chronic wounds, the panel
from a most recent landmark multi-
members discussed other important
center RCT not only reconfirmed the
wound types that may benefit from
90% plus healing rates of EpiFix® in
treatment with EpiFix®, including burns,
the treatment of DFUs, the study also
reconstructive surgery, Mohs surgery,
demonstrated the superiority of Epi-
cosmetic or impaired healing situa-
Fix® over both Apligraf® and standard
tions such as radiation desquamation,
of care in complete healing, speed
non-healing wounds in elderly patients,
to healing and cost of treatment.23 A
and all diabetic wounds not healing in a
number of randomized, multicenter
timely sequence.
trials are being designed or are underway 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 increased 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 angiogenesis and healing to occur with
EpiFix® application, adequate wound
bed preparation is imperative. EpiFix®
application frequency for DFUs appears
18
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19
Freezers are for ice cream
Not for wound healing anymore
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 study 7
• Achieved ≥40% wound area closure at 4 weeks in 62% of
VLU study patients8
EpiFix sets the
new standard for
wound closure.
®
Store at ambient conditions • Sizes to fit a variety of wounds • Reduce graft waste & cost to closure
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
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.
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.