(dhacm) therapy: the new standard in bioactive wound healing

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


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


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


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


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


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


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


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


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


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


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® 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


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


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


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

(dhacm) therapy: the new standard in bioactive wound healing

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