emerging evidence on advanced wound care for diabetic … · emerging evidence on advanced wound...

Supported by Advanced BioHealing

Robert G. Frykberg, DPM, MPHLee C. Rogers, DPM

Emerging Evidence OnAdvanced Wound Care For Diabetic Foot UlcerationsApplying evidence-based medicine and the standard of care toimprove patient outcomes

Proceedings from the Superbones West conference heldOctober 21-24, 2010 in Las Vegas, Nevada.

Supplement to Podiatry Today

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Cannot be reprinted without written permission of Podiatry Today and HMP Communications

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Introduction ........................................................................................................................................3

Key Concepts From The 2010 Consensus Statement On Diabetic Foot UlcerationsReviewing the 2010 consensus recommendations on managing neuropathic foot ulcers in patients with diabetes, this author discusses theemerging evidence on the diagnostic workup of these patients, wound assessment, adjunctive debridement and when clinicians shouldconsider advanced therapies to expedite healing.

By Lee C. Rogers, DPM .......................................................................................................................4

The Science Of Advanced Wound Care: What Should You Be Using In Your Office?Given the sobering reality of mortality rates for those with diabetic foot complications, this author emphasizes thorough vascular workupsand appropriate referrals, underscores the importance of aggressive management to prevent complications such as amputation, and surveysthe literature on current and emerging advanced therapies.

By Robert G. Frykberg, DPM, MPH ......................................................................................................8

References .........................................................................................................................................13

Authors/Disclosures

Lee C. Rogers, DPM, is the Associate Medical Director of the Amputation Prevention Center at Valley Presbyterian Hospital in Los Angeles. Dr.

Rogers is the Chair of the Foot Care Council for the American Diabetes Association (ADA).

Dr. Rogers has disclosed that he is on the Speaker’s Bureau for Advanced BioHealing, KCI, Wound Care Technologies, Integra LifeSciences, Synovis

Orthopedic and Woundcare, and NetHealth, Inc.

Robert G. Frykberg, DPM, MPH, is Chief of the Podiatry Section and the Podiatric Residency Director at the Carl T. Hayden Veterans Affairs

Medical Center in Phoenix. Dr. Frykberg is a Fellow and Past President of the American College of Foot and Ankle Surgeons.

Dr. Frykberg has disclosed that he is on the Speaker’s Bureau for Advanced BioHealing and Regenesis Biomedical. He has received grant/research

support from Advanced BioHealing and Ogenix. Dr. Frykberg is a consultant for Advanced BioHealing, Regenesis Biomedical and Healthpoint.

Table of Contents

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Introduction

Chronic diabetic foot ulcers (DFUs) represent a major concern for pa-

tients with diabetes with an annual incidence rate of 2 percent and a

lifetime risk of 15 to 25 percent.1-3 Approximately 85 percent of lower

extremity diabetic amputations are preceded by a DFU and 15 percent of DFUs

lead to amputation.1,4 Delayed healing can impair patient mobility and quality of

life, and can significantly increase the risk of serious complications including drug-

resistant infection, hospitalization and amputation.5-7

In November 2009, a panel of experts from various disciplines related to wound

care convened to evaluate current standards for the management of DFUs in light

of newly emerging techniques and treatment modalities. The panel balanced sci-

entific evidence with the practicality of applying various methods, and concluded

that objective assessment of wound severity and healing progress followed by responsive treatment decisions was essential to achieve

timely healing. In April 2010, the panel published the “Consensus Recommendations on Advancing the Standard of Care for

Treating Neuropathic Foot Ulcers in Patients with Diabetes.”8

Practitioners are encouraged to utilize the consensus recommendations in conjunction with their own deductive reasoning and

good clinical judgment to improve healing outcomes for patients with DFUs.

In the following articles, based on lectures given at the Superbones West conference in October 2010, we discuss the imple-

mentation of the 2010 consensus recommendations for the treatment of DFUs in a practical clinical setting and share our strategies

for facilitating improved healing and optimal outcomes in this patient population.

— Robert G. Frykberg, DPM, MPH

Lee C. Rogers, DPM

Lee C. Rogers, DPMRobert G. Frykberg,DPM, MPH

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Reviewing the 2010 consensus recommendations on managing neuropathic foot ulcers in patients with diabetes, this authordiscusses the emerging evidence on the diagnostic workup of these patients, wound assessment, adjunctive debridement andwhen clinicians should consider advanced therapies to expedite healing.

Key Concepts From The 2010 Consensus Statement On Diabetic Foot Ulcerations

By Lee C. Rogers, DPM

It has been estimated that the number of people with diabeteswill nearly double worldwide in the next 18 to 20 years.9

Currently, in the United States, there are nearly 24 million

people with diabetes, approximately 8 percent of the population.10

Foot complications are the most common reason for people with

diabetes to be admitted to the hospital in both the U.S. and the

United Kingdom.11The lifetime risk of a diabetic foot ulcer ranges

between 15 to 25 percent among patients with diabetes and ap-

proximately 15 percent of diabetic foot ulcers will result in some

type of amputation.1-4

Given the challenges of treating this high-risk population, it is

critical to have a strong understanding of the current standard of

care in managing diabetic foot ulcerations. A consensus panel of

thought leaders in this arena recently published “Consensus Rec-

ommendations on Advancing the Standard Of Care For Treating

Neuropathic Foot Ulcers In Patients With Diabetes.”8 I would

like to discuss these recommendations that were published in 2010

as a supplement to Ostomy Wound Management and WOUNDS.

The supplement offers a concise, informative document of the

standard of care for diabetic foot ulcerations.

Not only is it important to look at this from a morbidity stand-

point and a quality of life standpoint, one should also consider

mortality rates among those who have had a diabetic foot ulcer

and amputation. One study cites a 68 percent mortality rate in

five years after an amputation.12 In a 10-year prospective study,

Iversen and colleagues found a history of diabetic foot ulcers to

be a significant predictor of mortality in patients 65 years of age

and older.13 If you look at these studies they reviewed in this con-

sensus supplement, just having a neuropathic ulcer has a 45 percent

mortality rate in five years.14This is not to say that having an ulcer

is going to tip the scale and the patient is going to die in five years.

However, when somebody has a diabetic foot ulcer, it really is the

tip of the iceberg of what is going on systemically inside of that

patient. These are very sick people and they do have a high risk of

death and, in many cases, a higher risk than some cancers.14

There is also a significant economic burden. A couple of years

ago, Armstrong, Lavery and I looked at 2007 data and estimated

that $30 billion was spent in the U.S. that year on diabetic foot

ulcers and amputations.15 More recently published estimates sug-

gest that somewhere between $70 and $80 billion is spent yearly

on diabetic foot ulcers, amputations and peripheral arterial disease

in the U.S.16

Citing a systematic literature review on the quality of care in

the U.S., the panelists for this consensus supplement noted that

somewhere between 30 and 50 percent of patients are not being

treated according to current evidence, and I think that is prob-

ably an underestimation.17Whether you work in a wound center

or an office, you see people come in who are referred from a

general doctor. What are the things they are doing with these

wounds? They are putting on betadine or a wet to dry dressing

or Silvadene. I see this a lot. These therapies are not evidence-

based at all so you get an idea of the type of treatments that are

out there for diabetic foot ulcers and the quality of the evidence

behind those treatments.

The consensus panel also note estimates that somewhere be-

tween 20 and 30 percent of the care is either inappropriate or

dangerous, and I think that some of these examples can be

lumped into the same category.17 Putting undiluted betadine on

an uninfected wound kills not only the bacteria but kills the

good cells as well.

In the consensus supplement, the panelists discuss several aspects

of treating a diabetic foot ulcer but they also review the various

assessments that need to be done to come up with the appropriate

diagnosis. They discuss the appropriate history and physical, labo-

ratory screening tests, and nutritional assessment as well as lifestyle

and psychosocial assessments, which are really important but often

are not considered in these patients. The consensus panel also dis-

cuss the neurologic and vascular evaluations, how to evaluate the



5

foot ulceration, various wound classification systems, how to look

for infection, different imaging modalities and when hyperbaric

oxygen therapy (HBOT) comes into play.

One of the key concepts that came out of this consensus sup-

plement is that any wound that stalls after two to four weeks needs

to be re-evaluated.8What is the definition of stalling? Well, in some

of the work that I do, I review these cases in which the physician

notes are pretty subjective and lack anything objective. For exam-

ple, there may be a note saying the wound is getting better or it is

staying the same. Noting objective measurements can help ensure

sound documentation. The best way to do something like this is

to make sure that you have accurate measurements. Most people

use a ruler to measure wounds or you can use something more

advanced like a three-dimensional Silhouette camera (ARANZ

Medical). It gives you an exact measurement of the wound as op-

posed to length times width, which is only accurate for a box.

Whatever approach you use to measure wounds, just make sure

you are using the same approach every time so you are consistent.

Insights On Diagnostic ScreeningWhen it comes to laboratory screening, you definitely need to

be paying attention to the patient’s glucose control. You cannot

just rely upon the patient’s general doctor, the internist or his

or her endocrinologist for this. Every person on the multidisci-

plinary team plays a role in helping educate these patients about

their glucose control.

The American Diabetes Association (ADA) recommends a hemo-

globin A1c (HbA1c) level of below 7%.18 I am also the chair for the

Foot Care Council for the ADA and I will be a little critical of our

own association because in Europe the HbA1c recommendation is

below 6.5% and I think the ADA is looking at this now.19 One good

thing that has come out recently is that the ADA now recognizes the

use of the HbA1c for the diagnosis of diabetes and not just for the

tracking of the patient’s overall glucose control.18That is important

because previous to this, you were either having to use fasting blood

sugars or a glucose tolerance test, and often patients would have to

come back on a separate visit or have a scheduled lab test done. Now

the ADA says you can just use the HbA1c for diagnosis.

We all know how to do neurologic screenings for those at risk

for diabetic foot ulcers. Often when somebody comes into your

office and he or she has a diabetic foot ulcer already, the patient is

going to have neuropathy. The late Paul Brand, MD, was an or-

thopedic surgeon who studied neuropathic injuries in feet in

India. He once observed that any patient who walks into your of-

fice with a wound and is not limping on that foot has neuropathy,

and I think that is true.

In regard to the vascular examination, the panelists for the con-

sensus supplement recommend doing a tiered approach via pri-

mary, secondary and tertiary tiers. Your primary tier is your clinical

exam. The clinical exam always involves the palpation of pedal

pulses. While the absence of pedal pulses is a good indicator of

poor blood flow, the presence of pedal pulses is not a good indi-

Armstrong and colleagues noted that patients who havea neuropathic ulcer have a 45 percent mortality rate infive years. They also found that patients with diabeticfoot ulcers, in many cases, have a higher mortality riskthan some cancers.14

Photo co

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PM.

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. Rog

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6

cator of good blood flow. One cannot assume the blood flow is good

if the patient has pedal pulses. You need to do something else to

look at the patient’s blood flow. If the patient has an ulcer, he or

she is going to have to get some type of noninvasive test and there

are a number of noninvasive tests that can be done. If the patient

has an ulcer and has gangrene or necrosis, you need to get a vas-

cular consult as well.

Keys To Assessing The WoundWhen it comes to the foot and ulcer examination, there are dif-

ferent wound classifications you can use. While people are most

familiar with the Wagner classification, the problem with this clas-

sification is that it lumps the depth of the wound and whether

there is gangrene present into the same linear relationship.20,21

When you are assessing the prognosis of these patients and

whether an amputation is necessary, this does not end up being a

linear relationship.

When Lavery and Armstrong were at the University of Texas,

they developed a different system, which is similar to how you

grade and stage cancers. They were grading and staging

wounds.22,23They looked at the combination of wound depth and

the presence of infection/ischemia. When you are assessing the

wound and the potential risk for amputation, this diabetic wound

classification system is a pretty powerful indicator of who is going

to have an amputation. It just makes sense that as the wound be-

comes deeper or as the wound becomes more complicated, the

risk of amputation increases.

When you are assessing for infection, it is important to realize

that infection is a clinical diagnosis. There is not one single lab test

you can do to diagnose an infection. Your culture and sensitivity

should only be taken if there is an infection, and that is only used

to ensure your patient is on the right antibiotic. It is not used to

diagnose an infection so that is an important concept.

The probe to bone test was popularized right after Grayson and

colleagues published their article in 1995.24 It was coined as the

“5 cent bone scan” because it had an 89 percent positive predictive

value for osteomyelitis. However, the problem with the probe to

bone test in that study is that it was done in a population of people

who had moderate and severe diabetic foot infections. They al-

ready had a high risk of having osteomyelitis when they entered

into the study. Accordingly, this inflates the positive predictive value

of the probe to bone test.

Fleischer and colleagues did a study and looked at the probe to

bone test in a clinic population, similar to what we see in our of-

fices or our wound centers. They found that the probe to bone

test was no better than flipping a coin in determining the presence

of osteomyelitis so it is important to consider that as well.25

Therefore, the probe to bone test is a useful modality but should

be limited to the same type of environment and scenario (moderate

to severe infections) that Grayson and colleagues studied.24

Pertinent Treatment PrinciplesIn regard to treatment, the consensus panel discussed the manage-

ment of arterial disease; addressing the wound environment; in-

fection control; offloading; hyperbaric oxygen therapy; advanced

therapies; and amputation.

When you look at the factors that lead to limb loss, the three

most common factors are gangrene, infection and a chronic or

non-healing wound. So those are paramount when you are eval-

uating these patients.

When it comes to debridement of foot wounds, it is important to

remove all the undermining tissue. Shear forces will prevent this tissue

from ever re-adhering to the underlying wound bed. You can also

consider something like hydrosurgical debridement or maggots. We

only use maggots in cases in which patients are too sick to go to the

operating room (OR). I would much rather take patients to the OR

to perform a thorough surgical debridement over using maggots but

they do have their place.

100

80

60

40

20

0

≥ 50% PAR

< 50% PAR

Week One Week Two Week Three Week Four

PAR Status at Weeks One-Four

No.

of D

FUs

Hea

led

by 1

2 W

eeks

Assessing The Percent Area Reduction (PAR) In DFUs At Four Weeks33

Snyder and colleagues corroborated that the percent area reduction (PAR) in DFUs at week four is the best prognostic indicator of healing by 12 weeks because it provides the highest specificity and sensitivity.

Adapted with permission from Snyder RJ, Kirsner RS, Warriner RA 3rd, et al.Consensus recommendations on advancing the standard of care for treatingneuropathic foot ulcers in patients with diabetes. Ostomy Wound Manage.2010;56(4 Suppl):S1-S24.



7

One of the important concepts with debridement is how it plays

into the whole paradigm of wound healing. In a randomized, mul-

ticenter study, Steed and colleagues looked at the use of a recombi-

nant human platelet-derived growth factor (Regranex, Systagenix)

and debridement for diabetic foot ulcers. They noted lower rates of

healing in centers where less debridement was performed and this

was independent of the treatment group.26

For example, for the placebo group at center #1, wound debride-

ment occurred on 19 percent of patient visits and only 10 percent

of the patients healed over 16 weeks. In the Regranex group at center

#1, wound debridement occurred on 15 percent of patient visits and

only 20 percent of patients healed at 16 weeks. At center #6, wound

debridement occurred on 87 percent of the visits for the placebo

group and 25 percent healed in 16 weeks. However, the combination

of Regranex and debridement at center #6 occurred on 81 percent

of visits and 83 percent of patients healed over 16 weeks.26

No matter what you are using, whether it is bioengineered tissue,

negative pressure wound therapy or Regranex, it is important to

combine debridement with that and perform debridement on a

weekly basis.

I will not go into a lot of detail on how to treat infections. It is

important to take an appropriate culture. Do not swab the top of the

wound as doing so will lead to recurrence of contaminating bacteria.

Offloading: When The ‘Gold Standard’ Isn’t PracticalOffloading is where the podiatrist plays a key role on the wound

healing team because nobody else on the multidisciplinary team un-

derstands anything about offloading and we can really help bring that

understanding to the team and educate the other members.

It is often said that the total contact cast is the gold standard in of-

floading and there is literature to support this.27-30 However, practical

use of this modality is another issue. There are a lot of impediments

to doing a total contact cast. It is time consuming and the materials

are sometimes difficult to get. The TCC-EZ (MedEfficiency) is a rel-

atively newer device. I just started using this but it seems to be a lot

easier to put on than the other total contact cast.

You can also consider taking a removable cast walker and rendering

it irremovable. One of the problems with removable cast walkers is

in the name. They are removable so patients will get home, take it

off, walk and fail to adhere to recommendations.

Knowing When To Consider Advanced TherapiesThere are five tenants to good wound care. These tenants include:

• management of vascular disease;

• management or ruling out of infection;

• offloading;

• debridement; and

• providing a moist wound healing environment.

However, even when conservative wound care is provided, there

is still a pretty pitiful healing rate. In a study involving 622 patients

with neuropathic ulcers, Margolis and colleagues found that after

employing these five tenants of wound care, only 24 percent of these

patients healed at 12 weeks and only 31 percent of them healed at

20 weeks.31 This is a big problem and you need to know when to

move to something more advanced.

One of the problems with considering advanced therapies is that

we as clinicians used to think of advanced therapies as last resorts and

I think this consensus panel supplement is helping to change the way

we think about advanced therapy modalities. While these modalities

are not first-line options, they should be put into the paradigm a little

bit earlier than where they are used now.

Sheehan and colleagues looked at the rate of wound closure for

diabetic foot ulcers and found that if the wound had not closed by

at least 50 percent over four weeks, there was a 91 percent chance it

was not going to heal in 12 weeks.32This is a very powerful indicator

to move to a more advanced modality. This four-week indicator for

moving to advanced therapy is one of the main tenants of the con-

sensus panel supplement. Snyder and co-workers noted similar find-

ings.33 They actually saw a dichotomy between healers and

non-healers after two weeks of conventional wound care, but they

still recommended four weeks as the strongest indicator. (See “As-

sessing The Percent Area Reduction (PAR) In DFUs At Four Weeks”

on page 6.)

When you are talking about advanced therapies, there are

only a handful of products that have gone through the rigors of

an FDA trial. The modalities that are FDA-approved for diabetic

foot ulcers are Regranex, Apligraf (Organogenesis) and Derma-

graft (Advanced BioHealing).26,34-36 There are a lot of other de-

vices and modalities that you hear about for diabetic foot ulcers,

but they don’t have the same level of evidence behind them as

the FDA-approved treatments do. Vacuum Assisted Closure

(VAC) therapy (KCI) may be an exception since it was origi-

nally FDA approved via 510K equivalency. However, there are

now large randomized, controlled trials proving its efficacy.37

The consensus panel shows that since prolonged healing times

increase the risks of morbidity, infections and hospitalizations,

expeditious wound closure is a primary goal of diabetic foot

ulcer treatment. The consensus panel recognizes that the afore-

mentioned 50 percent area reduction at four weeks should be

used as a clinical decision point to consider advanced therapies,

and they view this as the new standard of care in treating dia-

betic foot ulcers.8 n



8

First of all, we have to define what is a chronic wound.

Lazarus defined a chronic wound as one that fails to pro-

ceed through the normal temporal sequence of wound

repair.38This is in contrast to an acute wound which does follow

the normal temporal course of repair in a timely fashion. We

know that chronic wounds have great social, psychological, phys-

ical and economic cost in our country. Chronic wounds con-

sume a great deal of our healthcare dollars not just in the United

States but worldwide.39

Diabetic foot ulcers are a major problem. There are reportedly

over one million patients developing diabetic foot ulcers in the

U.S. each year, and approximately 15 percent of diabetic foot ul-

cers will progress to amputation.40

It is important for us to understand the important complex

interrelationships between the underlying pathophysiology of

the diabetic lower extremity and how they can merge to create

a foot ulcer. We discussed pathways to ulceration and amputation

in the diabetic foot guidelines we published in the Journal of Foot

and Ankle Surgery in 2006.41

We know that the primary risk factor for almost any lower

extremity problem in diabetes is usually neuropathy. Whether the

patient has an infection, amputation, foot ulceration or a defor-

mity like a Charcot deformity, neuropathy is always a primary

risk factor. When it comes to neuropathy, we shouldn’t just con-

sider sensory neuropathy. We also need to consider the important

roles of motor neuropathy and autonomic neuropathy.

Autonomic neuropathy leads to many of the microvascular

changes that we see. The microneurovascular changes found in

these patients are primarily due to increased arteriovenous

shunting due to the sympathetic failure. There is an inability to

mount a maximally hyperemic response to injury. These mi-

croneurovascular changes, as a result of autonomic neuropathy,

play an important role in the vascular dysfunction found in dia-

betes. When we think of vascular disease, we cannot always just

consider macrovascular occlusive disease. We must also remember

the important role of these microneurovascular changes as well.

When there is a high-risk foot in a patient with diabetes, there

may be neuropathy as well as vascular disease, both microvascular

and macrovascular. When trauma is applied to that high-risk foot,

this is the precipitating event that leads to foot ulcer. In the pres-

ence of a sensory deficit, these people keep walking on the in-

jured foot without the “gift of pain,” as the late Paul Brand, MD,

had said.42 This creates more problems as these wounds can be-

come infected. Once they become infected, gangrene can set in

and then amputation ensues.

Now the same risk factors for ulcers are always important risk

factors for amputation as well because ulcers are so closely asso-

ciated with this complication in the diabetic foot population. So

we need to have at least a basic understanding of these various

underlying pathophysiologic deficits or aberrations that may

occur in patients with diabetes. Not all patients will have every

one of these deficits but they are very common. When a patient

is seen with a diabetic foot ulcer, that patient has a lot of under-

lying comorbidities and many underlying physiologic changes

that one needs to be aware of because these problems can impair

the patient’s ability to heal.

A Closer Look At The Molecular Differences BetweenAcute Wounds and Chronic WoundsWhen speaking of chronic wounds, we must also be aware of

the difference in the biologic milieu that is present in the chronic

wound versus the healing or the acute wound. In his 2005 paper

in Diabetes Care, Lobmann discussed the molecular environment

of wounds. It is a good summary for what is going on in these

chronic diabetic foot wounds and what we have to do to change

this in order to facilitate healing.43

Given the sobering reality of mortality rates for those with diabetic foot complications, this author emphasizes thoroughvascular workups and appropriate referrals, underscores the importance of aggressive management to prevent complicationssuch as amputation, and surveys the literature on current and emerging advanced therapies.

The Science Of Advanced Wound Care: What Should You Be Using In Your Office?

By Robert G. Frykberg, DPM, MPH



9

With the chronic ulcers, the cells, especially the fibroblasts,

have low mitogenic activity and there is an increased level of

inflammatory cytokines. Chronic ulcers also have an increased

level of proteases, which are very hostile to growth factors,

growth factor receptors, fibroblasts and deposition of matrix.

There are also senescent cells that are not physiologically active.

These are incompetent cells. The molecular picture of these

chronic wounds is in contrast to healing wounds that are char-

acterized by cells with high mitogenic activity, low levels of in-

flammatory cytokines, low levels of harmful proteases and

mitotically competent cells.

Our goal in the management of these chronic wounds is to

tip the balance to the characteristics of a good acute wound and

subsequent healing. (See “An Overview Of The Molecular En-

vironment Of Wounds” on the right.)

Emphasizing Aggressive ManagementTo Prevent Diabetic Foot ComplicationsIt is important to put diabetic foot complications into proper

perspective. In 2003, Belch and colleagues noted that the five-

year mortality rate for peripheral arterial disease (PAD) (32 per-

cent) is worse than the five-year mortality rates for prostate

cancer (8 percent), Hodgkin’s disease (19 percent) and breast

cancer (22 percent).44,45 In 2010, Van Baal and co-workers re-

ported a 41 percent five-year mortality rate for Charcot foot

and they found that it was not significantly different than the

five-year mortality rate (44 percent) for diabetic foot ulcers.46

As I noted earlier, we need to recognize that people who have

diabetic foot ulcers have very significant underlying comorbidi-

ties that put them at risk for earlier mortality. The five-year mor-

tality rate for amputation is 68 percent and the five-year

mortality rates for lung cancer and pancreatic cancer are 86 per-

cent and 95 percent, respectively.12,45

These sobering numbers in regard to diabetic foot complica-

tions underscore the importance of aggressive management

when indicated. While we cannot always stop the development

of ulceration, we can certainly prevent ulceration from progress-

ing to an amputation if we are aggressive with our wound heal-

ing modalities. However, we need to pay attention to the basic

tenets of wound care. After all, it does not matter what kind of

advanced products you put on a wound if you have not paid at-

tention to the basic tenets of wound care.

Keys To The Diagnostic WorkupAccordingly, our treatment approach emphasizes medical man-

agement in partnership with our medical team. Recognizing

the important role that PAD plays in the etiology of these

wounds, we always assess the vascular status of these patients. We

are seeing an increasing number of neuroischemic wounds in

comparison to primarily neuropathic wounds. My colleagues in

America and Europe are seeing the same trend in which people

are living longer and those with ulcerations have more neurois-

chemic ulcers than neuropathic ulcers. We need to be very

aware of the role of vascular disease even if it is not the main

predisposing risk factor for failure to heal.

Accordingly, we need to do a very vigorous vascular assess-

ment. We always try to palpate pulses. We are also very liberal in

terms of getting our ankle-brachial indices and toe pressures,

and assessing transcutaneous oxygen (TcPO2) and skin perfusion

pressure (SPP). We correct those problems as we see them,

working very closely with our vascular colleagues.

When it comes to infection, we always need to drain abscesses,

perform appropriate debridement, determine whether os-

teomyelitis is present and consider appropriate antibiotics for in-

fected wounds. Unfortunately, there are many times when

indolent, smoldering infection is present under these apparently

non-infected ulcers. That is why we are so aggressive with our

probe to bone test, which has been under attack in recent years.47

We call the probe to bone test our “five cent bone scan” because

if I can see bone, feel bone, touch bone or probe to bone, I treat

that patient as though he or she has clinical osteomyelitis as this

will prevent these chronic wounds from healing.

Initial Treatment Considerations After we have done our assessment, we can then focus on proper

An Overview Of The Molecular Environment Of Wounds43

Chronic UlcersLow Mitogenic ActivityHigh Inflammatory CytokinesHigh ProteasesSenescent Cells

Healing WoundsHigh Mitogenic ActivityLow Inflammatory CytokinesLow ProteasesMitotically Competent Cells

Photos courtesy of David G. Armstrong, DPM, MD, PhD, and Brian Lepow, DPM.



10

wound care and again the basics are always debridement, wound

bed preparation by a variety of means, proper offloading or

compression if one is treating a venous leg ulcer. Without the off-

loading, debridement and proper assessment, you are not going to

be successful in your wound healing protocols.

I do not worry about advanced wound care products when I

am initially seeing a patient with a relatively uncomplicated

wound. We focus entirely on the basics and those basics are of-

floading and adequate debridement. Then we think about ther-

apeutic agents. What do we want to put on that wound after we

have considered and evaluated all of these other things? We

know there are many possible agents. Unfortunately, very few

of the things that you put on a wound have sufficient evidence

to support their efficacy when it comes to treating diabetic foot

ulcers. We recognize this and just have to admit that we do have

preferences, and sometimes some things seem to work better

for us in certain circumstances than others.

There are many topical agents. Diluted antiseptics include

povidone-iodine, super-oxidized solution (Dermacyn Wound

Care, Oculus Innovative Sciences) and peroxide. I admit some

of these are cytotoxic. However, if I have a very nasty wound

that is draining a lot, I like to get it dry and cleaned up. Then

there are hydrogels, saline hydrogels, topical antimicrobial

creams and ointments. The latter are not wound healing agents.

They just help to correct the bioburden that we know is present

on these wounds. In regard to enzymatic debridement agents,

the only one on the market now is the collagenase product

(Collagenase Santyl, Healthpoint). We do use collagenase to help

with what we call maintenance debridement. Patients may apply

this themselves on a daily basis between visits.

There are many types of wound dressings ranging from gauze

pads, foams and silver dressings to hydrocolloids, alginates and

collagen-based dressings. Manuka honey is a new type of dress-

ing on the market that we use on occasion as well. Most of these

wound dressings are secondary dressings that we put over a

freshly debrided wound. Sometimes these are primary dressings

as well.

When Do You Turn To Advanced Modalities? What The Literature RevealsAt what point do we need to consider advanced products? In

2003, Sheehan and colleagues examined the data from the failed

Promogran study and found that the majority of their patients

with diabetic foot ulcers who healed at 12 weeks had achieved

53 percent healing by four weeks, regardless of what treatment

they were on.32 As a result of the Sheehan findings and an ex-

tension of the 1999 consensus panel convened by the American

Diabetes Association, the recommendation came that if you do

not achieve 50 percent reduction in wound size at four weeks,

you need to step back, reassess and consider the use of advanced

therapeutic agents.48 Boulton and colleagues corroborated this

in 2004 as did Snyder and co-workers in 2010.33,49

Examining The Role Of Regranex When it comes to advanced wound care technologies, becapler-

min (Regranex, Systagenix) was the first agent for diabetic foot

ulcers to receive biologics license application (BLA) approval

from the FDA.

In a randomized, double-blind multicenter trial, Steed and

colleagues found that 48 percent of patients treated with Re-

granex healed at 20 weeks in comparison to 25 percent of pa-

tients in the placebo group.26 In 1998, Wieman and co-workers

published findings from a phase III multicenter trial showing

significantly improved efficacy in the Regranex group dosed at

100 µg/g (50 percent) versus another Regranex group dosed at

30 µg/g (36 percent) and the placebo group (35 percent) at 20

The Use Of Advanced TechnologyIn Wound Healing32,33,48,49

Look for and measure the healing rate within the first four weeks of therapy to decide on alternate approaches.

Good Wound Care

Period of Observation

Healing at Four Weeks ≥ 50%

Yes

• Educate patient about- Offloading- Edema control

• Provide regular follow-up

• Reassess wound for infection; check for circulation and compliance

• Consider adjuvant care

No

Advanced therapies



11

weeks.50 Not many of us use too much Regranex anymore al-

though it does have its role in our wound care armamentarium.

An Overview Of Extracellular Matrix ProductsThese are multiple extracellular matrix products. These include:

Oasis Wound Matrix (Healthpoint); Integra Bilayer Matrix

Wound Dressing (Integra LifeSciences); GammaGraft

(Promethean Life Sciences); Graftjacket Regenerative Tissue

Matrix (KCI); Pegasus/Unite (Synovis Orthopedic and Wound-

care); and Bacterin Pericardial Matrix (Bacterin International).

These acellular matrix scaffolds deliver a matrix, usually of col-

lagen, across which fibroblasts can travel, develop angiogenesis

and granulation tissue, and keratinocyte migration.

A randomized clinical trial found that Oasis Wound Matrix was

as effective as Regranex in healing full thickness diabetic foot ul-

cers at 12 weeks.51 In a multicenter, randomized controlled trial

(RCT), Reyzelman and colleagues found the use of Graftjacket

demonstrated a shorter time to healing (5.7 weeks) than standard

wound management (6.8 weeks) for diabetic foot ulcers.52

Assessing The EvidenceOn Negative Pressure Wound Therapy There is also vacuum-assisted closure (VAC therapy, KCI). In

2008, Blume and colleagues published a randomized controlled

trial on diabetic foot ulcers in which they found documented

evidence of the efficacy of VAC therapy in terms of accelerated

closure at 16 weeks.37 They found that the use of VAC therapy

improved ulcer closure, the Kaplan-Meier median time to heal-

ing was faster and there were fewer secondary amputations.

There are other negative pressure wound therapy (NPWT)

devices on the market. They include the NPD 1000 (Kalypto

Medical), the SNaP Wound Care System (Spiracur), the Sved-

man Wound Treatment system (Innovative Therapies) and Re-

nasys (Smith & Nephew). However, most of the data on NPWT

is with the KCI device.

A Closer Look At Cell-Based Tissue TechnologiesWe also have cell-based tissue technologies that I use quite fre-

quently. The only two on the market in the U.S. are Apligraf

(Organogenesis) and Dermagraft (Advanced BioHealing).

Apligraf is a bilayered product with keratinocytes and neonatal

fibroblasts. Dermagraft is a dermal replacement therapy with

neonatal fibroblasts on an absorbable mesh.

These FDA-approved, premarket approval (PMA) products

have very good data behind them. In 2001, Veves and colleagues

published their findings on Apligraf in a prospective randomized

controlled trial.35 They found that 56 percent healed in the ac-

tive group versus 38 percent in the control group at 12 weeks

0

20

40

60

80

100

TCC

81

Dermagraft† Graftjacket Apligraf† Regranex††

64

5147 43

Assessing The Percentage Of Improvement Over Control Groups In RCTs26,34,35,52,56

Consider the percentage of improvement over con-trol groups in published RCTs of modalities thatdemonstrated significant differences in healing withdiabetic foot ulcers in comparison to the gold stan-dard of total contact casting (81 percent).

Direct comparisons are difficult to make due to vari-ability in study designs and analyses.

† FDA-approved PMA products†† FDA-approved BLA product



12

with a 47 percent increased rate of healing in the Apligraf group.

In a multicenter, randomized controlled trial of Dermagraft

for chronic diabetic foot ulcers, Marston and colleagues found

that 30 percent of the Dermagraft group had complete healing

at 12 weeks in comparison to 18.3 percent in the placebo

group.34 This represented a 64 percent greater rate of closure in

the Dermagraft group versus the control group.

What You Should Know About Other Wound Care TherapiesOther wound care therapies include platelet-rich plasma (Autolo-

gel, Cytomedix), hyperbaric oxygen therapy (HBOT), ultrasonic

spray (MIST Ultrasound Healing Therapy, Celleration), super-ox-

idized water (Dermacyn Wound Care), manuka honey (Medi-

Honey, Derma Sciences), pulsed radio frequency energy (Provant,

Regenesis Biomedical), electrical stimulation and low intensity

pulsed ultrasound (Exogen, Smith & Nephew).

In regard to HBOT, there have been multiple trials, including

the recently published study by Londahl and colleagues, who

showed increased rates of healing with the use of HBOT in pa-

tients with diabetic foot ulcers.53

Ennis and co-workers evaluated the use of MIST therapy, an

ultrasonic spray, in chronic diabetic foot ulcers in a multicenter,

randomized controlled trial.54They found a higher proportion of

healed wounds in the active treatment group (40.7 percent) at 12

weeks in comparison to the control group (14.3 percent).

Piaggesi and colleagues assessed the use of super-oxidized water

in managing wide post-surgical lesions in the diabetic foot.55They

found that the use of Dermacyn Wound Care facilitated a shorter

duration of antibiotic therapy and less re-interventions in com-

parison to patients treated with povidone iodine.

Summing Up The Current RCT EvidenceOn The Advanced Modalities It is important to put things in proper perspective so you can make

your own decisions. Ask yourself the following questions: Why am

I using this product? What is the scientific basis for this?

Consider the percentage of improvement over control groups

in published RCTs of modalities that demonstrated significant dif-

ferences in healing with diabetic foot ulcers in comparison to the

gold standard of total contact casting (81 percent). There was a 43

percent improvement over control with Regranex; 47 percent

with Apligraf; 51 percent with Graftjacket; and 64 percent with

Dermagraft.26,34,35,52,56 (See “Assessing The Percentage Of Improve-

ment Over Control Groups In RCTs” on page 11.) In regard to

the one FDA-approved BLA product and the two FDA-approved

PMA modalities for diabetic foot ulcers, Dermagraft has the great-

est efficacy in the intent to treat analyses with these three products.

I would caution that direct comparisons between modalities are

difficult to make due to variability in study designs and analyses.

Final NotesBy using a combination of these advanced therapeutic products based

on their underlying clinical science and evidence, we can make

a good dent in these very difficult problems. However, we need

to remember that nothing supplants the role of good basic

wound care. That means proper offloading, proper debridement,

management of any existing infection and, of course, managing

ischemia as necessary.

The use of multimodal therapies is probably most consistent

with current clinical practice but you also need to remember that

wounds change over the course of treatment. You need to be pre-

pared to change your therapy as the wound characteristics change.

If a wound looks soupy and there is too much bioburden, one

needs to hold off on an advanced tissue product for a week or so.

Clean up that wound, ensure adequate wound bed preparation

and then reinstitute an appropriate advanced therapy. Always pay

attention to the basics of wound care and always reassess the

wound as necessary, especially if the wound is not healing.

Granted, not everything we have available is based on RCTs.

Otherwise, we would not have too much to use. However, you

should always ask yourself the question: Is there evidence to

support what I am doing? n

Here is a diabetic neuropathic ulcer. Physicians shouldbe prepared to change therapies as the wound charac-teristics change.

Photo co

urtesy

of R

ober

t G. F

rykb

erg,

DPM

, MPH

.



13

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15

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52. Reyzelman A, Crews RT, Moore JC, et al. Clinical effectivenessof an acellular dermal regenerative tissue matrix compared tostandard wound management in healing diabetic foot ulcers: aprospective, randomized, multicentre study. Int Wound J.2009:6(3):196-208.

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57. Reiber GE, Ledoux WR. Epidemiology of diabetic foot ulcersand amputations: evidence for prevention. In: Williams R,Herman W, Kinmonth AL, Wareham NJ (eds). The EvidenceBase for Diabetes Care. Hoboken, NJ: John Wiley & Sons;2002:641–665.

58. Boulton AJ, Vileikyte L, Ragnarson-Tennvall G, ApelqvistJ. The global burden of diabetic foot disease. Lancet.2005;366(9498):1719–1724.

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60. Armstrong DG, Granick MS, Marston WA, et al. A regimento optimize the results of a living dermal substitute (Derma-graft) for healing diabetic foot ulcers. US Endocrine Review.2007;(Spring b):60–66.

61. Moulik PK, Mtonga R, Gill GV. Amputation and mortality innew-onset diabetic foot ulcers stratified by etiology. DiabetesCare. 2003;26(2):491-4.

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