Expert Recommendations for Optimizing Outcomes ... - Wounds

Supplement to WOUNDS ® December 2012 

Expert Recommendations 

for Optimizing Outcomes Utilizing 

Apligraf ® for Diabetic Foot Ulcers 

This supplement was not subject to the peer review process of WOUNDS 

Supported by Organogenesis, Inc.

Table of Contents 

Purpose of this Supplement............................................................................................................4 

PART 1 

Patients with Diabetic Foot Ulcers 

1.1 The Challenge of Diabetic Foot Ulcers..................................................................................6 

1.2 Pathophysiology of Wound Healing in DFUs. .......................................................................7 

1.3 Initial Evaluation of Patients with a DFU... ............................................................................8 

1.4 Estimating the Likelihood of DFU Healing..........................................................................10 

1.5 Conventional Wound Therapies...........................................................................................11 

1.6 Evaluating Response to Conventional Therapy.....................................................................13 

Cover Photo Credit 

Photo Researchers Picture Number: BH3877 

Credit: Michele S. Graham / Photo Researchers, Inc 

License: Rights Managed 

Images and Text Copyright © 2012 Photo Researchers, Inc. All Rights Reserved. 

2 Expert Recommendations for Optimizing Outcomes Utilizing Apligraf ® for Diabetic Foot Ulcers

Table of Contents 

PART 2 

Advanced Therapy of DFUs with Apligraf ® 

2.1 Evidence-Based Selection of Advanced Therapy for DFUs.. ...................................................15 

2.2 Apligraf: Efficacy and Proposed Mechanism............................................................................17 

2.3 Initiating Apligraf Therapy.....................................................................................................18 

2.4 Evaluating Response to Apligraf & Reapplications.................................................................19 

2.5 Summary...............................................................................................................................20 

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Expert Recommendations for Optimizing Outcomes Utilizing Apligraf ® for Diabetic Foot Ulcers 3

Purpose of this Supplement 

Diabetic foot ulcers (DFUs) are one of the most common complications of diabetes mellitus (DM) and are associated 

with significant morbidity and mortality. Management of DFUs is complex and requires a systematic approach to 

achieve successful outcomes. The care of DFUs has evolved in recent years as new therapeutic options have become 

available with varying levels of evidence supporting their use. Education about the latest developments in the evaluation and 

treatment of DFUs has sometimes not kept up with the pace of this progress, especially with regards to advanced therapies, 

such as cell therapy, growth factors, negative-pressure therapy, and hyperbaric oxygen therapy. 

Six experienced wound care specialists reviewed the current status of evidence-based evaluation and therapy of DFUs with 

a focus on the optimal use of Apligraf ® , an allogeneic bilayered living-cell-based product that has FDA approval for treatment 

of DFUs. 

The objectives of this meeting were two-fold: 

(1) To highlight key aspects of the evaluation and evidence-based conventional therapy of DFUs 

(2) To make recommendations regarding the optimal use of Apligraf as evidence-based advanced therapy in the 

care of DFUs 

The overarching goal of both these objectives is to empower clinicians caring for patients with DFUs to optimize clinical 

outcomes by providing an educational resource that is concise and useful in their clinical practices. 

In this supplement, Part 1 | Initial Evaluation of Diabetic Foot Ulcers addresses the first objective and Part 2 | Advanced Therapy 

of DFUs with Apligraf addresses the second objective. 

Of note, this paper is not intended as an exhaustive review of DFU management. Rather, based on the group discussions 

during the meeting and the meeting participants’ extensive clinical experience with DFU management, the intention is to 

focus on a select number of issues that the group felt was most critical to achieving optimal clinical outcomes in DFU patients. 

The meeting participants provided a variety of perspectives including academic settings, teaching hospitals, and standalone 

wound care clinics. Robert Kirsner, MD, PhD, Professor and Vice Chairman of the Department of Dermatology 

and Cutaneous Surgery at the University of Miami Miller School of Medicine led the group discussions. Following the 

conference, a first draft summary of the group discussions was written and then extensively edited and finalized utilizing 

input from all meeting participants. 

Meeting Participants 

Dr. Robert S. Kirsner (Moderator) 

Dr. Kirsner is a tenured professor, Vice Chairman, and 

holds the endowed Stiefel Laboratories Chair in Dermatology 

in the Department of Dermatology and Cutaneous 

Surgery at the University of Miami Miller School of Medicine. 

He currently serves as director of the University of 

Miami Hospital Wound Center and chief of Dermatology 

at the University of Miami Hospital. Dr. Kirsner is also a 

recently retired board member of the Wound Healing Society 

and is past president of the Association for the Advancement 

of Wound Care. He co-directed the Symposium for 

Advanced wound Care (SAWC) for the past 18 years. In 

addition to career development awards and industry sponsored 

funding, he is a recipient of NIH, ACS, CDC funding 

for his research. Independent of books, book chapters and 

abstracts, he has published over 350 articles. 

Dr. Desmond Bell 

Dr. Desmond Bell is the co-founder and executive 

director of the “Save A Leg, Save A Life” Foundation, a 

multidisciplinary non-profit organization dedicated to the 

reduction in lower extremity amputations and improving 

wound healing outcomes through evidence-based methodology 

and community outreach. He is a board certified 

wound specialist (CWS/American Board of Wound Management) 

and has served on their Board of Directors since 

2009. He serves on the Board of Directors of the Association 

for the Advancement of Wound Care, the Barbara 

Bates-Jensen Wound Reach Foundation, the Communications 

Committee of the Jacksonville Chapter of the American 

Diabetes Association and the Conference Planning 

Committee of the Symposium on Advanced Wound Care. 

He is also a member of the Wound Healing Society and 

the Vascular Disease Foundation/PAD Coalition. Dr. Bell 

has been in private practice in Jacksonville, Florida since 

1997 and is on staff at Memorial Hospital of Jacksonville, St. 

Vincent’s Medical Center Southside and Specialty Hospital 

of Jacksonville. 


Dr. Gary Gibbons 

Dr. Gibbons is medical director for South Shore Hospital 

Center for Wound Care and Hyperbaric Medicine and Professor 

of Surgery at the Boston University School of Medicine. 

Trained as a vascular surgeon, Dr. Gibbons was the first director 

of the Joslin-Beth Israel Deaconess Foot Center in Boston 

and his career has centered on diabetic patients with lower extremity 

wounds, especially those complicated by vascular disease. 

He has published and spoken extensively on the subject 

and has been honored with the Pecoraro (ADA), Olmos, and 

Georgetown Distinguished Achievement awards for his work. 

Dr. Bill Ennis 

Dr. Ennis is a professor of clinical surgery and chief of the 

section of wound healing and tissue repair at the University of 

Illinois Hospital and Health Sciences System. His active areas 

of research include healing outcomes measures, microcirculation, 

macrophage function and the impact of stem cells on 

wound healing. 

Dr. Arti Masturzo 

Dr. Masturzo is a published educator who has dedicated 

her career to the advancement of wound care best practices 

and the development of comprehensive wound care programs. 

She completed her internal medicine residency at the University 

of Cincinnati and went on to pursue a practice focusing 

entirely on the care of chronic wounds. She is currently the 

Medical Director of Comprehensive Wound Programs for Tri- 

Health Associates, overseeing inpatient and outpatient wound 

care, including hyperbarics, for multiple hospitals and clinics 

in greater Cincinnati. In addition, she is the Corporate Director 

of Medical Affairs of Accelecare Wound Centers. Dr. 

Masturzo is board-certified in internal medicine and undersea 

hyperbaric medicine. 

Dr. Gary Rothenberg 

Dr. Rothenberg is a board certified podiatrist, certified diabetes 

educator and certified wound specialist who currently 

serves as director of resident training and attending podiatrist 

at the Department of Veteran Affairs Medical Center in Miami, 

Florida. A graduate of the Ohio College of Podiatric 

Medicine, he completed 3 years of residency training at the 

University of Texas Health Science Center in San Antonio. 

His previous private practice experience and now academic 

practice have focused on conservative and surgical management 

of the diabetic foot. 

Conflicts of Interest 

Dr. Kirsner indicates advisory board participation with Organogenesis, Shire, Healthpoint, and KCI. 

Dr. Bell indicates he is a member of the Speaker’s Bureau of Organogenesis and Cordis and serves as a consultant 

with ev3, Cook, and Healiance. 

Dr. Gibbons indicates he is a consultant, speaker, and participates in a clinical experience program for Organogenesis, and 

that he is principal investigator for a venous leg ulcer study sponsored by Celleration. 

Dr. Ennis indicates he is a consultant to Organogenesis, KCI, and Accelecare wound centers. 

Dr. Masturzo indicates she is a member of the Speaker’s Bureau of Organogenesis and KCI. She has also served as a 

consultant to Shire. 

Dr. Rothenberg indicates he is a member of the Speaker’s Bureau for Organogenesis and Healthpoint. 

Acknowledgements 

This article is supported by a grant from Organogenesis. The authors would like to thank Ed Perper, MD, and James Radke, 

PhD, for editorial and manuscript assistance. This supplement is provided as a courtesy to the readers of WOUNDS. This 

supplement was not subject to the peer review process of WOUNDS. 


PART 1 

Patients with Diabetic Foot Ulcers 

1.1 The Challenge of Diabetic Foot Ulcers 

Review of Evidence 

DFUs are a common complication in patients with DM. 

The lifetime risk of developing a DFU is 15% to 25% and 

the prevalence of DFUs among diabetics is 4% to 10%. 1 

The morbidity and mortality associated with DFUs is 

very high. For example, 85% of leg amputations are preceded 

by DFUs 1 and more than 60% of nontraumatic lower 

extremity amputations performed in the United States each 

year occur secondary to complications of DM. 2 Mortality 

rates following amputation are alarmingly high: up to 40% 

at 1 year and 80% at 5 years. 1 

Unfortunately, DFUs are notoriously difficult to heal. 

The healing rate even with good standard-of-care treatment 

is only 31% at 20 weeks 3 (Figure 1). Moreover, DFUs 

are frequently inadequately managed due to multiple factors 

including blunted signs of infection, limited understanding 

of current diagnostic and therapeutic approaches, 

and insufficient resources. 4 

Group Discussion 

The seriousness of DFUs is often underestimated by both 

clinicians and patients. A critical first step is for everyone involved 

to fully understand and explicitly acknowledge that 

achieving complete healing represents a significant challenge 

in a high-risk patient. This should motivate both the 

wound care practitioner and the patient to take all necessary 

steps to maximize the probability of success. It is important 

to not underestimate this disease as success is typically 

harder than many perceive. Educating patients about the 

challenge of healing their DFU will ideally motivate them 

to strictly comply with all therapeutic interventions; poor 

compliance is an important factor that often limits the success 

of therapy. Importantly, wound care clinicians should 

understand that even with well-delivered standard care of 

DFUs, the probability of complete healing is relatively low; 

therefore from the very start of treatment, clinicians should 

anticipate that advanced therapy will be required in many 

patients to achieve complete healing. 

% 

Weighted Mean Healing Rate 

100% 

75% 

25% 

0% 

24.2% 

30.9% 

12 Weeks 20 Weeks 

N = 4 trials 

N = 6 trials 

Time Elapsed 

Suggested Reading 

• Consensus Development Conference on Diabetic Foot Wound 

Care: 7-8 April 1999, Boston, Massachusetts. American Diabetes 

Association. Diabetes Care. 1999;22(8):1354-1360. 

• Singh N, Armstrong DG, Lipsky BA. Preventing foot ulcers 

in patients with diabetes. JAMA. 2005;293(2):217-228. 

• Margolis DJ, Kantor J, Berlin JA. Healing of diabetic neuropathic 

foot ulcers receiving standard treatment. Diabetes Care. 

1999;22(5):692-695. 

Figure 1. Healing rates of control groups from 

meta-analysis of 10 randomized clinical trials of 

standard DFU care. 3 

Margolis DJ, Kantor J, Berlin JA. Healing of diabetic neuropathic foot ulcers 

receiving standard treatment. Diabetes Care. 1999;22(5):692-695. 

• Maderal AD, Vivas AC, Zwick TG, Kirsner RS. Diabetic foot 

ulcers: evaluation and management. Hosp Pract (Minneap). 

2012;40(3):102-115. 

• Ramsey SD, Newton K, Blough D, et al. Incidence, outcomes, 

and cost of foot ulcers in patients with diabetes. 

Diabetes Care. 1999;22(3):382-387. n 


1.2 Pathophysiology of Wound Healing in DFUs 


Acute wounds heal through a normal highly regulated 

process of cell replication, migration, protein synthesis, 

matrix deposition, and organization. In an acute wound, 

multiple growth factors, cytokines, and cells—including 

keratinocytes and fibroblasts—work in concert to heal the 

wound completely. 5-7 DFUs are chronic wounds that fail 

to heal in a regulated and systematic manner due to multiple 

abnormal physiologic, anatomic, and cellular factors: 

(1) decreased angiogenic response; (2) neuropathy; (3) 

ischemia; (4) endothelial dysfunction; and (5) increased 

susceptibility to wound infection 5 (Figure 2). 

In addition, in DFUs there is poor and disorganized regulation 

of the cytokines, growth factors, proteases, extracellular 

matrix components, and cells needed to achieve 

complete wound closure 8,9 : (1) keratinocyte migration and 

proliferation is impaired 10 ; (2) fibroblast response to growth 

factors 9 and the ability to synthesize collagen is impaired 11 ; 

and (3) there is a relative deficiency of tissue inhibitors 

of matrix metalloproteinases, which results in degradation 

of the extracellular matrix. 8,12,13 All these pathophysiologic 

factors contribute to the poor healing rates observed in 

patients with DFUs. 


All wound care practitioners should understand the 

multiple pathophysiologic defects that contribute to poor 

healing rates of DFUs. By therapeutically addressing as 

many of these factors as possible, the likelihood of wound 

healing can be increased. For example, clinicians must 

assess and reassess for ischemia, infection, and other factors 

throughout the course of management that may slow or 

prevent healing. If healing stalls, some advanced therapies 

may address the growth factor, cytokine, and cellular 

abnormalities that interfere with healing of DFUs. 

Suggested Readings 

• Brem H, Young J, Tomic-Canic M, et al. Clinical efficacy 

and mechanism of bilayered living human skin equivalent 

(HSE) in treatment of diabetic foot ulcers. Surg Technol Int. 

2003;11:23-31. 

Figure 2. Pathophysiologic factors contributing to 

poor healing rates of DFUs. 

• Werner S, Krieg T, Smola H. Keratinocyte–fibroblast 

interactions in wound healing. J Invest Dermatol. 

2007;127(5):998-1008. 

• Ghahary A, Ghaffari A. Role of keratinocyte–fibroblast 

cross-talk in development of hypertrophic scar. Wound Repair 

Regen. 2007;15(suppl 1):S45-S53. n 


1.3 Initial Evaluation of Patients with a DFU 


Several published clinical guidelines exist to assist wound 

care practitioners with proper evaluation and management of 

DFUs, including those from the Infectious Diseases Society 

of America, 14 the American College of Foot and Ankle Surgeons, 

15 the Wound Healing Society, 16 and the International 

Working Group on the Diabetic Foot Editorial Board. 17 

Common to these guidelines is the recommendation for a 

meticulous initial clinical evaluation of every patient with a 

DFU. Particular attention should be on the following issues: 

1) peripheral artery disease; 2) neuropathy; 3) nutritional status; 

4) wound infection, including osteomyelitis; and 5) hyperglycemia 

(Figure 3). 

In addition, a wound-specific history must be obtained, 

including location, duration, inciting event or trauma, 

previous ulcers and recurrences, hospitalization, previous 

wound care treatments, off-loading technique, wound response 

to treatment, patient compliance, family or social 

problems that are interfering with care, previous foot trauma 

or surgery, presence of edema, and history of Charcot 

foot and its treatment. 15 

Classification of DFUs is generally predictive of outcomes 

and may facilitate treatment (Figure 4). The most commonly 

used classification system is the Wagner system, which divides 

foot lesions into 6 grades based on the depth of the wound 

and extent of tissue infection and necrosis. However, the 

Wagner system does not consider the roles of infection, ischemia, 

and other factors. The University of Texas San Antonio 

(UTSA) system associates lesion depth with both ischemia 

and infection; this system has been validated and is generally 

predictive of outcome. 15 

If possible, the initial evaluation of the DFU should involve 

a multidisciplinary team that includes wound care professionals 

and, when indicated, diabetologists or endocrinologists, 

surgeons (vascular and podiatric), nurses, nutritionists, 

and pedorthotists. 4 

Assess Patient 

• H & P 

• Glycemic control 

• Nutritional evaluation 

• Immune status 

• Neurological evaluation 

• Vascular evaluation 

• Psychosocial evaluation 

Assess DFU 

• Duration 

• Size (~area in cm 2 Estimate Likelihood of 

) 

Succesful Closure & 

• Depth 

Discuss with Patient 

• Location 

• Charcot 

• Soft tissue infection & osteomyelitis 

• Consider advanced testing & imaging 

Appropriate 

Interventions 

Standard Therapy 

for all DFUs 

Debridement Infection Control Off-Loading Appropriate Dressing 

Figure 3. Clinical algorithm for initial assessment of patients with DFUs. 

Lipsky BA, Berendt AR, Cornia PB, et al. 2012 Infectious Diseases Society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections. Clin Infect Dis. 

2012;54(12):e132-173. 

Frykberg RG, Zgonis T, Armstrong DG, et al. Diabetic foot disorders. A clinical practice guideline (2006 revision). J Foot Ankle Surg. 2006;45(5 Suppl):S1-66. 

Steed DL, Attinger C, Colaizzi T, et al. Guidelines for the treatment of diabetic ulcers. Wound Repair Regen. 2006;14(6):680-692. 

Bakker K, Apelqvist J, Schaper NC; International Working Group on Diabetic Foot Editorial Board. Practical guidelines on the management and prevention of the diabetic foot 2011. 

Diabetes Metab Res Rev. 2012;28 Suppl 1:225-231. 


Wagner Classification System of DFUs 

Grade Lesion 

0 No open lesions: may have deformity or cellulitis 

1 Superficial ulcer 

2 Deep ulcer to tendon or joint capsule 

3 Deep ulcer with abscess, osteomyelitis, or joint sepsis 

4 Local gangrene – forefoot or heel 

5 Gangrene of entire foot 

University of Texas Classification System of DFUs 

Stage 

A 

Pre- or post-ulcerative 

lesions, completely 

epithelized 

Grade 

0 I II III 

Superficial wound not 

involving tendon, 

capsule, or bone 

Wound penetrating in 

tendon or capsule 

Wound penetrating in bone 

or joint 

B Infected Infected Infected Infected 

C Ischemic Ischemic Ischemic Ischemic 

D Infected and ischemic Infected and ischemic Infected and ischemic Infected and ischemic 

Figure 4. Wagner and University of Texas Classification Systems for chronic wounds. 


Published evidenced-based guidelines should provide a 

roadmap for care for DFU. Clinicians should follow the 

recommendations of the published clinical guidelines for 

initial evaluation of patients with a DFU. Too often inadequate 

evaluation or treatment of peripheral arterial disease 

(PAD), or in more severe instances, critical limb ischemia, 

is a major factor that slows or prevents complete DFU 

healing. Assessment of vascular status is critical prior to 

proceeding with other elements of care in patients with a 

DFU. Another important issue related to the initial evaluation 

of patients with a DFU is precise baseline measurement 

of wound size so that the response to treatment 

can be reassessed quantitatively and accurately (Section 1.6 

below: “Evaluating Response to Conventional Therapy”). 


• Lipsky BA, Berendt AR, Cornia PB, et al. 2012 Infectious 

Diseases Society of America clinical practice guideline for the 

diagnosis and treatment of diabetic foot infections. Clin Infect 

Dis. 2012;54(12):e132-173. 

• Frykberg RG, Zgonis T, Armstrong DG, et al. Diabetic foot disorders. 

A clinical practice guideline (2006 revision). J Foot Ankle 

Surg. 2006;45(5 Suppl):S1-66. 

• Steed DL, Attinger C, Colaizzi T, et al. Guidelines for the treatment 

of diabetic ulcers. Wound Repair Regen. 2006;14(6):680-692. 

• Bakker K, Apelqvist J, Schaper NC; International Working 

Group on Diabetic Foot Editorial Board. Practical guidelines 

on the management and prevention of the diabetic foot 2011. 

Diabetes Metab Res Rev. 2012;28 Suppl 1:225-231. 

• Snyder RJ, Kirsner RS, Warriner RA, et al. Consensus recommendations 

for advancing the standard of care for treating 

neuropathic foot ulcers in patients with diabetes. Ostomy Wound 

Manage. 2010;56(suppl 4):S1-S24. 

• Gibbons GW, Shaw PM. Diabetic Vascular Disease: Characteristics 

of Vascular Disease Unique to the Diabetic Patient. Semin 

Vasc Surg. 2012;25:89-92. n 


1.4 Estimating the Likelihood of DFU Healing 


The likelihood of complete DFU healing is determined 

by multiple factors, both patient-related and wound-related. 

Important patient-related factors include vascular status, 

nutritional status, neurologic status, presence and severity of 

soft tissue infection, osteomyelitis, Charcot, and other factors, 

including glycemic control. Wound-related factors that have 

been demonstrated in prospective studies to have predictive 

value include the size, duration, depth, and grade of the 

DFU. Larger lesions (>2 cm 2 ), chronic lesions (>6 months 

- 12 months), deeper lesions, and higher grade lesions are 

associated with reduced likelihood of complete healing despite 

continued conventional therapy. 

Margolis et al 18 pooled data from the standard care arms 

of 5 clinical trials to determine the effect of wound size and 

duration on the probability of healing (Figure 5). Healing rates 

were lower in patients with larger wounds and longer duration 

wounds. For example, wounds 12 months, which had 

only a 26% probability of healing (n = 252 patients). 


Many DFUs heal slowly and many will not heal with 

standard treatment. Healthcare providers should be keenly 

aware of the serious challenges involved in treating any 

DFU successfully. Patients and families must be educated 

about the poor prognosis for healing in general and the 

critical importance of strict compliance in order to maximize 

the probability of success. The studies above clearly 

show that even in patients with DFUs that are small and 

of shorter duration, many lesions will not heal with conventional 

therapy, eg, in the Margolis trial described above, 

even among patients with small DFUs that were present 

for less than 6 months more than half (57%) did not heal at 

20 weeks. Of course, in larger wounds of greater duration 

the likelihood of healing is even lower. Therefore, from the 

first day of treatment onwards, all patients need to understand 

that DFUs are very difficult to heal with conventional 

therapy and that most patients will ultimately need 

to receive evidence-based advanced therapy to maximize 

their odds of achieving complete healing. 

In addition, the group believed that in many cases the 

likelihood of successful healing is overestimated by both 

clinicians and patients and that greater awareness of the 

challenges DFUs present may lead to better clinical decisions 

and higher compliance. 


• Margolis DJ, Kantor J, Santanna J, Strom BL, Berlin JA. Risk 

factors for delayed healing of neuropathic diabetic foot ulcers: 

a pooled analysis. Arch Dermatol. 2000;136:1531-1535. n 

100% 

% Healed Within 20 Weeks 

75% 

50% 

25% 

% Healed 

0 % 

4 12 12 

()*+,#-./0# ()*+,#1*234)+# ()*+,#-./0#3+,# 

Wound Size 1*234)+# 

& Duration 

Wound Size 

cm 2 

Wound Duration 

months 

cm 2 & months 

Sample Size: 347 123 116 202 88 189 120 252 

Figure 5. Cumulative healing rates within 20 weeks of care of DFUs. 

Adapted from Margolis DJ, et al. Risk factors for delayed healing of neuropathic diabetic foot ulcers: a pooled analysis. Arch Dermatol. 2000;136:1531-1535. 


1.5 Conventional Wound Therapies 


Management of DFUs is complex and 

requires a systematic approach to achieve 

more consistent and successful outcomes. 4 

This includes addressing multiple issues: 1) 

peripheral artery disease; 2) neuropathy; 3) 

nutritional status; 4) ulcer and bone infection; 

and 5) glycemic control. Detailed discussion 

of these factors is beyond the scope of this 

paper. Addressing peripheral artery disease is 

particularly important. Depending on the 

population being treated, peripheral ischemia 

contributes to poor wound healing in 50% to 

60% of patients with DFUs. 

In addition, the wound itself must be treated 

directly. Below is a brief review of the 

clinical evidence supporting the administration 

of conventional wound therapies that are 

mandated in all patients with DFUs: 

Before debridement 

After debridement 

Offloading. 

The main mechanism by which DFUs 

develop is due to increased, sustained and/ 

or repetitive trauma in the setting of peripheral 

neuropathy. Distributing and minimizing 

pressure in the affected area is crucial 

to achieve healing. Pressure offloading can 

be achieved with foot inserts, therapeutic 

shoes, casts, or by surgical procedures. The 

total-contact cast is considered the gold standard 

for the management of plantar DFUs as 

studies have shown the highest healing rates 

compared with other offloading devices. 19,20 

However, it is recognized that limitations to 

use of total-contact casting exist and alternatives 

are available which have been shown to 

be effective. 21,22 Poor patient compliance often 

limits success of offloading due in part to the fact that these 

devices limit performance of daily activities and the stability of 

patients’ gaits. 23 Therefore, the best device is one with high adherence 

that best adapts to the patient, permitting continuous 

use and effective decrease in pressure. 

Figure 6. Examples of DFUs before and after surgical debridement. 

Photo credit: Arti B Masturzo MD ABPM/UHM 

Medical Director Advanced Wound Programs 

Bethesda North & Good Samaritan Hospitals 

Cincinnati, OH 

Debridement. 

Debridement is considered essential in DFU care although 

this is supported by data from secondary analyses of 

controlled trials performed for reasons other than debridement. 

24 When undertaken, appropriate debridement includes 

removal of excess callus and necrotic tissue and likely results 

in reduction of unresponsive cells in the wound bed and 

edge, bacterial biofilms and excess matrix metalloproteinases. 

Among the different types of debridement (surgical, enzymatic, 

autolytic, mechanical, and biologic), surgical debridement 

is preferred. (See Figure 6 for examples of DFUs before 

and after surgical debridement.) Steed et al found topical 

application of a growth factor with frequent debridement 

increased the likelihood of healing as did debridement with- 


out growth factor application, but to a lesser extent. 25 The 

“Debridement Performance Index,” which evaluates the 

adequacy of debridement of the wound and wound edges, 

was found to be an independent factor of wound closure. 26 

Finally, it has been suggested that frequent debridement 

of DFUs may increase wound healing and closure rates, 

which may be in part due to superior overall care provided 

to patients. 27 

Dressings. 

Important wound bed preparation principles are moisture 

balance, minimization of inflammation, infection control, and 

epithelial edge advancement. The goal is to promote healing 

via epidermal migration, angiogenesis, and connective tissue 

synthesis. The type of dressing will be dependent on the 

wound size, depth, location, the presence of eschar or slough, 

the amount of exudates, the wound margins, the need for adhesiveness, 

concern for infection, and conformability. 5 However, 

there is not enough evidence to suggest that one dressing is 

more effective than another. Currently, no ideal dressing exists 

that possesses all properties ideal for all wound types. 4 


Standard wound management will succeed in healing 

only a percentage of DFUs. Unfortunately, optimal standard 

wound care is not always provided to all patients due 

to poor adherence to guidelines, diminished compliance, 

inadequate education of wound care practitioners, lack of 

close follow-up, insufficient resources, and other factors. Offloading 

is grossly underutilized, which is unfortunate given 

the strong evidence supporting its role in promoting wound 

healing. Practitioners are encouraged to remember that contact-casting 

is the most strongly supported by clinical evidence 

and is therefore considered the “gold standard.” 

Close follow-up with weekly reassessment is the standard 

of care; unfortunately, not all practitioners follow this guideline. 

Early, aggressive, and diligent management of DFUs is not 

only in the best interest of the patient but is also cost effective 

since it potentially prevents costly complications. 


• Brem H, Sheehan P, Boulton AJM. Protocol for treatment of 

diabetic foot ulcers. Amer J Surg. 2004;187(suppl):1S-10S. 

• Lipsky BA, Berendt AR, Cornia PB, et al. 2012 Infectious 

Diseases Society of America clinical practice guideline for the 

diagnosis and treatment of diabetic foot infections. Clin Infect 

Dis. 2012;54(12):e132-173. 

• Frykberg RG, Zgonis T, Armstrong DG, et al. Diabetic foot 

disorders. A clinical practice guideline (2006 revision). J Foot 

Ankle Surg. 2006;45(5 Suppl):S1-66. 

• Steed DL, Attinger C, Colaizzi T, et al. Guidelines for 

the treatment of diabetic ulcers. Wound Repair Regen. 

2006;14(6):680-692. 

• Bakker K, Apelqvist J, Schaper NC; International Working 

Group on Diabetic Foot Editorial Board. Practical guidelines 

on the management and prevention of the diabetic foot 2011. 

Diabetes Metab Res Rev. 2012;28 (suppl 1):225-231. 

• Snyder RJ, Kirsner RS, Warriner RA, et al. Consensus recommendations 

for advancing the standard of care for treating 

neuropathic foot ulcers in patients with diabetes. Ostomy Wound 

Manage. 2010;56(suppl 4):S1-S24.n 


1.6 Evaluating Response to Conventional Therapy 


Patients with DFUs should be followed closely with weekly 

visits. A 2012 study comparing 206 patients with Wagner 

grade 1 or 2 DFUs who had weekly vs every-other-week 

visits found that weekly follow-up reduced the median time 

to wound closure by more than 50% (28 days vs 66 days). 43 

Several studies have shown that re-evaluation 4 weeks after 

initiation of standard wound healing therapy is clinically 

useful. These studies demonstrate that if wound size has not 

decreased by at least 50% by the 4th week of treatment, the 

likelihood of complete wound healing using the same treatment 

approach is very low. 28-30 For example, in a study of 704 

patients, only 18% of DFUs that were not healing adequately 

at 4 weeks healed at 12 weeks, whereas 58% of DFUs that 

were healing adequately at 4 weeks did so. 28 In another study, 

patients with DFUs receiving 4 weeks of conventional therapy 

whose wounds did not reduce in size by more than 53% 

had a decreased likelihood of healing at 12 weeks. 30 In addition 

to percent wound size reduction, Robson et al examined 

the data from 11 clinical trials and observed that by week 

4, the trajectories of the wounds that eventually would heal 

versus those that did not heal could be differentiated. 31 The 

Standard Therapy of DFU 

Reassess DFU within 4 Weeks 

• Wound healing trajectory 

• % area reduction 

Healing 

adequately 

Not healing 

adequately 

Follow-up 

Address factors 

interfering 

with healing 

• Ulcer infection 

• Osteomyelitis 

• Ischemia 


• Inadequate offloading 

• Poor nutrition 

• Other factors 

Complete 

closure 

Evidence-based 

advanced 

therapy 

Figure 7. Clinical algorithm for initial assessment of patients with DFUs. 


Wound Healing Society’s guidelines recommend a change in 

treatment if wound size reduction is not observed at 4 weeks 

of conventional therapy. 16 


The evidence in favor of following DFU patients weekly 

is strong. Once the patient with a DFU is started on standard 

wound therapies, response to therapy should be re-evaluated 

at no later than 4 weeks. It is mandatory to perform serial 

wound size measurements in all cases; but in real-world settings 

this is not always done. Although a ≥ 50% reduction 

in wound size is desirable and moderately predictive of the 

likelihood of healing, the overall trajectory of wound healing 

is most important. Other factors such as initial size, presence 

of infection, and quality of granulation tissue, in addition to 

percentage wound size reduction, should be considered in 

assessing the overall trajectory of wound healing. A suggested 

algorithm for follow-up evaluation is shown in Figure 7. 

If the clinician assesses that the wound healing trajectory 

is inadequate at 4 weeks, reassessment of the wound should 

be performed and evidence-based advanced therapy should 

be considered. It is also important to note that the trials described 

above indicated that a sizeable proportion of patients 

(42% in one study 30 ) who are healing adequately at 4 weeks 

will ultimately fail to completely heal; these patients will also 

require advanced therapy. 


• Coerper S, Beckert S, Küper MA, Jekov M, Königsrainer 

A. Fifty percent area reduction after 4 weeks of treatment 

is a reliable indicator for healing--analysis of a single-center 

cohort of 704 diabetic patients. J Diabetes Complications. 

2009;23:49-53. 

• Margolis DJ, Hoffstad O, Gelfand JM, Berlin JA. Surrogate 

end points for the treatment of diabetic neuropathic foot 

ulcers. Diabetes Care. 2003;26:1696-1700. 

• Sheehan P, Jones P, Casselli A, Giurini JM, Veves A. Percent 

change in wound area of diabetic foot ulcers over a 4-week 

period is a robust predictor of complete healing in a 12-week 

prospective trial. Diabetes Care. 2003;26:1879-1882. 

• Robson MC, Hill DP, Woodske ME, Steed DL. Wound healing 

trajectories as predictors of effectiveness of therapeutic 

agents. Arch Surg. 2000;135(7):773-777. n 


PART 2 

Advanced Therapy of DFUs with Apligraf 

2.1 Evidence-Based Selection of 

Advanced Therapy for DFUs 


In many cases, standard DFU therapy is not sufficient to 

heal the wound. The appropriate use of advanced therapies 

in chronic, nonhealing wounds, can prevent limb loss, 

as well as improve quality of life for patients. 4 The use of 

advanced therapies is currently included in evidence-based 

treatment guidelines and algorithms for DFUs. 16 

At present there are only three products that are approved 

by the FDA for treatment of DFUs based on the 

results of rigorous clinical studies: 

1) Apligraf ® — bilayered (fibroblast/keratinocyte) 

cell-based product 32 

2) Dermagraft ® — human-fibroblast-derived 

dermal substitute 33 

3) Regranex ® — platelet-derived growth factor 34 

Level 1 

RCTs* 

Highest Level of Evidence 

Level 2 

COHORT 

StuDies 

Level 3 

Case-Controlled 

Studies 

Level 4 

Case Series 

Level 5 

Case Report or 

Expert Opinion 

Lowest Level of Evidence 

* RCT = randomized clinical trial 

Figure 8. The Centre for Evidence-Based Medicine: levels of clinical evidence. 

Adapted from Centre for Evidence-based Medicine. http://www.cebm.net/index.aspxo=1025. Accessed August 22, 2011. 


The FDA differentiates between wound dressings, 

which are intended to manage wounds and are classified 

as “non-interactive,” and cell-based wound care therapies, 

which are intended to heal wounds and are classified as 

“interactive.” To gain FDA approval for the treatment of 

DFUs, each of the above products was evaluated in large 

randomized multicenter clinical trials performed in a DFU 

patient population. 

In contrast, many wound dressings and human tissue 

products receive a “510(K) Clearance,” which does not require 

clinical data and for which even preclinical efficacy 

studies are typically not performed. 38 

The Centre for Evidence-Based Medicine published 

a “Levels of Evidence” document to help define a process 

for determining the value of clinical evidence-based on its 

source 35 (Figure 8). This pyramid ranks evidence from the 

highest (Level 1: randomized controlled trials) to the lowest 

(Level 5: expert opinion or case report). This process provides 

a guide to clinicians in their decision making to determine 

the merits of published clinical data. 


DFUs are a serious complication of DM associated with 

high morbidity, including limb loss and increased risk of mortality. 

Practitioners owe it to their patients to utilize the most 

proven therapies to maximize the likelihood of achieving successful 

healing, thereby potentially preventing additional complications. 

This commitment requires using evidence-based 

therapies that are supported by the highest level of scientific 

evidence, ie, randomized clinical trials. In real-world settings 

evidence-based medicine is sometimes delayed or not used as 

well as it should be. 39 

When a patient with a DFU fails to show wound progression 

with standard care (Section 1.6 above Evaluating Response 

to Therapy), transition to an evidence-based advanced therapy 

is appropriate. Three wound healing products have received 

FDA or postmarketing approval by the FDA for the treatment 

of DFUs: Apligraf, Dermagraft, and Regranex. Discussion of 

each of these products is beyond the scope of this paper. The 

main point here is that when new wound products become 

available, clinicians should inquire what level of clinical evidence 

supports their use. In the “hierarchy of scientific evidence,” 

randomized clinical trials represent the highest level of 

evidence while expert opinion and case reports represent the 

lowest level. 


• Apligraf [prescribing information]. 

Canton MA: Organogenesis Inc; December 2010. 

• Dermagraft [prescribing information]. Westpoint CT: Advanced 

Biohealing;2012. 

• Regranex (becaplermin) [prescribing information].Fort 

Worth, TX: Healthpoint Biotherapeutics; 2012. 

• Veves A, Falanga V, Armstrong DG, Sabolinski ML, Apligraf 

Diabetic Foot Ulcer Study. Graftskin, a human skin equivalent, 

is effective in the management of noninfected neuropathic 

diabetic foot ulcers: a prospective randomized multicenter 

clinical trial. Diabetes Care. 2001;24(2):290–295. 

• Marston WA, Hanft J, Norwood P, Pollak R, Dermagraft 

Diabetic Foot Ulcer Study Group. The efficacy and safety 

of Dermagraft in improving the healing of chronic diabetic 

foot ulcers. Diabetes Care. 2003;26(6):1701–1705. 

• Wieman TJ, Smiell JM, Su Y. Efficacy and safety of a topical 

gel formulation of recombinant human platelet-derived 

growth factor-BB (becaplermin) in patients with chronic 

neuropathic diabetic ulcers: a phase III randomized 

placebo-controlled double-blind study. Diabetes Care. 

1998;21(5):822–827. 

• Centre for Evidence-based Medicine. http://www.cebm. 

net/index.aspxo=1025. Accessed August 22, 2011. 

• Maderal AD, Vivas AC, Zwick TG, Kirsner RS. Diabetic foot 

ulcers: evaluation and management. Hosp Pract (Minneap). 

2012;40(3):102-115. n 


2.2 Apligraf: Efficacy and Proposed Mechanism 


Apligraf is a bioengineered allogeneic bilayered living-cellbased 

product that is FDA-approved for treatment of DFUs of 

greater than 3 weeks duration. It consists of an epidermal layer 

of human keratinocytes overlying a dermal layer of human fibroblasts 

in a collagen matrix. Although the precise mechanism 

by which Apligraf promotes wound healing is not known, the 

mechanism of action is believed to be primarily related to its 

ability to modulate the healing response through the delivery of 

cytokines and growth factors (Figure 9). 

Apligraf was evaluated for treatment of DFUs in a randomized 

controlled trial by Veves et al 36 in which patients with chronic 

neuropathic DFUs (plantar, medial and lateral aspects of the foot) 

were randomized to receive up to 5 weekly applications of Apligraf 

(n=112) plus standard care or standard care alone (n=96). 

Standard care consisted of saline moistened gauze, wound debridement 

and offloading. Patients in the Apligraf group had 

higher rates of complete healing than those in the control group 

by 12 weeks (56% Apligraf, 38% control, P=0.0042). In addition, 

the median time to complete closure was reduced in the 

Apligraf group (65 days vs 90 days, P=0.0026). 

Similar results were observed in a second randomized controlled 

trial by Edmonds et al, 37 a multicenter randomized 

controlled trial in which patients with DFUs received Apligraf 

(n=33) or standard wound care (n=39). While this study was 

terminated prematurely for non-scientific reasons, at 12 weeks 

twice as many Apligraf subjects had achieved complete wound 

closure compared to conventional therapy subjects (52% vs 26%, 

P=0.049). Rates of adverse events were similar in the Apligraf 

and control groups in both of these trials. 


Use of Apligraf as an advanced treatment for DFUs is supported 

by two randomized clinical trials, which provides a high 

level of evidence for its use. Overall healing rates and the time 

to complete healing were substantially improved compared to 

standard wound therapy. From a pathophysiologic standpoint, 

this clinical response is understandable since Apligraf provides 

the cells (fibroblasts and keratinocytes), growth factors, and cytokines 

that are believed to play important roles in wound healing. 


• Apligraf [prescription information]. Canton MA: Organogenesis 

Inc; December 2010. 


Diabetic Foot Ulcer Study. Graftskin, a human skin equivalent, is 

effective in the management of noninfected neuropathic diabetic 

foot ulcers: a prospective randomized multicenter clinical trial. 

Diabetes Care. 2001;24(2):290–295. 

• Edmonds M; European and Australian Apligraf Diabetic Foot 

Ulcer Study Group. Apligraf in the treatment of neuropathic 

diabetic foot ulcers. Int J Low Extrem Wounds. 2009;8(1):11-18. 

• Kirsner RS. The science of bilayer cell therapy. Wounds. 2005 

(suppl):6-9. n 

Function 1 

Angiogenesis 

Growth, development, 

and differentiation 

Inflammation 

Proliferation 

Growth Factor or 

Cytokine* 

PDGF-A‡ 

PDGF-B‡ 

VEGF‡ 

IGF-1 

IGF-2 

TGF-ß1 

TGF-ß3 

IL-1a‡ 

IL-6‡ 

IL-8‡ 

IL-11‡ 

FGF-1 

FGF-2 

FGF-7 

TGF-a‡ 

Human 2 

Human 2 

Apligraf 2 

Keratinocytes † Fibroblasts † 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

3 

*As measured by mRNA levels † Cells were grown in monolayer cultures ‡ Cytokines and growth factors were also detected using enzyme-linked immunosorbent assay. 

1 

Barrientos S, et al. Wound Repair Regen. 2008;16:585-601 2 

Brem H, et al. Surg Technol Int. 2003;11:23-31 

Figure 9. Growth factors and cytokines identified in human keratinocytes, human fibroblasts, and Apligraf. 


2.3 Initiating Apligraf Therapy 


The technique used to apply various wound therapies, including 

Apligraf, varies among different practitioners. However, 

since the goal of evidence-based therapy is to replicate 

the results of clinical studies in real-world clinical care, below 

is a summary of selected study entry criteria and application 

techniques employed in the 2 randomized controlled trials 

of Apligraf: 

Veves et al study (2001). 36 Study patients included patients 

with a full-thickness neuropathic DFU on the plantar, lateral 

or medial surface of the foot of ≥3 weeks duration and a 

post-debridement ulcer size between 1 and 16 cm 2 ; without 

signs of clinical infection at the ulcer site or active Charcot’s 

disease; and, with a good vascular supply as indicated by an 

audible dorsalis pedis and posterior tibialis pulses and ABI 

>0.65. The ulcer was debrided and irrigated with saline prior 

to initial application of Apligraf, which was placed directly 

over the ulcer site. Any excess edge was trimmed to fit the 

ulcer. The site was covered with a saline moistened non-adherent 

primary dressing (Tegapore) and secured with hypoallergenic 

tape. The wound was then covered with a layer of 

dry gauze, a layer of petrolatum gauze, and Kling ® . 

Edmonds et al study (2009). 37 Study patients had a full-thickness 

DFU of at least 4 weeks duration; with a surface area between 

1 and 16 cm 2 ; limited to the plantar forefoot region; 

with no signs of infection; and, with an adequate vascular 

supply to the target extremity. All patients received standard 

care therapies, including sharp debridement, saline-moistened 

dressings, and nonweight-bearing regimen. Apligraf 

was applied directly on the ulcer and Mepitel ® , a porous 

wound contact layer, was applied as a primary non-adherent 

dressing. Secondary dressings were also applied. 


What types of DFUs are appropriate for Apligraf Apligraf is 

appropriate for treatment of neuropathic DFUs, including 

large and deep ulcers (partial- and full-thickness ulcers). Ulcers 

at any location on the foot—including the plantar surface—are 

appropriate for Apligraf. Although Charcot disease 

was excluded in the clinical trials, with appropriate offloading 

this is not a contraindication to treatment with Apligraf. 

There is insufficient evidence to make recommendations 

regarding the use of Apligraf in patients with exposed bone 

or tendon, despite reports of clinical success. Frankly infected 

ulcers should not be treated and significant bioburden 

reduced, but optimization of granulation should not delay 

needed treatment. 

How should the wound be prepared Careful and complete 

sharp debridement followed by irrigation is essential. This 

may provide for a healing milieu and reduce bacterial load. 

How should Apligraf be applied to the ulcer Apligraf should 

be applied directly to the ulcer bed leaving a border (~5 

mm) beyond the edge of the ulcer. No evidence exists to 

suggest differences in outcomes between different types of 

dressings. Detailed directions regarding the application of 

Apligraf are beyond the scope of this paper. 

What post-Apligraf application measures are recommended 

Adhering Apligraf is critical, which is typically achieved 

with Steri-Strips TM , but other methods can be utilized. Negative 

pressure wound therapy may augment Apligraf wound 

bed interaction in highly exudative wounds. It is extremely 

important that offloading be continued. 


•Apligraf [prescription information]. Canton MA: Organogenesis 

Inc; December 2010. 


Diabetic Foot Ulcer Study. Graftskin, a human skin equivalent, 

is effective in the management of noninfected neuropathic diabetic 

foot ulcers: a prospective randomized multicenter clinical 

trial. Diabetes Care. 2001;24(2):290–295. 

• Zaulyanov L, Kirsner RS. A review of a bi-layered living cell 

treatment (Apligraf) in the treatment of venous leg ulcers and 

diabetic foot ulcers. Clin Interv Aging. 2007;2(1):93-98. 

• Graftskin (Apligraf) in neuropathic diabetic foot ulcers. Wounds. 

2000;12(5 suppl A):33A-36A. 

• Steinberg JS. Putting bilayered cell therapy to use. Wounds. 

2005 (Suppl):10-14. n 


2.4 Evaluating Response to Apligraf & Reapplications 


In the randomized controlled trial of Apligraf by Veves et 

al, 36 DFU patients in the treatment group could have Apligraf 

reapplied at 4 weekly follow-up visits following the initial 

application, up to 5 applications. If Apligraf appeared to cover 

the wound at these follow-up visits, no reapplication was performed. 

The average number of Apligraf applications was 3.9 

(range: 1 to 5); 9% of patients required one application, 10% 

two applications, 13% three applications, 15% four applications, 

and 53% five applications. 

In the randomized controlled trial of Apligraf by Edmonds 

et al, 37 all patients were followed weekly for clinical assessment 

of the target ulcer and, if necessary, debridement of the wound. 

The Apligraf group could have additional monthly applications 

of Apligraf at week 4 and week 8 if the wound was judged to 

not be healing, for a maximum of 3 applications. In the treatment 

group, 13 of the 33 subjects required only 1 application, 

15 received 2 applications, and 5 received 3 applications. 

Therefore, in these controlled studies a majority of patients 

required multiple applications of Apligraf. This is 

consistent with findings from several small studies with different 

wound types that showed limited persistence. DNA 

evidence of Apligraf was short-lived, typically 3 weeks to 6 

weeks after application. 40-42 

Reassess 

Weekly 

Apligraf Application Healing #1 

adequately 

Application #2 

in 1 to 3 weeks 

H 

E 



A 

Address factors 

interfering with healing 

No 

Wound 

healing 

progressing 

L 

• Ulcer infection 

• Osteomyelitis 

• Ischemia 


• Inadequate offloading 

• Poor nutrition 

• Other factors 

Factors above 

addressed 

Yes 

Yes 





E 

D 

Figure 10. Clinical algorithm for Apligraf management of patients with DFUs. 



As with standard care of DFUs, patients treated with 

Apligraf should continue to be followed up on a weekly 

basis. Based on the available data and clinical experience, 

dosing of Apligraf should be undertaken as follows (Figure 

10): Initial Apligraf application (Apligraf #1) can be 

followed by reapplication (Apligraf #2) 1 to 3 weeks later. 

After an additional 1 to 3 weeks, Apligraf reapplication can 

be considered again (Apligraf #3). Apligrafs #2 and #3 can 

be applied even if healing is not progressing because the 

trajectory of healing may not become evident during the 

initial phase of therapy. However, if after 3 applications the 

wound is not progressing, reevaluate the patient for factors 

that may be interfering with healing, especially ischemia, 

ulcer infection, osteomyelitis, inadequate off-loading, poor 

nutritional status, and poor glycemic control. If these factors 

are under control, the patient should be considered for 

2 additional applications (Apligraf #4 and Apligraf #5) to 

maintain the trajectory of healing. If these factors are not 

under control, they should be addressed before proceeding 

with additional applications. A maximum of 5 Apligraf applications 

is considered one course of therapy. The goal of 

treatment is complete closure of the DFU. 


• Marston WA; Dermagraft Diabetic Foot Ulcer Study 

Group. Risk factors associated with healing chronic diabetic 

foot ulcers: the importance of hyperglycemia. Ostomy 

Wound Manage. 2006;52(3):26-32. 

• Apligraf [prescribing information]. Canton MA: 

Organogenesis Inc; December 2010. n 

2.5 Summary 

The care of patients with a DFU requires careful attention to critical elements to optimize the potential for successful 

treatment. Thorough assessment of the patient, especially vascular status and the presence of soft tissue and bone infection, 

will lead to accurate staging of patients. Once peripheral arterial disease and infection have been either excluded or 

addressed, vigilance in offloading is the most important aspect of standard care. Coupled with debridement and appropriate 

dressing selection, conscientious weekly evaluation is recommended. Should a patient fail to improve by 4 weeks 

of care, reassessment is warranted as is consideration of advanced therapy. 

Three products have received FDA approval for the treatment of DFUs that have not responded to conventional therapy, 

Apligraf, Dermagraft and Regranex. Apligraf, a bilayered living-cell-based product, is supported by two randomized 

clinical trials showing benefit and effectiveness data demonstrating clinical utility. Optimally, wounds should be debrided 

and fastidious offloading continued as serial applications every 1 to 3 weeks of Apligraf are applied. If the wound has not 

responded after three applications, reassess factors that may be interfering with healing before proceeding with the two 

additional applications. 

Patients with DFUs are at risk for limb loss and death. The seriousness of this problem cannot be overstated and the 

best results are achieved with a thorough evidenced-based process of care. n 


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trial. Diabetes Care. 2001;24(2):290-295. 


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Expert Recommendations for Optimizing Outcomes ... - Wounds

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