Expert Recommendations for Optimizing Outcomes Utilizing Apligraf

Supplement to WOUNDS® December 2012

Expert Recommendations for Optimizing Outcomes Utilizing Apligraf® for Diabetic Foot UlcersThis supplement was not subject to the peer review process of WOUNDS

Supported by Organogenesis, Inc.

Organo_Supplement.indd 1 12/12/12 9:25 AM

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

Table of Contents

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

PART 1Patients 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

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

©2012 HMP Communications, LLC (HMP). All rights reserved. Reproduction in whole or in part prohibited. Opinions expressed by authors, contributors, and advertisers are their own and not necessarily those of HMP Communications, the editorial staff, or any member of the editorial advisory board. HMP Communications is not responsible for accuracy of dosages given in articles printed herein. The appearance of advertisements in this journal is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality, or safety. HMP Communications disclaims responsibility for any injury to persons or property resulting from any ideas or products referred to in the articles or advertisements. Content may not be reproduced in any form without written permission. Reprints of articles are available. Rights, permission, reprint, and translation information is available at: www.hmpcommunications.com. HMP Communications, LLC (HMP) is the authoritative source for comprehensive information and education servicing healthcare professionals. HMP’s products include peer-reviewed and non–peer-reviewed medical journals, national tradeshows and conferences, online programs, and customized clinical programs. HMP is a wholly owned subsidiary of HMP Communications Holdings LLC. Discover more about HMP’s products and services at www.hmpcommunications.com.

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PART 2Advanced 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

Table of Contents



Purpose of this Supplement

Dr. Robert S. Kirsner (Moderator)Dr. Kirsner is a tenured professor, Vice Chairman, and

holds the endowed Stiefel Laboratories Chair in Derma-tology in the Department of Dermatology and Cutaneous Surgery at the University of Miami Miller School of Med-icine. 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 Soci-ety and is past president of the Association for the Advance-ment 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 spon-sored 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 BellDr. 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 meth-odology and community outreach. He is a board certified wound specialist (CWS/American Board of Wound Man-agement) and has served on their Board of Directors since 2009. He serves on the Board of Directors of the Asso-ciation for the Advancement of Wound Care, the Barbara Bates-Jensen Wound Reach Foundation, the Communica-tions Committee of the Jacksonville Chapter of the Amer-ican 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.

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 DFUsThe 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 stand-alone 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. Gary GibbonsDr. Gibbons is medical director for South Shore Hospital

Center for Wound Care and Hyperbaric Medicine and Pro-fessor of Surgery at the Boston University School of Medicine. Trained as a vascular surgeon, Dr. Gibbons was the first direc-tor of the Joslin-Beth Israel Deaconess Foot Center in Boston and his career has centered on diabetic patients with lower ex-tremity wounds, especially those complicated by vascular dis-ease. 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 EnnisDr. 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, microcircu-lation, macrophage function and the impact of stem cells on wound healing.

Dr. Arti MasturzoDr. 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 Univer-sity 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 Di-rector of Medical Affairs of Accelecare Wound Centers. Dr. Masturzo is board-certified in internal medicine and undersea hyperbaric medicine.

Dr. Gary RothenbergDr. Rothenberg is a board certified podiatrist, certified di-

abetes 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 Mi-ami, 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 manage-ment of the diabetic foot.

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.

AcknowledgementsThis 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.

Conflicts of Interest



PART 1

Review of EvidenceDFUs 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 pre-ceded by DFUs1 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 treat-ment is only 31% at 20 weeks3 (Figure 1). Moreover, DFUs are frequently inadequately managed due to multiple fac-tors including blunted signs of infection, limited under-standing of current diagnostic and therapeutic approaches, and insufficient resources.4

Group DiscussionThe seriousness of DFUs is often underestimated by both

clinicians and patients. A critical first step is for everyone in-volved to fully understand and explicitly acknowledge that achieving complete healing represents a significant chal-lenge 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 import-ant 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 suc-cess 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.

Suggested Reading• Consensus Development Conference on Diabetic Foot Wound

Care: 7-8 April 1999, Boston, Massachusetts. American Diabe-tes 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 neuro-pathic 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, out-comes, and cost of foot ulcers in patients with diabetes. Diabetes Care. 1999;22(3):382-387. n

Patients with Diabetic Foot Ulcers

1.1 The Challenge of Diabetic Foot Ulcers

24.2% 30.9%

0%

25%

75%

100%

12 Weeks

Time Elapsed

Wei

ghte

d M

ean

Hea

ling

Rate

N = 4 trials N = 6 trials

%

12 Weeks 20 Weeks

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.



1.2 Pathophysiology of Wound Healing in DFUs

Review of EvidenceAcute wounds heal through a normal highly regulat-

ed 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 mul-tiple abnormal physiologic, anatomic, and cellular factors: (1) decreased angiogenic response; (2) neuropathy; (3) ischemia; (4) endothelial dysfunction; and (5) increased susceptibility to wound infection5 (Figure 2).

In addition, in DFUs there is poor and disorganized reg-ulation of the cytokines, growth factors, proteases, extra-cellular matrix components, and cells needed to achieve complete wound closure8,9: (1) keratinocyte migration and proliferation is impaired10; (2) fibroblast response to growth factors9 and the ability to synthesize collagen is impaired11; 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.

Group DiscussionAll 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.

• Werner S, Krieg T, Smola H. Keratinocyte–fibro-blast 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

Figure 2. Pathophysiologic factors contributing to poor healing rates of DFUs.



1.3 Initial Evaluation of Patients with a DFU

Review of EvidenceSeveral 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 Sur-geons,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 sta-tus; 4) wound infection, including osteomyelitis; and 5) hy-perglycemia (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 re-sponse to treatment, patient compliance, family or social

problems that are interfering with care, previous foot trau-ma 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, isch-emia, 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 in-volve a multidisciplinary team that includes wound care pro-fessionals and, when indicated, diabetologists or endocrinol-ogists, surgeons (vascular and podiatric), nurses, nutritionists, and pedorthotists.4

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.

Assess Patient

• H & P• Glycemic control• Nutritional evaluation• Immune status• Neurological evaluation• Vascular evaluation• Psychosocial evaluation

Appropriate Interventions

Assess DFU

Standard Therapy for all DFUs

Debridement Infection Control Off-Loading Appropriate Dressing

• Duration• Size (~area in cm2)• Depth• Location• Charcot• Soft tissue infection & osteomyelitis• Consider advanced testing & imaging

Estimate Likelihood of Succesful Closure & Discuss with Patient



Group DiscussionPublished 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 inade-quate 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 eval-uation of patients with a DFU is precise baseline mea-surement of wound size so that the response to treatment can be reassessed quantitatively and accurately (Section 1.6 below: “Evaluating Response to Conventional Therapy”).

Suggested Reading• 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 dis-orders. 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 treat-ment 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 rec-ommendations 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: Character-istics of Vascular Disease Unique to the Diabetic Patient. Semin Vasc Surg. 2012;25:89-92. n

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

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 Grade

0 I II III

APre- or post-ulcerative lesions, completely epithelized

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



1.4 Estimating the Likelihood of DFU Healing

Review of EvidenceThe likelihood of complete DFU healing is determined

by multiple factors, both patient-related and wound-relat-ed. 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 predic-tive value include the size, duration, depth, and grade of the DFU. Larger lesions (>2 cm2), chronic lesions (>6 months - 12 months), deeper lesions, and higher grade lesions are associated with reduced likelihood of complete healing de-spite continued conventional therapy.

Margolis et al18 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 dura-tion wounds. For example, wounds <2 cm2 and <6 months had a 43% probability of healing at 20 weeks (n = 120 patients) compared to wounds >4 cm2 and >12 months, which had only a 26% probability of healing (n = 252 patients).

Group DiscussionMany 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 max-imize 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 con-ventional 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 under-stand that DFUs are very difficult to heal with conven-tional 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 deci-sions and higher compliance.

Suggested Readings• 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

%

25%

50%

75%

100%

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

cm 2

Wound Duration months

Wound Size & Duration cm 2 & months

% H

eale

d W

ithin

20

Wee

ks

<2 2-4 >4 <6 6-12 >12 <2 & <6 >4 & >12

347 Sample Size: 123 116 202 88 189 120 252

0

% Healed

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

Review of EvidenceManagement 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 treat-ed directly. Below is a brief review of the clinical evidence supporting the administra-tion of conventional wound therapies that are mandated in all patients with DFUs:

Offloading. The main mechanism by which DFUs

develop is due to increased, sustained and/or repetitive trauma in the setting of periph-eral neuropathy. Distributing and minimiz-ing 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 stan-dard 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 alterna-tives are available which have been shown to be effective.21,22 Poor patient compliance of-ten 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 ad-herence that best adapts to the patient, permitting continuous use and effective decrease in pressure.

Debridement. Debridement is considered essential in DFU care al-

though this is supported by data from secondary analyses of controlled trials performed for reasons other than debride-

ment.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, enzy-matic, autolytic, mechanical, and biologic), surgical debride-ment 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-

Figure 6. Examples of DFUs before and after surgical debridement. Photo credit: Arti B Masturzo MD ABPM/UHMMedical Director Advanced Wound ProgramsBethesda North & Good Samaritan HospitalsCincinnati, OH

Before debridement After debridement



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 tis-sue 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 ad-hesiveness, concern for infection, and conformability.5 Howev-er, 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

Group Discussion

Standard wound management will succeed in healing only a percentage of DFUs. Unfortunately, optimal stan-dard 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. Off-loading is grossly underutilized, which is unfortunate given the strong evidence supporting its role in promoting wound healing. Practitioners are encouraged to remember that con-tact-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 guide-line. 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.

Suggested Readings• 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 rec-ommendations 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



Review of EvidencePatients with DFUs should be followed closely with week-

ly 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 af-ter 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 treat-

ment 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 ther-apy whose wounds did not reduce in size by more than 53% had a decreased likelihood of healing at 12 weeks.30 In addi-tion 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

1.6 Evaluating Response to Conventional Therapy

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

• Wound healing trajectory• % area reduction

• Ulcer infection• Osteomyelitis• Ischemia• Glycemic control• Inadequate offloading• Poor nutrition• Other factors

Healingadequately

Not healingadequately

Follow-up

Completeclosure

Evidence-based advanced therapy

Address factorsinterfering

with healing

Standard Therapy of DFU

Reassess DFU within 4 Weeks



Wound Healing Society’s guidelines recommend a change in treatment if wound size reduction is not observed at 4 weeks of conventional therapy.16

Group DiscussionThe 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 set-tings 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 de-scribed above indicated that a sizeable proportion of patients

(42% in one study30) who are healing adequately at 4 weeks will ultimately fail to completely heal; these patients will also require advanced therapy.

Suggested Readings• 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-cen-ter 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 heal-ing trajectories as predictors of effectiveness of therapeutic agents. Arch Surg. 2000;135(7):773-777. n



PART 2

Advanced Therapy of DFUs with Apligraf

Review of EvidenceIn many cases, standard DFU therapy is not sufficient to

heal the wound. The appropriate use of advanced thera-pies 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 ap-

proved by the FDA for treatment of DFUs based on the results of rigorous clinical studies:

1) Apligraf® — bilayered (fibroblast/keratinocyte) cell-based product32

2) Dermagraft® — human-fibroblast-derived dermal substitute33

3) Regranex® — platelet-derived growth factor34

2.1 Evidence-Based Selection of Advanced Therapy for DFUs

Figure 8. The Centre for Evidence-Based Medicine: levels of clinical evidence.Adapted from Centre for Evidence-based Medicine. http://www.cebm.net/index.aspx?o=1025. Accessed August 22, 2011.

RCTs*

COHORTSTUDIES

CASE-CONTROLLEDSTUDIES

CASE SERIES

CASE REPORT OR ExPERT OPINION

* RCT = RANDOmIzED CLINICAL TRIAL

LEVEL 1

LEVEL 2

LEVEL 3

LEVEL 4

LEVEL 5

HIGHEST LEVEL OF EVIDENCE

LOWEST LEVEL OF EVIDENCE


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 re-quire 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 source35 (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.

Group DiscussionDFUs are a serious complication of DM associated with

high morbidity, including limb loss and increased risk of mor-tality. Practitioners owe it to their patients to utilize the most proven therapies to maximize the likelihood of achieving suc-cessful healing, thereby potentially preventing additional com-plications. 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 progres-sion 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 evi-dence supports their use. In the “hierarchy of scientific evi-dence,” randomized clinical trials represent the highest level of evidence while expert opinion and case reports represent the lowest level.

Suggested Reading• Apligraf [prescribing information].

Canton MA: Organogenesis Inc; December 2010.

• Dermagraft [prescribing information]. Westpoint CT: Ad-vanced 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 equiv-alent, is effective in the management of noninfected neuro-pathic diabetic foot ulcers: a prospective randomized multi-center 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 chron-ic 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.aspx?o=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




Review of EvidenceApligraf is a bioengineered allogeneic bilayered living-cell-

based 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 fi-broblasts 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 al36 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 Apli-graf (n=112) plus standard care or standard care alone (n=96). Standard care consisted of saline moistened gauze, wound de-bridement 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 addi-tion, 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 con-trolled 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.

Group DiscussionUse of Apligraf as an advanced treatment for DFUs is sup-

ported 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 cyto-kines that are believed to play important roles in wound healing.

Suggested Readings• Apligraf [prescription information]. Canton MA: Organogene-sis Inc; December 2010.

• 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.

• 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

2.2 Apligraf: Efficacy and Proposed Mechanism

Function1 Growth Factor or Cytokine*

Human2

Keratinocytes†Human2

Fibroblasts†Apligraf2

Angiogenesis PDGF-A‡PDGF-B‡VEGF‡

333

333

333

Growth, development, and differentiation

IGF-1IGF-2

TGF-ß1TGF-ß3

333

3333

Inflammation

IL-1a‡IL-6‡IL-8‡

IL-11‡

3

3333

3333

Proliferation

FGF-1FGF-2FGF-7TGF-a‡

3

3

333

3333

*As measured by mRNA levels † Cells were grown in monolayer cultures ‡ Cytokines and growth factors were also detected using enzyme-linked immunosorbent assay.1Barrientos S, et al. Wound Repair Regen. 2008;16:585-601 2Brem H, et al. Surg Technol Int. 2003;11:23-31

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



Review of EvidenceThe technique used to apply various wound therapies, in-

cluding Apligraf, varies among different practitioners. How-ever, 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 cm2; 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-ad-herent primary dressing (Tegapore) and secured with hypo-allergenic 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-thick-ness DFU of at least 4 weeks duration; with a surface area be-tween 1 and 16 cm2; 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-moist-ened 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.

Group DiscussionWhat 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). Ul-cers at any location on the foot—including the plantar sur-face—are appropriate for Apligraf. Although Charcot disease was excluded in the clinical trials, with appropriate offload-ing 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 infect-ed 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-StripsTM, but other methods can be utilized. Neg-ative pressure wound therapy may augment Apligraf wound bed interaction in highly exudative wounds. It is extremely important that offloading be continued.

Suggested Readings• Apligraf [prescription information]. Canton MA: Organogene-sis Inc; December 2010.

• 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 dia-betic 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

2.3 Initiating Apligraf Therapy



Review of EvidenceIn the randomized controlled trial of Apligraf by Veves et

al,36 DFU patients in the treatment group could have Apli-graf 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 per-formed. 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 treat-ment 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 pa-tients required multiple applications of Apligraf. This is consistent with findings from several small studies with dif-ferent wound types that showed limited persistence. DNA evidence of Apligraf was short-lived, typically 3 weeks to 6 weeks after application.40-42

2.4 Evaluating Response to Apligraf & Reapplications

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

Address factors interfering with healing

• Ulcer infection• Osteomyelitis• Ischemia• Glycemic control• Inadequate offloading• Poor nutrition• Other factors

Healingadequately

H

E

A

L

E

D

ReassessWeekly

Apligraf Application #1

Application #2 in 1 to 3 weeks




No

Yes

Woundhealing

progressing?

Factors above addressed?

Yes



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 infec-tion, 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 appro-priate 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 ther-apy, 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

2.5 Summary

Group DiscussionAs 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 (Fig-ure 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 fac-

tors 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 ap-plications is considered one course of therapy. The goal of treatment is complete closure of the DFU.

Suggested Readings• Marston WA; Dermagraft Diabetic Foot Ulcer Study

Group. Risk factors associated with healing chronic dia-betic 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

1. Singh N, Armstrong DG, Lipsky BA. Prevent-ing foot ulcers in patients with diabetes. JAMA. 2005;293(2):217-228.

2. American Diabetes Association. Data from the 2011 National Diabetes Fact Sheet (released Jan. 26, 2011). http://www.diabetes.org/diabetes-ba-sics/diabetes-statistics/. Accessed August 22, 2011.

3. Margolis DJ, Kantor J, Berlin JA. Healing of dia-betic neuropathic foot ulcers receiving standard treatment. Diabetes Care. 1999;22(5):692-695.

4. Maderal AD, Vivas AC, Zwick TG, Kirsner RS.

Diabetic foot ulcers: evaluation and management. Hosp Pract (Minneap). 2012;40(3):102-115.

5. 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.

6. Werner S, Krieg T, Smola H. Keratinocyte–fi-broblast interactions in wound healing. J Invest Dermatol. 2007;127(5):998-1008.

7. Ghahary A, Ghaffari A. Role of keratinocyte–fi-broblast cross-talk in development of hypertro-phic scar. Wound Repair Regen. 2007;15(suppl 1):S45-S53.

8. Lobmann R, Schultz G, Lehnert H. Proteas-es and the diabetic foot syndrome: mecha-nisms and therapeutic implications. Diabetes Care.2005;28(2):461-471.

9. Harding KG, Moore K, Phillips TJ. Wound chro-nicity and fibroblast senescence-implications for treatment. lnt Wound J. 2005;2(4):364-368.

10. Martin P. Wound healing--aiming for perfect skin regeneration. Science. 1997;276(5309):75-81.

11. Herrick SE, Ireland GW, Simon D, McCollum CN, Ferguson MW. Venous ulcer fibroblasts com-pared with normal fibroblasts show differences in collagen but not fibronectin production under both normal and hypoxic conditions. J Invest Der-matol. 1996;106(1):187-193.

12. Vaalamo M, Leiva T, Saarialho-Kere U. Differential expression of tissue inhibitors of metalloproteinas-es (lIMP-I. -2, -l, and -4) in normal and aberrant wound healing. Hum Pathol. 1999;30(7):795-802.

13. Muller M, Trocme C, Lardy B, et al. Matrix metal-loproteinases and diabetic foot ulcers: the ratio of MMP-1 and TlMP-1 is a predictor of wound healing. Diabet Med. 2006;25(4):419-426.

14. Lipsky BA, Berendt AR, Cornia PB, et al. 2012 Infectious Diseases Society of America clinical practice guideline for the diagnosis and treat-ment of diabetic foot infections. Clin Infect Dis. 2012;54(12):e132-173.

15. Frykberg RG, Zgonis T, Armstrong DG, et al.

Diabetic foot disorders. A clinical practice guide-line (2006 revision). J Foot Ankle Surg. 2006;45(5 Suppl):S1-66.

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

17. Bakker K, Apelqvist J, Schaper NC; International Working Group on Diabetic Foot Editorial Board. Practical guidelines on the management and pre-vention of the diabetic foot 2011. Diabetes Metab Res Rev. 2012;28 Suppl 1:225-231.

References



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

19. Ali R, Qureshi A, Yagoob MY, Shakil M. Total con-tact cast for neuropathic diabetic foot ulcers. J Coll Physicians Surg Pak. 2008;18(11):695-698.

20. Hanft JR, Surprenant MS. Is total contact casting the gold standard for the treatment of diabetic foot ulcerations? Abstract presented at American College of Foot and Ankle Surgeons Joint Annual Meeting and Scientific Seminar; February 9, 2000; Miami, FL.

21. Faglia E, Caravaggi C, Clerici G, et al. Effectiveness of removable walker cast versus nonremovable fiberglass off-bearing cast in the healing of diabetic plantar foot ulcer: a randomized controlled trial. Diabetes Care. 2010;33(7):1419-1423.

22. Armstrong DG, Short B, Espensen EH, Abu-Rum-man PL, Nixon BP, Boulton AJ. Technique for fabri-cation of an “instant total-contact cast” for treatment of neuropathic diabetic foot ulcers. J Am Podiatr Med Assoc. 2002;92(7):405-408.

23. van Deursen R. Footwear for the neuropathic pa-tient: offloading and stability. Diabetes Metab Res Rev. 2008;24(suppl 1):S96-100.

24. The effect of intensive treatment of diabetes on the development and progression of long-term compli-cations in insulin-dependent diabetes mellitus: the Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993;329(14):977-986.

25. Steed DL, Donohoe D, Webster MW, Lindsley L. Effect of extensive debridement and treatment on the healing of diabetic foot ulcers. Diabetic Ulcer Study Group. J Am Coll Surg. 1996;183(1):61-64.

26. Saap LJ, Falanga V. Debridement performance index and its correlation with complete clo-sure of diabetic foot ulcers. Wound Repair Regen. 2002;10(6):354-359.

27. Cardinal M, Eisenbud DE, Armstrong DG, et al. Serial surgical debridement: a retrospective study on clinical outcomes in chronic lower extremity wounds. Wound Repair Regen. 2009;17(3):306-311.

28. Coerper S, Beckert S, Küper MA, Jekov M, Königs-rainer A. Fifty percent area reduction after 4 weeks of treatment is a reliable indicator for healing--anal-ysis of a single-center cohort of 704 diabetic pa-tients. J Diabetes Complications. 2009;23:49-53.

29. Margolis DJ, Hoffstad O, Gelfand JM, Berlin JA. Surrogate end points for the treatment of di-abetic neuropathic foot ulcers. Diabetes Care. 2003;26:1696-1700.

30. 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.

31. Robson MC, Hill DP, Woodske ME, Steed DL. Wound healing trajectories as predictors of effective-ness of therapeutic agents. 2000;135(7):773-777.

32. Apligraf [prescription information]. Canton MA: Organogenesis Inc; December 2010.

33. Dermagraft [prescription information]. Westpoint CT: Advanced Biohealing; 2012.

34. Regranex (becaplermin) [prescription information].Fort Worth, TX: Healthpoint Biotherapeutics; 2012.

35. Centre for Evidence-based Medicine. http://www.cebm.net/index.aspx?o=1025. Accessed August 22, 2011.

36. Veves A, Falanga V, Armstrong DG, Sabolinski ML, Apligraf Diabetic Foot Ulcer Study. Graftskin, a human skin equivalent, is effective in the manage-ment of noninfected neuropathic diabetic foot ul-cers: a prospective randomized multicenter clinical trial. Diabetes Care. 2001;24(2):290-295.



37. 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.

38. Maderal AD, Vivas AC, Eaglstein WH, Kirsner RS. The FDA and designing clinical trials for chronic cutaneous ulcers. Semin Cell Dev Biol. 2012 Oct 9. doi:pii: S1084-9521(12)00179-6. 10.1016/j.sem-cdb.2012.09.014. [Epub ahead of print]

39. Kirsner RS, Warriner R, Michela M, Stasik L, Free-man K. Advanced biological therapies for diabetic foot ulcers. Arch Dermatol. 2010 Aug;146(8):857-862.

40. Falabella AF, Valencia IC, Eaglstein WH, Schachner LA. Tissue-engineered skin (Apligraf) in the healing of patients with epidermolysis bullosa wounds. Arch Dermatol. 2000;136:1225-1230.

41. Griffiths M, Ojeh N, Livingstone R, Price R, Navsaria H. Survival of Apligraf in acute human wounds. Tissue Eng. 2004;10:1180-1195.

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Expert Recommendations for Optimizing Outcomes Utilizing Apligraf