Evidence-based Synthesis Program Department of Veterans Affairs

Health Services Research & Development Service

November 2012

Prepared for:

Department of Veterans Affairs

Veterans Health Administration

Quality Enhancement Research Initiative

Health Services Research & Development Service

Washington, DC 20420

Prepared by:

Evidence-based Synthesis Program (ESP) Center

Minneapolis VA Medical Center

Minneapolis, MN

Timothy J. Wilt, M.D., M.P.H., Director

Advanced Wound Care Therapies for 

Non-Healing Diabetic, Venous, and 

Arterial Ulcers: A Systematic Review

Investigators:

Principal Investigators:

Nancy Greer, Ph.D.

Neal Foman, M.D., M.S.

Timothy Wilt, M.D., M.P.H.

Co-Investigators: 

James Dorrian, B.S.

Patrick Fitzgerald, M.P.H.

Roderick MacDonald, M.S.

Research Assistant:

Indy Rutks, B.S.
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Advanced Wound Care Therapies for Non-Healing Diabetic, 

Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

PREFACE

Quality Enhancement Research Initiative’s (QUERI) Evidence-based Synthesis Program 

(ESP) was established to provide timely and accurate syntheses of targeted healthcare topics 

of particular importance to Veterans Affairs (VA) managers and policymakers, as they work to 

improve the health and healthcare of Veterans. The ESP disseminates these reports throughout 

VA.

QUERI provides funding for four ESP Centers and each Center has an active VA affiliation. The ESP 

Centers generate evidence syntheses on important clinical practice topics, and these reports help:

• develop clinical policies informed by evidence,

• guide the implementation of effective services to improve patient 

outcomes and to support VA clinical practice guidelines and 

performance measures, and 

• set the direction for future research to address gaps in clinical 

knowledge.

In 2009, the ESP Coordinating Center was created to expand the capacity of QUERI Central 

Office and the four ESP sites by developing and maintaining program processes. In addition, 

the Center established a Steering Committee comprised of QUERI field-based investigators, 

VA Patient Care Services, Office of Quality and Performance, and Veterans Integrated Service 

Networks (VISN) Clinical Management Officers. The Steering Committee provides program 

oversight, guides strategic planning, coordinates dissemination activities, and develops 

collaborations with VA leadership to identify new ESP topics of importance to Veterans and the 

VA healthcare system.

Comments on this evidence report are welcome and can be sent to Nicole Floyd, ESP 

Coordinating Center Program Manager, at nicole.floyd@va.gov.

Recommended citation: Greer N, Foman N, Dorrian J, Fitzgerald P, MacDonald R, Rutks I, 

Wilt T. Advanced Wound Care Therapies for Non-Healing Diabetic, Venous, and Arterial Ulcers: 

A Systematic Review. VA-ESP Project #09-009; 2012.

This report is based on research conducted by the Evidence-based Synthesis Program 

(ESP) Center located at the Minneapolis VA Medical Center, Minneapolis, MN funded 

by the Department of Veterans Affairs, Veterans Health Administration, Office of 

Research and Development, Quality Enhancement Research Initiative. The findings 

and conclusions in this document are those of the author(s) who are responsible for 

its contents; the findings and conclusions do not necessarily represent the views of 

the Department of Veterans Affairs or the United States government. Therefore, no 

statement in this article should be construed as an official position of the Department 

of Veterans Affairs. No investigators have any affiliations or financial involvement (e.g., 

employment, consultancies, honoraria, stock ownership or options, expert testimony, 

grants or patents received or pending, or royalties) that conflict with material presented 

in the report.
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Advanced Wound Care Therapies for Non-Healing Diabetic, 

Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

TABLE OF CONTENTS

Executive Summary

Background.................................................................................................................................................... 1

Methods......................................................................................................................................................... 2

Data Synthesis............................................................................................................................................... 3

Peer Review................................................................................................................................................... 3

Results ........................................................................................................................................................... 3

Executive Summary Table 1. Strength of Evidence – Advanced Wound Care Therapies 

for Diabetic Ulcers.................................................................................................................................9

Executive Summary Table 2. Strength of Evidence – Advanced Wound Care Therapies for 

Venous Ulcers ......................................................................................................................................15

Discussion......................................................................................................................................................18

Applicability and Cost Effectiveness ............................................................................................................20

Future Research.............................................................................................................................................20

Abbreviations Table.......................................................................................................................................22

Introduction

Ulcer Types....................................................................................................................................................23

Advanced Wound Care Therapies.................................................................................................................25

Purpose and Scope of Review .......................................................................................................................26

Methods

Topic Development........................................................................................................................................27

Search Strategy..............................................................................................................................................27

Study Selection..............................................................................................................................................27

Data Abstraction ............................................................................................................................................28

Quality Assessment .......................................................................................................................................28

Data Synthesis...............................................................................................................................................28

Rating the Body of Evidence.........................................................................................................................29

Peer Review...................................................................................................................................................29

Results

Literature Flow ..............................................................................................................................................30

Key Question #1. What are the efficacy and harms of therapies for diabetic ulcers? Is efficacy 

dependent on ancillary therapies? Does efficacy differ according to patient demographics, 

comorbid conditions, treatment compliance, or activity level?.....................................................................31

Key Question #2. What are the efficacy and harms of therapies for venous ulcers? Is efficacy 

dependent on ancillary therapies? Does efficacy differ according to patient demographics, 

comorbid conditions, treatment compliance, or activity level?.....................................................................56

Key Question #3. What are the efficacy and harms of therapies for arterial ulcers? Is efficacy 

dependent on ancillary therapies? Does efficacy differ according to patient demographics, 

comorbid conditions, treatment compliance, or activity level?.....................................................................75
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Advanced Wound Care Therapies for Non-Healing Diabetic, 

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Summary and Discussion....................................................................................................................................82

Applicability and Cost Effectiveness ............................................................................................................84

Recommendations for Future Research.........................................................................................................84

References.............................................................................................................................................................. 86

Tables

Table 1. Overview of Therapies for Diabetic Ulcers..................................................................................33

Table 2. Summary of Baseline Characteristics: Collagen .........................................................................35

Table 3. Summary of Baseline Characteristics: Biological Dressings ......................................................36

Table 4. Summary of Baseline Characteristics: Biological Skin Equivalents...........................................37

Table 5. Summary of Baseline Characteristics: Platelet-Derived Growth Factors....................................40

Table 6. Summary of Baseline Characteristics: Platelet Rich Plasma.......................................................44

Table 7. Summary of Baseline Characteristics: Silver Products...............................................................45

Table 8. Summary of Baseline Characteristics: Negative Pressure Wound Therapy ................................47

Table 9. Summary of Baseline Characteristics: Hyperbaric Oxygen Therapy versus 

Standard Care/Sham .....................................................................................................................48

Table 10. Ulcer Size, Ulcer Duration, and Definitions of Closure: Hyperbaric Oxygen 

Therapy versus Standard Care/Sham............................................................................................49

Table 11. Strength of Evidence - Advanced Wound Care Therapies for Diabetic Ulcers............................54

Table 12. Overview of Therapies for Venous Ulcers....................................................................................58

Table 13. Baseline Study Characteristics: Biological Skin Equivalents .....................................................60

Table 14. Baseline Study Characteristics: Keratinocytes............................................................................62

Table 15. Summary of Baseline Characteristics: Silver Products...............................................................65

Table 16 Ulcer Size, Ulcer Duration, and Definitions of Closure: Electromagnetic Therapy.....................69

Table 17 Strength of Evidence – Advanced Wound Care Therapies for Venous Ulcers.............................73

Table 18. Overview of Therapies for Arterial Ulcers, Mixed Lower Extremity Ulcers, and 

Amputation Wounds.....................................................................................................................77

Figures

Figure 1. Literature Flow Diagram ..............................................................................................................30

Figure 2. Proportion of Diabetic Ulcers Healed – Biological Skin Equivalent (Dermagraft) versus 

Standard Care................................................................................................................................38

Figure 3. Proportion of Diabetic Ulcers Healed – Biological Skin Equivalent (Apligraf) versus 

Standard Care................................................................................................................................39

Figure 4. Proportion of Diabetic Ulcers Healed – Platelet-Derived Growth Factors versus Comparator ......42

Figure 5. Proportion of Diabetic Ulcers Healed – Silver Products................................................................46

Figure 6. Time to Complete Healing, Diabetic Ulcers – Negative Pressure Wound Therapy .....................48

Figure 7. Proportion of Diabetic Ulcers Healed – Hyperbaric Oxygen Therapy.........................................50 

Figure 8. Proportion of Venous Ulcers Healed - Biological Skin Equivalent (Dermagraft) versus 

Compression Bandage ..................................................................................................................61

Figure 9. Proportion of Venous Ulcers Healed – Keratinocytes versus Standard Care ...............................63

Figure 10.Proportion of Venous Ulcers Healed – Silver Products................................................................67

Figure 11.Proportion of Venous Ulcers Healed – Electromagnetic Therapy versus Sham...........................70
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Advanced Wound Care Therapies for Non-Healing Diabetic, 

Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Appendix A. Therapy Descriptions and References ........................................................................94

Appendix B. Search Strategy .................................................................................................................103

Appendix C. Peer review Comments/Author Responses..............................................................105

Appendix D. Evidence Tables

Table 1. Study Characteristics Table ........................................................................................................ 112

Table 2. Primary Outcomes......................................................................................................................147

Table 3. Secondary Outcomes – Part A ....................................................................................................156

Table 4. Secondary Outcomes – Part B....................................................................................................164

Table 5. Secondary Outcomes – Part C....................................................................................................167

Appendix E. Common Methodological Errors and Recommendations for

 Future Clinical Trials of Wound Healing ............................................................175
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Advanced Wound Care Therapies for Non-Healing Diabetic, 

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EVIDENCE REPORT

INTRODUCTION

Chronic ulcers (i.e., ulcers that are unresponsive to initial therapy or that persist despite 

appropriate care) are estimated to affect over 6 million people in the United States.1 The 

incidence is expected to increase as the population ages and as the number of individuals with 

diabetes increases.1 Chronic ulcers negatively affect the quality of life and productivity of the 

patient and represent a financial burden to the health care system.1,2,3 Within the Veterans Health 

Administration, during fiscal year 2011, there were over 227,000 ulcer encounters (inpatient 

and outpatient) involving over 54,000 patients and nearly 77,000 new ulcers.(Source: PAVE 

ProClarity Cubes (Prevention of Amputations in Veterans Every ProClarity Cubes)).

We focus on chronic ulcers of the lower extremity, in particular, ulcers attributed to either 

diabetes, venous disease, or arterial disease. Because advanced wound care therapies are 

typically used for ulcer healing following amputation, we also included post-amputation 

wounds. Identifying the ulcer etiology is important because the correct diagnosis is one factor 

in determining appropriate wound care interventions.4 Treatment modalities and wound care 

therapies are also selected based on patient factors, past treatment, and provider choice. A brief 

description of each ulcer type is provided below. We recognize that a non-healing ulcer is likely 

a result of multiple factors and comorbid conditions. We categorize included studies as diabetic, 

venous, or arterial according to the study author’s description of the ulcer type. 

Ulcer Types

Diabetic Ulcers

Approximately 15% to 25% of individuals with diabetes develop a foot ulcer at some point 

in their lifetime and an estimated 12% of those patients require lower extremity amputation.1

Diabetic foot ulcers account for nearly 2/3 of all nontraumatic amputations.4 Ulcer healing is 

complicated by diabetic neuropathy, decreased cellular synthesis, and susceptability to infection.5

Neuropathy can be categorized as sensory (loss of protective sensation), motor (the anatomic 

structure of foot is deformed creating areas where pressure from an ill-fitting shoe can create 

ulcers), or autonomic (resulting in denervation of sweat glands so the skin becomes dry and 

cracked predisposing the foot to infection, calluses etc.).3,4 Diabetic ulcers are typically located 

on the plantar aspect of the foot, over the metatarsal heads, or under the heel.6 The ulcers are 

characterized by even wound margins, a deep wound bed, cellulitis or underlying osteomyelitis, 

granular tissue (unless peripheral vascular disease is also present), and low to moderate 

drainage.6 Patients should be assessed for adequacy of circulation (claudication or extremity pain 

at rest, diminished or absent pulses, cool temperature, pallor on elevation, ABI), although due 

to issues with non-compressible vessels, toe pressures, ultrasonography, or other noninvasive 

vascular studies may be needed.7 Diabetic ulcers are typically graded using the Wagner8

classification: 

Grade 0 – no open lesions in a high-risk foot

Grade 1 – superficial ulcer involving full skin thickness but not underlying tissue
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Advanced Wound Care Therapies for Non-Healing Diabetic, 

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Grade 2 – deeper ulcer; penetrating to tendon, bone, or joint capsule 

Grade 3 – deeper ulcer with cellulitis or abscess formation, often with osteomyelitis or 

tendinitis

Grade 4 – localized gangrene

Grade 5 – extensive gangrene involving the whole foot 

The University of Texas Diabetic Wound Classification System is also used.9 This system 

incorporates ischemia and infection in ulcer assessment. Standard treatment for Grade 1 

and 2 diabetic ulcers includes debridement of necrotic tissue, infection control, local ulcer 

care (keeping the ulcer clean and moist but free of excess fluids), mechanical off-loading, 

management of blood glucose levels, and education on foot care.4,7 Osteomyelitis is a serious 

complication and a delay in diagnosis is associated with significant morbidity (e.g., non-healing, 

ulcer sepsis, limb loss).5

Venous Leg Ulcers

The most common cause of lower extremity ulcers is venous insufficiency. This accounts for 

70-90% of leg ulcers.1,5 The ulcers develop within the setting of venous hypertension; elevated 

pressures are most commonly caused by valvular incompetence and result in an inefficient return 

of venous blood upon muscle contraction. Although a number of initiating factors may lead to the 

valvular incompetence of deep or perforating veins (e.g., deep vein thrombosis, phlebitis, trauma, 

surgery, or obesity), the resulting clinical picture of chronic venous insufficiency is the same. 

The congested vessels and pooling of blood result in increased vascular permeability. Water, 

proteins, and red blood cells leak out into the interstitial space, and pericapillary fibrin deposition 

occurs. This results in the symptoms of leg edema, hyperpigmentation (from extravasation of red 

blood cells and hemosiderin buildup), and lipodermosclerosis. Ulcers are thought to develop in 

this setting of venous stasis for a number of reasons: pericapillary fibrin deposits limit diffusion 

of oxygen and nutrients to skin tissue; leaked extravascular proteins may trap growth factors 

and matrix materials necessary for preventing and repairing the breakdown of tissue; and the 

accumulation or “trapping” of white blood cells may cause the release of proteolytic enzymes 

and inflammatory mediators.10 Venous ulcers occur most commonly in the leg (compared with 

the foot predominance of arterial and diabetic ulcers) and are characteristically found over the 

medial malleolus. These ulcers are often shallow and can be very large relative to other types of 

ulcers.11 Standard treatment is centered on the use of mechanical compression and limb elevation 

to reverse tissue edema and improve venous blood flow by increasing the hydrostatic pressure.12

Arterial Leg Ulcers

Ulcers associated with peripheral artery disease, also commonly known as ischemic ulcers, 

account for approximately 10% of lower extremity ulcers.3 This ulcer type develops due to 

arterial occlusion, which limits the blood supply and results in ischemia and necrosis of tissue in 

the supplied area. This occlusion is most commonly from atherosclerotic disease, so major risk 

factors for ischemic ulcers are the same as those in peripheral arterial disease (PAD); cigarette 

smoking, diabetes, hyperlipidemia, and hypertension.3 Similarly, patients with ischemic ulcers 

will complain of PAD-related symptoms such as intermittent claudication or pain that continues 

despite leg elevation. Other signs of decreased limb perfusion may also be present, such as a 

shiny, atrophic appearance of the skin, diminished leg hair, cold feet, and dystrophic nails.4,6
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Advanced Wound Care Therapies for Non-Healing Diabetic, 

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Evidence of diminished arterial blood flow may be established by finding diminished or absent 

pedal pulses or, most importantly, by measuring an ankle-brachial index (ABI).4,5 Because 

ischemic ulcers are related to poor perfusion, they typically occur at the most distal sites (e.g., 

the tips of toes) or in areas of increased pressure (e.g., over bony prominences). These painful 

ulcers often present as well-demarcated, deep lesions, giving the lesions a classically described 

“punched-out” appearance.5

 Care for ischemic ulcers is centered on reestablishing blood flow 

and minimizing further losses of perfusion. With severe ischemia, the primary methods for 

achieving this are vascular surgery and lifestyle modifications. It is important to avoid treatment 

with mechanical compression if arterial occlusion is a contributing source for the development of 

an ulcer, as this leads to a worsening of tissue ischemia and necrosis.4

Advanced Wound Care Therapies

If ulcers do not adequately heal with standard treatment, additional modalities may be required. 

We define advanced wound care therapies as interventions used when standard wound care has 

failed. A large and growing array of advanced wound care therapies of different composition and 

indications have been developed though their efficacy, comparative effectiveness and harm is 

not well established. Therapies included in this review are: collagen products (COL), biological 

dressings (BD), biological skin equivalents (BSE), keratinocytes, platelet-derived growth factor 

(PDGF), platelet-rich plasma (PRP), silver products, intermittent pneumatic compression therapy 

(IPC), negative pressure wound therapy (NPWT), electromagnetic therapy (EMT), hyperbaric 

oxygen (HBOT), topical oxygen, and ozone oxygen. Because collagen may be a vehicle to 

deliver other bioactive ingredients, we have included in the collagen section only studies of 

collagen as a matrix material. 

A complete description of these therapies, including reference citations, is presented in Appendix 

A; a brief description follows.

Collagen: Naturally occurring proteins known as collagens have diverse roles in ulcer healing 

including 1) acting as a substrate for hemostasis, 2) chemotactic properties that attract 

granulocytes, macrophages, and fibroblasts to aid healing, 3) providing a scaffold for more rapid 

transition to mature collagen production and alignment, or 4) providing a template for cellular 

attachment, migration, and proliferation. 

Biological Dressings: These dressings consist of biomaterials made from various components 

of the extracellular matrix and are theorized to stimulate ulcer healing by providing a structural 

scaffold and the growth signals important to complex cellular interactions within ulcers, both of 

which are dysfunctional and contribute to the persistence of chronic ulcers. 

Biological Skin Equivalents: These products are laboratory-derived tissue constructs, designed to 

resemble various layers of real human skin. They are thought to increase healing by stimulating 

fibrovascular ingrowth and epithelialization of host tissues. 

Keratinocytes: Keratinocyte-based therapies for wound healing exist in a variety of forms and 

are proposed to work by stimulating proliferation and migration of host epithelium from wound 

edges through the production of growth factors and other cytokines. 
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Advanced Wound Care Therapies for Non-Healing Diabetic, 

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Platelet-Derived Growth Factors: These products are designed to help repair and replace dead skin 

and other tissues by attracting cells that repair wounds and helping to close and heal the ulcers. 

Platelet-Rich Plasma: Plasma with a high platelet concentration aids wound healing by attracting 

undifferentiated cells and activating cell division. 

Silver Products: Multiple silver-based products have been developed to aid wound healing due to 

their broad bactericidal action. Cytotoxicity to host cells, including keratinocytes and fibroblasts, 

may delay wound closure. 

Intermittent Pneumatic Compression: Delivered through inflatable garments containing one or 

more air chambers, compression propels deep venous blood towards the heart. This treatment 

benefits the non-ambulatory patient by increasing blood flow velocity in the deep veins and 

reducing stasis, decreasing venous hypertension, flushing valve pockets, and decreasing 

interstitial edema. 

Negative Pressure Wound Therapy: This therapy involves creating a tightly sealed dressing 

around a wound and using a suction pump to apply negative pressure evenly across the surface 

in a continuous or intermittent manner. This process is proposed to enhance wound healing by 

increasing granulation tissue and local perfusion, reducing tissue edema, decreasing bacterial 

load, and stimulating cellular proliferation via induction of mechanical stress. 

Electromagnetic Therapy: This process uses the electrical field that develops from exposure to an 

oscillating magnetic field. The treatment is thought to work by mimicking or enhancing natural 

wound-induced electrical fields produced in normal human skin. 

Hyperbaric Oxygen Therapy: This therapy requires specialized compression chambers capable 

of delivering increased concentrations of oxygen (usually 100% oxygen) under elevated 

atmospheric pressures. Many key aspects of ulcer healing are oxygen dependent and raising 

arterial oxygen tension and the blood-oxygen level delivered to a chronic ulcer is thought to 

supply a missing nutrient, promote the oxygen dependent steps in ulcer healing, up regulate local 

growth factors, and down regulate inhibitory cytokines.

Topical Oxygen Therapy: These products aim to promote ulcer healing by correcting the low 

oxygen levels found within chronic ulcer.

Ozone Oxygen Therapy: Ozone is an oxidizing agent theorized to promote tissue healing by 

assisting in the destruction of defective cells, bacteria, and viruses.

Purpose and Scope of Review

A large and growing array of advanced wound care therapies of different composition and for 

different indications has been developed though the effectiveness, comparative effectiveness, and 

potential harm is not well established. The purpose of this review is to synthesize the evidence on 

advanced wound care therapies for treatment of non-healing diabetic, venous, and arterial lower

extremity ulcers. We focus on FDA-approved therapies used in adult patients. Our outcomes of 

interest are complete healing and time to complete healing. Secondary outcomes and adverse 

events are also reported. 
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Advanced Wound Care Therapies for Non-Healing Diabetic, 

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METHODS

TOPIC DEVELOPMENT

This project was nominated by Rajiv Jain, MD (Chief Consultant, Office of Patient Care 

Services) and Jeffrey Robbins, DPM (Director, Podiatry Service). Our key questions were 

developed with input from a technical expert panel. We also received guidance from Carolyn 

Robinson, NP, MSN, and Eric Affeldt, DPM, both from the Minneapolis VA Health Care System.

We address the following key questions:

1. What are the efficacy and harms of therapies for diabetic ulcers? Is efficacy dependent 

on ancillary therapies? Does efficacy differ according to patient demographics, comorbid 

conditions, treatment compliance, or activity level?

2. What are the efficacy and harms of therapies for venous ulcers? Is efficacy dependent on 

ancillary therapies? Does efficacy differ according to patient demographics, comorbid 

conditions, treatment compliance, or activity level?

3. What are the efficacy and harms of therapies for arterial ulcers? Is efficacy dependent on 

ancillary therapies? Does efficacy differ according to patient demographics, comorbid 

conditions, treatment compliance, or activity level?

SEARCH STRATEGY

We searched MEDLINE (Ovid) for randomized controlled trials (RCTs) published from 1995 

to August 2012 using standard search terms. We limited the search to articles with adults and 

published in the English language. Search terms included: skin ulcer, foot ulcer, leg ulcer, 

varicose ulcer, diabetic ulcer, diabetic foot, wound healing, venous insufficiency, artificial 

skin, biological dressings, negative-pressure wound therapy, collagen, silver, topical oxygen, 

hyperbaric oxygen, electromagnetic, platelet-derived growth factor, platelet-rich plasma, and 

intermittent pneumatic compression devices. The search strategy is presented in Appendix B.

We did a similar search of the Cochrane Library, and obtained additional articles by a handsearch of reference lists of pertinent studies and systematic reviews and suggestions from 

members of our technical expert panel.

STUDY SELECTION

Titles and abstracts were reviewed by researchers trained in the critical analysis of literature. Full 

text versions of potentially eligible articles were retrieved for review. Our inclusion criteria were 

as follows:

•	 Randomized controlled trials

•	 Studies reported in the English language

•	 Studies involving adults (18 years and older)
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Advanced Wound Care Therapies for Non-Healing Diabetic, 

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•	 Intervention must involve collagen-based products, biologic dressings, biologic skin 

equivalents, keratinocytes, platelet-derived growth factors, platelet-rich plasma, silver 

products, intermittent pneumatic compression therapy, negative pressure wound therapy, 

electromagnetic therapy, or hyperbaric or topical oxygen

•	 Study reports patient outcomes of interest (healed ulcers or time to healing)

•	 Study published in a peer-reviewed publication after 1995

DATA ABSTRACTION

We abstracted the following data for each included study: author, date of publication, country 

where study was conducted, funding source, Therapy type, sample characteristics (gender, 

age, race/ethnicity, body mass index [BMI], hemoglobin A1

c [HbA1c], smoking status, work 

days missed, ankle-brachial index [ABI]), ulcer characteristics (type, size, location, grade, 

duration, infection status), comorbid conditions (hypertension, peripheral vascular disease 

[PVD], cardiovascular disease, diabetes, or amputation), study inclusion and exclusion criteria, 

treatment groups, intervention characteristics (product descriptions and application frequency/

duration), treatment duration, follow-up duration, study withdrawals, treatment compliance and 

study quality (allocation concealment, blinding, analysis approach, description of withdrawals). 

We abstracted primary outcomes (ulcers healed, time to complete ulcer closure, patient global 

assessment, and return to daily activities) and secondary outcomes (ulcer infection, amputation, 

revascularization surgery, ulcer recurrence, time to ulcer recurrence, pain or discomfort, 

hospitalizations, need for home care, quality of life, all-cause mortality, study withdrawals due 

to adverse events, and allergic reactions to treatment), by ulcer type, for each treatment. We 

assessed outcomes following treatment and at follow-up, or as reported. All abstraction was done 

by trained research personnel and verified by a second research associate under the supervision 

of a Principal Investigator.

QUALITY ASSESSMENT

We assessed the quality of studies pertaining to the key questions. Individual randomized studies 

were rated as good, fair, or poor quality based the following criteria: allocation concealment, 

blinding, analysis approach, and description of withdrawals – a modification of the Cochrane 

approach to determining risk of bias.13 We assessed studies for applicability to U.S. Veterans. 

DATA SYNTHESIS

We constructed evidence tables showing the study characteristics and results for all included 

studies, organized by key question and intervention. We critically analyzed studies to compare 

their characteristics, methods, and findings. We compiled a summary of findings for each key 

question or clinical topic, and drew conclusions based on qualitative synthesis of the findings. 

Where feasible, results were pooled.
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Advanced Wound Care Therapies for Non-Healing Diabetic, 

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RATING THE BODY OF EVIDENCE

We assessed the overall strength of evidence using the method reported by Owens et al.14 The 

overall evidence was rated as: (1) high, meaning high confidence that the evidence reflects the 

true effect; (2) moderate, indicating moderate confidence that further research may change our 

confidence in the estimate of effect and may change the estimate; (3) low, meaning there is low 

confidence that the evidence reflects the true effect; or (4) insufficient, indicating that evidence 

either is unavailable or does not permit a conclusion.

PEER REVIEW

A draft version of this report was reviewed by clinical content experts as well as clinical 

leadership. Their comments and our responses are presented in Appendix C.
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Advanced Wound Care Therapies for Non-Healing Diabetic, 

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RESULTS

LITERATURE FLOW

We reviewed 1,230 titles and abstracts from the electronic searches. After applying inclusion/

exclusion criteria at the abstract level 1,053 references were excluded. We retrieved 177 fulltext articles for further review and another 130 references were excluded leaving 47 included 

references. We added 21 articles from reviewing reference lists of relevant articles and 

systematic reviews for a total of 68 articles on 64 trials. We grouped the studies by ulcer etiology 

to address our key questions (see Figure 1). 

Figure 1. Literature Flow Diagram 

Excluded in Abstract 

Review (n=1053)

Medline and Cochrane 

Search Results (n=1230)

Full Text Review

(n=177) Excluded (n=130)

Non-human = 0

Non-English language = 0

Non-RCT = 79

Published prior to 1995 = 1

Does not involve treatments 

of interest = 10

Does not report outcomes 

of interest = 40

Full Text Includes

(n=47)

Hand Search/

Reviewer 

Suggestion (n=21)

References Included in Full 

Evidence Review (n=68)

Venous Ulcers

(n=22)*

(20 trials)

Arterial Ulcers 

(n=1)

(1 trial)

Diabetic Ulcers 

(n=36)*

(35 trials)

Mixed Etiology

(n=7)

(7 trials)

Amputation Wounds 

(n=2)

(1 trial) *One article provided outcomes for both diabetic and venous ulcers
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Advanced Wound Care Therapies for Non-Healing Diabetic, 

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KEY QUESTION #1. What are the efficacy and harms of therapies 

for diabetic ulcers? Is efficacy dependent on ancillary therapies? 

Does efficacy differ according to patient demographics, comorbid 

conditions, treatment compliance, or activity level?

Overview of Studies

Table 1 contains an overview of studies of treatments for diabetic ulcers.15-50 Thirty-six articles 

(35 trials) met eligibility criteria including 4 trials of collagen (n=489 randomized), 2 trials 

of biological dressings (n=124), 7 trials of biological skin equivalents (one trial included a 

biological dressing arm) (n=989), 9 trials (in 10 articles) of platelet-derived growth factors 

(one trial included a biological dressing arm) (n=990), 2 trials of platelet-rich plasma (n=96), 4 

trials of silver products (n=280), 3 trials of negative pressure wound therapy (n=418), 5 trials of 

hyperbaric oxygen therapy (n=326), and 1 trial of ozone-oxygen therapy (n=61). Twenty-five 

trials compared an advanced wound care therapy to standard care or placebo. In nine trials, the 

comparator was a different advanced therapy. One trial included both comparators.

Overall, the mean age of study participants ranged from 51 to 71 years; in the majority of studies 

the mean age was between 55 and 65 years. Between 28% and 100% were male although in 

all but 3 studies, 60% or more were male. Few studies reported race. In those reporting, 58% 

to 86% were white, 8% to 16% were black, 6% to 30% were Hispanic, and 2% to 12% were 

Native American. Mean ulcer sizes ranged from 1.9 to 41.5 cm2

, however, the mean ulcer size 

was greater than 10 cm2 in only 6 of 29 studies reporting. Mean ulcer durations ranged from 14.5 

days to 21.6 months with durations of greater than 1 year in 6 of 21 studies reporting. 

In 26 trials the ulcer was described as a “foot” ulcer, in 7 trials the ulcer was described as a “lower 

extremity” ulcer, and in 2 trials ulcer was described only as a “diabetic ulcer.” Of the “foot” 

ulcer trials, 7 provided more detail. Three trials included only plantar ulcers and 1 included only 

calcaneal, dorsal, and plantar ulcers. In 1 trial, 38% of ulcers were located on the toes and 39% on 

the heel, in a second trial, 68% were plantar and 32% were non-plantar, and in third trial 61% were 

on the heel and sole and 39% were on the toes. The ulcer type was further described as neuropathic 

in 11 trials, ischemic in 1 trial, neuroischemic in 1 trial, and mixed in 3 trials. Of the remaining 

trials, 16 had inclusion criteria related to adequate circulation or exclusion criteria related to severe 

arterial disease and 3 did not specify criteria related to circulation.

Collagen

Four randomized controlled trials with a total enrollment of 489 patients compared the efficacy 

of collagen to standard care for the treatment of diabetic ulcers.15-18 Three of the trials described 

the ulcers as “foot” ulcers; one included lower extremity and foot ulcers.15 A fifth trial of 19 

patients with type 2 diabetes and chronic diabetic foot lesions randomized participants to 

collagen or to standard care.51 The focus of this trial was on changes to biomarkers over 5 days of 

treatment. The authors did report that, at a mean treatment duration of 26 days, 8 of 13 patients 

treated with collagen (62%) achieved wound closure. In the standard care group, no wound 

closure was observed and after a mean of 19 days, patients received a different treatment (not 

specified). Due to the incomplete reporting, we have not included this study in the summary of 

collagen trials (below). 
32

Advanced Wound Care Therapies for Non-Healing Diabetic, 

Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

The four included studies were conducted in the United States and industry funded. Study quality 

was rated fair for all trials. Participants had mean age of 57 years; 74 percent were male (Table 

2). Collagen trial durations were eight17 and twelve weeks.15,16,18 The studies included non-healing 

diabetic ulcers of at least four weeks in duration. One study included a 2 week run-in with 

standard care (debridement, moist dressings, and off-loading) and excluded individuals with a 

greater than 30% decrease in ulcer size during the run-in period.15 Inclusion criteria allowed for 

all ulcers greater than 1.0 cm2

, and the average enrolled ulcer size was 3.1 cm2. None of the trials 

reported a difference between treatment arms in ulcer size or ulcer duration. Infected ulcers were 

excluded from all studies and use of antibiotics during the trial was not reported to be on an “as 

needed” basis in one trial. In all trials, adequate circulation was required for inclusion. Standard 

care included off-loading in all trials with one study reporting asking about compliance with offloading at each visit. Compliance with therapy was reported to be greater than 90% in one study 

(patients kept a diary of dressing changes).16 Two studies excluded patients for non-compliance 

but did not report how that was determined.15,18 The fourth study did not report compliance.17

One of the trials included a second intervention arm with a non-FDA approved product.15 Results 

from that treatment arm are not reported. A complete summary of patient demographics and ulcer 

characteristics is presented in Appendix D, Table 1.

Primary Outcomes (Appendix D, Table 2)

All studies reported the percentage of ulcers healed by study completion. One study (n=86) 

found collagen (Graftjacket) to significantly improve ulcer healing compared to standard care 

(70% versus 46%; ARD=23%, 95% CI 3% to 44%).18 The difference was maintained after 

adjusting for baseline ulcer size. There was no significant difference in the percentage of healed 

ulcers with Promogran (37% versus 28%),16 Fibracol (48% versus 36%),17 or formulated collagen 

gel (45% versus 31%)15 compared to standard care. One study reported a trend toward a higher 

percentages of ulcers healed in ulcers of less than 6 months duration (45% versus 33%, p=0.06); 

ulcer size (<10 cm2 versus ≥10 cm2) was not a factor.16 Two studies found no difference between 

collagen and standard care in time to complete healing17,18 while in a third study, time to healing 

was significantly shorter in patients receiving standard care (7.0 weeks versus 5.8 weeks, 

p<0.0001).16
33

es for Non-Healing Diabetic, 

Systematic Review Evidence-based Synthesis Program

s for Diabetic Ulcers

Product

Comparator

Healed ulcers

Mean time to 

ulcer healing

Global 

assessment 

Return to daily 

activities 

Ulcers infected 

during treatment

Amputation

Revascularization/

surgery

Recurrence

Time to 

recurrence

Pain/discomfort

Hospitalization

Required home 

care

Quality of life

Withdrawals 

due to adverse 

events

Patients with ≥ 1

adverse event 

All-cause 

mortality

Allergic 

reactions to 

treatment

Formulated Collagen Gel Standard - -Promogran Standard - ↓ - - -Fibracol Standard - - - -Graftjacket Standard + - - - - - -OASIS PDGF (becaplermin)

- - - - ± - -

OASIS Dermagraft - -Dermagraft Standard + - - - -Dermagraft Standard - ± - - ± -Dermagraft Standard + + - - -Apligraf (Graftskin) Standard + + - + - -Apligraf Standard + - - - - - - - -Apligraf Theraskin - - -Autologous platelet extract Silver sulfadiazine

- ±

rhPDGF Placebo gel + -rhPDGF Placebo gel + + - -rhPDGF Standard - + -Regranex (2 doses) Placebo gel + + - - - - -Becaplermin

Biologic dressing (OASIS)

- - - - ± - -

rhPDGF Inactive gel - -rhPDGF Placebo gel + + - - ± - - -Becaplermin gel NaCMC gel or standard care + vs std*

- - - - - -
34

es for Non-Healing Diabetic, 

Systematic Review Evidence-based Synthesis Program

Product

Comparator

Healed ulcers

Mean time to 

ulcer healing

Global 

assessment 

Return to daily 

activities 

Ulcers infected 

during treatment

Amputation

Revascularization/

surgery

Recurrence

Time to 

recurrence

Pain/discomfort

Hospitalization

Required home 

care

Quality of life Withdrawals 

due to adverse 

events

Patients with ≥ 1

adverse event 

All-cause 

mortality

Allergic 

reactions to 

treatment

PRP Platelet poor plasma - +AutoloGel Placebo gel

- - - - -

t Aidance Standard + - - -

k 

Bensal HP Silver cream - - - -AQUA-CEL Calcium dressing - - - - - - -

Silver cream

- - - - - -

V.A.C.

Advanced moist wound therapy

+ ± - + - -

V.A.C. Standard care + +V.A.C. Saline gauze - - -

EST ↓Sham + - - - - - -Standard + + + -Standard - - - -Sham + - - - - - -

Ozoter Sham - - - -

cal Skin Equivalent; Col – Collagen; EST – Extracorporeal Shock Wave Therapy; HBOT – Hyperbaric Oxygen Therapy; NaCMC - Sodium Carboxymethylcellulose; 

rapy; PDGF – Platelet-derived Growth Factor; PRP – Platelet Rich Plasma

or (p< 0.05)

ficant benefit

or
35

Advanced Wound Care Therapies for Non-Healing Diabetic, 

Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Table 2. Summary of Baseline Characteristics: Collagen

Characteristic Number of Studies 

Reporting

Mean (unless 

noted) Range

Number of Patients Randomized 4 489 total 52 - 276

Age (years) 3 57 56 - 59

Gender (% male) 3 74 72 - 77

Race/Ethnicity (%) - -

White 2 63 63 - 64

Black 2 10 10 - 12

Other 2 27 25 - 28

Pre-Albumin 1 3.7 -

HbA1

C (%) 3 8.4 7.9 - 8.6

Ulcer Size (cm2

) 4 3.1 2.7 - 4.3

Ulcer Duration (months) 4 5.1 3 - 15.1

Infection (%) 4 0 -

Study Duration (weeks) 4 11.3 8 - 12

Secondary Outcomes (Appendix D, Tables 3, 4, and 5)

No difference between Graftjacket and standard care was reported for need for amputation or 

revascularization surgery.18 In two studies reporting, there was no significant difference in ulcers 

infected during treatment between collagen ulcer treatment and standard care.16,17 Only one study 

reported the percentage of patients experiencing infection – 12% in the intervention group, 19% 

in the standard care group.16 No differences were observed between collagen and standard care in 

the incidence of adverse events (serious [18% versus 25%] or non-serious [27% versus 25%]),16

adverse events resulting in study withdrawal (7% overall in one study, 6% versus 0% in a second 

study, and 6% versus 5% in a third study),15,17,18 or all-cause mortality (0% in one study, 1.4% 

versus 4.3% in another study).16,18

Biological Dressings

Two studies enrolling 124 patients met eligibility criteria and reported on use of biological 

dressings in ulcers of diabetic etiology.19,20 One study described the ulcers as “foot” ulcers; the 

second study did not provide any information on ulcer location. Both studies were multisite 

RCTs that took place in the United States; one study also had sites in Canada.19 One of the 

trials was of fair quality, industry sponsored, with average ulcer area of 4.1 cm2

 at baseline.19

The other study was of poor quality, did not include financial disclosures, and had a smaller 

average baseline ulcer size of 1.9 cm2.

20 Mean age in the two studies was 59 years and 62% of 

the enrolled patients were male. Both studies excluded patients with infected ulcers and severe 

arterial insufficiency. One study reported baseline differences in the distribution of type 1 and 

type 2 diabetes and the proportion of plantar surface ulcers.19 One trial included a 1 week run-in 

period with standard care but did not report if patients were excluded following the run-in period. 

Compliance with off-loading was monitored in one study.20 Additional details of the studies are 

provided in Table 3 and Appendix D, Table 1.
36

Advanced Wound Care Therapies for Non-Healing Diabetic, 

Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Table 3. Summary of Baseline Characteristics: Biological Dressings

Characteristic Number of Studies 

Reporting

Mean (unless 

noted) Range

Number of Patients Randomized 2 124 total 26 - 98

Age 2 59 58 - 63

Gender (% male) 2 62 60 - 69

Race/Ethnicity NR - -

BMI 1 33 -

HbA1

c (%) 1 8.3 -

ABI 2a,b - -

Ulcer Size (cm2

) 2 3.5 1.9 - 4.1

Ulcer Duration 2c

Study Duration (weeks) 2 12 12

a

Niezgoda, 200519 reported a mean Toe-Brachial-Index (TBI) of 1.00 b

Mean ABI for Landsman, 200820 was not reported, but all participants were >0.65 by exclusion criteria c

Landsman 2008:20 No mean, but >5 weeks duration before treatment per inclusion; Niezgoda 2005:19 1-3 months: 49.3%, 4-6 

months: 16.4%, 7-12 months: 15.1%, >12 months: 19.2%

Primary Outcomes (Appendix D, Table 2)

Biological dressings were tested against other advanced ulcer care therapies in both studies. One 

study, a non-inferiority study compared OASIS Wound Matrix biological dressing to rhPDGF 

[Regranex].19 For the 73 patients completing the trial, OASIS was no different than rhPDGF for 

ulcer healing (49% of the OASIS arm and 28% of the Regranex arm had complete ulcer healing 

at 12 weeks) or time to healing (67 days for OASIS, 73 days for Regranex). The second study 

compared OASIS to the biological skin equivalent Dermagraft in 26 patients over 12 weeks.20 No 

significant difference was noted in complete ulcer healing (77% in OASIS, 85% in Dermagraft) 

or average time to healing (36 days with OASIS; 41 days with Dermagraft). No comparisons 

could be made within or between studies regarding the use of ancillary therapies or their effect 

on healing outcomes.

One study reported on the possible effect of baseline patient characteristics on efficacy, finding 

in an a priori subgroup analysis that the biological dressing did not improve healing of ulcers 

on the plantar surface compared to rhPDGF. The biological dressing significantly healed more 

ulcers in patients with type 2 diabetes (p=0.03) but not type 1 diabetes. It is important to note 

that these subgroup analyses were based on very small sample sizes and only the comparison 

involving plantar surface ulcers was pre-specified.19

Secondary Outcomes (Appendix D, Tables 3, 4, and 5)

Only one study reported any of our secondary outcomes of interest. There were no differences 

between treatment groups for ulcers infected, ulcer recurrence, pain, proportion of patients 

experiencing an adverse event, or all-cause mortality.19
37

Advanced Wound Care Therapies for Non-Healing Diabetic, 

Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Biological Skin Equivalents

We identified a total of seven studies that evaluated use of biological skin equivalents in 

diabetic ulcers; four discussed the use of Dermagraft and three discussed the use of Apligraf. All 

described the ulcers as “foot” ulcers with no further details on ulcer location. Three fair quality 

trials with sample sizes of 245,23 281,22 and 5021 compared Dermagraft (up to 8 grafts) to standard 

care. A small study (n=26) of poor quality compared Dermagraft (up to 3 grafts) to a biological 

dressing.20 All four Dermagraft studies were multisite RCTs that took place in the United States, 

and all included only ulcers greater than 1.0 cm2

 at baseline (average ulcer size ranged from 

1.86 cm2 to 2.4 cm2). One study did not report study sponsorship;20 the others were all industry 

sponsored. Of the three studies of Apligraf, one was a small trial of poor quality enrolling 

patients from a single podiatric practice (n=29).26 Apligraf (up to 5 treatments) was compared 

to cryopreserved split-thickness skin allograft. This study included ulcers 0.5 to 4.0 cm2

 in size 

(mean of 1.86 cm2

) and followed patients for 20 weeks. The two other Apligraf trials compared 

Apligraf to standard care. One enrolled 82 patients in the European Union and Australia25 and 

the other enrolled 277 patients in the United States.24 The trial in Europe and Australia allowed 

up to 3 treatments over 8 weeks. The trial in the United States allowed up to 5 treatments over 

5 weeks. Both were multicenter studies of good quality that included ulcers between 1 and 16 

cm2 in size (average area was approximately 3.0 cm2) with 12 weeks as the primary endpoint. 

Overall, 6 of the 7 trials excluded patients with infection and required adequate circulation. The 

remaining trial did not report on these factors. None of the trials reported on antibiotic use. A 

run-in period with standard care was included in 4 trials20,22,24,25 with 2 trials excluding patients 

whose ulcers decreased in size during the run-in period.24,25 Five trials reported no differences 

between treatment groups at baseline; one reported lower age in the control group21 and one did 

not report on the groups at baseline.22 Four of the studies monitored compliance with off-loading 

either checking the condition of a shoe liner,20 having patients keep a diary of ambulation,23 or 

asking patients about off-loading.24,25 Additional information is provided in Appendix D, Table 1 

and Table 4, below.

Table 4. Summary of Baseline Characteristics: Biological Skin Equivalents

Characteristic Number of Studies 

Reporting

Mean (unless 

noted) Range

Number of Patients Randomized 7 989 total 26 - 281

Age 5 57 56 - 63

Gender (% male) 5 77 69 - 86

Race/Ethnicity 2a

White 2 71 69 - 72

Other 2 28 28 - 29

BMI 2 32 31 - 32

HbA1

c (%) 2 8.6 8.4 - 8.6

ABI 3b,c 1 1

Ulcer Size (cm2

) 6 2.6 1.9 - 3.0

Ulcer Duration (weeks) 4 57.1 49.0 - 95.7

Study Duration (weeks) 7 11 8 - 12

a

Marston, 2003: Caucasian (72%), Non-Caucasian (28%)

Veves, 2001 White (69.5%), African-American (16.6%), Hispanic (13.5%)

b

Marston, 2003: all participates were >0.7 by exclusion criteria c

Veves, 2001: 0.65-0.80: 9.6%, 0.80-1.00: 33.2%, >1.0: 54.4%
38

Advanced Wound Care Therapies for Non-Healing Diabetic, 

Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Primary Outcomes (Appendix D, Table 2)

Three studies compared Dermagraft to standard care. Two of these showed statistically 

significant improvements in ulcer healing. One reported that Dermagraft resulted in an increased 

incidence of complete ulcer healing (30.0% versus 18.3%, p=0.049) and resulted in a faster time 

to closure (p=0.04).23 The second study also found a benefit in the proportion of completely 

healed ulcers with weekly Dermagraft administration (50% versus 8%, Fisher’s exact test

p=0.03). A statistical benefit in time to closure was not reached (p=0.056) due to small group 

sizes.21 The third trial comparing Dermagraft to standard care did not show a benefit for the 

treatment group when taken as a whole.22 However, among patients who received a metabolically 

active Dermagraft at least for the first implant, the percentage of ulcers healed was significantly 

higher than those who received standard care (49% versus 32%, p<0.01).22 In this older trial, 

some of the Dermagraft samples were found to have a level of metabolic activity outside of the 

therapeutic range. We pooled the findings from the three studies of Dermagraft versus standard 

care (Figure 2). The overall risk ratio was 1.49 (95% CI 0.96 to 2.32) indicating a non-significant 

benefit of Dermagraft over standard care in ulcer healing. The fourth study compared Dermagraft 

(up to 3 applications) to the biological dressing OASIS in 26 patients and, as noted above, found 

both produced similar improvements for incidence and time to complete ulcer healing.20

Figure 2. Proportion of Diabetic Ulcers Healed - Biological Skin Equivalent (Dermagraft) versus 

Standard Care 

Study or Subgroup

Gentzkow 1996

Marston 2003

Naughton 1997

Total (95% CI)

Total events

Heterogeneity: Tau2 = 0.06; Chi2 = 3.53, df = 2 (P = 0.17); I2 = 43%

Test for overall effect: Z = 1.78 (P = 0.08)

Events

6

39

42

87

Total

12

130

109

251

Events

1

21

40

62

Total

13

115

126

254

Weight

4.7%

42.1%

53.2%

100.0%

M-H, Random, 95% CI

6.50 [0.91, 46.43]

1.64 [1.03, 2.62]

1.21 [0.86, 1.72]

1.49 [0.96, 2.32]

Control Treatment Risk Ratio Risk Ratio

M-H, Random, 95% CI

0.2 0.5 1 2 5

Favors Control Favors Dermagraft

*Gentzkow 1996 – Analysis is for Group A (one piece of Dermagraft applied weekly) versus Control

The two largest studies of Apligraf used standard care (sharp debridement, moist dressings, and 

off-loading) as the comparator. The largest study24 showed significant benefit for Apligraf in 

complete ulcer healing at 12 weeks (56% versus 38%, p=0.004) and for median time to closure 

(65 versus 90 days for control, p=0.003). The second trial25 also showed a significant benefit for 

Apligraf for incidence of complete ulcer healing (52% versus 26%, p=0.049), but the benefit 

of more rapid healing did not reach statistical significance (p=0.059) before trial enrollment 

was prematurely terminated due to registration difficulties. Pooled analysis of these trials 

(Figure 3) shows a significant overall benefit of Apligraf over standard care (ARD=21%, 95% 

CI 9% to 32%; RR=1.58, 95% CI 1.20 to 2.08, I2

=0%). The third study compared Apligraf to 

cryopreserved split-thickness skin allografts. This small (n=29 ulcers), poor-quality study did not 

report statistically significant differences between treatments for the incidence of complete ulcer 

healing or time to complete healing.26
39

Advanced Wound Care Therapies for Non-Healing Diabetic, 

Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Figure 3. Proportion of Diabetic Ulcers Healed - Biological Skin Equivalent (Apligraf) versus Standard Care 

Study or Subgroup

Edmonds 2009

Veves 2001

Total (95% CI)

Total events

Heterogeneity: Tau2 = 0.00; Chi2 = 0.56, df = 1 (P = 0.45); I2 = 0%

Test for overall effect: Z = 3.26 (P = 0.001)

Events

17

63

80

Total

33

112

145

Events

10

36

46

Total

38

96

134

weight

19.2%

80.8%

100.0%

M-H, Random, 95% CI

1.96 [1.05, 3.66]

1.50 [1.11, 2.04]

1.58 [1.20, 2.08]

Apligraf Standard Care Risk Ratio Risk Ratio

M-H, Random, 95% CI

0.2 0.5 1 2 5

Favors Std Care Favors Apligraf

No comparisons could be made within or between studies regarding the use of ancillary 

therapies. However, in one study, were allowed to be ambulatory, using extra-depth custom 

inserts or healing sandals.23 Patients recorded being on their feet an average of 8 hours a day. 

Most other studies limited patients to use of a wheelchair or crutches for large portions of the 

study or asked patients to limit ambulation to a minimal level. While no controlled comparisons 

can be made, it is important to note that use of Dermagraft in this trial still produced a beneficial 

effect. This suggests the benefits of this biological skin equivalent may be maintained when 

applied to clinic patients not willing or able to limit ambulation for several months during the 

period of treatment.

Two of the Dermagraft studies reported on factors associated with ulcer healing. In one study, 

neither patient age, gender, ulcer size or duration, diabetes type, ankle-arm index, nor HbA1c

were significantly associated with time to closure.21 Another study reported outcomes based on 

ulcer location.23 There was a trend for more forefoot/toe ulcers (n=214) to heal with Dermagraft 

(29.5% versus 19.6%, p=0.065). For heel ulcers (n=31), 33% of those treated with Dermagraft 

achieved closure compared to 8% in the control group (p=0.01). This trial was originally 

intended to include ulcers of any duration. At interim analysis, the benefits of Dermagraft on 

ulcer healing were not statistically significant when considering all patients, but a statistically 

significant benefit was evident for the treatment of ulcers present for more than 6 weeks prior 

to entering the 2 week screening. This resulted in a trial amendment to change the desired study 

population and further enroll only chronic ulcers of more than 6 weeks. 

Secondary Outcomes (Appendix D, Tables 3, 4, and 5)

Rate of recurrence was reported for two of the Dermagraft studies with no difference between the 

Dermagraft and standard care groups.21,22 Similarly, two studies reported no significant difference 

in rate of recurrence between Apligraf and standard care.24,25 Three Dermagraft studies22-23 and 

one Apligraf study25 reported no differences between a biological skin equivalent and standard 

care in incidence of ulcers infected during treatment. One Dermagraft study found a significantly 

lower incidence of infection, osteomyelitis, and cellulitus (combined) in the Dermagraft group 

than in the standard care group (19% versus 33%, p=0.007).23 One Apligraf study found a 

significantly lower incidence of osteomyelitis (but not infection or cellulitis) in the advanced 

therapy group compared to standard care (2.7% versus 10.4%, p=0.04).24 One study reported 

fewer amputations among patients treated with Apligraf than standard care (6% versus 16%, 
40

Advanced Wound Care Therapies for Non-Healing Diabetic, 

Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

p=0.03)24 although a second study found no significant difference.25 No studies reported pain or 

discomfort. Six studies reported a low number of patients experiencing adverse events, adverse 

events leading to study withdrawal, or all-cause mortality with no differences between the 

biological skin equivalent and either standard care21-25 or allograft.26

Platelet-Derived Wound Healing (Platelet-Derived Growth Factors, PDGF)

Nine randomized controlled trials enrolling a total of 990 patients evaluated the efficacy of plateletderived growth factors (PDGFs) used in the treatment of diabetic ulcers. Comparator treatments 

included standard care or placebo,28-34 biological dressing,19 silver sulfadiazine,27 and either standard 

care or sodium carboxymethylcellulose (NaCMC) gel.35 Ulcer locations were described as lower 

limb or lower extremity in 5 studies,29,31-35 foot in 2 studies,28,30 with one specifying plantar surface,30

and not defined in 2 studies.19,27 Four studies were conducted in India,28-30,32 three in the United 

States,31,33-35 one in the United States and Canada,19 and one in Iran.27 Five of nine studies reported a 

funding source; four received industry funding19,31,33-35 and one reported government support.27 The 

mean age of the participants was 58 years; 69 percent were males (Table 5). PDGF trials ranged 

in duration from eight to twenty weeks and all included chronic, non-healing, diabetic ulcers of 

at least four weeks in duration. Three studies excluded patients with infection and the remaining 

studies required infection to be controlled before starting the study therapy. Six trials allowed 

antibiotics during the study on an as needed basis. Eight studies reported only including patients 

with adequate blood flow; one provided no information on blood supply. Three studies reported 

monitoring compliance with care. One tracked dressing changes and off-loading,29 one provided 

a diary to record dressing changes,33,34 and the third reported compliance but did not specify what 

was monitored.31 Two studies included a run-in period.27,29 Inclusion criteria across studies allowed 

for ulcer sizes ranging from 1 cm2

 to 100 cm2; average ulcer size was 7.3 cm2. One study reported 

a significant difference in ulcer area at baseline with larger ulcers found in the PDGF arm (54.3 

cm2 versus 28.7 cm2 in the control arm, p=0.003).28 As noted in the section on biological dressings 

(above) one trial reported baseline differences in ulcer location (plantar vs. non-plantar) and 

distribution of type 1 and type 2 diabetes between groups.19 No trials reported a difference between 

treatments in ulcer duration or use of ancillary therapies. Two studies were good quality,32-34 5 were 

fair quality,19,28,30,31,35 and 2 were poor quality.27,29 A complete summary of study characteristics is 

presented in Appendix D, Table 1.

Table 5. Summary of Baseline Characteristics: Platelet-Derived Growth Factor 

Characteristic Number of Studies 

Reporting

Mean (unless 

noted)

Range

Number of Patients Randomized 9 990 total 9 - 382

Age (years) 9 58 51 - 61

Gender (% male) 8 69 60 - 100

Race/Ethnicity (%)

White 3 83 81 - 86

Black 2 11 9.9 - 12

Hispanic 1 6 -

Asian 1 <1 -

Indian 1 100 -

Other 3 4 0.3 - 14

BMI 4 27.4 22.4 - 32.5
41

Advanced Wound Care Therapies for Non-Healing Diabetic, 

Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

HbA1c (%) 3 8.0 7.5 - 8.8

ABI 2 1.1 1.1

Ulcer Size (cm2

) 9 7.3 2.7 - 41.5

Ulcer Duration (weeks) 5a 48 13 - 78

Infection 4 0 -

Study Duration (weeks) 9 16 8 - 20

History of Amputation 2b 35 -

History of PVD 1 0 -

a

Jaiswal 201032 reported a median of 5 weeks b

Jaiswal 201032 reported amputation or previous ulcer (2%) and was not included in the calculation

Primary Outcomes (Appendix D, Table 2)

All nine trials reported the percentage of ulcers healed by study completion for PDGF and 

comparator. Seven of nine compared PDGF to placebo or inactive gel28,29,31-34 or to standard ulcer 

care30,35 and three of nine compared PDGF to another advanced wound therapy.19,27,35 A pooled 

analysis of the studies comparing PDGF to placebo gel or standard ulcer care (Figure 4) found 

significantly greater healing with PDGF (ARD=21%, 95% CI 14% to 29%; RR=1.45, 95% CI 

1.03 to 2.05) but there was substantial heterogeneity (I2

=85%). Five of the seven individual trials 

also showed significantly greater healing with PDGF with individual risk ratios ranging from 

1.60 to 3.00. 

Separate analyses of studies with placebo gel and standard care as comparators revealed a 

significant finding for the 5 placebo gel studies (RR=1.45, 95% CI 1.07 to 1.97, I2=63%) and a 

non-significant finding for the 2 standard care studies (RR=1.40, 95% CI 0.33 to 5.95, I2=96%). 

Pooling only studies rated as good or fair quality showed no benefit of PDGF compared to 

placebo gel or standard care (RR=1.45, 95% CI 0.94 to 2.23) with substantial heterogeneity 

(I2=80%). An analysis based on the country in which the study was conducted found a significant 

benefit of PDGF over placebo gel in 2 studies done in the United States (RR=1.54, 95% CI 1.19 

to 2.00, I2=0%) but not in 3 studies done in India (RR=1.39, 95% CI 0.77 to 2.51, I2=79%). 

Significant results favoring PDGF were also found for studies with more than 100 patients (k=3), 

but not studies with less than 100 (k=2) and studies with treatment lasting 20 weeks (k=3) but 

not studies less than 20 weeks (k=3 due to multiple reporting times in one trial). Ulcer size did 

not appear to be a factor with non-significant findings when pooling the 2 studies with the largest 

ulcer sizes (greater than 25 cm2

) or the 3 studies with ulcer size less than 25 cm2.

Three of nine studies reported the percentage of ulcers healed by study completion for PDGF 

compared to another advanced wound therapy. The percentage of ulcers healed did not differ 

significantly for PDGF compared to biological dressings (OASIS),19 silver sulfadiazine,27 or 

NaCMC gel35 (Figure 4). 
42

Advanced Wound Care Therapies for Non-Healing Diabetic, 

Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Figure 4. Proportion of Diabetic Ulcers Healed – Platelet-Derived Growth Factor versus Comparator 

Study or Subgroup

2.1.1 Diabetic Wounds: PDGF versus Standard Care

Agarwal 2009

Bhansali 2009

d'Hemecourt 1998

Hardikar 2005

Jaiswal 2010

Steed 1995, 1996, 2006

Wieman 1998

Subtotal (95% CI)

Total events

Heterogeneity: Tau2 = 0.16; Chi2 = 39.50, df = 6 (P < 0.00001); I2 = 85%

Test for overall effect: Z = 2.11 (P = 0.04)

2.1.2 Diabetic Wounds: PDGF versus Silver Sulfadiazine

Aminian 2000

Subtotal (95% CI)

Total events

Heterogeneity: Not applicable

Test for overall effect: Z = 1.37 (P = 0.17)

2.1.3 Diabetic Wounds: PDGF versus OASIS Biological Dressing

Niezgoda 2005

Subtotal (95% CI)

Total events

Heterogeneity: Not applicable

Test for overall effect: Z = 1.77 (P = 0.08)

2.1.4 Diabetic Wounds: PDGF versus Sodium carboxymethylcellulose (NaCMC)

d'Hemecourt 1998

Subtotal (95% CI)

Total events

Heterogeneity: Not applicable

Test for overall effect: Z = 0.84 (P = 0.40)

Events

9

13

15

47

15

29

61

189

4

4

10

10

15

15

Total

14

13

34

55

25

61

123

325

7

7

36

36

34

34

Events

3

11

15

31

18

14

41

133

0

0

18

18

25

25

Total

14

11

68

58

25

57

127

360

5

5

37

37

70

70

Weight

6.7%

18.5%

12.4%

17.3%

15.2%

13.3%

16.6%

100.0%

100.0%

100.0%

100.0%

100.0%

100.0%

100.0%

M-H, Random, 95% CI

3.00 [1.02, 8.80]

1.00 [0.86, 1.17]

2.00 [1.11, 3.59]

1.60 [1.23, 2.08]

0.83 [0.56, 1.25]

1.94 [1.14, 3.27]

1.54 [1.13, 2.09]

1.45 [1.03, 2.05]

6.75 [0.44, 102.80]

6.75 [0.44, 102.80]

0.57 [0.31, 1.06]

0.57 [0.31, 1.06]

1.24 [0.76, 2.02]

1.24 [0.76, 2.02]

Experimental Control Risk Ratio Risk Ratio

M-H, Random, 95% CI

0.02 0.1 1 10 50

Favors Control Favors PDGF

Five studies reported time to complete ulcer closure for PDGF compared to placebo gel or 

standard care.29-31,33-35 Four of the five studies reported significantly shorter time to ulcer healing 

in PDGF compared to placebo gel or standard care (differences of 30 to 40 days);29-31,33,34 one 

study found no significant difference.35 In studies comparing PDGF to another advanced therapy, 

time to complete ulcer closure did not differ significantly for PDGF compared to biological 

dressings (OASIS),19 silver sulfadiazine,27 or NaCMC gel.35

Several individual studies looked at factors associated with ulcer healing. In one study, ulcers 

less than 9 cm2

, ulcers located on non-weight-bearing surfaces, and the use of antibiotics 

significantly improved healing.29 Another study reported that healing did not vary by age and 

baseline HbA1c but that compliance with off-loading was positively associated with healing (p 

not reported).31 As noted above, healing of plantar surface ulcers was comparable for patients 

treated with either a biological dressing or rhPDGF.19
43

Advanced Wound Care Therapies for Non-Healing Diabetic, 

Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Secondary Outcomes (Appendix D, Tables 3, 4, and 5)

Four studies reported the percentage of ulcers infected during treatment with no significant 

differences between PDGF and placebo or standard care,31,33-35 a biological dressing,19 or NaCMC 

gel.35 Three studies reported ulcer recurrence with no significant differences between PDGF and 

placebo or standard care31,33,34 or a biological dressing.19 Time to recurrence was similar between 

PDGF and placebo in the one study reporting that outcome.33,34 Pain or discomfort was reported 

in four studies with no significant differences between PDGF and placebo or standard care,31,33-35

a biological dressing,19 or NaCMC gel.35 Three studies found no significant difference between 

PDGF and placebo gel or standard care29,31,35 or between PDGF and NaCMC gel35 for patient 

withdrawals attributed to adverse events. Two studies reported no adverse events during the 

study period30,32 and three studies found no significant difference in the occurrence of adverse 

events between treatment groups (PDGF versus placebo gel,33,34 standard care,35 biological 

dressing,19 or NaCMC.35 All-cause mortality was reported in five studies with no significant 

difference between PDGF and standard care, placebo, or other advanced treatments.19,29,31,33-35

Only one study reported allergic reaction to the treatment with no difference between PDGF and 

placebo gel.28

Platelet Rich Plasma (PRP)

Two randomized controlled trials met eligibility criteria and compared the efficacy of PRP to 

placebo gel37 or platelet poor plasma (PPP).36 One study was conducted in the United States and 

reported government funding37 and one was done in Egypt with no funding source reported.36

Study quality was rated as poor for one trial36 and fair for the second.37 Ulcer location was 

described only as “foot” for one study;36 the other study included plantar, medial, and lateral 

ulcers (including 38% on the toes and 29% on the heel).37 One study reported patient age (57 

years) and gender (80% male).37 The trial durations were twelve37 or twenty weeks,36 and 

included chronic, non-healing ulcers greater than four37 or twelve36 weeks in duration. Treatments 

were applied two times a week with 3 to 4 day intervals between dressing changes until the 

respective study duration was complete or healing had occurred. Both studies excluded patients 

with infection and inadequate blood flow. Antibiotic use was not reported nor was compliance 

with treatment. One study reported no baseline differences between groups;36 the second reported 

differences in race in the per protocol analysis sample.37 One study included a 1-week run-in 

period and excluded patients if ulcer area decreased by more than 50%.37 Inclusion criteria 

allowed for all ulcers greater than 0.5 cm2; the average enrolled ulcer size was 5.6 cm2. Neither 

trial reported a difference between treatment arms in ulcer size, ulcer duration, or ancillary 

therapies. Additional baseline characteristics are presented in Table 6. A complete summary of 

study characteristics is presented in Appendix D, Table 1.
44

Advanced Wound Care Therapies for Non-Healing Diabetic, 

Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Table 6. Summary of Baseline Characteristics: Platelet Rich Plasma 

Characteristic Number of Studies 

Reporting

Mean (unless 

noted)

Range

Number of Patients Randomized 2 96 total 24 - 72

Age (years) 1 57 -

Gender (% male) 1 80 -

Race/Ethnicity (%)

White 1 60 -

Black 1 7.5 -

Hispanic 1 30 -

Other 1 2.5 -

HbA1

c (%) 1 7.9 -

Smoking 1 33.3 -

Ulcer Size (cm2

) 2 5.6 3.5 - 9.4

Infection 1 0 -

Study Duration (weeks) 2 11 12 - 20

History of HTN (%) 1 70 -

Primary Outcomes (Appendix D, Table 2)

Both trials reported the percentage of ulcers healed by study completion for PRP compared to 

PPP (100% versus 75%)36 or placebo gel (33% versus 28%).37 Neither difference was significant. 

One study36 reported a significantly shorter time to healed ulcers for PRP compared to PPP (11.5 

versus 17 weeks, p<0.005); the other study found no significant difference between treatment 

groups.37

Secondary Outcomes (Appendix D, Tables 3, 4, and 5)

One study reported no difference in ulcer recurrence at 12 weeks between PRP and placebo gel.37

This trial also reported no significant differences in adverse events or all-cause mortality.37 The 

second study did not report any secondary outcomes.

Silver Products

Four trials enrolling a total of 280 patients met eligibility criteria.38-41 One study compared silver 

ointment to standard care38 and one compared a silver dressing to a calcium-based dressing.40

In two trials, silver cream was the control group; the interventions were oak bark extract39 and 

a polyherbal treatment.41 The studies were done in the United States,39 Europe,40 Italy,38 and 

India.41 Two reported industry support40,41 and two did not report a funding source. Enrollments 

ranged from 4039,41 to 134.40 Ulcer locations were described as “foot” for two studies38,40 with one 

specifying that 68% were plantar and 32% were non-plantar.40 The other two studies included 

only plantar surface ulcers.39,41 One study excluded patients with infection (with antibiotic use 

during the trial not reported),39 one study excluded patients with “severe” infection and allowed 

antibiotic use during the trial,41 one study stratified patients based on antibiotic use,40 and one 

noted that infection was the cause of some of the included ulcers (antibiotic use not reported).38 

Three studied required adequate blood supply;38-40 the fourth allowed patients with peripheral 

arterial disease.41 None of the studies included a run-in period with standard care, none reported 

monitoring compliance with therapy, two specified off-loading as part of standard care, and none 

reported baseline differences between treatment groups. All studies were of fair quality. Study 

characteristics are summarized in Table 7; more detail is provided in Appendix D, Table 1.
45

Advanced Wound Care Therapies for Non-Healing Diabetic, 

Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Table 7. Summary of Baseline Characteristics: Silver Products 

Characteristic Number of Studies 

Reporting

Mean (unless 

noted) Range

Number of Patients Randomized 4 280 total 40 - 134

Age (years) 3 58.7 55.9 - 60.0

Gender (% male) 2 58.6 44 - 74

Race/Ethnicity (%) NR

HbA1

c (%) 2 8.6 8.0 - 10.7

ABI 1 1.8 -

Ulcer Size (cm2

) 2a 3.2 2.2 - 3.7

Ulcer Duration (months) 2 12.3 0.48 - 15.6

Infection (%) 1b 100 -

Study Duration (weeks) 3 6.6 4 - 8

History of PVD 1 23.7% -

a

One study included only ulcers ≤3 cm in diameter; one study reported mean length of 4.6 cm and mean width of 3.3 cm b

Three studies excluded patients with clinical signs of infection or taking antibiotics at screening

One study included only ulcers with a diameter of 3 cm or less.39 In the other studies, the mean 

ulcer size was 2.2 cm2

,

38 3.7 cm2

,

40 or 4.6 cm (length) and 3.3 cm (width).41 Mean ulcer duration 

was 14.5 days in one study41 and 1.3 years in another.40 Two studies did not report duration. Two 

studies included only Wagner Grade 1 or 2 ulcers39,40 while a third included Grade 1, 2, or 3 

ulcers.41

Three studies were done to assess the efficacy and safety of the intervention for ulcer 

healing.38,40,41 The fourth study was focused on reduction in size of the ulcer.39

Primary Outcomes (Appendix D, Table 2)

Three of the four studies reported percentage of ulcers healed. In one study, the percentage of 

ulcers healed at 4 weeks was significantly higher in the group treated with silver ointment than 

the group receiving standard care (39% versus 16%, ARD=23%, 95% CI 2% to 43%, p<0.05). 

Mean size of the ulcers included in the study was 2.2 cm2.

38 Mean time to healing was not 

reported. In two other studies that reported healing, one found no difference in healed ulcers 

after 6 weeks of treatment, between an oak bark extract and a silver cream (40% versus 30%, 

respectively).39 The second study found no difference in healed ulcers (31% versus 22%) or time 

to healing (53 days versus 58 days) for a silver dressing compared to a calcium dressing.40 The 

findings for proportion of ulcers healed are presented in Figure 5. The study comparing silver 

and calcium dressings also reported a global assessment of healing with 88% of ulcers healed or 

improved in the silver dressing group compared to 71% in the calcium dressing group (a nonsignificant difference).40 Subgroup analyses based on location (plantar, non-plantar) and type of 

ulcer (neuropathic, neuroischemic) also were non-significant. The only significant finding was a 

greater percentage of ulcers healed or improved (92% versus 50%) in the silver dressing group 

among patients taking systemic antibiotics at baseline.40 The third study reported only time to 

healing with no difference between a polyherbal extract and a silver cream (43 days versus 44 

days).41
46

Advanced Wound Care Therapies for Non-Healing Diabetic, 

Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Figure 5. Proportion of Diabetic Ulcers Healed – Silver Products

Study or Subgroup

1.1.1 Silver cream versus standard care

Belcaro 2010

1.1.2 Silver cream versus oak bark extract

Jacobs 2008

1.1.3 Silver dressing versus calcium dressing

Jude 2008

Events

13

6

21

Total

34

20

67

Events

5

8

15

Total

32

20

67

M-H, Random, 95% CI

2.45 [0.98, 6.09]

0.75 [0.32, 1.77]

1.40 [0.79, 2.47]

Silver Control Risk Ratio Risk Ratio

M-H, Random, 95% CI

0.1 0.2 0.5 1 2 5 10

Favors Control Favors Silver

Secondary Outcomes (Appendix D, Tables 3, 4, and 5)

Few secondary outcomes were reported. Two studies found no difference in ulcers infected 

during treatment when a silver dressing was compared to a calcium dressing40 or a silver cream 

was compared to a polyherbal cream.41 There was also no difference in ulcer recurrence between 

a silver cream and a polyherbal cream (42% versus 47%, respectively).41 Adverse events and 

withdrawals from the study due to adverse events were comparable for the two treatment groups 

within each of the four studies. In three studies, no patients experienced adverse events.38,39,41

In the fourth study, 37% of patients in the silver dressing group experienced an adverse event 

compared to 39% of those in the calcium dressing group.40 Serious adverse events were reported 

in 12% and 16% of participants, respectively, with study-related adverse events in 16% and 

13%, respectively.40 All-cause mortality was reported in two studies. Overall values were low 

(maximum of 1 patient per group) with no differences between a silver dressing and a calcium 

dressing40 or a silver cream and a polyherbal cream.41 Two studies assessed allergic reactions to 

treatments but reported no events.38,39

Negative Pressure Wound Therapy

Three trials of NPWT met inclusion criteria. In one study, a small pilot study with 10 patients, 

the goal of NPWT was to prepare the ulcer for final closure.44 In the other two studies, with 

enrollments of 34142 and 6743 the goal was ulcer healing. All three studies compared NPWT to 

standard care. Ulcer location was described as “foot” for two studies43,44 and calcaneal, dorsal, or 

plantar for the third study.42 Two studies were done in the United States42,44 and one in Turkey.43

One study received industry support42 while no source of funding was reported for the other two 

studies.43,44 One study was of good quality.42 Quality of the other two studies could not accurately 

be assessed due to either incomplete reporting43 or the fact that the study was a small pilot 

study.44 Study characteristics are presented in Table 8 and Appendix D, Table 1.
47

Advanced Wound Care Therapies for Non-Healing Diabetic, 

Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Table 8. Summary of Baseline Characteristics: Negative Pressure Wound Therapy 

Characteristic Number of Studies 

Reporting

Mean (unless 

noted) Range

Number of Patients Randomized 3 418 total 10 - 341

Age (years) 3 60 53 - 67

Gender (% male) 2 70 28 - 78

Race/Ethnicity (%)

White 1 58 -

Black 1 15 -

Hispanic 1 24 -

Native American 1 2 -

Other 1 1 -

Pre-Albumin 1 20.5 -

HbA1

c (%) 1 8.2 -

Smoking 1 19 -

ABI 1 1.0 -

Ulcer Size (cm2

) 2 15.7 12.3 - 32.4

Ulcer Duration (weeks) 2 26 10 - 29

Study Duration (weeks) 2 a 10 8 - 12

a

One study followed participants to healing (mean of 4 months)

The mean age of study participants was 60 years. Two studies reported gender with 78%42 and 

28%43 male. Only one study reported race with 58% Caucasian, 24% Hispanic, and 15% AfricanAmerican.42 Initial ulcer sizes and ulcer durations were reported in the two studies with complete 

healing as the goal. Mean size (duration) was 12.3 cm2

 (29 weeks) in one study42 and 32.4 cm2

(10 weeks) in the other.43 No study reported on comorbid conditions other than diabetes. Two 

studies reported excluding patients with either venous disease44 or inadequate lower extremity 

perfusion.42 These studies also excluded patients with active or uncontrolled infection. Antibiotic 

use during the trial was not reported but both reported that off-loading was a component of care 

for all44 or 97.5%42 of patients. One study reported excluding patients for non-compliance but did 

not specify how that was determined.42 None of the trials required a run-in period with standard 

care and two reported no baseline differences between groups.42,43

Primary Outcomes (Appendix D, Table 2)

Percentage of ulcers healed was reported in only one of the trials.42 In that trial, 43% of the 

patients treated with NPWT experienced ulcer healing compared to 29% of those treated with 

standard care (ARD=14%, 95% CI 4% to 24%, p<0.05). Median time to ulcer healing was 96 

days (13.7 weeks) in the NPWT group but could not be estimated in the standard care group. 

In the second trial with complete healing as the goal, mean time to healing was reported to be 

significantly shorter (4.2 versus 5.3 weeks, p<0.05) among patients receiving NPWT compared 

to those receiving standard care.43 The third trial reported satisfactory healing (definitive closure 

of the ulcer) at a mean of 3.3 weeks in the NPWT group and at a mean of 6.1 weeks in the 

standard care group; the difference was not significant.44 In the NPWT group, 80% (4 of 5) 

ulcers achieved complete closure by delayed primary intention (skin graft, myocutaneous flap, or 

suture closure by surgeon) compared to 40% (2 of 5) in the standard care group. We pooled time 

to complete healing data from these two studies (Figure 6) and found a significant benefit for 

patients treated with NPWT (mean difference=-8.07, 95% CI -13.70 to -2.45, p=0.005).
48

Advanced Wound Care Therapies for Non-Healing Diabetic, 

Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Figure 6. Time to Complete Healing, Diabetic Ulcers – Negative Pressure Wound Therapy

Study or Subgroup

Karatepe 2011

McCallon 2000

Total (95% CI)

Heterogeneity: Tau2 = 0.00; Chi2 = 0.54, df = 1 (P = 0.46); I2 = 0%

Test for overall effect: Z = 2.81 (P = 0.005)

Mean

29.4

22.8

SD

13.3

17.4

Total

30

5

35

Mean

37.1

42.8

SD

9.8

32.5

Total

37

5

42

Weight

97.0%

3.0%

100.0%

IV, Random, 95% CI

-7.70 [-13.41, -1.99]

-20.00 [-52.31, 12.31]

-8.07 [-13.70, -2.45]

NPWT Control Mean Difference Mean Difference

IV, Random, 95% CI

-100 -50 0 50 100

Favors NPWT Favors Control

Secondary Outcomes (Appendix D, Tables 3, 4, and 5)

In one study, although more ulcers became infected during NPWT (2.4% versus 0.6% in the 

standard care group, p=ns), significantly fewer patients in the NPWT group required a secondary 

amputation (4.1% versus 10.2%, p<0.05).42 One study reported a positive effect of NPTW 

on the mental (p=0.03) and physical (p=0.004) health components of the SF-36 compared to 

conventional treatment.43 Two studies reported no significant differences in withdrawals due to 

adverse events or all-cause mortality.42,44

Hyperbaric Oxygen Therapy (HBOT)

HBOT versus Standard Care With or Without Sham

Four RCTs evaluating adjunctive hyperbaric oxygen therapy (HBOT) for the treatment of chronic 

diabetic ulcers met inclusion criteria (Table 9).46-49 One of the trials enrolled patients with ischemic 

diabetic ulcers.49 Ulcers were described as located on the lower extremity,49 below the ankle,46 and 

“foot”.47 One study reported that 61% of the ulcers were on the heel or sole and 39% were on the 

toe.48 A total of 240 patients, 123 receiving HBOT and 117 receiving control, with a mean age of 

65 were enrolled. Most patients were male (57%). Comorbidities were not uniformly reported 

but some of the trials reported histories of coronary or cardiovascular disease, hypertension, or 

hyperlipidemia (see Appendix D, Table 1). The trials were conducted in Europe46,48,49 or Turkey.47

Table 9. Summary of Baseline Characteristic: Hyperbaric Oxygen Therapy versus Standard Care/Sham

Characteristic Number of Studies 

Reporting

Mean (unless 

noted)

Range

Number of Patients Randomized 4 244 total 18 - 100

Age (years) 4 65 61 - 71

Gender (% male) 4 57 32 - 81

Race/Ethnicity (%) NR

HbA1

c (%) 3 8.2 7.9 - 8.8

Smoking 3 39 19 - 56

History of CAD/CVD (%) 2 27 22 - 29

History of Amputation (%) 3 36 11 - 39

History of HTN (%) 2 67 60 - 75

Wagner Wound Grade I (%) 1* 6 -

Wagner Wound Grade II (%) 3* 28 18 - 94

Wagner Wound Grade III (%) 3* 42 0 - 56

Wagner Wound Grade IV (%) 3* 29 0 - 45

Treatment Duration (weeks) 4 2 - 8

Follow-up Duration (weeks) 4 2 - 92

*One trial reported I through III with no further detail
49

Advanced Wound Care Therapies for Non-Healing Diabetic, 

Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Inclusion varied by ulcer grade, size, and duration (Table 10). Based on Wagner classification, 

28% were wound grade 2 (range 18 to 94), 42% wound grade 3 (range 0 to 56), and 29% ulcer 

grade 4 (range 0 to 45).46,47,49 One trial reported Wagner grades 1-3 with no further details.48 Mean 

ulcer sizes at baseline were 2.6 cm2(48) and 3.0 cm2

.

46 One trial specified ulcer size between >1 cm 

between <10 cm.49 Duration of ulcers required for inclusion ranged from at least 4 weeks to at 

least 3 months. Two studies allowed patients with infected ulcers to enroll,47,49 one study enrolled 

patients when the infection was controlled,46 and the third excluded patients with severe sepsis.48 

All trials allowed antibiotics, as needed. One study enrolled patients with ischemic ulcers,49 two 

studies excluded patients with ischemia,46,48 and one did not report exclusion criteria related to 

ischemia.47 In three of the studies, the patients had to have completed at least 6 weeks of standard 

care.46,48,49 These trials also specified off-loading as part of standard care. One study excluded 

patients for suspected poor compliance,46 one noted that the protocol was followed,49 one 

hospitalized patients for 2 weeks,48 and one did not report on compliance.47 There were variations 

between trials on the applications of HBOT. Treatment pressure (atmospheres absolute) ranged 

from 2 to 3 ATA, typically around 2.5 ATA. Treatment periods ranged from 2 weeks48 to 8 

weeks46 with the number of sessions ranging from 20 to approximately 40. One session was 90 

minutes. The control arms utilized standard multi-disciplinary ulcer care but two of the trials also 

used an adjunct blinded sham procedure.46,49 Mean follow-up times ranged from 2 weeks48 to 92 

weeks.47

The aggregate study quality of the included trials was fair. Only one study satisfactorily met 

the four study quality domains.49 In one study, there were statistically significant differences at 

baseline in the percentage of males, current smokers, obese patients, all more prevalent in the 

HBOT arm.47

Table 10. Ulcer Size, Ulcer Duration, and Definitions of Closure: Hyperbaric Oxygen Therapy versus Standard Care/Sham

Study / Location Mean ulcer size, cm2

(range or SD)

Duration of ulcer,

months (range)

Definition of ulcer closure

Löndahl 2010 /

Sweden46

HBOT: 3.1 (0.6 to 55)

Control: 2.8 (0.6 to 55)

HBOT: 9 (3 to 44)

Control: 10 (3 to 39)

Complete epithelial regeneration and 

remaining so until the next visit in the study

Duzgun 2008 /

Turkey47

HBOT: NR

Control: NR

HBOT: NR

Control: NR

Total closure of the ulcer without the need for 

surgical intervention in the operating room

Abidia 2003 /

UK49

HBOT: 10.6 (1.2 to 82.3)

Control: 7.8 (1.8 to 86.6)

HBOT: 6 (2 to 18)

Control: 9 (3 to 60)

Complete epithelialization

Kessler 2003 /

France48

HBOT: 2.31 (2.18)

Control: 2.82 (2.43)

HBOT: NR, ≥3 mos

Control: NR, ≥3 mos

Not reported

Primary Outcomes (Appendix D, Table 2)

Due to variations in follow-up durations all of the trials could not be statistically pooled (Figure 

7). Three of the trials had a follow-up duration of at least one year46,47,49 and one trial evaluated 

ulcer healing within 2 weeks of therapy.48 One long-term, placebo-controlled trial (1-year of 

follow-up) reported that 52% of patients allocated to adjunctive HBOT had completely healed 

ulcers compared to 29% of patients in the control arm (RR=1.85, 95% CI 1.05 to 3.16).46 Another 

smaller sham-controlled trial (n=18) found a higher proportion of patients49 with healed ischemic 

diabetic ulcers with adjunct HBOT compared to control at one year, 63% versus 0% (p=0.026, 

Fisher’s exact test), respectively. Another long-term study (n=100) with a mean follow-up 
50

Advanced Wound Care Therapies for Non-Healing Diabetic, 

Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

duration of 92 weeks reported that 66% of patients receiving adjunct HBOT had completely 

healed ulcers without requiring surgery versus 0% of the patients in the standard therapy arm 

(p<0.001).47 In the short-term trial by Kessler, within 2 weeks of therapy 2 of 14 patients had 

complete healing versus none of the 13 patients in the control group.48 None of the studies 

reported mean time to healing.

Figure 7. Proportion of Diabetic Ulcers Healed – Hyperbaric Oxygen Therapy 

Study or Subgroup

1.2.1 HBOT versus sham (+ multidisicplinary wound care, both arms): any duration

Abidia 2003

Duzgun 2008

Kessler 2003

Londahl 2010

1.2.5 HBOT versus Extracorporeal shockwave therapy: short-term duration (4 weeks)

Wang 2011

Events

5

33

2

25

10

Total

8

50

14

48

40

Events

0

0

0

12

24

Total

8

50

13

42

44

M-H, Random, 95% CI

11.00 [0.71, 170.98]

67.00 [4.22, 1064.23]

4.67 [0.24, 88.96]

1.82 [1.05, 3.16]

0.46 [0.25, 0.84]

HBOT Control Risk Ratio Risk Ratio

M-H, Random, 95% CI

0.01 0.1 1 10 100

Favors control Favors HBOT

Secondary Outcomes (Appendix D, Tables 3, 4, and 5)

In one study, four major amputations and eight minor amputations were performed within the 

first year but differences between the HBOT and sham treatment groups were not significant.46

A second study also reported no differences between HBOT and sham treatment in major or 

minor amputations.49 One study, however, did report fewer distal and proximal amputations and 

fewer debridement procedures in the HBOT group than in the standard therapy group.47 All of the 

standard therapy patients required some form of surgical management (i.e. debridement, graft or 

flap, or distal amputation) to achieve ulcer closure compared to 8 (16%) patients in the HBOT

group.47

Other reported secondary outcomes included no difference between HBOT and sham treatment 

in the number of percutaneous transluminal angioplasty procedures done46 and no difference 

between HBOT and sham treatment in ulcers infected during treatment.49

Adverse events, reported in 2 studies,48,49 and withdrawals due to adverse events, reported in all 

4 studies.46-49 did not differ between HBOT and sham treatment or standard care. Three trials 

reported all-cause mortality with no deaths in 2 studies48,49 and a non-significant difference 

between HBOT and sham treatment in the third.46 Two studies observed barometric otitis in one 

patient in the HBOT group and no patients in the sham treatment or standard care groups.46,48 No 

incidences of oxygen toxicity were reported.

HBOT versus Extracorporeal Shockwave Therapy

One comparative effectiveness study conducted in Taiwan compared HBOT (38 patients/40 

feet) to extracorporeal shockwave therapy (EST, 39 patients/44 feet).45 Mean age of the patients 

was 62 years; gender was not reported. Median size of the ulcers was 7 cm2 (range 2 to 12) in 

the HBOT group and 4 cm2 (range 1.5 to 9) in the EST group, a nearly statistically significant 
51

Advanced Wound Care Therapies for Non-Healing Diabetic, 

Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

difference (p=0.059). Median duration of the ulcers was 6 months. Patients with active infection 

were excluded but could be enrolled when no sepsis or necrosis. Antibiotics were used as needed 

during the trial. There were no inclusion or exclusion criteria related to blood supply and no 

run-in with standard care. HBOT was performed in a sealed multi-place chamber at a pressure 

of 2.5 ATA five times per week for a total of 20 treatments over four weeks duration. EST was 

performed with a dermaPACE device (Sanuwave, Alpharetta, GA). Treatment dosage was 

dependent on ulcer size with a minimum of 500 impulses at energy setting E2 (equivalent to 0.23 

mJ/mm2 energy flux density) at a rate of 4 shocks per second. Treatments were conducted two 

times per week totaling 6 treatments over 3 weeks duration. Study quality was rated as poor due 

to an inadequate method of allocation concealment and lack of blinding (patients and healthcare 

providers). Nine patients were excluded from the final analyses, two in the EST group due to 

poor compliance (not defined) and seven in the HBOT group due to incomplete follow-up data. 

The definition of a completely healed ulcer was not reported. 

Completely healed ulcers were reported in 25% in the HBOT group versus 55% in the EST 

group (RR=0.46, 95% CI 0.25 to 0.84) after one course of therapy, four weeks for HBOT and 

three weeks for EST. No ulcers worsened in either group but there were significantly more 

unchanged ulcers in the HBOT group compared to the EST group, 60% versus 11%, respectively. 

Twenty-seven patients (EST 12 patients/14 feet and HBOT 15/17 feet) with improved but 

incomplete healing received a second course of treatment four-to-six weeks from the first 

treatment. Only one ulcer of 17 (6%) completely healed in the HBOT group compared to seven 

of 14 (50%) ulcers in the EST group (p=0.005). Four patients receiving HBOT developed middle 

ear barotraumas and sinus pain. No adverse events were reported in the EST group.

Ozone-Oxygen Therapy 

One fair quality, double-blinded trial compared ozone-oxygen therapy to sham (placebo) for 

diabetic foot ulcers of at least 8 weeks in duration at study initiation.50 A total of 61 patients, 

32 in the ozone group and 29 in the sham group, were randomized. Mean age was 63 years 

and the proportion of men was 62%. Patients with infected ulcers (but no gangrene or active 

osteomyelitis) were included with antibiotic treatment as needed. Those with an ABI less than 

0.65 were excluded. Most patients had diabetes type 2 (97%) and the baseline ulcer size was 

slightly larger in the ozone group (4.9 cm2) compared to the sham group (3.5 cm2). The ulcers 

were Wagner classification stage 2/3 or stage 4 following debridement. Study duration was 24 

weeks. Patients received treatment or sham for 12 weeks followed by another 12 weeks until 

wound assessment. In the ozone group, therapy was divided into two phases. The patients 

initially received treatment sessions with the Ozoter device (OZ Recovery Tecnologies, Ramat 

Gan, Israel) four times weekly up to 4 weeks, or until granulation appeared in 50% of the wound 

area. Gas concentrations were 96% oxygen and 4% ozone with intervals between treatments not 

to exceed 1 day in 5 days a week. In the second phase, the sessions were reduced to two times 

weekly to complete the 12 weeks of treatment, and gas concentration was altered to 98% oxygen 

and 2% ozone. The control group received sham treatments with the ozone device circulating 

air only. Each treatment session lasted 26 minutes. The method of allocation concealment was 

unclear. Patients and investigators were blinded to mode of therapy. The intention-to-treat 

analyses included all enrolled patients and study withdrawals were adequately described. A perprotocol analysis, including only “completers,” was also conducted. 
52

Advanced Wound Care Therapies for Non-Healing Diabetic, 

Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

After 24 weeks there was no statistically significant difference in the proportion of patients 

with completely healed wounds between the ozone group and sham group. In the ozone group, 

41% of the patients had full wound closure versus 33% in the sham group (p=0.34). A large 

percentage of the study population discontinued prematurely, 16 (50%) in the ozone group and 

11 (38%) in the sham group (p=0.44). When the analysis was limited to completers (n=34, 56% 

of the patients), complete wound closure was reported in 81% of the ozone group compared to 

44% of the sham group (p=0.03). Post-hoc subgroup findings in patients with ulcers of 5 cm2 or 

less found that active treatment resulted in 100% closure compared to 50% in the sham treatment 

group (p=0.006). 

No differences were reported between active and sham therapy for ulcers infected during 

treatment, amputation, or withdrawals due to adverse events. Seven patients withdrew from 

the trial due to adverse events or complications, five in the ozone group and two in the sham 

group. Adverse events or complications in the ozone group included osteomyelitis, fever, 

wound infection, and pulmonary congestion. Events in the sham group included amputation and 

infection. 

Summary of Key Question 1

Nine different advanced wound care therapies used for treatment of diabetic ulcers provided 

information on our primary and secondary outcomes. Most compared outcomes to standard care, 

placebo or sham treatments with few reporting comparative effectiveness findings versus other 

advanced wound care therapies. Advanced wound care therapies included collagen, biological 

dressings, biological skin equivalents, platelet-derived growth factors, platelet-rich plasma, 

silver products, negative pressure wound therapy, hyperbaric oxygen therapy, and ozoneoxygen therapy. We summarize our primary and secondary outcome findings below. We found 

insufficient evidence to address the question whether efficacy and comparative effectiveness 

differed according to patient demographics, comorbid conditions, treatment compliance, or 

activity level.

Primary Outcomes 

Advanced wound care therapies using platelet-rich plasma or ozone oxygen therapy did not 

improve diabetic ulcer healing compared to standard care (2 studies) or another advanced care 

therapy (1 study). Other therapies provided mixed results. Four studies compared collagen 

products to standard care with only one study reporting significantly better healing in the 

collagen group (70% versus 46%, p=0.03). Pooled results from three studies indicate that the 

biological skin equivalent Dermagraft compared to standard care results in a non-significant 

improvement in ulcer healing favoring Dermagraft (35% versus 24%, low strength of evidence, 

see Executive Summary Table 1). We found moderate strength of evidence that the biological 

skin equivalent, bi-layer Apligraf, improved healing compared to standard care (55% versus 

34%; p=0.001; 2 studies). While pooled results from studies of platelet-derived growth factor 

showed improvement in the percentage of ulcers healed compared to placebo or standard care 

(58% versus 37%; p=0.04; 7 studies) the strength of evidence was low due to high heterogeneity 

of results between studies. One good quality study provided moderate strength evidence that 

negative pressure wound therapy improved healing more than standard care (43% versus 29%, 
53

Advanced Wound Care Therapies for Non-Healing Diabetic, 

Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

p<0.05). Three long-term, fair quality studies of HBOT reported significantly better healing with 

HBOT (52% to 66%) than sham therapy or standard care (0% to 29%).

Few studies reported time to ulcer healing and other primary outcomes. We found no benefit in 

time to ulcer healing for collagen, biological dressings, or silver products. We found mixed but 

generally negative results for biological skin equivalents (1 of 4 Dermagraft and 1 of 3 Apligraf 

studies showing benefit compared to standard care), platelet-derived growth factors (4 of 8 

studies reporting showing benefit compared to placebo or standard care), platelet-rich plasma 

(1 of 2 studies showing benefit compared to another advanced therapy), and negative pressure 

wound therapy (1 of 3 studies showing benefit compared to standard care). Strength of evidence 

was low or insufficient for all findings related to time to ulcer healing. One study of a silver 

dressing versus a calcium dressing reported a global outcome of healed or improved ulcers with 

no difference between groups. No studies reported on return to daily activities.

Secondary Outcomes 

The most commonly reported secondary outcomes were ulcers infected during treatment 

and ulcer recurrence. No study reported a benefit for these outcomes for any of the advanced 

therapies reviewed. Fewer amputations were reported in three studies (one each of a biological 

skin equivalent, negative pressure wound therapy, and hyperbaric oxygen therapy all compared 

to standard care) while five studies reported no difference. Few studies reported other secondary 

outcomes of interest including revascularization or surgery, pain or discomfort, hospitalization, 

need for home care, or quality of life. No significant differences between treatment groups 

(including 12 studies comparing an advanced therapy to standard care, 3 studies comparing 

one advanced therapy to another advanced therapy, and 1 study with both standard therapy and 

advanced therapy comparison arms) were seen in all-cause mortality though studies were not 

designed to assess this outcome. We found no significant differences in study withdrawals due to 

adverse events or allergic reactions to treatment.

.
54

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Systematic Review Evidence-based Synthesis Program

 - Advanced Wound Care Therapies for Diabetic Ulcers

Outcome

Number of 

Studies (n 

for Primary 

Outcome)*

Comments Strength of Evidence

Percentage of ulcers healed

4 (483)

One study reported significant improvement compared to standard care. Three 

studies reported no significant difference between collagen and standard care. Trials were rated as fair quality. 

Low

Mean time to ulcer healing

One trial found a significant difference favoring standard care; two found no difference. Low

y 

Percentage of ulcers healed 2 (99)

Two fair quality trials showed no difference compared to other advanced wound care therapies. Low

Mean time to ulcer healing No trial was significantly different versus control. LowPercentage of ulcers healed

3 (505)

A trend toward statistically significant improvement compared to standard care (RR=1.49, 95% CI 0.96 to 2.32, I2=43%). Trials were rated as fair quality. Low

Mean time to ulcer healing

Inconsistent results, with one trial reporting a significant difference versus standard care. Trials were rated as fair quality. Low

Percentage of ulcers healed

2 (279)

Two trials of fair quality found statistically significant improvement versus standard care (RR=1.58, 95% CI 1.20 to 2.08, I2=0%). Moderate

Mean time to ulcer healing One trial reported a significant difference between Apligraf and standard care. Low

y 

Percentage of ulcers healed 1 (29 ulcers) One fair quality trial found no significant difference versus Theraskin. Low Mean time to ulcer 

healing No significant difference versus Theraskin. Low

d 

Percentage of ulcers healed 7 (685)

Overall statistically significant improvement versus placebo (RR 1.45 [95% CI 1.03 to 2.05]) but results were inconsistent (I2 85%). Overall study quality was 

rated as fair.

Low

Mean time to ulcer healing 5 (731) Overall, PDGF demonstrated shorter duration of time to ulcer healing versus placebo. Low

y 

ver, 

Percentage of ulcers healed 3 (189)

No significant differences compared to an advanced therapy comparator. Trials were rated as fair quality. Low

Mean time to ulcer healing No significant differences compared to an advanced therapy comparator. LowPercentage of ulcers healed

2 (96)

Neither of the studies (fair to poor quality) demonstrated a significant difference between PRP and its respective control. Low

Mean time to ulcer healing

Significantly shorter healing time compared to platelet-poor plasma. No significant difference versus placebo gel. Low
55

es for Non-Healing Diabetic, 

Systematic Review Evidence-based Synthesis Program

Outcome

Number of 

Studies (n 

for Primary 

Outcome)*

Comments Strength of Evidence

 

y



oak 

m

Percentage of ulcers healed 4 (280)

One trial found silver ointment more effective than standard care. Two trials found no difference in healing between a silver cream or dressing and another advanced care product. Studies were of fair quality. 

Low

Mean time to ulcer healing 2 (174) Two trials found no difference between silver and another advanced wound care product. Low

 

Percentage of ulcers healed 1 (335)

One trial of good quality found 43% in the NPWT group experienced ulcer healing compared to 29% treated with standard care (RR=1.49, 95% CI 1.11 to 2.01).

Moderate

Mean time to ulcer healing 3 (432) Results for time to healing were inconsistent based on 3 trials of mixed quality. Low

d 

Percentage of ulcers healed 4 (233)

Three long-term studies of fair quality found significant improvement with adjunctive HBOT versus sham or standard care; one short-term study found no difference.

Low

Mean time to ulcer healing

- Outcome not reported. Insufficient

y 

py)

Percentage of ulcers healed 1 (84) One trial of poor quality found adjunctive HBOT less effective than extracorporeal shockwave therapy. Low

Mean time to ulcer healing

- Outcome not reported. Insufficient

Percentage of ulcers healed 1 (61) One trial of fair quality found no significant difference between ozone-oxygen and sham. LowMean time to ulcer healing

- Outcome not reported. Insufficient

ary outcome

 grades: (1) high strength indicates further research is very unlikely to change the confidence in the estimate of effect, meaning that the evidence reflects the true 

ther research may change our confidence in the estimate of effect and may change the estimate; (3) low strength indicates further research is very likely to have 

 the estimate of effect and is likely to change the estimate, meaning there is low confidence that the evidence reflects the true effect; and (4) insufficient, indicating 

not permit a conclusion.
56

Advanced Wound Care Therapies for Non-Healing Diabetic, 

Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

KEY QUESTION #2. What are the efficacy and harms of therapies 

for venous ulcers? Is efficacy dependent on ancillary therapies? 

Does efficacy differ according to patient demographics, comorbid 

conditions, treatment compliance, or activity level?

Overview of Studies

Table 12 contains an overview of studies of therapies for venous ulcers.52-72 Twenty trials (in 22 

articles) met eligibility criteria including 1 trial of collagen (n=73), 1 trial of biological dressings 

(n=120), 3 trials of biological skin equivalents (n=380), 4 trials of keratinocytes (n=502), 1 

trial of platelet-rich plasma (n=86), 6 trials of silver products (n=771), 1 trial of intermittent 

pneumatic compression therapy (n=54), 2 trials of electromagnetic therapy (n=63), and 1 trial of 

hyperbaric oxygen therapy (n=16). Sixteen trials compared an advanced wound care therapy to 

standard care or placebo. In four trials, the comparator was a different advanced therapy.

Overall, the mean age of study participants ranged from 56 to 73 years and 26% to 61% were 

male. In 5 studies reporting race, 62% to 100% were white, 0% to 33% were black, 0% to 6% 

were Hispanic, and 0% to 2% were Asian. Mean ulcer sizes ranged from 1.2 to 11.1 cm2

 with 

ulcer durations of 7 to 626 weeks.

In 14 trials, the ulcer was described as a “leg” ulcer (with 1 trial specifying the location as medial 

distal one-third of the leg). In 2 trials, the ulcer was described as a “lower extremity” ulcer (with 

1 trial specifying that 80% of the ulcers were on the angle or calf). Three trials did not report the 

ulcer location describing the ulcer only as a “venous ulcer.” In 12 trials, the diagnosis of venous 

ulcer was based on clinical signs or symptoms of venous insufficiency. The remaining 8 trials 

required either patients to have adequate arterial circulation or specifically excluded patients with 

known arterial insufficiency.

Collagen

One fair quality RCT enrolled 73 patients with a venous leg ulcer and followed them over 

twelve weeks of treatment with Promogran or standard wound care.52 Standard care included 

compression therapy. Participants in the study had an average age of 73 years; 35 percent were 

males. Patients with infected ulcers and ulcers linked to diabetes were excluded; an ABI of 

greater than 0.8 was required for inclusion. The trial did not include a run-in period with standard 

care and compliance with treatment was not reported. The mean ulcer size was 8.2 cm2 and 

the mean ulcer duration was 9.2 months. The study reported no significant difference between 

treatment arms in ulcer size, ulcer duration, or ancillary therapies. Demographic and ulcer 

characteristics are reported in Appendix D, Table 1. 

Primary Outcomes (Appendix D, Table 2)

The percentage of venous ulcers healed by study completion did not differ significantly between 

the Promogran and standard wound care groups (49% versus 33%, p=0.18; ARD=16%, 95% 

CI -7% to 38%).52 The effects of patient factors or ancillary therapies on outcomes were not 

reported.
57

Advanced Wound Care Therapies for Non-Healing Diabetic, 

Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Secondary Outcomes (Appendix D, Tables 3, 4, and 5)

Significantly fewer ulcers were infected during treatment with collagen compared to standard 

care (0% versus 14%, p=0.03). No significant differences between collagen and standard care 

were noted for the percentage of withdrawals due to adverse events or percentage of patients 

having an allergic reaction to treatment.52

Biological Dressings

One study, enrolling 120 patients,53 compared OASIS Wound Matrix plus compression therapy 

to compression therapy alone (standard care) in treatment of chronic leg ulcers unresponsive to 

standard therapy. This industry-sponsored study was of fair quality and took place in multiple 

sites across the United States, United Kingdom, and Canada. Patients with infected ulcers, 

uncontrolled diabetes, or an ABI less than 0.8 were excluded. Compliance with treatment was 

not reported. The average ulcer size at baseline was 11.1 cm2. The mean age of the patients was 

64 years, 42% were male, and 81% were white. Thirty-four percent of ulcers were present for 

1 to 3 months; 37% were present for more than 12 months. Additional study characteristics are 

presented in Appendix D, Table 1.

Primary Outcomes (Appendix D, Table 2)

Treatment with OASIS resulted in a statistically significant improvement in incidence of ulcer 

healing, with 55% of treated patients achieving complete healing at 12 weeks, versus 34% in the 

standard care group (ARD=20%, 95% CI 3% to 38%; p=0.02) but not at 6 months (67% versus 

46%, p=ns).53

Debridement was only performed if deemed clinically necessary. This allowed for covariate 

and subgroup analysis comparing those who received baseline debridement to those who did 

not. Covariate analysis showed that OASIS had a consistently higher rate of healing compared 

to standard care regardless of debridement status, but subgroup analysis found the difference 

between study groups was exaggerated in patients who received baseline debridement. Sixtythree percent of OASIS patients who underwent baseline debridement healed at 12 weeks, versus 

30% of standard care patients who received initial debridement (p=0.02).53 Covariate analysis 

also showed the higher incidence of healing with OASIS was consistently observed when 

accounting for the presence of vascular disease (p=0.03), type 2 diabetes (p=0.02), endocrine 

disease (p=0.03), and hypertension (p=0.02).

Secondary Outcomes (Appendix D, Tables 3, 4, and 5)

At 6 months follow-up, there was a significant difference in recurrence (0% of healed ulcers 

originally treated with OASIS versus 30% of healed ulcers in the standard care arm, p=0.03). 

There was no difference between groups in ulcers infected during treatment. Two patients in the 

OASIS group were hospitalized and unable to complete the study versus none in the standard 

care group (p=ns).53 No statistically significant differences between treatment groups were 

reported for withdrawals due to adverse events, proportion of patients with adverse events, allcause mortality, or allergic reaction to treatment.
58

es for Non-Healing Diabetic, 

Systematic Review Evidence-based Synthesis Program

es for Venous Ulcers

Product

Comparator

Healed ulcers

Mean time to ulcer 

healing

Global 

assessment 

Return to daily 

activities 

Ulcers infected 

during treatment

Amputation

Revascularization/ 

surgery

Recurrence

Time to 

recurrence 

Pain/discomfort

Hospitalization

Required home 

care

Quality of life

Withdrawals due 

to adverse events

Patients with ≥ 1 

adverse event 

All-cause mortality

Allergic reactions 

to treatment

Promogran Non-adherent - + - - -

OASIS Compression bandage

+ - + - - - - ±

Apligraf Compression bandage

+ + - - - - -

Apligraf Compression bandage

+ + -

Dermagraft Compression bandage 

- - - ± -

Dermagraft Compression bandage

-

yte

Keratinocyte sheets + pneumatic compression therapy

Pneumatic compression therapy

-

yte Cryopreserved keratinocytes Lyophilized keratinocytes

- - -

yte Keratinocytes

Vehicle + std care or std care only

- - - - - - - - -

yte Keratinocytes (autologous) Compression bandage

+ + - -

Platelet lysate Placebo -

Aidance Standard + - - -

 

Silver Cream (Silvadene) or Tri-peptide placebo

↓* + - - -
59

es for Non-Healing Diabetic, 

Systematic Review Evidence-based Synthesis Program

Product

Comparator

Healed ulcers

Mean time to ulcer 

healing

Global 

assessment 

Return to daily 

activities 

Ulcers infected 

during treatment

Amputation

Revascularization/ 

surgery

Recurrence

Time to 

recurrence 

Pain/discomfort

Hospitalization

Required home 

care

Quality of life Withdrawals due 

to adverse events

Patients with ≥ 1 

adverse event 

All-cause mortality

Allergic reactions 

to treatment

am Flamazine

Non-adherent + Nonocclusive dressing

- -

Standard + ± ±

r 

AQUA-CEL Lipidocolloid silver - + - - - - -6 options Non-silver dressing - - - - - -

Unna’s Boot (Compression)

- - - -

Dermagan Sham + ± - - ± - - - -Elmedistraal Sham - ± - + - - -

Sham

-

cal Skin Equivalent; Col – Collagen; EMT – Electromagnetic therapy; EST – Extracorporeal Shock Wave Therapy; HBOT – Hyperbaric Oxygen Therapy; IPC 

herapy; NaCMC - Sodium Carboxymethylcellulose; NPWT – Negative Pressure Wound Therapy; PDGF – Platelet-derived Growth Factor; PRP – Platelet Rich 

or (p< 0.05)

ficant benefit

or
60

Advanced Wound Care Therapies for Non-Healing Diabetic, 

Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Biological Skin Equivalents

We identified three RCTs related to the use of biological skin equivalents in ulcers of venous 

etiology. Two studies evaluated the use of Dermagraft for ulcers described only as “leg” ulcers. 

One study evaluated the use of Apligraf but did not describe the ulcer location. The comparator 

in all three studies was standard care including compression bandages. One Dermagraft study 

was a small (n=18), single center trial of fair quality that was done in the UK.57 No study sponsor 

was reported. The other Dermagraft study was a small (n=53), industry sponsored trial of fair 

quality that took place in six centers across the UK and Canada.56 Both studies allowed ulcers 

with an initial area of 3 to 25 cm2 and took place over a period of 12 weeks. The Apligraf study 

was a large (n=309), industry-sponsored study of fair quality, which took place at 15 sites across 

the U.S.54 The average ulcer size in this study was significantly smaller than the other studies, 

with a mean ulcer area of 1.2 cm2

 at baseline. This trial followed patients for 6 months. None 

of the studies reported compliance with standard care. None reported differences between study 

arms at baseline but one did not report a statistical analysis.56 No study enrolled patients with 

infected ulcers; only one reported allowing antibiotics as needed.56 All of the studies excluded 

patients with arterial insufficiency. One included a 14 day run-in period with compression.56

Summary baseline data are presented in Table 13. Additional information about the studies is 

presented in Appendix D, Table 1.

Table 13. Baseline Study Characteristics: Biological Skin Equivalents

Characteristic Number of Studies 

Reporting

Mean (unless 

noted)

Range

Number of Patients Randomized 3 380 total 18 - 309

Age 3 62 60 - 69

Gender (% male) 3 51 42 - 61

Race/Ethnicity (%)

White 2 79 76 - 94

Black 2 16 4 - 18

Other 2 5 2 - 5

BMI 1 30.4 30.4

ABI 2a 1.1 1.06 - 1.1

Ulcer Size (cm2

) 3 2.5 1.2 - 10.7

Ulcer Duration 3b

Study Duration (weeks) 3 9 8 - 12

a

Mean/median ABI not reported in one study, but all participants were >0.65 by exclusion criteria

b

All 3 studies reported ulcer duration in a different format: Krishnamoorthy 2003:56 median duration of 47.7 days; Omar, 2004:57

mean duration of 119.3 weeks; Falanga, 1998:54 <6 months: 30.6%, 6-12 months: 21.1%, 1-2 years: 13.8%, >2 years: 34.5%

Primary Outcomes (Appendix D, Table 2)

In two small studies of Dermagraft, there was no significant difference in healed ulcers compared 

to standard care.56,57 Pooled results are presented in Figure 8. The overall risk ratio was 2.96 

(95% CI 0.93 to 9.44, I2

=0%). The large trial using Apligraf did show a significant benefit 

compared to standard compression bandage therapy for incidence of complete ulcer healing at 6 

months (63% versus 49%; ARD=14%, 95% CI 3% to 26%; p=0.02) and median time to closure 

(61 days versus 181 days, p=0.003).54 A similar pattern was observed when only ulcers of greater 

than 1 year duration were considered.55 Additional subgroup analyses from this trial found 

significant differences in treatment efficacy for certain patient subpopulations. In ulcers with 
61

Advanced Wound Care Therapies for Non-Healing Diabetic, 

Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

a duration less than 6 months at the beginning of the study time to ulcer healing did not differ 

significantly between biological skin equivalent and standard care. In ulcers present for over 6 

months, significantly more rapid healing was observed in the biological skin equivalent group 

(median of 92 days versus 190 days for control, p=0.001). Similarly, a significant benefit in time 

to closure was seen for biological skin equivalent compared to standard compression bandage 

therapy in patients with deeper ulcers (83 days versus 183 days, p=0.003). Stratification by initial 

ulcer area found that Apligraf significantly improved ulcer healing (p<0.05) when used in both 

large (defined as greater than 1000 mm2) and small ulcers.54 The effect of ancillary therapies on 

treatment efficacy could not be assessed from any of the studies.

Figure 8. Proportion of Venous Ulcers Healed - Biological Skin Equivalent (Dermagraft) versus 

Compression Bandage 

Study or Subgroup

Krishnamoorthy 2003

Omar 2004

Total (95% CI)

Total events

Heterogeneity: Tau2 = 0.00; Chi2 = 0.15, df = 1 (P = 0.70); I2 = 0%

Test for overall effect: Z = 1.83 (P = 0.07)

Events

5

5

10

Total

13

10

23

Events

2

1

3

Total

13

8

21

Weight

64.1%

35.9%

100.0%

M-H, Random, 95% CI

2.50 [0.59, 10.64]

4.00 [0.58, 27.70]

2.96 [0.93, 9.44]

Dermagraft Control Risk Ratio Risk Ratio

M-H, Random, 95% CI

0.05 0.2 1 5 20

Favors Control Favors Dermagraft

*Kishnamoorthy 2003 – Analysis is for Group 2 (4 pieces of Dermagraft applied on day 0, and weeks 1, 4, and 8) versus 

compression bandage

Secondary Outcomes (Appendix D, Tables 3, 4, and 5)

Two studies, one of Dermagraft56 and one of Apligraf54 reported no difference between treatment 

with biological skin equivalent or standard compression bandage therapy in the incidence of 

infection. The Apligraf study also reported no difference in the incidence of cellulitis.54 Rate 

of recurrence was reported in the Apligraf study. No significant difference was seen in the 

percentage of ulcers recurring within one year (12% versus 16% of control patients)54 with 

similar findings for the subgroup with ulcers of greater than 1 year duration.55 In the Apligraf 

study, there was also no difference in pain between treatment groups.54 Of the two studies that 

reported adverse events, both reported no differences between biological skin equivalent and 

standard compression bandage therapy in withdrawals due to adverse events.54,56 There was also 

no difference in all-cause mortality. One study reported no difference in the incidence of adverse 

events or serious adverse events.56 No instances of immune intolerance or reactivity to grafts 

were reported.
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Advanced Wound Care Therapies for Non-Healing Diabetic, 

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Keratinocytes

Four RCTs met eligibility criteria and looked at the use of keratinocytes in venous ulcers. Three 

studies described the ulcers only as “leg” ulcers; one specified the location as medial distal onethird of the leg.58 These trials had marked heterogeneity across several important parameters: 

keratinocyte source (autologous or allogeneic); cellular state of keratinocytes (fresh, frozen, or 

lysed); comparators (other keratinocyte product, standard of care); and study size, protocols, and 

quality. This variability hampered aggregation and the ability to generalize results. The four studies 

consisted of the following: a large, multinational study of fair quality that took place in Belgium, 

Germany, Poland, and the UK60 (n=200); a large, multinational study of fair quality that took 

place in Hungary, Germany, and the Czech Republic61 (n=225); a smaller study of poor quality 

that took place at a single site in the Czech Republic59 (n=50); and a small study of fair quality 

that took place in Sweden58 (n=27). Inclusion criteria for ulcer size varied. One study included 

ulcers between 1 and 20 cm2

; the median size was 5.2 cm2.

60 Another study included ulcers of 2 

to 50 cm2 with 60% of the study ulcers between 2 and 10 cm2 and 39% over 10 cm2.

61 The third 

study included ulcers greater than 2 cm2

 and the mean ulcer size was 10.7 cm2.

59 In the last study, 

all ulcers were greater than 2 cm2 with a mean ulcer size of 8.4 cm2.

58 One study reported having 

industry sponsorship;60 the other studies did not include financial disclosures. One study reported 

study compliance and identified protocol violations in 5.3%.60 Three of the studies either excluded 

patients with infection or required treatment before study entry; one did not report infection 

status.61 Two studies reported antibiotic use during the study, either for cellulitis58 or prior to graft 

placement, if infection was present.59 All of the studies excluded patients with arterial insufficiency; 

one study excluded patients with diabetic ulcers.60 None of the studies reported significant 

differences between study arms at baseline. Two of the studies included a run-in period with 

standard care, either 2 weeks61 or 4 weeks.60 Summary baseline characteristics are reported in Table 

14. Additional study characteristics are presented in Appendix D, Table 1. 

Table 14. Baseline Study Characteristics: Keratinocytes 

Characteristic Number of Studies 

Reporting

Mean (unless 

noted)

Range

Number of Patients Randomized 4 502 total 27 - 225

Age 2a 66 63 - 67

Gender (% male) 4 38 33 - 39

Race/Ethnicity (%) 1

White 1 100 -

BMI 2b 28.9 28.6 - 30.1

Smoking (%) 1 19.1 -

ABI 2c

Ulcer Size (cm2) 2d 9.2 6.3 - 10.7

Ulcer Duration (weeks) 1e 102.7 -

Study Duration (weeks) 4 23 8 - 26

History of DM 1 6% -

a

Two additional studies reported median ages of 76 years and 67.5 years

b

One additional study reported median BMI of 28.9

c

Two studies reported median ABI of 1.0 and 1.1; all patients in 2 other studies had ABI >0.8 per exclusion criteria

d

Two other studies reported ulcer size using other formats: Harding, 2005:60 median ulcer size=5.2 cm2; Vanscheidt, 2007:61 ulcer 

size 2-10 cm2

: 60.4%; ulcer size >10 cm2: 38.7% e

3 additional studies reported ulcer duration in other formats: Harding, 2005:60 median duration of 43 weeks; Lindgren, 1998:58 <2 

years: 44.4%, >2 years: 55.6%; Vanscheidt, 2007:61 3-12 months: 59.1%, >12 months: 40.9%
63

Advanced Wound Care Therapies for Non-Healing Diabetic, 

Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Primary Outcomes (Appendix D, Table 2)

One trial demonstrated significant improvements in both proportion of ulcers healed (38% 

versus 22%, p=0.01) and median time to complete healing (176 days versus more than 201 

days, p<0.0001) when BioSeed-S (autologous keratinocytes in fibrin sealant) was compared 

to standard compression bandage therapy. In subgroups of patients with ulcers of 12 months 

or less, greater than 12 months, 2 to 10 cm2, or greater than10 cm2, the proportion of ulcers 

healed was significantly greater in the keratinocyte group only for patients with larger ulcers at 

baseline (greater than 10 cm2). Time to ulcer healing was significantly higher for patients treated 

with keratinocytes in all of the subgroups.61 In other studies, no statistical differences in ulcer 

healing were seen when cryopreserved, cultured epidermal allografts (CEA) were compared with 

pneumatic compression therapy,58 when cryopreserved CEA were compared to lyophilized CEA,59

and when lyophilized keratinocytes were compared to a combined control group of standard 

compression therapy and standard therapy plus keratinocyte vehicle.60 Pooled ulcer healing 

results for the two studies comparing keratinocyte treatment to standard care (with compression 

therapy) are presented in Figure 9. The absolute risk difference was 14%, 95% CI 5% to 23%. The 

overall risk ratio was 1.57 (95% CI 1.16 to 2.11, I2

=0%) indicating a significant overall benefit 

of keratinocyte therapy compared to standard care. Two studies reported time to healing with no 

differences between treatment groups in either study, one a comparison of keratinocytes to standard 

care,60 the other a comparison to another advanced therapy.59 No comparisons could be made within 

or between studies regarding the effect of ancillary therapies on treatment efficacy.

Figure 9. Proportion of Venous Ulcers Healed - Keratinocytes versus Standard Care

Study or Subgroup

Harding 2005

Vanscheidt 2007

Total (95% CI)

Total events

Heterogeneity: Tau2 = 0.00; Chi2 = 0.38, df = 1 (P = 0.54); I2 = 0%

Test for overall effect: Z = 2.96 (P = 0.003)

Events

36

44

80

Total

95

116

211

Events

26

24

50

Total

98

109

207

Weight

50.6%

49.4%

100.0%

M-H, Random, 95% CI

1.43 [0.94, 2.17]

1.72 [1.13, 2.63]

1.57 [1.16, 2.11]

Keratinocytes Standard Care Risk Ratio Risk Ratio

M-H, Random, 95% CI

0.2 0.5 1 2 5

Favors Std. Care Favors Keratinocytes

*Harding 2005 – Analysis is for the “as treated” ITT cohort.

Secondary Outcomes (Appendix D, Tables 3, 4, and 5)

Few secondary outcomes were reported. In one study, the percentage of ulcers infected during 

treatment, ulcer recurrence, and pain during treatment or follow-up did not differ between 

keratinocyte therapy and a combined (standard care and vehicle) control group.60 Another study 

reported that pain was significantly reduced during the first week after treatment application with 

no difference between the two keratinocyte products.59 Only the two large studies reported adverse 

events.60,61 One study reported 65 events in 38 patients in the keratinocyte group and 51 events in 

27 patients in the compression therapy group. Of the 116 patients receiving keratinocyte therapy, 1 

experienced a minor adverse event “certainly” related to the treatment, 2 were “probably” related, and 

6 were “possibly” related.61 The other study reported no difference between advanced treatment and a 

combined standard care and vehicle control group in “burning, stinging, pain, or itching” sensations.60

There was no difference in all-cause mortality between treatment groups in either study. 
64

Advanced Wound Care Therapies for Non-Healing Diabetic, 

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Platelet Rich Plasma (PRP)

One RCT enrolling 86 patients with ulcers described only as “leg” ulcers, compared the efficacy 

of PRP to placebo over 39 weeks.62 This fair quality trial was conducted in Australia and 

funded by a combination of industry and government sources. Both groups received standard 

compression therapy. The authors did not report inclusion or exclusion criteria related to 

infection, whether there was a run-in period with standard care, or whether compliance with 

treatment was monitored. Patients were required to have an ABI greater than 0.9 for inclusion. 

The mean age of participants was 71 years; 42 percent were male. Mean ulcer size was 4.9 

cm2

 and the mean ulcer duration prior to enrollment was 3 months. The study reported no 

significant difference between treatment arms in ulcer size, ulcer duration, or ancillary therapies. 

Treatments were applied twice weekly until wound healing or up to the 9 month study duration. 

Demographic and ulcer characteristics are reported in Appendix D, Table 1. 

Primary Outcomes (Appendix D, Table 2)

There was no significant difference between PRP and placebo in the percentage of ulcers healed 

at study completion (79% versus 77%, p=ns).62 Time to complete healing was not reported.

Secondary Outcomes (Appendix D, Tables 3, 4, and 5)

Two hospitalizations leading to study withdrawal were reported but the treatment group the 

patients were assigned to was not provided. There were 6 withdrawals from the study due 

to adverse events (5 with allergy to the paste bandage and 1 with leg trauma related to the 

bandages) but the treatment group was not reported.62

Silver Products

We identified six studies of silver products used to treat venous ulcers.38,63-68 Two studies 

compared a silver dressing to a dressing without silver,65,67,68 two compared silver ointment 

to standard care,38,60 one compared silver cream to a tri-peptide copper cream or tri-peptide 

placebo (with silver as the control treatment),63 and one compared an ionic silver dressing to 

a lipidocolloid silver dressing.66 The studies were conducted in the United States,63 the United 

Kingdom,64,67,68 Greece,65 Italy,38 and Europe.66 Enrollments ranged from 42 to 281 with a total 

enrollment of 771. Two studies were of good quality64,66 and four were of fair quality. A summary 

of study characteristics is presented in Table 15 with additional information about the studies in 

Appendix D, Table 1.
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Advanced Wound Care Therapies for Non-Healing Diabetic, 

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Table 15. Summary of Baseline Characteristics: Silver Products 

Characteristic Number of Studies 

Reporting

Mean (unless 

noted) Range

Number of Patients Randomized 6 771 total 42 - 281

Age (years) 6 65.6 47 - 71

Gender (% male) 5 41.6 35 - 50

Race/Ethnicity (%)

White 1 62 -

Black 1 33 -

Other 1 5 -

BMI 1 30 -

Smoking, Current (%) 2 22.7 18.3 - 33.7

ABI 1 1.04 -

Ulcer Size (cm2

) 3a 6.0 3.2 - 10.5

Ulcer Duration (months) 3b 19.4 9.0 - 46.4

Infection (%) 4c,d - -

Study Duration (weeks) 6 8.6 4 - 12

History of Diabetes (%) 2e 9 -

History of MI or Cardiac Failure (%) 1 14 -

History of Stroke or TIA (%) 1 8 -

a

One study reported that 72% were <3 cm diameter; another reported that 52% were <3 cm diameter

b

One study reported that 38.5% were >12 weeks

c

Three studies reported excluding 1) >105 bacteria/gram of tissue, systemic sepsis or bone infection; 2) clinically infected ulcers or 

receiving local or systemic antibiotics (included ulcers with at least 3 of the following: pain, perilesional skin erythema, edema, foul 

odor, or high levels of exudate); or 3) receiving oral or parenteral antibiotics

d

One study included only patients with infected ulcers

e

One study excluded patients with diabetes

Ulcers were described as “leg” ulcers in 3 studies64,65,67,68 and lower extremity ulcers in 1 study.63

One study did not specify ulcer location38 and one reported that 47% were ankle, 33% calf, 

18% gaiter, and 2% foot ulcers.66 Three studies excluded patients with signs of infection or 

patients who were receiving antibiotics;63,66-68 all patients had infected ulcers in two studies,64,64

and one did not report infection status.38 Only one reported use of antibiotics, as needed.65 All 

trials excluded patients with arterial insufficiency. None of the trials included a run-in period 

with standard care. Compression bandaging was part of standard care in all of the trials; one 

trial reported monitoring compliance with treatment but did not provide results based on 

compliance.63 Four studies reported no baseline differences between treatment groups while 

one noted gender distribution and height varied (not found to be related to outcomes),63 and 

one found differences in BMI and ulcer location (right versus left leg).67,68 Two studies reported 

mean ulcer sizes of 3.2 cm2(38)and 3.4 cm2

.

64 The latter study included only ulcers up to 10 cm2

. 

One study reported a mean ulcer size of 10.5 cm2 with ulcers of 3 cm2 to 50 cm2 included in the 

trial.63 Another study included ulcers between 5 cm2 to 40 cm2 but did not report a mean size.60

One study reported that 72% of the study ulcers were less than 3 cm in diameter67,68 and a second 

study reported that 52% were less than 3 cm in diameter.65 Ulcer duration was reported in 4 

studies. In three studies, the mean ulcer duration ranged from 9 months to 46.4 months.64-66 In 

the fourth study, only ulcers of greater than 6 weeks were included; 38.5% were of greater than 

12 weeks.67,68 The studies were designed to address effectiveness and safety with one looking at 

non-inferiority of a new silver product.66
66

Advanced Wound Care Therapies for Non-Healing Diabetic, 

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Primary Outcomes (Appendix D, Table 2)

All six studies reported ulcer healing. Two studies found significantly greater rates of healing in 

the silver cream/ointment groups at 4 weeks when compared to standard care (42% versus 22%, 

p<0.05)38 or to copper cream (21% versus 0%, p=0.01).63 No difference was found between silver 

cream and the copper cream placebo (31% versus 3%, p=0.05).63 One study comparing silver 

cream to a non-adherent and non-occlusive dressing found no benefit for the silver cream at 12 

weeks (63% versus 80%).64 Pooled results from three studies (Figure 10) showed no statistically 

significant difference in ulcer healing with silver cream (range 21% to 63%) versus standard care 

or placebo copper cream (range 3% to 80%) with evidence of large heterogeneity (RR=1.65, 

95% CI 0.54 to 5.03, I2

=84%).

One study found a higher rate of ulcer healing in the silver dressing group compared to standard 

care (non-silver dressing) at 9 weeks (81% versus 48%, p=0.02).65 The two remaining studies 

found no difference at 8 weeks between two silver-based dressings (17% versus 15%)66 and no 

differences at 12 weeks (60% versus 57%) or 1 year (96% in both groups) between a silver and a 

non-silver dressing.67,68 Pooled data from two studies of silver versus non-silver dressings (Figure 

10) again show no statistically significant difference with evidence of heterogeneity (RR=1.27, 

95% CI 0.80 to 2.01, I2

=67%).

Two studies presented data on factors related to healing. In one study comparing silver to nonsilver dressings, female gender (p=0.01) and smaller ulcer size (up to 3 cm versus above 3 cm; 

p=0.008) were significant predictors of healing at 12 weeks.67,68 In the other study, the significant 

overall benefit of the silver dressing compared to standard care was also observed among the 30 

study ulcers of less than 0.5 cm depth with 93% healing in the silver group versus 56% in the 

non-silver group (p=0.04). For ulcers greater than 0.5 cm depth (12 of the 42 study ulcers) there 

was no benefit of the silver dressing (57% versus 20%).65 In the silver dressing group, 100% 

(6/6) of ulcers with a high degree of exudation were healed following treatment; in the non-silver 

group, none of 8 ulcers with a high degree of exudation were healed.65

Two studies, both comparing silver dressings to non-silver dressings, reported time to healing. 

One study found no difference between groups (medians of 67 [silver] and 58 [non-silver] 

days),67,68 the other study reported mean times to healing of 6.1 weeks (silver) and 6.4 weeks 

(non-silver) but whether the difference was significant was not reported.65 Silver cream was 

superior to tri-peptide copper cream in a composite measure of the degree of erythemia, 

exudation, and granulation63 and an ionic silver dressing was superior to a lipidocolloid silver 

dressing in a composite outcome of healed or markedly improved ulcers.66
67

Advanced Wound Care Therapies for Non-Healing Diabetic, 

Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Figure 10. Proportion of Venous Ulcers Healed – Silver Products 

Study or Subgroup

3.1.1 Cream

Belcaro 2010

Bishop 1992

Blair 1998

Subtotal (95% CI)

Total events

Heterogeneity: Tau2 = 0.71; Chi2 = 12.22, df = 2 (P = 0.002); I2 = 84%

Test for overall effect: Z = 0.88 (P = 0.38)

3.1.2 Silver cream versus copper cream

Bishop 1992

Subtotal (95% CI)

Total events

Heterogeneity: Not applicable

Test for overall effect: Z = 1.80 (P = 0.07)

3.1.3 Dressing

Dimakakos 2009

Michaels 2009

Subtotal (95% CI)

Total events

Heterogeneity: Tau2 = 0.08; Chi2 = 2.99, df = 1 (P = 0.08); I2 = 67%

Test for overall effect: Z = 1.01 (P = 0.31)

Test for subgroup differences: Chi2 = 2.71, df = 2 (P = 0.26), I2 = 26.2%

Events

19

6

19

44

6

6

17

62

79

Total

44

28

30

102

28

28

21

104

125

Events

8

1

24

33

0

0

10

59

69

Total

38

29

30

97

29

29

21

104

125

Weight

38.4%

17.9%

43.7%

100.0%

100.0%

100.0%

39.3%

60.7%

100.0%

M-H, Random, 95% CI

2.05 [1.02, 4.14]

6.21 [0.80, 48.38]

0.79 [0.57, 1.10]

1.65 [0.54, 5.03]

13.45 [0.79, 228.07]

13.45 [0.79, 228.07]

1.70 [1.04, 2.79]

1.05 [0.83, 1.32]

1.27 [0.80, 2.01]

Silver Control Risk Ratio Risk Ratio

M-H, Random, 95% CI

0.02 0.1 1 10 50

Favors Control Favors Silver

Secondary Outcomes (Appendix D, Tables 3, 4, and 5)

One study reported on ulcers infected during treatment with no difference between an ionic 

silver dressing (11%) and a lipidocolloid silver dressing (9%).66 Two studies reported on ulcer 

recurrence. In one study, no difference was observed in recurrence between ulcers treated with 

a silver dressing versus a non-silver dressing (12% versus 14%).67,68 Another study reported 

that 17% of the ulcers treated with silver cream recurred. There were no healed ulcers in the 

tri-peptide copper cream group and the one healed ulcer in the tri-peptide placebo cream group 

did not recur.63 Pain was assessed in three studies, one comparing silver cream to tri-peptide 

copper cream,63 one comparing an ionic silver dressing to a lipidocolloid silver dressing,66 and 

one comparing a silver dressing to a non-silver dressing.65 No differences between treatment 

groups were observed in the two studies comparing advanced wound therapies.63,66 In the third 

study, it was reported that 100% of patients in the silver dressing group were pain-free by the 

end of the eighth week of treatment; 62% of the standard care (non-silver dressing) patients were 

pain-free after 9 weeks of treatment.65 Quality of life was reported in one study, a comparison 

of silver and non-silver dressings. No difference was found between groups at either 12 weeks 

(post-treatment) or 1 year.67,68 Study withdrawals due to adverse events were documented in 
68

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three studies with no differences between silver cream and standard care,38 two silver dressings,66

or silver and non-silver dressings.67,68 In one study, there were no withdrawals and no adverse 

events.38 In the second study, the percentages of patients withdrawing were 6% (ionic silver 

dressing group) and 9% (lipidocolloid silver dressing group).66 Overall adverse event rates were 

50% and 42%, respectively; study-related adverse event rates were 23% and 18%. The third 

study reported one withdrawal in the silver dressing group.67,68 No differences were observed 

between two silver dressings or a silver and a non-silver dressing in all-cause mortality with 

post-treatment (8 or 12 weeks) rates of 0% to 1.4%66,67,68 and a 1 year follow-up rate of 4% 

(both treatment groups).67,68 Allergic reactions to treatment were reported in 3 studies with no 

differences between silver cream and standard care,38 silver cream and copper cream,63 or silver 

cream and non-adherent dressing.64 One study reported no treatment-related adverse events 

associated with a silver or non-silver foam dressing.65

Intermittent Pneumatic Compression Therapy 

One fair quality RCT followed 54 patients over 26 weeks comparing intermittent pneumatic 

compression (IPC) therapy to compression bandaging (Unna’s boot).69 Ulcer location was not 

reported and the trial did not include a run-in period. The mean age of the participants was 57 

years; 46% were male. Mean ulcer area was 9.9 cm2 and mean ulcer duration was 44 weeks. 

Patients with an ABI of less than 0.9 were excluded; no information was provided about infection 

status or antibiotic use. The study reported no significant differences between treatment arms 

in ulcer size or ulcer duration but there were gender differences. In addition to IPC treatment 

(HRx, Kendall Healthcare Products Co., Mansfield MA) twice a day for 3 hours total, patients in 

the IPC group wore a HomeRx Therapeutic (Kendall) below-knee gradient compression elastic 

stocking. It was reported that 93% complied with therapy. Demographic and ulcer characteristics 

are reported in Appendix D, Table 1. 

Primary Outcomes (Appendix D, Table 2)

There was no significant difference between IPC therapy and Unna’s boot in percentage of 

ulcers healed (71% versus 60%, p=ns).69 It was noted that 100% of ulcers less than 3 cm2 healed 

regardless of the treatment group.

Secondary Outcomes (Appendix D, Tables 3, 4, and 5)

Pain ratings on a visual analog scale (VAS) did not differ between intermittent pneumatic 

compression and compression bandaging.69 There were no significant differences between 

treatment groups in the percentage of withdrawals due to adverse events or the percentage of 

patients having an allergic reaction to treatment.
69

Advanced Wound Care Therapies for Non-Healing Diabetic, 

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Electromagnetic Therapy

Two RCTs evaluated electromagnetic therapy (EMT) compared to sham for the treatment of 

ulcers due to venous insufficiency.70,71 Both studies included “leg” ulcers with no further detail 

on ulcer location. One study was conducted in the UK71 and one in Italy.70 Neither study included 

a run-in period with standard care. One study reported that patients with arterial occlusive 

disease were excluded. This study also prohibited standard compression therapy and monitored 

use of EMT by a clock built into the device.70 Neither study reported inclusion or exclusion 

criteria for infection. A total of 63 patients, 32 receiving EMT and 31 receiving control were 

enrolled. The overall mean age in one study was 71 years with a significant difference (p<0.05) 

in age between groups (EMT 600 Hz mean age=59; EMT 600 Hz mean age=78; control mean 

age=71).71 The mean age in the second study was 66 years and two-thirds of the patients were 

female.70 Comorbidities were not uniformly reported (see Appendix D Table 1). Information 

about ulcer size and duration is presented in Table 16 (below). In one trial, mean ulcer duration 

was significantly longer in the placebo group than in the two active treatment groups.71 Patients 

in both trials had to have had unsatisfactorily healing venous ulcers of at least 4 weeks duration. 

The aggregate study quality of the included trials was fair. Funding for one study was provided 

by industry;71 the funding source for the second trial was not reported.70

EMT in one trial was applied with a single pulse of electrical current generating a magnetic field 

of 2.8 micro Teslas (mT) at a frequency of 75 Hz with an impulse width of 1.3 ms over 3 to 4 

hours a day up to 90 days or until the ulcer healed.70 No compression therapy was administered 

during the study. In the second trial, there were two treatment arms of EMT, 600 Hz and a 

magnetic field of 25 mT, and 800 Hz and a magnetic field of 25 mT.71 Treatments were delivered 

5 days a week for 30 days followed by a month of observation.

Table 16. Ulcer Size, Ulcer Duration, and Definitions of Closure: Electromagnetic Therapy

Study / 

Location

Mean ulcer size, 

(range or SD)

Duration of ulcer,

(range)

Definition of 

ulcer closure

Kenkre 1996 /

UK71

EMT 600 Hz: 63 mg (6 to 269)

EMT 800 Hz: 81 mg (46 to 197)

Control: 119 mg (35 to 526)

EMT 600 Hz: 230.4 weeks (36 to 

728)

EMT 800 Hz: 418 weeks (36 to 

1368)

Control: 962.6 weeks (160 to 2548)

NR

Ieran 1990 /

Italy70

EMT: <15 cm2 4.8, >15 cm2 34.2

Control: <15 cm2

 5.0, >15 cm2

39.9

EMT: 30 months (3 to 360)

Control: 23 months (3 to 240)

Complete 

epithelialization

Primary Outcomes (Appendix D, Table 2)

Due to variations in follow-up durations the trials were not statistically pooled. Individual trial risk 

ratios are presented in Figure 11. The longer-term trial reported a statistically significant difference 

in healed ulcers in favor of EMT therapy.70 At day 90, 67% of patients in the EMT group had 

healed venous ulcers versus 32% of patients in the sham control group arm (ARD=35%, 95% CI 

5% to 65%; RR=2.11, 95% CI 1.01 to 4.42).70 At one-year following the initiation of treatment, 

16 patients (89%) in the EMT had healed ulcers compared to 8 patients (42%) in the sham control 

arm (RR=2.11, 95% CI 1.22 to 3.67). In the second trial, at 50 days from initiation of therapy, 20% 

of the patients in the combined EMT groups had healed venous ulcers compared to 22% of the 

patients in the sham control group (RR=0.90, 95% CI 0.16 to 5.13).71
70

Advanced Wound Care Therapies for Non-Healing Diabetic, 

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Figure 11. Proportion of ulcers healed – Electromagnetic Therapy versus Sham

Study or Subgroup

2.1.1 EMT versus sham (90 days)

Ieran 1990

2.1.2 EMT versus sham (50 days)

Kenkre 1996

Events

12

2

Total

18

10

Events

6

2

Total

19

9

M-H, Random, 95% CI

2.11 [1.01, 4.42]

0.90 [0.16, 5.13]

EMT Control Risk Ratio Risk Ratio

M-H, Random, 95% CI

0.2 0.5 1 2 5

Favors EMT Favors control

One trial reported average times to healing of 76 days in the EMT group and 71 days in the sham 

control group but the significance of this difference was not reported.70 Effectiveness of treatment 

was also reported. Based on assessment by three physicians blinded to treatment, 15 patients in 

the EMT group were rated as “excellent” (n=5), or “good” (n=10) compared to 10 patients in 

the sham control group (2 and 8, respectively). Four patients in the control group and no EMT 

patients had ulcers rated as “bad” (worsening) (p=0.02). The percentage of patients considered 

“not restricted” in activity did not differ significantly between the EMT and sham groups.70

The second trial also reported on activity level. Patients in the 800 Hz and sham control groups 

improved in their ability to walk up a flight of stairs following treatment.71 All treatment arms 

improved in walking a distance consistent with a block of houses and frequency of participating 

in social activities.

Secondary Outcomes (Appendix D, Tables 3, 4, and 5)

One study reported ulcer recurrence.70 At follow-up of one year or greater after healing, ulcers 

recurred in 4 EMT patients and 4 sham control patients. The proportion of healed ulcers after 

at least one year of follow-up from time of healing was 67% in the EMT group (12 patients) 

and 21% in the sham control group (4 patients) (RR=3.17, 95% CI 1.25 to 8.03). Both studies 

reported ulcers infected during treatment. In one study, at day 90, infected ulcers were reported 

in 3 EMT and 11 control patients.70 In the other study, no EMT patients and 2 control group 

patients had infected ulcers.71 Both studies also reported pain scores. In one study, there was 

no significant difference between the groups in the amount of pain reported at day 90.70 In the 

other study, there were significant reductions (p<0.05) in pain scores from baseline to day 30 for 

both EMT groups with a non-significant reduction in the control group. The reductions in pain 

scores in the EMT groups were significantly greater than the reduction in the control group.71

In one trial, 68% (13/19) of all patients were reported to have experienced adverse events, none 

leading to study withdrawal.71 These included moderate-to-severe headaches (2 EMT patients) 

and sensations of heat, tingling, and “needles and pins” in the limbs (3 patients in each group). 

Adverse events were not reported in the second trial but 2 of 7 patients not included in the 

analyses (both in the EMT group) were withdrawn from the study, one after suffering an allergic 

reaction to medications and one after being diagnosed with rheumatoid arthritis.70 One study 

reported no deaths;70 the second reported no deaths in the EMT group.71
71

Advanced Wound Care Therapies for Non-Healing Diabetic, 

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Hyberbaric Oxygen

We identified one small double-blinded trial evaluating HBOT for the treatment of venous leg 

ulcers.72 Patients were allocated to either HBOT or air at 2.5 ATA for 90 minutes for five days 

a week for a total of 30 treatments over 6 weeks. The authors reported 100% compliance with 

the treatment sessions. Patients also continued their pre-study treatment regimen. The trial of 16 

patients was conducted in Sweden and included eight men and eight women. Infection status at 

baseline was not reported. All patients had “normal” ABI values. The median age was 67 years 

(range 42 to 75). All patients had chronic (greater than 1 year duration), non-diabetic ulcers that 

ranged from 20.9 to 307.0 cm2

 in size in the HBOT group (8 patients) and 22.1 to 196.9 cm2

in size in the sham (air) group (8 patients). The trial satisfactorily met the four study quality 

domains and was therefore considered good quality. Study details are presented in Appendix D, 

Table 1.

Primary Outcomes (Appendix D, Table 2)

No ulcers were reported healed at post-treatment (week 6). Within 12 weeks after the posttreatment assessment (i.e., week 18), two patients (25%) in the HBOT group had healed ulcers 

and none in the sham group. Five patients were not available for evaluation at this time-point, 

three in the sham group and two in the HBOT group. Both of the healed ulcers were initially 

among the smallest, measuring less than 40 cm2 at baseline. No definition of healing was 

provided.72

Secondary Outcomes (Appendix D, Tables 3, 4, and 5)

No secondary outcomes were reported. 

Summary of Key Question 2

We identified 20 trials of nine different advanced ulcer care therapies for patients with venous 

ulcers: collagen, biological dressings, biological skin equivalents, keratinocytes, platelet-rich 

plasma, silver products, intermittent pneumatic compression therapy, electromagnetic therapy, 

and hyperbaric oxygen therapy. Sixteen of twenty studies compared an advanced therapy to 

standard therapy.

Primary Outcomes 

For collagen, platelet-rich plasma, intermittent pneumatic compression therapy, and hyperbaric 

oxygen therapy, no eligible studies reported a significant improvement in the number of ulcers 

healed. Strength of evidence was low for each of those comparisons with only one trial for each 

advanced wound care therapy (see Executive Summary Table 2). For biological dressings, we 

found low strength of evidence of improved healing compared with standard care (55% versus 

34% healed). The biological skin equivalent Apligraf significantly increased healed ulcers 

compared to compression bandaging in one trial (63% versus 49%) but the strength of evidence 

was low. In two trials, Dermagraft was not significantly better than compression bandaging. One 

trial comparing a keratinocyte product to standard care found improved healing versus standard 

care although a second trial found no difference. The pooled risk ratio was significant with 

healing in 38% versus 24% (RR=1.57, 95% CI 1.16-2.11; p=0.003). Two trials of keratinocyte 
72

Advanced Wound Care Therapies for Non-Healing Diabetic, 

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therapies found no difference in ulcer healing when compared to another advanced wound 

care therapy. Silver creams improved healing in two studies (one comparing silver cream to 

standard care and one comparing silver cream to a copper-based cream) while three studies of 

silver dressings found mixed results (significant benefit in one study of silver dressing compared 

to non-silver dressing and no differences in two studies with non-silver or alternative silver 

dressings as the comparator). Strength of evidence was low for these outcomes. Two trials of 

electromagnetic therapy found mixed results; strength of evidence was low.

Few studies reported time to ulcer healing. Two studies of the biological skin equivalent Apligraf 

found shorter time to ulcer healing as did the study comparing a keratinocyte product to standard 

care. Two other keratinocyte studies reported no significant differences in time to ulcer healing as 

did a study comparing a silver dressing to a non-silver dressing. Strength of evidence was low for 

these comparisons. Two studies of silver products reported higher global assessment outcomes 

in the silver groups; a study of electromagnetic therapy reported no difference between groups. 

Only studies of electromagnetic therapy reported patient activity levels; one finding no difference 

between treatment groups and one noting improvements pre- to post-treatment.

Secondary Outcomes 

The most commonly reported secondary outcomes were ulcers infected during treatment (8 

studies), ulcer recurrence (7 studies), and pain (9 studies). The collagen treatment study reported 

fewer ulcers infected in the collagen group. No other study reported a difference between 

treatment groups. The biological dressings study reported fewer recurring ulcers in the active 

treatment group compared to standard care. No other differences were reported. One of the EMT 

studies reported a significant reduction in pain from baseline to 30 days in patients receiving 

EMT. Other studies reporting pain found no differences between treatment groups. No studies 

reported amputation, revascularization or other surgery, time to recurrence, or need for home 

care. Two studies reported hospitalization and one reported quality of life with no difference 

between treatment arms in the studies. No significant differences were observed in all-cause 

mortality, study withdrawals due to adverse events, or allergic reactions to treatment.
73

es for Non-Healing Diabetic, 

Systematic Review Evidence-based Synthesis Program

 – Advanced Wound Care Therapies for Venous Ulcers

Outcome

Number of

Studies (n 

for Primary 

Outcome)*

Comments Strength of Evidence

Percentage of ulcers healed 1 (73) One fair quality RCT found no significant differences between treatment groups. Low Mean time to ulcer healing Outcome not reported. Insufficient

on 

Percentage of ulcers healed 1 (120)

One fair quality study found biological dressing (OASIS) more effective at 12 weeks but not 6 months versus standard care. Low

Mean time to ulcer healing Outcome not reported. Insufficient

on 

Percentage of ulcers healed 2 (44)

Data from two small trials (fair quality) found Dermagraft was not more effective than standard care. Low

Mean time to ulcer healing Outcome not reported. Insufficient

on 

Percentage of ulcers healed 1 (275)

One large fair quality trial found significant improvement with Apligraf versus standard 

compression therapy. Low

Mean time to ulcer healing Significant improvement with Apligraf versus standard compression therapy. Low

on 

Percentage of ulcers healed

2 (418)

Keratinocyte therapy was more effective than standard care (RR=1.57, 95% CI 1.16 to 2.11, I2=0%). The trials were rated fair quality. Moderate

Mean time to ulcer healing

Inconsistent results, one trial found a significant difference versus standard care and one found no difference between groups. Low

py 

Percentage of ulcers healed

1 (50)

One poor quality trial reported no differences between treatment groups. Low

Mean time to ulcer healing No difference between groups. Low

py 

Percentage of ulcers healed

1 (27)

One fair quality trial reported no differences between treatment groups. Low

Mean time to ulcer healing Outcome not reported. InsufficientPercentage of ulcers healed 1 (86) One fair quality trial reported no differences between treatment groups. Low Mean time to ulcer healing Outcome not reported. Insufficient
74

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Outcome

Number of

Studies (n 

for Primary 

Outcome)*

Comments Strength of Evidence

ilver 

Percentage of ulcers healed 3 (536)

Inconsistent results from two fair quality trials, one found a significant difference 

versus non-silver dressing and one found no difference. One fair quality trial found no difference between two silver dressing groups.

Low

Mean time to ulcer healing 2 (250) Two fair quality trials; one found no significant difference between silver and non-silver dressings; one did not report significance Low

bo, 

ard 

Percentage of ulcers healed 3 (199)

One fair quality trial found significant benefit compared to standard care; one fair and one good quality trail found no benefit compared to placebo or standard dressing Low

Mean time to ulcer healing Outcome not reported. Insufficient

tide 

Percentage of ulcers healed 1 (86)

One three-armed trial of fair quality trial found silver more effective than tri-peptide copper cream but not placebo. Low

Mean time to ulcer healing Outcome not reported. InsufficientPercentage of ulcers healed 1 (53) One fair quality trial found no significant difference between groups. Low Mean time to ulcer healing Outcome not reported. InsufficientPercentage of ulcers healed 2 (56) Inconsistent results between trials. Study quality was fair. LowMean time to ulcer healing 1 (37) Comparable between groups. LowPercentage of ulcers healed

1 (16)

One good quality trial found no significant difference between groups. Low

Mean time to ulcer healing Outcome not reported. Insufficient

ary outcome.

 grades: (1) high strength indicates further research is very unlikely to change the confidence in the estimate of effect, meaning that the evidence reflects the true 

ther research may change our confidence in the estimate of effect and may change the estimate; (3) low strength indicates further research is very likely to have 

 the estimate of effect and is likely to change the estimate, meaning there is low confidence that the evidence reflects the true effect; and (4) insufficient, indicating 

not permit a conclusion.
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Advanced Wound Care Therapies for Non-Healing Diabetic, 

Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

KEY QUESTION #3. What are the efficacy and harms of therapies 

for arterial ulcers? Is efficacy dependent on ancillary therapies? 

Does efficacy differ according to patient demographics, comorbid 

conditions, treatment compliance, or activity level?

Overview of Studies

We identified one trial of advanced wound care for ulcers attributed to arterial insufficiency,73

seven trials of advance wound care for lower extremity ulcers of mixed etiology,74-80 and one trial 

of advanced wound care for amputation ulcers81,82 (Table 18). 

The study of arterial ulcers compared a biological skin equivalent to standard care. Forty-eight 

percent of the included ulcers were located on the forefoot, 7% were located on the heel, and 

45% were partial open foot amputations (transmetatarsal level).

The studies of mixed ulcer etiologies included 3 studies of biological dressings, 3 studies of 

silver products, and 1 trial of negative pressure wound therapy. The ulcers were described only 

as leg ulcers in 4 studies. One study included lower leg extremity ulcers (foot and ankle). In one 

study, 97% of the ulcers were located on the lower leg and 3% on the ankle or foot. 

The trial of amputation ulcers compared negative pressure wound therapy to standard care in 

patients with partial foot amputation wounds. 

No trials of collagen, keratinocytes, platelet-derived growth factors, platelet-rich plasma, 

pneumatic compression therapy, electromagnetic therapy, hyperbaric oxygen therapy, topical 

oxygen therapy, or ozone-oxygen therapy were identified that addressed Key Question #3.

Arterial Ulcers

Biological Skin Equivalent

We identified a single RCT of 31 patients that evaluated the use of Apligraf in arterial ulcers 

following revascularization surgery.73 This study, based in the United States, was of fair quality. 

The source of funding was not reported. The mean age of the study participants was 70 years and 

77% were male. Race/ethnicity was not reported. All study ulcers were 2.0 cm2 or larger with 

an average ulcer size of 4.8 cm2

 at baseline. Ulcer duration was not reported. Participants were 

patients with ischemic ulcers who had successfully undergone revascularization surgery (ABI 

<0.5 pre-surgery, >0.7 post-surgery) within 60 days of entering the trial. Patients were followed 

until ulcer closure or up to 6 months after randomization. A single application of Apligraf was 

used in 21 patients (10 had a meshed graft and 11 had unmeshed graft) and was compared to 

10 patients receiving twice-daily moist dressing changes (considered standard care). Additional 

study information is presented in Appendix D, Table 1.

Primary Outcomes (Appendix D, Table 2)

Statistically significant improvements in the incidence of complete ulcer healing were seen 

for the Apligraf group at weeks 8, 12, and 24. At 12 weeks, 86% of Apligraf patients and 40% 

of control patients had completely healed (p<0.01). At 6 months, complete healing occurred 
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in 100% of the Apligraf group and 75% of the controls. A significant benefit in median time 

to closure was also seen for Apligraf (7 weeks versus 15 weeks for standard care, p=0.002).73

Patients in the treatment group also received continuous Unna boot dressing changes until the 

skin equivalent graft matured (around 5 weeks, on average). As there was no internal control for 

the additional dressing, more frequent ulcer checks, and recommendation for off-loading in the 

treatment group, the effect of ancillary therapies could not be measured.
77

es for Non-Healing Diabetic, 

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es for Arterial Ulcers, Mixed Lower Extremity Ulcers, and Amputation Wounds

Product

Comparator

Healed ulcers

Mean time to ulcer 

healing

Global 

assessment 

Return to daily 

activities 

Ulcers infected 

during treatment

Amputation

Revascularization/ 

surgery

Recurrence

Time to 

Recurrence 

Pain/discomfort

Hospitalization

Required home 

care

Quality of life Withdrawals due 

to adverse events

Patients with ≥ 1 

adverse event 

All-cause mortality

Allergic reactions 

to treatment

Apligraf Standard + + - - - - -Graftjacket

Sharp debridement + Curasol gel

+ ± - -

OASIS Hyaluronic acid dressing + + - - -OASIS Standard + + - - - - -Contreet Non-silver foam dressing 

- - - -

Multiple products Cadexomer iodine dressing - - -

Standard

-

V.A.C Standard - + - - - +/- - - -V.A.C. Standard + + ↓ - - -

cal Skin Equivalent; Col – Collagen; NPWT – Negative Pressure Wound Therapy

or (p< 0.05)

ficant benefit

or
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Secondary Outcomes (Appendix D, Tables 3, 4, and 5)

Three localized, indolent ulcer infections were reported in the Apligraf group with no infections 

in the control group. The difference between groups was not significant. There was also no 

difference between treatment groups in ulcer recurrence. No differences between groups were 

reported for adverse events, withdrawals due to adverse events, or all-cause mortality.73

Studies of Mixed Ulcer Types

Collagen

One fair quality trial (n=28) compared a collagen product (Graftjacket) to standard care.74 Study 

characteristics and outcomes data are reported in Appendix D, Tables 1 to 5. The mean age of 

the patients was 64 years. Gender, ulcer size, and ulcer duration were not provided but it was 

reported that patient age and ulcer size were similar for the two treatment groups at baseline. 

Patients were required to have a palpable/audible pulse in the affected lower extremity; patients 

with infected ulcers were excluded. Standard care included off-loading but compliance was not 

reported. A significantly higher percentage of healed ulcers was found in the Graftjacket group 

compared to standard care (86% versus 29%, p=0.01). No difference was observed in mean time 

to ulcer healing. Number of ulcers infected during treatment and number of patients experiencing 

adverse events also did not differ between the collagen and standard care groups.

Biological Dressings 

Two randomized controlled trials evaluated biological dressings (OASIS) in patients with mixed 

(arterial or venous) or non-specific chronic lower-extremity ulcers.75,76 One study comparing 

a biological dressing with another advanced therapy (hyaluronic acid dressing) was of poor 

quality75 and one study comparing a biological dressing with standard care was of fair quality.76

Neither study included a run-in period with standard care or reported on compliance with therapy 

or antibiotic use. Both trials excluded patients with infected wounds and ABI less than 0.6. One 

study reported mean age (63 years);75 in both studies 48% of the patients were male. Mean ulcer 

size was 6 cm2 in one study75 and 24.4 cm2 in the other.76 Mean ulcer durations were similar (7.8 

and 7.1 weeks). The studies reported no differences between treatment arms at baseline. Study 

characteristics and outcomes data are presented in Appendix D, Tables 1 to 5.

Both studies reported a significantly higher percentage of ulcers healed by study completion for 

the biological dressing compared to either another advanced wound therapy (81% versus 46%, 

p<0.001)75 or standard care (80% versus 65%, p<0.05).76 One study reported time to complete 

ulcer healing finding a significantly shorter mean time to ulcer healing with biological dressing 

compared to standard care (5.4 weeks versus 8.3 weeks, p=0.02).76 One study reported no 

difference between a biological dressing and standard care in ulcers infected during treatment.76

Both studies reported on pain. One found a significant reduction in pain in the biological dressing 

group compared to another advanced wound therapy;75 the second reported no difference 

between biological dressing and standard care.76 No significant differences in withdrawals due to 

adverse events, patients experiencing adverse events, or all-cause mortality were observed (no 

events in either treatment group in either study).
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Silver Products

Three fair quality studies reported on the use of silver products for patients with mixed ulcer 

types. One study included 129 patients with chronic venous or mixed venous/arterial ulcers 

of at least 2 cm2 (with no decrease in area of greater than 0.5 cm in the past 4 weeks), ABI of 

0.65 or higher, and signs of infection.77 Median age was 74 years and 36% of the patients were 

male. Median ulcer size was 6.4 cm2

 and median ulcer duration was 1.1 years. Patients were 

treated with a silver-releasing foam dressing or a similar dressing without silver. The second 

study included 281 patients with venous and mixed ulcers with a diameter of 15 cm or less.78 All 

patients had clinical signs of infection and an ABI of 0.6 or higher; patients with a diagnosis of 

diabetes were excluded. Approximately 20% of the patients required antibiotics. Seventy-four 

percent of the ulcers were venous. One group received a silver-based dressing and the other 

group received an iodine-based dressing. Compression bandaging was part of the treatment for 

both groups and compliance with compression was monitored. Mean age of the participants was 

80 years with 41% male. The mean ulcer size was 705 mm2

 and mean ulcer duration was 54 

weeks. There was a significant difference in baseline ulcer size between the silver dressing group 

(597 mm2

) and the iodine dressing group (912 mm2). The third study enrolled 17 patients with at 

least 2 chronic leg ulcers.79 Patients with infection, diabetes, or arterial occlusion were excluded. 

Mean age of the participants was 55 years; other baseline characteristics were not reported. 

Two similar looking ulcers on each patient were randomly assigned to treatment with silver 

sulfadiazine cream or standard care for 6 weeks. 

The two studies reporting healed ulcers found no significant difference between a silver-releasing 

foam dressing and a similar dressing without silver (9.6% versus 8.8% at 4 weeks)77 or a silver 

dressing and an iodine dressing (64% versus 63% at 12 weeks).78 The study comparing silver and 

iodine dressings also reported no significant difference in days to healing.78 The third study did 

not report healed ulcers but did report a non-significant difference in time to healing (15 weeks 

for silver-treated ulcers, 16 weeks for standard care).79 One study looked at subgroups.78 There 

was no difference in number of ulcers healed with silver or iodine dressings for “young” ulcers 

(less than 12 weeks), “old” ulcers (more than 12 weeks), “small” ulcers (3.6 cm2

 or smaller), 

or “large” ulcers (greater than 3.6 cm2).78 Decrease in pain during the treatment period and 

quality of life were found to be similar in patients treated with silver-releasing foam dressing 

compared to non-silver foam dressing.77 Two studies reported adverse events. The percentages of 

patients with adverse events (silver dressing versus iodine dressing)78 or device-related adverse 

events(silver-releasing foam dressing versus non-silver foam dressing)77 did not differ. Additional 

information about these studies is presented in Appendix D, Tables 1 to 5.

Negative Pressure Wound Therapy

One study of NPWT compared to standard care included venous ulcers (43%), mixed venous 

and arterial ulcers (13%), and microangiopathic ulcers (43%).80 The study was of fair quality. 

Patients with infected ulcers or an ABI of less than 0.6 were excluded. The median age of 

the participants was 72 years, 23% were male, the median ulcer surface area was 38 cm2

, and 

the median ulcer duration was 7.5 months. Although not significant, mean ulcer area differed 

between groups by 10 cm2 at baseline. Patients were hospitalized for chronic leg ulcers at the 

time of enrollment and remained hospitalized until complete healing. They were mobile for 
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hygiene only. Antibiotics were allowed as needed (approximately 3.5% of patients at baseline). 

Patients in the NPWT group received treatment (125 mmHg permanent negative pressure) until 

granulation tissue covered 100% of the surface and secretion was minimal. They then underwent 

skin graft transplantation, 4 days of negative pressure therapy, and standard ulcer care until 

complete healing. The standard care group was treated with either hydrogel or alginate dressings 

and compression bandage therapy until granulation followed by skin graft transplantation and 

additional compression therapy. 

Complete healing occurred in 96% of patients in both the NPWT and standard care groups. 

The time to complete healing was shorter in the NPWT group (median of 29 days versus 45 

days in the standard care group, p=0.0001). After adjustment for ulcer area, smoking, baseline 

infection signs, history of ulcers, use of angiotensin-converting enzyme inhibitors, and use of 

anticlotting therapy, the time to healing remained significantly shorter in the NPTW group than 

in the standard care group (HR=3.2, 95% CI 1.7 to 6.2, p<0.001). Time to preparation of the 

ulcer for skin graft transplantation was also shorter in the NPTW group (median of 7 days versus 

17 days in the standard care group, p=0.005) and remained shorter after adjustment for baseline 

factors (HR=2.4, 95% CI 1.2 to 4.7, p<0.01). Ulcer recurrence was similar between the groups 

(52% NPWT, 42% standard care) but skin graft survival was significantly better in the NPWT 

group (83% versus 70%, p=0.01). Quality of life scores increased over time with no differences 

between groups. Pain scores decreased over time and at week 5 and beyond, were significantly 

lower in the NPWT group. Most ulcers in the NPWT group were healed by that point. There 

were no differences between NPWT and standard care in infection, mortality, percentage of 

patient who experienced an adverse event, or percentage of patients who reported pain as an 

adverse event. More detailed study characteristics and outcomes are presented in Appendix D, 

Tables 1 to 5.

Amputation Wounds

We identified one good quality study that compared NPWT to standard wound therapy in 

162 patients with partial diabetic foot amputation wounds.81,82 Patients with severely infected 

wounds or inadequate blood supply were excluded. Standard care included off-loading, as 

needed; compliance was not reported. The mean age of the patients was 59 years and 81% were 

male. The mean wound size was 20.7 cm2 and mean duration was 1.5 months. The percentage 

of healed wounds (56% versus 39%, p=0.04) was higher and the time to healing was shorter 

(median days: 56 versus 77, p=0.005) in the NPWT group compared to standard care. A second 

amputation was required by 3% of the NPWT group and 11% of the standard care group 

(RR=0.23, 95% CI 0.05 to 1.1, p=0.06). Adverse events were reported for 52% of the NPWT 

group and 54% of the standard care group (p=0.88) with infections most common (17% in the 

NPWT group, 6% in the standard care group, p=0.04).81 An analysis of resource utilization 

among patients in the study who were treated for a minimum of 8 weeks (n=135) found similar 

hospital stays with means of 10.6 and 9.9 inpatient days in the NPWT and standard care groups, 

respectively. The overall number of procedures performed (e.g., debridement, dressing changes, 

grafts) was significantly higher in the standard care group (mean of 120 procedures versus 43 in 

the NPWT group, p<0.001). There were also significantly more outpatient visits in the standard 

care group (mean of 11 visits versus 4 in the NPWT group, p<0.05).82 Appendix D, Tables 1 to 5 

contain more details about the study.
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Advanced Wound Care Therapies for Non-Healing Diabetic, 

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Summary of Key Question 3

For arterial ulcers, one small, fair quality study found that a biological skin equivalent, may 

improve the incidence and rate of complete ulcer healing when used on ischemic foot ulcers 

following revascularization surgery. Other outcomes did not differ significantly from standard 

care. The effects of ancillary therapies or baseline patient characteristics were not explored in 

the study. We found no RCTs that included any of the other therapies of interest exclusively in 

patients with arterial lower extremity ulcers.

In seven studies of mixed ulcer types, collagen and biological dressings were found to improve 

ulcer healing; silver products and negative pressure wound therapy did not. There were mixed 

results for time to ulcer healing and, overall, no differences between investigational treatment 

and control on other outcomes. The studies were of poor to fair quality.

One good quality study of ulcers associated with partial foot amputation showed a benefit of 

NPWT with respect to healed ulcers and mean time to healing. There were significantly more 

infections in the NPWT group but the incidence of other adverse events did not differ between 

the NPWT and standard care groups.
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Advanced Wound Care Therapies for Non-Healing Diabetic, 

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SUMMARY AND DISCUSSION

Chronic lower extremity ulcers are a common and serious health problem. A wide range of 

standard treatment approaches to achieve ulcer healing are used (e.g., off-loading, compression, 

leg elevation etc.) based on patient and ulcer factors and provider preferences. While many ulcers 

heal completely within several weeks, a significant portion either do not heal or increase in size, 

depth, and severity. These chronic ulcers can result in considerable clinical morbidity and health 

care costs. 

Many types of advanced wound care therapies exist but all represent considerably greater 

product costs compared to standard therapy. These costs may be justified if they result in 

improved ulcer healing, reduced morbidity, fewer lower extremity amputations, and improved 

patient functional status. In addition to the treatment selected, many potential factors contribute 

to the success or failure of the ulcer healing process including ulcer etiology; ulcer area, depth, 

duration, and location; patient comorbid conditions; and patient compliance with the treatment 

protocol. Much of the existing research on advanced wound care therapies has attempted to 

minimize the influence of many of these factors by limiting enrollment to patients with ulcers 

of a particular size, including only patients with adequate circulation, and excluding patients 

taking certain classes of medications.83,84 Furthermore, many of the trials are industry sponsored 

(55% of the studies included in our review) and the role of the sponsor is typically not stated, 

definitions of “chronic” ulcers vary widely, and few studies are of sufficient duration to assess 

whether healing is maintained.84,85

Our systematic review of randomized controlled trials found discouragingly low strength 

evidence regarding the effectiveness and comparative effectiveness of advanced wound care 

therapies for treatment of lower extremity ulcers. This was primarily due to the fact that for each 

ulcer type (diabetic, venous, or arterial) individual categories of advanced wound care therapies 

were only evaluated in a few studies, often in highly selected populations, and frequently had 

conflicting findings. Furthermore, within each category of wound care therapies several different 

types of interventions were used making it difficult to determine if results were replicable in 

other studies or generalizable to broader clinical settings. Additionally, most studies compared 

advanced wound care therapies to standard care or placebo. Therefore there is little comparative 

effectiveness research evaluating one advanced wound care therapy to another. It has been noted 

that standard care is an inappropriate comparator for studies of advanced therapy since patients 

have likely already failed standard care.86,87 For arterial ulcers we identified only a single study of 

any advanced wound care therapy (and this was compared to standard care) despite the clinical 

importance of arterial ulcers. 

However, based on the available findings we conclude that for patients with diabetic chronic 

ulcers, there is moderate strength of evidence that the biological skin equivalent Apligraf 

and negative pressure wound therapy improve healing compared to standard care. There is 

low strength evidence that advanced wound care therapies improved the percentage of ulcers 

healed compared to standard care for the following therapies: collagen (notably Graftjacket), 

the biological skin equivalent Dermagraft, platelet-derived growth factors, silver cream, and 

hyperbaric oxygen therapy but results were not uniform for any treatment group. Most beneficial 

effects were derived from single or few studies so we recommend caution regarding translating 
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Advanced Wound Care Therapies for Non-Healing Diabetic, 

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these findings of effectiveness into broader clinical application. Pooled analyses were possible 

for several therapies and demonstrated a significant improvement in ulcer healing compared to 

standard care for Apligraf (a biological skin equivalent), platelet-derived growth factors, and 

negative pressure wound therapy; no improvement was observed for Dermagraft (a biological 

skin equivalent). Few studies compared one advanced treatment to another but in those studies, 

no differences in percentage of ulcers healed were found between the two treatment arms. For 

time to ulcer healing, the pattern of findings was similar and strength of evidence was low for 

all treatment comparisons reporting that outcome. No studies reported a significant difference in 

adverse events for any treatment comparison.

Findings for venous ulcers were similar. Although some individual trials of biological dressings 

(notably OASIS), biological skin equivalents (Apligraf), keratinocytes, silver cream and 

dressing, and electromagnetic therapy noted significant benefit of the therapy in percentage of 

ulcers healed compared to standard care, overall the results for each therapy were mixed. In 

pooled analyses only keratinocytes resulted in significantly better healing compared to standard 

care. Strength of evidence was moderate for the benefit of keratinocyte therapy and low for 

the other therapies. Few studies of venous ulcers compared two advanced therapies and, where 

reported, typically found no differences. Time to ulcer healing was reported infrequently. No 

advanced wound care therapy was observed to result in an increase in adverse events.

We identified only one study of patients with arterial ulcers despite the clinical importance of 

this population. It is possible that patients with arterial disease were included in the studies of 

diabetic ulcers or venous ulcers (i.e., mixed etiology). In one study of patients with non-healing 

lower extremity ulcers or amputation wounds following a revascularization procedure, Apligraf 

increased ulcer healing and decreased time to healing compared to standard care with no 

difference in adverse events. 

For amputation wounds, one study of negative pressure wound therapy versus standard care 

found significantly better healing with no difference in adverse events.

Despite finding benefits of some therapies compared to standard care, the methodological 

quality of individual studies reviewed was predominantly fair or poor. Common factors limiting 

the quality were inadequate allocation concealment, no blinding (including no blinding of 

outcome assessment), failure to use intention-to-treat analysis methods, and failure to adequately 

describe study dropouts and withdrawals. With methodological flaws, few trials reporting, and 

heterogeneity in the comparators, study duration, and how outcomes were assessed, the overall 

strength of evidence was low. While a wide range of patients were enrolled in studies most were 

older than age 60 years, male, of white race, likely compliant with treatment protocols, and 

possessed ulcers that were relatively small as measured by surface area. However, authors rarely 

reported outcomes by patient demographic, comorbidity or ulcer characteristics. Therefore, we 

found insufficient evidence to guide clinicians and policy makers regarding whether efficacy 

differs according to patient demographics, comorbid conditions, treatment compliance, or 

activity level.
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Applicability and Cost Effectiveness

It is not well known how outcomes reported in studies of selected populations will translate to 

daily practice settings including in Veterans Health Administration facilities. There is evidence 

of good success in ulcer healing with strict adherence to off-loading for diabetic ulcers and 

compression therapy for venous ulcers.88-91 The patients enrolled in trials were likely more 

compliant than typical patients and received very close monitoring. Therefore, results from these 

studies may overestimate benefits and underestimate harms in non-study populations.

Our review was limited to studies of FDA approved products. We excluded studies with wounds 

of multiple etiologies (e.g., vascular, pressure, trauma, surgery) if they did not report results by 

etiology. We also excluded studies if they did not report our primary outcomes of healed wounds 

or time to complete healing. Many studies report change in ulcer size but the clinical benefit of 

change in ulcer size has not been established.92

Furthermore, we did not conduct cost effectiveness analyses or assess additional costs of care 

associated with chronic ulcers. Despite the high costs of advanced wound care therapies it is 

possible that they may be cost effective or even cost saving if found to improve ulcer healing; 

reduce ulcer associated morbidity, hospitalizations, medical care and amputations; and improve 

functional status and quality of life. Based on our findings from randomized controlled trials 

the decision of if, when, and in whom to use advanced wound care therapies as well as the type 

of advanced wound care therapy selected is difficult. Additionally, because little comparative 

effectiveness research exists to guide choices, decisions may be based on other factors including 

wound care product cost, ease of use, and patient and provider preferences (the latter also 

influenced by personal experience with ulcer and patient characteristics).

RECOMMENDATIONS FOR FUTURE RESEARCH

Our review highlights several much needed areas for future research. Most studies compared 

an advanced therapy to either standard ulcer care or placebo treatment. Few studies (10 of the 

35 eligible studies of diabetic ulcers, 4 of the 20 eligible studies of venous ulcers, and none for 

arterial or mixed ulcers) directly compared two advanced therapies. Furthermore, few studies 

provided a run-in period with carefully monitored standard care to exclude patients for whom 

carefully monitored standard care would obviate the need for advanced therapy. Therefore, 

additional randomized trials of advanced wound care therapies versus standard care are needed to 

replicate or refute current findings. Comparative effectiveness research is also needed to evaluate 

the relative benefits and harms of different advanced wound care therapies. In both effectiveness 

and comparative effectiveness research, the sample sizes should be adequate to report specific 

outcome reporting according to key patient and ulcer characteristics including age, race, gender, 

and ulcer size, location, and depth. We note below the limitations of the existing research by type 

of ulcer and therapy assessed.

Of the studies of diabetic ulcers included in this review, only two focused on biological dressings 

(using different products) and two on platelet-rich plasma. We identified no studies of topical 

oxygen or electromagnetic therapy. No studies reported on return to daily activities or the 

need for home care related to ulcer treatment and only one study reported quality of life or 
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Advanced Wound Care Therapies for Non-Healing Diabetic, 

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hospitalization. The need for amputation or revascularization and the incidence of and time to 

ulcer recurrence require further investigation. The majority of studies described the ulcers as 

diabetic foot ulcers with only six providing greater detail about ulcer location. Future research 

should report healing by ulcer location. Future research should also examine microvascular 

disease to more clearly distinguish diabetic ulcers from arterial ulcers.

For venous ulcers, we identified only one study of the following advanced wound care therapies: 

collagen, biological dressings, platelet rich plasma, intermittent pneumatic compression, and 

hyperbaric oxygen therapy. There were no studies of platelet-derived growth factors or typical 

oxygen. We found no studies that reported on amputations, time to ulcer recurrence, or need 

for home health care related to the ulcer. One study reported hospitalization, one study reported 

quality of life, and two studies reported return to work or daily activities. 

We identified only one study of patients with arterial disease requiring advanced wound care 

following revascularization. Only this study and one other included patients with partial foot 

amputations with delayed healing. Neither of these studies reported on return to daily activities, 

pain, quality of life, or need for home health assistance related to the wound. There is a paucity 

of research on advanced wound care therapies in patients with strictly arterial disease.

In addition to specific topics needing further research, several organizations have outlined overall 

methodological standards for future research of wound healing therapies (see Appendix E). 

The standards focus on study design, patient population, comparators, outcomes and outcome 

assessment, and potential sources of bias. Randomized trials, with allocation concealment 

and, at a minimum, blinding of third-party outcomes assessors, are recommended. The patient 

population should be appropriate for the treatment being studied and exclusion criteria should 

be minimal to enhance generalizability. Endpoints should be selected based on the purpose of 

the intervention (i.e., closure versus preparation for surgery) and adequate follow-up should be 

included to confirm healing. Dropouts and study withdrawals should be documented, including 

withdrawals due to ulcer deterioration. Additional research, conducted in accordance with the 

standards, is needed to establish the safety and efficacy of advanced wound care therapies. 

Finally, future research is needed to determine the effectiveness, comparative effectiveness 

and harms of advanced wound care therapies as used in general clinical practice settings (e.g., 

vascular and dermatology clinics) where patients may have more severe and larger ulcers, greater 

comorbidities, or increased difficulty with treatment compliance.
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