Department of Veterans Affairs 

Health Services Research & Development Service Evidence-based Synthesis Program 

November 2012 

Advanced Wound Care Therapies for 

Non-Healing Diabetic, Venous, and 

Arterial Ulcers: A Systematic Review 

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 

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, 

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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, 

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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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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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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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EXECUTIVE SUMMARY
 

BACKGROUND 

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. The incidence 

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

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

represent a substantial financial burden to the health care system. 

Lower extremity ulcers, especially those attributed to either diabetes, venous disease, or arterial 

disease comprise a substantial proportion of chronic 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. Healing is complicated by diabetic 

neuropathy and susceptibility to infection. Venous disease accounts for the majority of chronic 

lower extremity ulcers. Venous hypertension secondary to various cuases results in damage to 

vessel walls and ultimately leads to skin breakdown. Arterial ulcers are less common and are a 

result of impaired circulation which can affect healing lead to ulceration. 

Standard treatment for diabetic ulcers includes debridement of necrotic tissue, infection control, 

local ulcer care, mechanical off-loading, management of blood glucose levels, and education 

on foot care. For venous ulcers, standard treatment typically includes the use of mechanical 

compression and limb elevation to reverse tissue edema and improve venous blood flow. Care for 

ulcers caused by arterial insufficiency is centered on reestablishing blood flow and minimizing 

further loss of tissue perfusion. 

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

these are often termed “advanced wound care therapies.” Lower extremity ulcers are frequently 

classified etiologically as diabetic, venous or arterial, though overlap may exist. Treatment 

modalities and wound care therapies are often selected based on the ulcer characteristics as well 

as patient factors, past treatment, and provider preference. 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. 

The purpose of this review is to synthesize the evidence on therapies for non-healing diabetic, 

venous, and arterial lower extremity ulcers. This work was nominated by Rajiv Jain, MD (Chief 

Consultant, Office of Patient Care Services) and Jeffrey Robbins, DPM (Director, Podiatry 

Service) and is intended to provide an evidence base to guide clinical practice and policy needs 

within the VA. We recognize that a non-healing ulcer is likely a result of multiple factors and 

comorbid conditions. We group studies in the review according to the study authors’ description 

of the included ulcer type. The review focuses on FDA-approved therapies and examines 

clinically relevant outcomes. We address the following key questions: 

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? 
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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? 

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? 

Advanced wound care therapies included in this review are: collagen, biological dressings, 

biological skin equivalents, keratinocytes, platelet-derived growth factor, platelet-rich plasma, 

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

electromagnetic therapy, hyperbaric oxygen, topical oxygen, and ozone oxygen. We included 

studies that compared these therapies to standard care (as defined above) as well as to other 

advanced therapies. We recognize that collagen may be used as a vehicle for the delivery of 

other therapies (e.g., growth factors, silver). Under the collagen heading, we report findings from 

studies of collagen used as an inert matrix material. 

METHODS 

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

through August, 2012 using standard search terms. We limited the search to studies involving 

human subjects over age 18 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. Investigators and research 

associates trained in the critical analysis of literature assessed for relevance the abstracts of 

citations identified from literature searches. We obtained additional articles from a search of the 

Cochrane Library, existing systematic reviews, and reference lists of pertinent studies. 

Study, patient, ulcer and treatment characteristics, primary and secondary outcomes, and 

adverse events were extracted by trained research associates under the supervision of the 

Principal Investigator. Our primary outcome was the percentage of ulcers healed at study 

completion. Additional “primary outcomes” included time to complete ulcer healing, patient 

global assessment, and return to daily activities. Secondary outcomes included ulcer infection, 

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

discomfort, hospitalization, progression to require home care, quality of life, all-cause mortality, 

adverse events, and adverse reactions to treatment. Where feasible, pooled analyses were 

performed for outcomes from studies of equivalent therapies used to treat like ulcer types. We 

calculated absolute risk differences for the primary outcome of ulcers healed. All other data 

were narratively summarized. We assessed quality of individual studies according to established 

criteria for randomized controlled trials. Strength of evidence was determined for primary 

outcomes. 
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DATA SYNTHESIS 

We constructed evidence tables showing study, patient, and intervention characteristics; 

methodological quality; and outcomes, organized by ulcer type (diabetic, venous, arterial) 

and then by treatment. We analyzed studies to compare their characteristics, methods, and 

findings. We compiled a summary of findings for each ulcer type based on qualitative and 

semi-quantitative synthesis of the findings. We identified and highlighted findings from VA or 

Department of Defense (DoD) populations. 

PEER REVIEw 

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

leadership. Reviewer comments were addressed and our responses are incorporated in the final 

report. 

RESULTS 

We screened 1,230 titles and abstracts, excluded 1,053, and performed a more detailed review on 

177 articles. From these, we identified 68 articles representing 64 randomized controlled trials 

(RCTs) (35 trials involved patients with diabetic ulcers, 20 with venous ulcers, 1 with arterial 

ulcers, and 8 with mixed etiology or amputation ulcers) that addressed one of the key questions. 

Most studies compared advanced wound care therapies to standard care or placebo. Direct 

comparison of one advanced wound care therapy to another was done in 10 of 35 studies (29%) 

of diabetic ulcers, 4 of 20 studies (20%) of venous ulcers, and 2 of 9 studies (22%) of arterial 

or mixed ulcers. Overall, studies enrolled a diverse group of participants as determined by age, 

gender and race/ethnicity. The majority of enrollees were male, white, aged 60 years and older, 

and demographics did not differ markedly by ulcer type. However, studies rarely reported results 

separately by important baseline characteristics. 

In studies of diabetic ulcers, 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 ulcer size. 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 studies of venous ulcers, mean ulcer sizes ranged from 1.2 to 11.1 cm2 in 16 

studies reporting with 4 of 16 studies reporting mean ulcer sizes of greater than 10 cm2

. Ulcer 

durations ranged from 7 weeks to 626 weeks with durations of greater than 1 year in 6 of 11 

studies reporting ulcer duration. The mean ulcer size in the single study of arterial ulcers was 4.8 

cm2; ulcer duration was not reported. In the single amputation wound study, the mean ulcer size 

was 20.7 cm2 with of a mean duration of 1.5 months. 

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? 

We identified 35 eligible trials of 9 different advanced wound care therapies for diabetic ulcers. 

In 26 of these trials the ulcer was described as a “foot” ulcer, in 7 trials the ulcer was described as 
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a “lower extremity” ulcer, and in 2 trials the ulcer was described only as a “diabetic ulcer.” 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 (4 RCTs) 

Four RCTs (n=489 randomized) reported outcomes of interest. All were rated as fair quality. 

One study (n=86) found collagen (Graftjacket) to significantly improve ulcer healing compared 

to standard care (70% healed in the biological dressing group, 46% in the standard care group; 

ARD=23%, 95% CI 3% to 44%). This difference was maintained after adjusting for baseline 

ulcer size. Three trials found no significant difference between collagen matrix products and 

standard care in the percentage of ulcers healed (differences of 9% to 14% between groups). No 

study found collagen to improve time to complete ulcer healing at study completion (3 studies 

reporting, differences of 0.4, 1.1, and 1.2 weeks). Two studies reported no significant difference 

between collagen treatment and standard care for ulcers infected during treatment. No differences 

were observed in withdrawals due to adverse events (3 studies, 7% overall, 6% versus 0%, and 

6% versus 5%) or all-cause mortality (two studies, 1.4% versus 4.3% and 0% overall). One study 

reported no difference between groups in amputation or need for revascularization surgery. 

Biological Dressings (2 RCTs) 

Two studies (n=124 randomized), both multisite RCTs, were identified. Both studies, one of 

which was a non-inferiority study, showed no difference between a biological dressing and other 

advanced wound care therapies. Neither study found a difference in mean time to healing and no 

statistical differences were seen between biological dressings and PDGF in the type or number 

of adverse events. Only one study reported on the possible effect of patient characteristics on 

efficacy. Results from an a priori subgroup analysis indicated that the biological dressing did not 

improve healing (p=0.14) of plantar surface ulcers more than the advanced therapy comparator 

(PDGF). A second subgroup analysis found that biological dressing significantly healed more 

ulcers in patients with type 2 (p=0.03) but not type 1 diabetes. 

Biological Skin Equivalents (7 RCTs) 

In three fair quality studies (n=576 randomized), Dermagraft statistically significantly improved 

ulcer healing compared to standard care in two of the trials (30% versus 18% in one study, 50% 

versus 8% in the other), one of which also reported a significant faster time to closure. The third 

trial found significant differences in ulcer healing only in patients receiving metabolically active 

Dermagraft. In this older trial, some Dermagraft samples had a level of metabolic activity outside 

of the therapeutic range. All of the trials allowed for up to 8 pieces of Dermagraft. A pooled 

analysis showed an overall non-significant benefit of Dermagraft compared to standard care 

for ulcer healing (RR=1.49, 95% CI 0.96 to 2.32, I2

=43%). A fourth study, a small trial (n=26) 

of poor quality, allowed for up to 3 grafts and found no difference in ulcer healing between 

Dermagraft and a biological dressing. Two fair quality studies (n=359 randomized) compared 

Apligraf to standard care and showed significant benefits in ulcer healing (55% versus 34%; 

ARD=21%, 95% CI 9% to 32%; RR=1.58, 95% CI 1.20 to 2.08, I2=0%). One trial allowed up 
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to 5 treatments over 5 weeks while the other allowed up to 3 treatments over 8 weeks. A small 

(n=29 ulcers), poor-quality study compared up to 5 Apligraf treatments to cryopreserved splitthickness skin allograft and showed patients benefited from both therapies, although a larger 

percentage of ulcers healed with the allograft. No statistical analyses were provided. 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 HbA1

c were significantly 

associated with time to closure. In another study, an interim analysis showed a relationship 

between ulcer duration and healing and therefore the analysis focused on ulcers of greater than 

6 weeks duration. This study also reported outcomes based on ulcer location. Although both 

analyses resulted in non-significant differences, 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). 

Four studies found no difference in recurrence between either Dermagraft or Apligraf and 

standard care. One study reported fewer amputations in the Apligraf group compared to standard 

care; a second study reported no difference. Overall, the number of adverse events was low with 

no differences between treatment groups. 

Platelet-Derived Wound Healing (Platelet-Derived Growth Factors [PDGF]) (9 RCTs) 

Nine RCTs (n=990 randomized) compared PDGF to placebo gel or standard ulcer care (n=6), 

an advanced wound care therapy (n=2), or both (n=1). Two studies were of poor quality, five 

were of fair quality, and two were of good quality. Compared to standard care (7 trials), PDGF 

demonstrated a greater percentage of healed ulcers at study completion, although there was 

evidence of substantial heterogeneity (58% versus 37%; ARD=21%, 95% CI 14% to 29%; 

RR=1.45, 95% CI 1.03 to 2.05, I2

=85%). In five studies reporting, time to ulcer healing was 

significantly shorter in the PDGF treated groups in four studies (29 to 41 days; p≤0.01) with 

one study reporting no difference. However, when compared to silver sulfadiazine, sodium 

carboxymethylcellulose gel, or biological dressing there was no significant difference in 

percentage of ulcers healed or time to healing. Several 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. 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). No studies reported significant differences between 

treatment arms for secondary outcomes or adverse events. 

Platelet-Rich Plasma (PRP) (2 RCTs) 

One poor quality and one fair quality study (n=96 randomized) evaluated the efficacy of PRP 

compared to placebo or another advance wound therapy (platelet poor plasma, PPP). PRP 

was applied twice per week for up to 12 weeks in one study and up to 20 weeks in the other 

study. Neither study demonstrated a significant effect on the percentage of ulcers healed (PRP 

compared to placebo: 33% versus 28% healed; PRP compared to PPP: 100% versus 75% healed). 

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

weeks versus 17.0 weeks, p<0.005) and the other showed no significant difference between PRP 

and placebo (43 days versus 47 days). One study reported on secondary outcomes of interest and 

adverse events with no difference between PRP and placebo. 
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Silver Products (4 RCTs) 

We identified four fair quality RCTs (n=280 randomized) of silver products; three were versus 

another advanced wound care product. Three studies reported healed ulcers with mixed results. 

In one study (n=66), ulcers treated with silver ointment were more likely to heal than those 

treated with standard care (39% versus 16%; ARD=23%, 95% CI 2% to 43%); in the other 2 

studies, there was no difference in healing between silver products (dressing or cream) versus 

oak bark extract or a calcium-based dressing. There were no differences between silver dressing 

and calcium dressing or silver cream and poly-herbal cream for time to ulcer healing. No 

differences between silver dressing or creams and either standard care or other advanced wound 

care therapies were observed for our secondary outcomes and adverse events of interest. 

Negative Pressure Wound Therapy (NPWT) (3 RCTs) 

Three RCTs (n=418 randomized) compared NPWT to standard care. One study was of good 

quality, one appeared to be of moderate quality but reporting was limited, one was a small pilot 

study. Only the good quality study (n=335 with primary outcome) reported on the percentage 

of healed ulcers finding improved healing in the NPWT group compared to standard care of 

advanced moist wound therapy (43% versus 29%; ARD=14%, 95% CI 4% to 24%). All three 

studies reported on the time to healing and found mixed results. In the good quality study, NPWT 

reduced second amputations compared to advanced moist wound therapy (4.1% versus 10.2%, 

p=0.04). The moderate quality study reported a significant positive effect of NPWT on mental 

and physical health compared to standard care. No differences in adverse events were observed 

in any study although reporting was sparse. 

Hyperbaric Oxygen Therapy (HBOT) (5 RCTs) 

Five RCTs of fair quality, enrolling a total of 326 subjects, met inclusion criteria. Four studies 

(n=240) compared HBOT to standard or sham therapy. The findings could not be pooled due 

to variations in follow-up duration. Three studies with at least one year of follow-up reported 

a significantly higher percentage of ulcers healed (using Fisher’s exact test) among patients 

allocated to adjunctive HBOT (range 52% to 66%) than sham therapy or standard care (range 0% 

to 29%). In one of the studies, 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 16% of patients in the HBOT group. A short-term trial found that, within 2 weeks 

of therapy, 2 of 14 patients had complete healing versus none of the 13 patients in the standard 

care control group; the difference was not significant. None of the studies reported mean time to 

healing. Two studies reported no difference in amputations required between HBOT and sham 

therapy; one study reported fewer amputations in the HBOT group compared to the standard 

therapy group. Adverse events were similar between the HBOT and standard care/sham groups. 

HBOT resulted in significantly less healing (25% versus 55%, p=0.008) than extracorporeal 

shock wave therapy (EST) in one poor quality study. 

Ozone-Oxygen Therapy (1 RCT) 

One RCT of fair quality (n=61 randomized) compared ozone-oxygen therapy to sham treatments 

and found no significant difference between groups in the proportion of patients with completely 
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healed ulcers (41% versus 34%, p=0.34). 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. 

Summary 

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%, 

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. 
8 

Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

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. 
9 

es for Non-Healing Diabetic, 

Systematic Review Evidence-based Synthesis Program

trength of Evidence - Advanced Wound Care Therapies for Diabetic Ulcers 

s) 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 

py 

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. Low Percentage 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 

py 

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 

rd care 

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 

py 

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. Low 

asma 

Percentage 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 
10 

es for Non-Healing Diabetic, 

Systematic Review Evidence-based Synthesis Program

s) Outcome 

Number of 

Studies (n 

for Primary 

Outcome)* 

Comments Strength of Evidence 

r 

y 

m

oak 

yherbal 

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 

t wound 

auze) 

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 care 

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 

py 

apy) 

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. 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. 
11 

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? 

We identified 20 eligible trials of 9 different advanced wound care therapies for venous ulcers. In 

14 trials the ulcer was described as a “leg” ulcer, in 2 trials the ulcer was described as a “lower 

extremity” ulcer, and 3 trials did not report the ulcer location describing the ulcer only as a 

“venous ulcer.” In 12 trials a diagnosis of venous ulcers 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 (1 RCT) 

One fair quality small RCT (n=73 randomized) compared collagen to standard care. No 

significant differences were found between collagen and standard ulcer care for the percentage of 

ulcers healed by study completion (49% versus 33%, p=0.18; ARD=16%, 95% CI -7% to 38%) 

though the confidence interval was wide and cannot exclude a clinically meaningful difference. 

Fewer ulcers were infected during treatment in the collagen group. There were no significant 

differences between collagen and standard care for pain, the number of withdrawals due to 

adverse events, or allergic reaction to treatment. The effects of ancillary therapies or patient 

factors on outcomes were not reported. 

Biological Dressings (1 RCT) 

We identified one multisite RCT enrolling 120 patients. This fair quality study found that 

biological dressing, OASIS Wound Matrix, increased complete ulcer healing at 12 weeks 

compared to standard care (55% versus 34%; ARD=20%, 95% CI 3% to 38%). The benefit of 

the biological dressing was significantly increased in patients who received ulcer debridement 

at baseline. At 6 months follow-up, recurrence was significantly less frequent in the biological 

dressing group than in the standard care group (0% versus 30%, p=0.03). No statistically 

significant differences were seen in adverse events between groups. 

Biological Skin Equivalents (3 RCTs) 

We identified three trials, all of fair quality (total n=380) and all comparing a biological skin 

equivalent to standard care with compression bandage. Two trials evaluated Dermagraft and one 

evaluated Apligraf. Both studies of Dermagraft were small in size and did not reach statistical 

significance for our primary efficacy outcomes when compared to standard care including 

compression bandages. The Apligraf study was a large (n=309), multicenter trial that found 

significant increases in the proportion of completely healed ulcers (63% versus 49%; ARD=14%, 

95% CI 3% to 26%; p=0.02) and reduction in the time to complete healing (61 days versus 181 

days, p=0.003) when compared to standard compression bandage therapy. Of the two studies 

reporting on adverse events, no significant differences were seen between treatment and control 

groups. One study reported subgroup analyses. In ulcers of more than 6 months duration, Apligraf 

resulted in faster healing than standard compression bandage therapy (p=0.001). A similar result 

was observed for patients with ulcers reaching muscle tissue (p=0.003). For both large ulcers 

(>1000mm2

; p=0.02) and small ulcers (<1000mm2; p=0.04), Apligraf resulted in faster healing. 
12 

Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

Keratinocytes (4 RCTs) 

Four RCTs were identified (n=502 randomized). 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. One large, fair quality trial demonstrated significant 

improvements in both proportion of ulcers healed (38% versus 22%, p=0.01) and 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 care. In the other studies, no statistical 

differences in ulcer healing were seen when cryopreserved, cultured epidermal allografts (CEA) 

were compared with standard compression therapy (fair quality study), cryopreserved CEA 

were compared to lyophilized CEA (poor quality study), and when lyophilized keratinocytes 

were compared to standard care in a large, fair quality, multinational study. Pooled results from 

the two studies with standard care as the comparator yielded a significant benefit of treatment 

with keratinocytes (38% versus 24%; ARD=14%, 95% CI 5% to 23%; RR=1.57, 95% CI 1.16 

to 2.11, I2=0%). One study reported recurrence with no different between keratinocyte therapy 

and standard care. Only the two large studies reported adverse events; one demonstrated similar 

type and frequency of events compared to standard care, and the other reported a total of 9 minor 

adverse events that were deemed at least “possibly” related to treatment over the 6 month study. 

In one study, subgroup analyses found the benefit of keratinocytes in achieving ulcer closure 

was more pronounced in patients with larger ulcers (>10 cm2) at baseline (25.5% versus 7.7%, 

p=0.03). Ulcer duration (greater than 12 months versus less than 12 months) did not influence 

outcomes. A second study found that the likelihood of healing was higher in small ulcers 

(p<0.001), ulcers decreasing in size between screening and baseline visits (p=0.001), and ulcers 

in patients with a higher BMI (p=0.02). 

Platelet Rich Plasma (PRP) (1 RCT) 

One fair quality study (enrolling 86 patients) found no difference between platelet lysate (applied 

twice per week for up to 9 months) and standard care regarding the percentage of ulcers healed 

at study completion (79% versus 77%). When the effects of ulcer area, ulcer duration, gender, 

and ulcer history were analyzed, only ulcer size was a significant factor in time to heal. No other 

outcomes or harms of interest were reported. 

Silver Products (6 RCTs) 

Six studies (n=771 randomized) reported on the use of silver products. One good quality 

study and one fair quality study compared silver cream/ointment to standard care. One fair 

quality study compared silver cream to copper cream or to placebo copper cream. Overall, no 

statistically significant difference in ulcer healing was observed with silver therapy (range 21% 

to 63%) versus standard care or placebo (range 3% to 80%) with evidence of large heterogeneity 

(RR=1.65, 95% CI 0.54 to 5.03, I2

=84%). Compared to the copper-based cream, the silverbased cream significantly improved healed ulcers (21% versus 0%, p=0.01 with Fisher’s exact 

test). Results were mixed for two studies, both fair quality, that compared a silver dressing to a 

similar non-silver dressing. One of the trials (n=42) found a higher rate of healing in the silver 

dressing group compared to the control dressing at 9 weeks (81% versus 48%; ARD=33%, 95% 
13 

Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

CI 6% to 61%); a larger trial (n=204) found no difference (60% versus 57%). One study (n=281) 

comparing two silver dressings also found no difference (17% vs. 15%). Pooled data from two 

studies of silver versus non-silver dressings show a non-significant outcome and evidence of 

heterogeneity (RR=1.27, 95% CI 0.80 to 2.01, I2

=67%). Two studies, of fair quality, reported 

time to ulcer healing when a silver dressing was compared to a non-silver dressing. One found 

no significant difference; one did not report significance. No differences were observed between 

silver-based therapies and other treatments or standard care for other outcomes or adverse events. 

In one study, female gender (p=0.01), and smaller ulcer size (up to 3 cm diameter, p=0.008) were 

significantly related to ulcer healing. In another study, a significant difference in healing between 

treatment and control was observed for shallow ulcers (p=0.04) but not for deep ulcers (p=0.29) 

Intermittent Pneumatic Compression Therapy (1 RCT) 

One fair quality RCT (n=54 randomized) compared intermittent pneumatic compression (IPC) 

therapy to compression bandaging (Unna’s boot). There was no significant difference between 

IPC and Unna’s boot in the percentage of ulcers healed by study completion (71% versus 60%) 

or pain/discomfort. There were no significant differences between the number of withdrawals 

due to adverse events or allergic reactions to treatment. An analysis of ulcer healing by ulcer size 

found that 100% of ulcers less than 3 cm2

 were healed regardless of treatment group. 

Electromagnetic Therapy (EMT) (2 RCTs) 

Two fair quality trials of EMT versus sham treatment (n=63 randomized ) produced mixed 

results for percentage of ulcers healed. One trial (n=37) reported a significant increase in the 

percentage of healed ulcers compared to sham after 90 days (67% versus 32%; ARD=35%, 

95% CI 5% to 65%). The other trial (n=19) reported no significant difference after 50 days 

(20% versus 22%). One study also reported lower pain in the EMT group. No other outcomes or 

adverse events differed between groups. 

Hyperbaric Oxygen Therapy (HBOT) (1 RCT) 

One small (n=16 randomized) good quality RCT comparing HBOT to sham found no difference 

between groups. No other outcomes were reported. 

Summary 

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 
14 

Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

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 

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. 
15 

es for Non-Healing Diabetic, 

Systematic Review Evidence-based Synthesis Program

trength of Evidence - Advanced Wound Care Therapies for Venous Ulcers 

s) 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 

ith 

ndage 

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 

ith 

ndage 

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 

ith 

ndage 

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 

ith 

ndage 

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. Insufficient 

Percentage 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 
16 

es for Non-Healing Diabetic, 

Systematic Review Evidence-based Synthesis Program

s) Outcome 

Number of 

Studies (n 

for Primary 

Outcome)* 

Comments 

Strength 

of 

Evidence 

ver 

ilver vs. 

er) 

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 

o, 

essing, 

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 

ide 

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. Insufficient 

ssing 

Percentage of ulcers healed 

1 (53) 

One fair quality trial found no significant difference between groups. Low 

Mean time to ulcer healing Outcome not reported. Insufficient 

Percentage of ulcers healed 2 (56) Inconsistent results between trials. Study quality was fair. Low 

Mean time to ulcer healing 1 (37) Comparable between groups. Low 

Percentage 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. 
17 

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? 

We identified only one small (n=31), fair quality study of advanced wound care therapies for 

patients specifically identified as having arterial ulcers. This small study suggested that biological 

skin equivalent, may improve ulcer healing when used on ischemic foot ulcers or partial open 

foot amputations following revascularization surgery. At 12 weeks, healing was reported in 86% 

of the biological skin equivalent group and 40% of the standard care control group (p<0.01). 

Median time to healing was shorter in the biological skin equivalent group (7 weeks versus 15 

weeks; p=0.002). Other outcomes did not differ significantly from standard care. The mean age 

of patients was 70 years and 75% of enrollees were men. Race/ethnicity data were not reported. 

Authors did not report on the effect of baseline patient characteristics, treatment compliance, or 

activity level on ulcer healing. 

In studies of mixed ulcer types, a collagen matrix product (one fair quality study comparing 

collagen to standard care, n=24 randomized) improved ulcer healing (86% versus 29%, p=0.01). 

Improved healing was also observed in two studies of biological dressings - one fair quality 

study comparing biological dressing to standard care (n=50; 80% versus 65%, p<0.05), one 

poor quality study comparing biological dressing to another advanced wound care therapy 

(hyaluronic acid dressing, n=54; 81% versus 46%, p<0.001). Silver products (2 studies reporting, 

both fair quality and comparing a silver foam dressing to a non-silver foam dressing and a silver 

dressing to an advanced iodine-based dressing, n=410 randomized) and negative pressure wound 

therapy (1 study comparing NPWT to standard care, n=60) did not improve healing. There 

were mixed results for time to ulcer healing and, overall, no differences between investigational 

treatment and either standard care (5 studies) or another advanced care therapy (2 studies) on 

other outcomes. Only one study (of fair quality and comparing a silver dressing to an iodinebased advanced care dressing) looked at the effects of ulcer duration and ulcer size finding no 

difference in healing for ulcers of less than 12 weeks versus more than 12 weeks or ulcers of 3.6 

cm2

 or less versus greater than 3.6 cm2. 

One good quality study of wounds associated with partial foot amputation (n=162) found that 

NPWT (compared to standard care) improved wound healing (56% versus 39%, p=0.04) and 

decreased mean time to healing (56 days versus 77 days, p=0.005). There were significantly 

more infections in the NPWT group (17% versus 6%, p=0.04), but the incidence of other adverse 

events did not differ between the NPWT and standard care groups. The effects of ancillary 

therapies, baseline characteristics, activity level and compliance were not explored. 

Summary 

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. 
18 

Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

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. 

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. 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. 

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. 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. 
19 

Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

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 

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 
20 

Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

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. 

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. 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. 

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). 

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. 
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Advanced Wound Care Therapies for Non-Healing Diabetic, 

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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 

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. 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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CI 

ABBREVIATIONS TABLE
 

ABI 

ARD 

BD 

BMI 

BSE 

CMS 

Col 

EMT 

EST 

FDA 

HbA1

c 

HBOT 

IPC 

NPWT 

PAD/PVD 

PDGF 

PPP 

PRP 

RCT 

RR 

VA 

VAMC 

Ankle-Brachial Index 

Absolute Risk difference 

Biological Dressing 

Body Mass Index 

Biological Skin Equivalent 

Confidence Interval 

Centers for Medicare and Medicaid Services 

Collagen 

Electromagnetic Therapy 

Extracorporeal Shock Wave Therapy 

Food and Drug Administration 

Hemoglobin A1

c 

Hyperbaric Oxygen Therapy 

Intermittent Pneumatic Compression 

Negative Pressure Wound Therapy 

Peripheral Artery Disease or Peripheral Vascular Disease 

Platelet-derived Growth Factor 

Platelet-Poor Plasma 

Platelet Rich Plasma 

Randomized Controlled Trial 

Risk Ratio 

Veterans Affairs 

VA Medical Center 
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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. 
27 

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. 
29 

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. 
30 

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 
31 

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). 
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Advanced Wound Care Therapies for Non-Healing Diabetic, 

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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 
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* 

- - - - - -

33 
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 

34
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 

Control Treatment Risk Ratio Risk Ratio
 

Study or Subgroup Events Total Events Total weight M-H, Random, 95% CI M-H, Random, 95% CI
	

Gentzkow 1996 6 12 1 13 4.7% 6.50 [0.91, 46.43] 

Marston 2003 39 130 21 115 42.1% 1.64 [1.03, 2.62] 

Naughton 1997 42 109 40 126 53.2% 1.21 [0.86, 1.72] 

Total (95% CI) 251 254 100.0% 1.49 [0.96, 2.32] 

Total events 87 62
 

Heterogeneity: Tau2 = 0.06; Chi2 = 3.53, df = 2 (P = 0.17); I2 = 43%
 0.2 0.5 1 2 5 Test for overall effect: Z = 1.78 (P = 0.08) 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 

Apligraf Standard Care Risk Ratio Risk Ratio 

Study or Subgroup Events Total Events Total weight M-H, Random, 95% CI M-H, Random, 95% CI 

Edmonds 2009 17 33 10 38 19.2% 1.96 [1.05, 3.66] 

Veves 2001 63 112 36 96 80.8% 1.50 [1.11, 2.04] 

Total (95% CI) 145 134 100.0% 1.58 [1.20, 2.08] 

Total events 80 46
 

Heterogeneity: Tau2 = 0.00; Chi2 = 0.56, df = 1 (P = 0.45); I2 = 0%
 0.2 0.5 1 2 5 Test for overall effect: Z = 3.26 (P = 0.001) 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, 

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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 

Experimental Control Risk Ratio Risk Ratio
 

Study or Subgroup Events Total Events Total weight M-H, Random, 95% CI M-H, Random, 95% CI
	

2.1.1 Diabetic Wounds: PDGF versus Standard Care 

Agarwal 2009 9 14 3 14 6.7% 3.00 [1.02, 8.80] 

Bhansali 2009 13 13 11 11 18.5% 1.00 [0.86, 1.17] 

d'Hemecourt 1998 15 34 15 68 12.4% 2.00 [1.11, 3.59] 

Hardikar 2005 47 55 31 58 17.3% 1.60 [1.23, 2.08] 

Jaiswal 2010 15 25 18 25 15.2% 0.83 [0.56, 1.25] 

Steed 1995, 1996, 2006 29 61 14 57 13.3% 1.94 [1.14, 3.27] 

Wieman 1998 61 123 41 127 16.6% 1.54 [1.13, 2.09] 

Subtotal (95% CI) 325 360 100.0% 1.45 [1.03, 2.05] 

Total events 189 133 

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 4 7 0 5 100.0% 6.75 [0.44, 102.80] 

Subtotal (95% CI) 7 5 100.0% 6.75 [0.44, 102.80] 

Total events 4 0 

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 10 36 18 37 100.0% 0.57 [0.31, 1.06] 

Subtotal (95% CI) 36 37 100.0% 0.57 [0.31, 1.06] 

Total events 10 18 

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 15 34 25 70 100.0% 1.24 [0.76, 2.02] 

Subtotal (95% CI) 34 70 100.0% 1.24 [0.76, 2.02] 

Total events 15 25 

Heterogeneity: Not applicable 

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

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, 

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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. 
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Advanced Wound Care Therapies for Non-Healing Diabetic, 

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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. 
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Advanced Wound Care Therapies for Non-Healing Diabetic, 

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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, 

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Figure 5. Proportion of Diabetic Ulcers Healed – Silver Products 

Silver Control Risk Ratio Risk Ratio 

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] 

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, 

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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, 

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

NPwT Control Mean Difference Mean Difference 

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] 

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 
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Advanced Wound Care Therapies for Non-Healing Diabetic, 

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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 
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Advanced Wound Care Therapies for Non-Healing Diabetic, 

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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 

HBOT Control Risk Ratio Risk Ratio
 

Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI
	

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

Abidia 2003 5 8 0 8 11.00 [0.71, 170.98] 

Duzgun 2008 33 50 0 50 67.00 [4.22, 1064.23] 

Kessler 2003 2 14 0 13 4.67 [0.24, 88.96] 

Londahl 2010 25 48 12 42 1.82 [1.05, 3.16] 

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

Wang 2011 10 40 24 44 0.46 [0.25, 0.84] 

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, 

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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, 

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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. Low Percentage 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. Low Percentage 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. 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. 
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. 
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 

↓* + - - -

58 
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 

59
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 

Dermagraft Control Risk Ratio Risk Ratio
 

Study or Subgroup Events Total Events Total weight M-H, Random, 95% CI M-H, Random, 95% CI
	

Krishnamoorthy 2003 5 13 2 13 64.1% 2.50 [0.59, 10.64] 

Omar 2004 5 10 1 8 35.9% 4.00 [0.58, 27.70] 

Total (95% CI) 23 21 100.0% 2.96 [0.93, 9.44] 

Total events 10 3
 

Heterogeneity: Tau2 = 0.00; Chi2 = 0.15, df = 1 (P = 0.70); I2 = 0%
 0.05 0.2 1 5 20 Test for overall effect: Z = 1.83 (P = 0.07) 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. 
62 

Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

 

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 

Keratinocytes Standard Care Risk Ratio Risk Ratio 

Study or Subgroup Events Total Events Total weight M-H, Random, 95% CI M-H, Random, 95% CI 

Harding 2005 36 95 26 98 50.6% 1.43 [0.94, 2.17] 

Vanscheidt 2007 44 116 24 109 49.4% 1.72 [1.13, 2.63] 

Total (95% CI) 211 207 100.0% 1.57 [1.16, 2.11] 

Total events 80 50 

Heterogeneity: Tau2 = 0.00; Chi2 = 0.38, df = 1 (P = 0.54); I2 = 0% 

Test for overall effect: Z = 2.96 (P = 0.003) 0.2 

Fav

0.5 

ors Std. Care 

1 

Favors Kerat

2 

i

5 

nocytes 

*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, 

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

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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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 

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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 
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Figure 10. Proportion of Venous Ulcers Healed – Silver Products 

Silver Control Risk Ratio Risk Ratio 

Study or Subgroup Events Total Events Total weight M-H, Random, 95% CI M-H, Random, 95% CI 

3.1.1 Cream 

Belcaro 2010 19 44 8 38 38.4% 2.05 [1.02, 4.14] 

Bishop 1992 6 28 1 29 17.9% 6.21 [0.80, 48.38] 

Blair 1998 19 30 24 30 43.7% 0.79 [0.57, 1.10] 

Subtotal (95% CI) 102 97 100.0% 1.65 [0.54, 5.03] 

Total events 44 33 

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 6 28 0 29 100.0% 13.45 [0.79, 228.07] 

Subtotal (95% CI) 28 29 100.0% 13.45 [0.79, 228.07] 

Total events 6 0 

Heterogeneity: Not applicable 

Test for overall effect: Z = 1.80 (P = 0.07) 

3.1.3 Dressing 

Dimakakos 2009 17 21 10 21 39.3% 1.70 [1.04, 2.79] 

Michaels 2009 62 104 59 104 60.7% 1.05 [0.83, 1.32] 

Subtotal (95% CI) 125 125 100.0% 1.27 [0.80, 2.01] 

Total events 79 69
 

Heterogeneity: Tau2 = 0.08; Chi2 = 2.99, df = 1 (P = 0.08); I2 = 67%
 

Test for overall effect: Z = 1.01 (P = 0.31)
 

0.02 0.1 1 10 50 

Favors Control Favors Silver 

Test for subgroup differences: Chi2 = 2.71, df = 2 (P = 0.26), I2 = 26.2% 

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 
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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. 
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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 

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Figure 11. Proportion of ulcers healed – Electromagnetic Therapy versus Sham 

EMT Control Risk Ratio Risk Ratio 

Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI 

2.1.1 EMT versus sham (90 days) 

Ieran 1990 12 18 6 19 2.11 [1.01, 4.42] 

2.1.2 EMT versus sham (50 days) 

Kenkre 1996 2 10 2 9 0.90 [0.16, 5.13] 

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 

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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 

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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. Insufficient Percentage 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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Systematic Review Evidence-based Synthesis Program

 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. Insufficient Percentage of ulcers healed 1 (53) One fair quality trial found no significant difference between groups. Low Mean time to ulcer healing Outcome not reported. Insufficient Percentage of ulcers healed 2 (56) Inconsistent results between trials. Study quality was fair. Low Mean time to ulcer healing 1 (37) Comparable between groups. Low Percentage 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. 
75 

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. 
es for Non-Healing Diabetic, 

Systematic Review Evidence-based Synthesis Program

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 

77
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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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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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91.	 O’Meara S, Cullum NA, Nelson EA. Compression for venous leg ulcers. Cochrane 

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APPENDIX A. THERAPY DESCRIPTIONS AND REFERENCES 

Collagen 

The term collagen is applied to a species of chemically distinct macromolecular proteins. The 

variety of collagen structures is one reason for their diverse roles in ulcer healing. The roles 

of collagen wound products in ulcer healing may be 1) to act as a substrate for hemostasis, 2) 

chemotaxis to cellular elements of healing such as granulocytes, macrophages, and fibroblasts, 

3) to provide a scaffold for more rapid transition to mature collagen production and alignment, 

or 4) to provide a template for cellular attachment, migration, and proliferation (Purna 2000). 

FIBRACOL Collagen-Alginate wound dressing (Johnson and Johnson, New Brunswick, NJ) is 

an advanced wound care device composed of collagen and calcium alginate fibers. It received 

FDA approval in August of 1998 for topical use for burns and pressure, venous, and diabetic 

ulcers. Promogran (Johnson and Johnson) consists of 55% collagen and 45% oxidized generated 

cellulose. It was approved by the FDA in February of 2002. Promogran is an absorbent openpored, sterile, freeze-dried matrix used as a topical treatment for chronic ulcers including diabetic 

and venous ulcers. Promogran is composed of natural materials which physically bind to and 

inactivate damaging proteases while binding and protecting growth factors. (Cullen 2002). 

Biological Dressings 

This category of wound healing therapies consists of biomaterials made from various 

components of the extracellular matrix (ECM). These acellular matrices are usually derived from 

animal or cadaver sources and have undergone processing to remove and retain specific elements 

of the tissue. A commonly used biologically active dressing, the OASIS Wound Matrix (Cook 

Biotech, West Lafayette, IN), is an ECM product derived from the small intestinal submucosa 

of pigs. It received FDA 510(k) approval in 2000 and is indicated for the treatment of diabetic 

ulcers, venous ulcers, and chronic vascular ulcers, in addition to several other dermatologic 

conditions. This product retains additional active components found within the ECM, including 

many growth factors (Hodde 2001; Hodde, 2005; McDevitt, 2003) and several elements of 

ground substance (Hodde, 1996; McPherson, 1998). OASIS becomes incorporated into the ulcer 

base and is thought 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 (Hodde, 2007). Lacking a cellular component, 

these products have the benefit of a long shelf life and are relatively uncomplicated to administer. 

Biological Skin Equivalents (BSE) 

These wound-healing therapies are laboratory-derived tissue constructs, designed to resemble 

various layers of real human skin. They consist of cultured, metabolically active skin cells grown 

over a scaffold or mesh framework. Two commercially available skin equivalents with FDA 

approval for treating chronic leg ulcers are Dermagraft and Apligraf. Dermagraft (Advanced 

BioHealing, Inc., La Jolla, CA) is a dermal tissue substitute that received FDA approval in 2001 

for treating diabetic foot ulcers lasting more than 6 weeks. It is formed by culturing human 

fibroblasts from neonatal foreskin and then growing these fibroblasts over a bioabsorbable 

polyglactin scaffold. As the cells proliferate in vitro, they secrete important components of the 

extracellular matrix and a large variety of local growth factors (Naughton, 1997). The product 
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is cryopreserved for storage and delivery, but metabolic activity is regained upon thawing and 

application to the wound bed (Mansbridge, 1998). Apligraf (Organogenesis, Inc., Canton, MA) 

is a similar skin substitute made from cultured skin cells but is a bilayer construct that contains 

both dermal and epidermal components. Apligraf (formerly known as Graftskin, Human Skin 

Equivalent, and Living Skin Equivalent) received FDA approval in 1998 for chronic venous 

ulcers and in 2000 was granted further approval for use in diabetic foot ulcers. The human cells 

in both layers, fibroblasts in the dermis and keratinocytes in the epidermis, are derived from 

purified cultures of neonatal foreskin. The final metabolically active product has a limited shelf 

life since it is not cryopreserved but delivered “fresh” to sites for clinical use. Both Apligraf 

and Dermagraft are metabolically active products thought to increase healing by stimulating 

fibrovascular ingrowth and epithelialization of host tissues (Ehrenreich, 2006; Límová, 2010). 

They do not “take” like traditional skin grafts that are meant to replace lost tissue with fully 

functioning skin, but instead become incorporated into the wound bed and stimulate regrowth of 

the host’s own skin tissue (Ehrenreich, 2006; Límová, 2010; Mansbridge, 1999; Phillips, 2002). 

Keratinocytes 

Keratinocyte-based therapies for wound healing exist in a variety of forms. Use of cultured 

epidermal keratinocytes to treat chronic leg ulcers was first attempted with autologous (Hefton, 

1986; Leigh, 1986) and allogeneic (Leigh, 1987) cells in 1986 and 1987, respectively. Since 

then, different keratinocyte sources have been utilized; the patient’s own skin cells, donor cells 

from cadavers or patients undergoing cosmetic procedures, and bioengineered “immortalized” 

keratinocytes have all been used. In addition to using different cellular sources, therapies may 

vary in their use of fresh, cryopreserved, or lyophilized keratinocytes. These products differ 

in level of metabolic activity and ease of storage and transportation. Furthermore, various 

application strategies have been attempted for delivering keratinocytes onto wounds, including 

various suspension mediums (e.g., fibrin sealant), aerosolized sprays, cellular microcarriers, 

and gels. These products do not act as grafts or serve as permanent skin replacements, as they 

are rapidly replaced by the host’s own keratinocytes (Kaawach, 1991; Burt, 1989; Auböck, 

1988). They are thought to work by stimulating proliferation and migration of host epithelium 

from wound edges through the production of growth factors and other cytokines (DeLuca, 

1992; Duinslaeger, 1994; McKay, 1991). Although there have been multiple studies focusing 

on keratinocyte use in chronic ulcers, currently the only commercially available products in the 

U.S. are not indicated for use in leg ulcers. However, there are various products on the market, 

and with ongoing efforts to expand indications and the continuing research focus in this area, an 

understanding of the current literature on the topic is important in recognizing the limitations and 

future expectations of keratinocyte-based wound healing 

Platelet-derived wound Healing - Platelet-derived Growth Factors (PDGF) 

Human platelet-derived growth factor is a substance naturally produced by the body to help in 

wound healing. It works by helping to repair and replace dead skin and other tissues, attracting 

cells that repair wounds, and helping to close and heal the ulcers. (Pierce 1991). Regranex Gel 

(becaplermin 0.01%, Johnson & Johnson, New Brunswick, NJ) was approved by the FDA in 

1997 for the treatment of diabetic foot ulcers. Regranex is a genetically engineered product 

that mimics PDGF in the body. It is indicated for treating lower-extremity neuropathic ulcers 
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that extend into the subcutaneous tissue or beyond, but which have an adequate blood supply. 

It is intended for use as an adjunct to traditional ulcer care strategies, such as initial sharp 

debridement, daily dressing changes, pressure relief and treatment of infection if present (Label 

indication 1997). 

Platelet Rich Plasma 

Platelet-rich plasma (PRP) is derived from newly drawn whole blood prepared by specialized 

centrifugation to create plasma having a platelet concentration above baseline. PRPs themselves 

are have been used in wound healing since 1985 and do not require FDA approval, but 

centrifuges used to spin whole blood for the creation of PRP do require approval. PRP contains 

a high level of platelets and a full complement of clotting and growth factors which aid in 

healing by attracting undifferentiated cells and activating cell division (Lacci 2010). Autologel 

System (Cytomedix Inc) received FDA approval in September of 2007 and consists of a table top 

centrifuge (AutoloGel II Centrifuge) and blood access and processing devices. 

Silver 

The therapeutic potential of silver has long been recognized, and reports of its use in chronic 

ulcers have been documented in surgical textbooks as early as 1617 (Klasen, 2000). Due to 

the broad bactericidal action of silver (Ip, 2006) and the understanding that wound healing is 

impaired when bacterial levels surpass a particular threshold (Bowler, 2001), multiple silverbased products have been developed to aid in wound healing. These products incorporate 

silver into topical creams (silver sulfadiazine or Silvadene; King Pharmaceuticals, Bristol, 

TN) or within various types of dressings, including foams (Contreet Ag; Coloplast, Marietta, 

GA), hydrocolloids (Contreet H; Coloplast, Marietta, GA), hydrofibers (Aquacel-Ag; Covatec, 

Skillman, NJ), alginates (Silvercel; Systagenix, Quincy, MA), film polymers (Arglaes; Medline, 

Mundelein, IL), and a polyethylene mesh with nanocrystalline silver (Acticoat-7; Smith and 

Nephew, Hull, UK). These products work through the release of reactive silver cations, [Ag+

], 

which may disrupt components of the bacterial cell wall, inhibit microbial respiratory enzymes 

and elements of the electron transport chain, and impair the synthesis and function of DNA and 

RNA (Atiyeh, 2007). Although these effects are desirable when directed against bacterial and 

fungal organisms, it is important to recognize the indiscriminant action of silver. Cytotoxicity 

of various host cells, including keratinocytes and fibroblasts, has been shown to occur from 

silver, and a delicate balance exists between the beneficial decrease in bacterial burden and the 

deleterious effects on host cells that can also delay wound closure (Atiyeh, 2007; Poon, 2004; 

Hollinger, 1996) 

Intermittent Pneumatic Compression Therapy 

Intermittent pneumatic compression (IPC) therapy is delivered through inflatable, single-patientuse, garments containing one or more air chambers. Garments are applied to the foot, calf, or 

calf and thigh and intermittently inflated and deflated with air by means of a powered pneumatic 

pump to simulate the normal ambulatory calf and foot pump. This action propels the blood of the 

deep veins towards the heart and 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 (Comerota 2011). Pneumatic compression devices 
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are cleared for marketing under the FDA 510(k) process as Class II devices intended for use 

in prevention of blood pooling in a limb by periodically inflating a sleeve around the limb. No 

clinical data was needed for FDA approval since they existed prior to the passage of the Medical 

Device Amendments of 1976. 

Negative Pressure Wound Therapy (NPWT) 

NPWT, also referred to as “vacuum assisted wound closure,” is the process of creating a tightly 

sealed dressing around a wound and using a suction pump to apply a sub-atmospheric (or 

“negative”) pressure evenly across the surface in a continuous or intermittent manner (Venturi, 

2005). A drainage canister is attached to store fluid collected from wound suction. The first FDA 

approved, commercially available NPWT product was the Vacuum Assisted ClosureTM device 

(Kinetic Concepts, Inc., San Antonio, TX), introduced to the market in 1995. Since then, the 

approved indications for its use have continually expanded and currently include diabetic foot 

ulcers, venous leg ulcers, and pressure ulcers, as well as several non-ulcerative conditions. Other 

NPWT devices include the Versatile 1TM (BlueSky Medical, Carlsbad, CA), which received FDA 

approval in 2004, and the RenasysTMEZ and RenasysTMGo (Smith and Nephew Inc., Largo, FL), 

approved in 2008 and 2009, respectively. These devices are proposed to enhance wound healing 

by increasing granulation tissue and local perfusion (Morykwas, 1997), reducing tissue edema, 

decreasing bacterial load (Morykwas, 1997), and stimulating cellular proliferation via induction 

of mechanical stress (Olenius, 1993; Saxena, 2004). NPWT may be used as either a primary 

treatment to achieve complete wound healing, or as a temporary therapy to prepare a wound so 

that another treatment can be attempted to achieve complete wound closure. 

Electromagnetic Therapy (EMT) 

EMT utilizes the electrical field created between large, oppositely charged capacitors or, more 

commonly, the electrical field that develops from exposure to an oscillating magnetic field (Lee, 

1993). There are various potential mechanisms by which EMT may enhance wound healing. 

Normal human skin has been found to produce a steady state transcutaneous electrical potential 

(Foulds, 1983) that, upon epithelial disruption, short-circuits to produce an endogenous electrical 

current (Burr, 1940; Illingworth, 1980; Nuccitelli, 2003; Zhao, 2006) and a resultant electrical 

field (Nuccitelli, 2003; Zhao, 2006). This wound-induced electrical field has been shown to 

regulate cell division in wound healing (Song, 2002) and to guide the cellular migration through 

specific signaling pathways (Zhao, 2006; Fang, 1999). EMT is thought to work by mimicking or 

enhancing these natural wound-induced electrical fields. No EMT devices have received FDA 

approval for use in chronic wounds; however, these products have received approval for other 

indications and are commercially available. Despite the lack of FDA approval, the Centers for 

Medicare and Medicaid Services (CMS) has deemed EMT to be a reasonable adjuvant treatment 

for chronic ulcers of diabetic, venous, and arterial etiologies. Because of this, CMS covers the 

use of EMT for chronic ulcers not responding to standard care. 

Hyperbaric Oxygen Therapy (HBOT) 

HBOT involves the use of specialized compression chambers capable of delivering increased 

concentrations of oxygen (usually 100% O2

) under elevated atmospheric pressures (usually 1.5­

3.0 ATA). This greatly increases systemic levels of oxygen (Sheffield, 1985), achieving arterial 
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oxygen tensions upwards of 2000 mmHg (normally 100 mmHg) and tissue oxygen tensions up to 

500 mmHg (normally 55 mmHg) (Gill, 2004). Individual treatment sessions usually last between 

45 and 120 minutes and may be done once or twice a day for a total of 10-30 sessions. HBOT is 

FDA approved for a dynamic list of indications, including wound healing, as deemed appropriate 

by the Undersea and Hyperbaric Medical Society. Examples of devices include the OxyHeal 

1000 Monoplace Hyperbaric Chamber (OxyHeal Health Group, LaJolla, CA) and the Multiplace 

Hyperbaric Chambers (Makai Marine Industries, Inc., Boca Raton, FL), which received FDA 

approval in 2005 and 2004 respectively. The role oxygen plays in the process of normal wound 

healing is complex. Although hypoxia stimulates certain steps in wound healing (Knighton, 

1983; Jensen, 1986), and the low oxygen levels in the center of a wound are important in 

initiating repair (Thackham, 2008), many key aspects of wound healing are oxygen dependent 

(Gordillo, 2003). These include collagen deposition (Jonsson, 1991), angiogenesis (Hopf, 2005), 

fibroblast and endothelial cell proliferation (Tompach, 1997), and bacterial clearance (Knighton, 

1986; Allen, 1997; Hopf, 1997; Greif, 2000). By raising arterial oxygen tension and the bloodoxygen level delivered to a chronic wound (Rollins, 2006), HBOT is thought not only to supply 

a missing nutrient but also to promote the oxygen dependent steps in wound healing, to up 

regulate local growth factors (Thom, 2009), and to down regulate inhibitory cytokines (Thom, 

2009). Although thought to be a relatively safe treatment, this delivery of concentrated oxygen 

in a compression chamber can be complicated by the increased pressure (e.g. ear and sinus 

barotrauma) or oxygen toxicity (e.g. acute cerebral toxicity and chronic pulmonary toxicity) 

(Plafki 2000; Sheffield, 2003). 

Topical Oxygen Therapy (TOT) 

Similar to HBOT, this category of products aims to promote ulcer healing by correcting 

the low oxygen levels found within chronic wounds. TOT was developed in an effort to 

overcome drawbacks inherent with HBOT and works to promote wound oxygenation through 

a physiological distinct mechanism. While HBOT uses a compression chamber to systemically 

deliver high O2 levels under an elevated atmospheric pressure, TOT works by covering a wound 

with an airtight bag or chamber and using a portable device to fill the container with concentrated 

oxygen. Although this results in very slight elevations in local pressure (usually 1.004 - 1.013 

ATA), this is far less than the levels reached in HBOT (up to 2.5 - 3.0 ATA) and is not considered 

truly “hyperbaric” (Feldmeier, 2005). TOT is thought to increase local oxygen levels by simple 

diffusion of the externally applied gas into superficial wound tissues (Fries, 2005). This method 

of wound oxygenation may induce angiogenesis through upregulation of specific growth factors 

(Gordillo, 2008; Scott, 2005) and has been postulated to promote cell motility, extracellular 

matrix formation, and angiogenesis by correcting hypoxia at the wound center (Gordillo, 2003). 

Examples of these products include the Hyper-Box Topical Wound Oxygen System (Qualtech 

House, Gateway, Ireland) that received FDA approval in 2008 and EpiFlo (Ogenix, Corp., 

Beachwood, OH), most recently approved in 2012 for chronic skin ulcerations due to diabetes 

and venous stasis. Although CMS covers use of HBOT in some chronic wounds, it does not 

reimburse for TOT. 
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Ozone Oxygen Therapy 

Ozone is an oxidizing agent. When ozone molecules are administered via gas or liquid, the 

ozone is theorized to promote tissue healing. Healthy cells are reported to survive and multiply 

while defective cells, bacteria, and viruses are destroyed. Ozone has been used to treat medical 

conditions since the late 19th century, however, there is little known about its safety and efficacy. 

Ozone can be administered to chronic wounds using a technique known as ozone bagging, a 

technique in which the effected limb is sealed for up to two hours in a bag containing ozone. 

Alternatively, ozone-enriched water or vegetable oil may be applied to the skin. Opinions are 

mixed about the safety of ozone therapy. While some advocates suggest that there is a very 

low risk of side effects the fact that it is a toxic gas has caused others to question the safety. 

(Intelihealth, Natural Standard) 

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--------------------------------------------------------------------------------

5

10

15

20

25

30

APPENDIX B. SEARCH STRATEGY 

Search Strategy: 

1 exp Skin Ulcer/ (31597) 

2 exp Foot Ulcer/ (5874) 

3 exp Leg Ulcer/ (15666) 

4 exp Varicose Ulcer/ (3490) 

exp Diabetic Foot/ (4864) 

6 exp Wound Healing/ (83186) 

7 exp Venous Insufficiency/ (5352) 

8 or/1-7 (114315) 

9 limit 8 to (clinical trial, all or clinical trial, phase i or clinical trial, phase ii or clinical 

trial, phase iii or clinical trial, phase iv or clinical trial or controlled clinical trial or meta analysis 

or randomized controlled trial) (6955) 

randomized controlled trial.pt. (321315) 

11 controlled clinical trial.pt. (83663) 

12 random*.ti,ab. (545362) 

13 placebo.ti,ab. (132724) 

14 or/10-13 (736326) 

(animals not (humans and animals)).sh. (3590935) 

16 14 not 15 (659693) 

17 8 and 16 (5990) 

18 9 or 17 (8200) 

19 limit 18 to (english language and humans and yr=”1995 -Current”) (5646) [a few more 

important limits] 

artificial skin.mp. or exp Skin, Artificial/ (1844) 

21 19 and 20 (65)
 

22 biological dressings.mp. or exp Biological Dressings/ (1128)
 

23 19 and 22 (38)
 

24 exp Negative-Pressure Wound Therapy/ or exp Lower Body Negative Pressure/ or 

negative pressure.mp. (5422)
 

19 and 24 (84) 

26 exp Collagen/ or collagen.mp. (145508) 

27 19 and 26 (287) 

28 exp Silver/ or exp Silver Proteins/ or silver.mp. (37481) 

29 19 and 28 (105) 

exp Oxygen/ or topical oxygen.mp. (134274) 

31 19 and 30 (51) 

32 exp Hyperbaric Oxygenation/ or hyperbaric oxygen*.mp. (10425) 

33 19 and 32 (62) 

34 electromagnet*.mp. or exp Electromagnetic Phenomena/ (311999) 
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35 19 and 34 (55)
 

36 exp Platelet-Derived Growth Factor/ or platelet-derived.mp. or exp Growth Substances/ 

(570646)
 

37 19 and 36 (179)
 

38 exp Platelet-Rich Plasma/ or platelet-rich.mp. (5704)
 

39 19 and 38 (66)
 

40 exp Intermittent Pneumatic Compression Devices/ or pneumatic compress*.mp. or 

compress* therapy.mp. or compress* pump.mp. (1625)
 

41 19 and 40 (130)
 

42 21 or 23 or 25 or 27 or 29 or 31 or 33 or 35 or 37 or 39 or 41 (1014)
 
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APPENDIX C. PEER REVIEW COMMENTS/AUTHOR RESPONSES
 

REVIEWER COMMENT RESPONSE 

1. Are the objectives, scope, and methods for this review clearly described? 

Yes 

Yes 

Yes 

Yes 

Yes 

Yes. This report represents a monumental work effort. It is, in my judgment, the most 

comprehensive and objective review I have seen to date. The persons who prepared this 

report are to be commended for their efforts. 

Thank you. 

2. Is there any indication of bias in our synthesis of the evidence? 

Not sure that like was compared to like. I would worry about your RCT grading system if 

RCTs used for FDA approval (PDGF and synthetic skin) are graded lower than a NPWT 

study that was not really blinded. I also worry at all of your studies did not treat similar 

groups of individuals. For example, the HBO RCTs were very inconsistent with respect to the 

Wagner grade. 

We assigned grades based on established criteria for evaluating risk of bias in 

RCTs. These criteria may be different than criteria for FDA approval. 

We agree that the populations varied from study to study and attempted to clarify 

that in the description of the studies. 

No 

No 

No (reviewer provided citation for Lancet article [2012] on spray-applied cell therapy) Thank you. We reviewed this citation. The treatment is not FDA approved (this was 

a phase 2 trial) and therefore is not eligible for inclusion in our review. 

No 

No 

3. Are there any published or unpublished studies that we may have overlooked? 

Yes – total contact cast literature We did not consider total contact casting to be an “advanced wound care product.” 

Although it may be an important therapeutic option, it was not recommended by our 

topic stakeholders and is outside the scope of our review. 

No 

No 
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REVIEWER COMMENT RESPONSE 

Yes We have clarified that the studies included in the collagen section are studies of an 

Considering collagen dressings as a stand-alone category presents challenges as they are inert collagen matrix product. 

frequently used as deliver vehicles for silver, growth factors, protease inhibitors, etc. This We have reviewed the suggested references: 

should be acknowledged as a limitation. As such there may be other studies to be considered 1. This trial has been added. 

for inclusion under collagen [1-5]; apligraf [6]; and silver.[2] 2. An abstract – not eligible for inclusion (we were unable to find the data in a peer1. Blume, P., et al., Formulated collagen gel accelerates healing rate immediately after reviewed publication) 

application in patients with diabetic neuropathic foot ulcers. Wound Repair & Regeneration, 3. A case series – not eligible for inclusion 

2011. 19(3): p. 302-8. 4. This study has been mentioned in the collagen section but due to a difference 

2. Gottrup, F., et al., Collagen/ORC/silver treatment of diabetic foot ulcers; A randomised in the goal of the study and incomplete reporting is not given as much attention as 

controlled trial. Wound Repair and Regeneration, 2011. 19(2): p. A24. other trials 

3. Letendre, S., et al., Pilot trial of biovance collagen-based wound covering for diabetic 5. A “cohort” study – not eligible for inclusion 

ulcers. Advances in Skin & Wound Care, 2009. 22(4): p. 161-6. 6. This report presents data from one site of a multisite trial that is included in the 

4. Motzkau, M., et al., Expression of matrix-metalloproteases in the fluid of chronic report (Veves 2001) 

diabetic foot wounds treated with a protease absorbent dressing. Experimental & Clinical 

Endocrinology & Diabetes, 2011. 119(5): p. 286-90. 

5. Mulder, G., et al., Treatment of nonhealing diabetic foot ulcers with a platelet-derived 

growth factor gene-activated matrix (GAM501): results of a phase 1/2 trial. Wound Repair & 

Regeneration, 2009. 17(6): p. 772-9. 

6. Sams, H.H., J. Chen, and L.E. King, Graftskin treatment of difficult to heal diabetic foot 

ulcers: one center’s experience. Dermatologic Surgery, 2002. 28(8): p. 698-703 

No. To the best of my knowledge, this report appears to have reviewed all of the pertinent 

information relevant to the topics studied. 

Thank you 

4. Please write any additional suggestions or comments below. If applicable, please 

indicate the page and line numbers from the draft report. 

I am concerned that the device assessments were not as rigorous as the FDA approved We identified and discussed one HBO trial conducted in Taiwan that directly 

products. Care needs to be made in recommendations. Also you did assess that HBO was compared HBO to shockwave therapy. We did not identify any trials meeting our 

inferior to shockwave and therapy that was later shown in the US to not be superior to inclusion criteria that directly compared shockwave therapy to standard off-loading 

standard off-loading of diabetic feet. of diabetic feet. We have added a paragraph with results from strictly controlled offloading studies for comparison purposes. 

Please see my comments within the body of the paper. (Investigator NOTE: comments from 

body of paper have been added to list below) The first 18 pages of the document need major 

revisions. After page 18, the material is written in more scientific manner which it appears 

more accurate than what is presented on the first initial pages. 

a. Page 1 Please define what you mean by diabetic ulcers. Arterial and venous ulcers can 

also happen in diabetic patients. How about neuropathic ulcers? Were they studied or 

reported in this paper? 

b. Page 1 Is your paper focused only on foot ulcers? Most venous ulcers occur in the legs. 

When studying the effectiveness of a device, please be more specific on location of the 

ulcers where the product was used. 

The first 18 pages of the document are the executive summary and we attempted to 

condense a great deal of information into a more readable format. As the reviewer has 

noted, there are many important details about the studies and we have attempted to 

include the essential elements in the executive summary without simply repeating the 

full text of the report. 

a. The studies included in the section on diabetic ulcers are studies of populations 

described by the study authors as having diabetic ulcers. Diabetic ulcers are caused 

by peripheral neuropathy and/or peripheral vascular disease. The most common cause 

of neuropathic ulcers is diabetes and many of these studies included only patients with 

neuropathic ulcers. Most studies excluded patients with inadequate circulation. We 

have added that information to the report when it was provided by the study authors. 

b. The paper is not focused on foot ulcers. We have added the location of the ulcers 

(an overview in the executive summary and more information in the body of the report). 
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REVIEWER COMMENT 

c. Page 1 How about the impact of PVD and plantar pressures? I can heal a wound that is 

neuropathic or has infection as long as there is blood flow to the tissue!!!! 

d. Page 1 I am not sure the statement “venous disease accounts for the majority of chronic 

ulcers” is correct. Venous ulcers is seen mostly on non-American populations, but current 

research shows occurrence of PAD related ulcers in US population 

e. Page 1 Please define what you mean by diabetic ulcers? Are these patients who are 

diabetic with normal arterial, venous and nerve supplies? How are these patient populations 

different than those who have “arterial” ulcers or “venous ulcers? 

f. Page 3. Is this study shared with Dr. Robbins, our VA Central Office Chief of Podiatry? 

He needs to be informed on this study as this study can impact the podiatry field at the VA 

tremendously. His input on who should review this paper is important. 

g. Page 3 – overview of sizes of ulcers – Where are these ulcers? On the leg/shin area? 

Dorsal foot? Plantar foot? Each location will respond differently to different wound care 

product) 

h. Page 3 – KQ1 (diabetic ulcers) – Did all the subject studied for this question have normal 

blood flow and sensate feet? 

i. Page 4 – Collagen – Were there any beneficial effect in using collagen? Are you then telling 

the reader that using collagen on wounds is a waste of money? Is there any wound type that 

collagen can be helpful, i.e., draining wound? As a reader, I get the conclusion that I will be 

wasting my money and time if I used collagen. Is that what you want your readers to get out 

of this paragraph? 

j. Page 4 – Biological Dressings – Did all the subjects have normal blood flow? Please define 

what you mean by biological dressing. Are these different than biological skin equivalents? 

k. Page 4 – Biological Skin Equivalents – a) I am not sure what you mean metabolically 

active dermagraft. As a practitioner who uses dermagraft, I have never heard of this 

terminology. b) It is helpful to include how many (in average) dermagraft or apligraf 

application took in order to heal the wounds, as there is always the cost of care than can also 

impact treatment regimen used. Also in the past we were told that one application of apligraf 

was enough to get the wound to heal but now they are recommending weekly applications. 

The same goes for dermagraft. When dermagraft first hit the market, we could only use it up 

to 3 applications and now it is up to 7 applications. It is important to include how many graft 

applications these studies used in order to get the reported results. 

l. Page 5 – Platelet-rich Plasma – Please add how many applications of PRP it took to get the 

wound to heal? Was it daily, weekly, monthly application? 

m. Page 5 – Silver Products – Please be more specific as to exact type of silver products 

used. The silver ointment used for many years is silvadene cream which is cheaper than 

most other wound products. Now we have so many silver dressings with nano and micro size 

silver in it and each product is different based on its technology! So not all silver products are 

the same. The paragraph above can be very misleading, does not have any scientific value 

to it as it does not specify which specific silver technology you are referring to. 

RESPONSE 

c. As noted in the overview of studies for KQ1, only one trial enrolled patients with 

strictly ischemic diabetic ulcers; in 27 of 35 trials, the ulcers were either neuropathic 

or patients with vascular disease were excluded. 

d. This statement is correct. In the US, venous disease is responsible for 72% of 

leg ulcers, mixed venous and arterial disease for 22%, and pure arterial disease for 

about 6%.References have been added. 

e. As noted in item “a” above, we categorized studies based on the study authors’ 

descriptions of their included populations. We have added an overview of the 

studies which shows that, in most cases, studies of patients with diabetic ulcers 

excluded patients with inadequate blood flow. We recognize that patients with 

diabetes who are judged to have “adequate circulation” via clinical examination 

including pulses and blood pressure assessment may have microvascular arterial 

insufficiency. Nonetheless, we have categorized patients according to authors’ 

definitions and included descriptions of the individual studies. 

f. Dr. Robbins was a member of the Technical Expert Panel for the report, provided 

input on the key questions, scope of review, study inclusion criteria and outcomes 

of interest (including categorization of populations and interventions) and has 

reviewed the report. 

g. We have added location to the overview of the studies. We also added this 

information to the results section in the full report and in the executive summary if 

there appeared to be differences in outcomes based on ulcer location. 

h. We have added this information to the overview of the studies. 

i. One study of collagen as a matrix material found a benefit for ulcer healing. We 

have clarified that other treatments may use collagen as a vehicle for delivery of 

the active substance (e.g., silver). 

j. One study excluded patients with severe arterial disease and the other included 

only patients with adequate circulation. We have defined biological dressings as 

acellular matrices with a biologically active component. We have defined biological 

skin equivalents as tissue constructs designed to resemble layers of human skin. 

k. The finding about metabolically active dermagraft was from an early trial 

(Naughton 1997). They found that some samples had lower metabolic activity (nontherapeutic range) and suggest that, as a result, the manufacturing process was 

modified to ensure that all samples have an appropriate therapeutic level. We have 

clarified this. We have also added information about the number of applications to 

the full report 

l. We have added this information to the executive summary and the report. 

m. This information was in the main report and has now been clarified in the 

executive summary. 
108 

Advanced Wound Care Therapies for Non-Healing Diabetic, 

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REVIEWER COMMENT 

n. Page 5 – NPWT – Please be more specific. How much better improvement? 50%?, 60%, 

70% better? Was it significantly or marginally better? How about time to gain complete 

healing? Or was this study based on wound reduction size only. 

Page 6-7 – KQ1 summary a) under Secondary Outcomes – were these ulcers “diabetic 

ulcers” or “arterial” ulcers? b) The above summary does not cover the answer to all of 

the questions specifically “Is efficacy dependent on ancillary therapies?” – not clearly 

covered for each individual treatment regimen and “Does efficacy differ according to patient 

demographics, comorbid conditions, treatment compliance, or activity level?” – not clearly 

covered for each individual treatment regimen 

o. Page 7 - Biological Skin Equivalents – The comments above contradict the FDA reported 

studies. Apligraf was initially approved by the FDA in 1998 for use in venous ulcers. Later, its 

indication expended to include arterial/diabetic ulcers in 2000. So is FDA wrong? 

p. Page 8 – Silver Products – please be specific on type of silver dressing used 

q. Page 8 – Intermittent Pneumatic Compression Therapy – How about time to healing? Did 

the IPC reduce the time to healing? How about ulcer recurrence rate? 

r. Page 10 – KQ3 – How come this is different than the answers to other questions above? 

Are not there device/product-specific studies for arterial ulcers? How about use of collagen? 

skin substitutes i.e., apligraf? How about HBO therapy? PRP? This section is too brief and 

does not do the justice to treatment of Arterial ulcers which are the most common ulcers seen 

in our practices. 

s. Page 10 Discussion – In your discussion, please focus on positive findings. The studies 

may be of poor or moderate quality as such studies are often difficult to do. Please 

remember (and emphasize in your paper) that there are many reasons and factors affecting 

the occurrence of a wound, the needed treatment and the effectiveness of therapy. Each 

wound is different as it is the patient who owns the wound! That is not what was concluded 

previously in the previous pages!! 

t. Page 10 – “No treatment produced greater healing when compared to another advanced 

therapy.” This statement is inaccurate! I do not believe that many of the studies (except a 

handful) compared one advanced therapy against another! 

u. Page 11 Paragraph beginning with “The findings for venous ulcers .. silver products ( that 

is not what was concluded previously in the previous pages!! ), electromagnetic therapy 

(this contradicts what was concluded previously in the previous pages!!), significantly better 

healing (really? How come this was not noted in the sections above?) 

v. Page 11 Paragraph beginning with “We identified only one study of ... “ Were these ulcers 

revascularized before use of apligraf or were they all ischemic wounds??? 

w. Main Report – Venous Leg Ulcer Description (70-90% of leg ulcers) – NOT foot ulcers! 

Location makes a huge difference on the etiology of the ulcer! 

x. Main Report – Arterial Leg Ulcer Description (6-10% of lower extremity ulcers) - Do these 

include ulcers in the foot? Or is it all in the leg. Please note, there is an anatomical difference 

when you talk about lower extremity, leg, or foot. Having said that you cannot combine the 

wound healing rate and success (or failure of) for all of these regions as each region heals 

differently? 

y. Main Report – Topical Oxygen Therapy Description – Is this even discussed in the above 

reported studies? 

RESPONSE 

n. We have added the absolute risk difference for NPWT and the other treatments. 

o. We found significant improvement in percentage of ulcers healed with Apligraf 

for both diabetic and venous ulcers. We did not review FDA reasoning behind 

their approval process (which may have included studies and data not available or 

eligible for this report) and make no statement regarding their approval. 

p. We have added this information. 

q. The IPC trial did not report time to healing or ulcer recurrence. 

r. We agree that arterial ulcers and treatment for these are important. However, we 

identified only one trial specifically focused on arterial ulcers. We noted in the text 

that some of the patients in the diabetic ulcer studies may have had microvascular 

disease despite the fact that most studies excluded patients with macrovascular 

disease. Similarly, patients may have had mixed venous and arterial disease. This 

is an important area requiring future research. 

s. We have reported the findings from our review of RCTs. We highlight findings 

(both positive and negative) where data support strong evidence to affect practice 

and policy. We agree that it is important to highlight positive findings if there 

is at least moderate certainty of benefit. However, it is also important to note 

areas where treatments are not effective or there is insufficient evidence, so that 

clinicians and patients can avoid use of treatments of low value/low effectiveness. 

We recognize that all patients have unique clinical circumstances-this is not unique 

to patients with chronic wound care needs. As with any condition, intervention, and 

outcome we summarize the findings from the available evidence, rate the quality of 

individual studies, determine strength of evidence, and make comments about the 

broader applicability to patients typically seen. Based on this evidence clinicians 

can make judgments regarding extrapolation to individual patients though we 

suggest that our findings can serve as the foundation for implementation. 

t. We have clarified that far fewer of the studies eligible for our review included an 

advanced therapy comparator. 

u. We have clarified this section. Overall the findings were mixed for each product 

group but there were some individual trials with positive results. 

v. We have clarified that the patients had undergone revascularization. 

w. We have clarified ulcer location for studies cited throughout the report. 

x. The literature typically refers to arterial ulcers as a group in the lower extremity. 

It does not tease out foot vs. leg. We agree that there are different factors involved 

in healing of the foot vs. the leg. We have clarified ulcer location for studies cited 

throughout the report. 

y. The topic nominators requested that we include topical oxygen but no studies 

met our inclusion criteria. We have noted that in the report.
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Advanced Wound Care Therapies for Non-Healing Diabetic, 

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REVIEWER COMMENT RESPONSE 

The report and tables are comprehensive but limitations to the methodology are not We reported recurrence and amputation if reported by the study authors. 

highlighted in test. For example, recurrence of ulceration (or amputation) are usually lacking. 

Additionally, whether or not compliance with standard wound healing practices,(debridement, We have added comments about compliance. Most studies indicated that off 

off-loading) is equally allocated between treatment and control groups is not highlighted. loading etc. was part of the treatment protocol but few reported compliance 

measures (for treatment or control groups). 

1. As expected the results of the synthesis confirms the paucity of high level evidence to 1. Thank you 

support the products used every day. The recommendations for criteria for future research 2. We have added more specific information to the limitations and future research 

are appreciated and will require that publications from this review be developed to get that sections. 

word out. 

2. Although the draft does speak somewhat to the limitations of the study I would recommend 

that it be highlighted and more specific to include important outcomes such as quality of life, 

recurrence, and prevention of amputations. 

1. None of the citations described on page 77 have accompanying references. 1. The reference list is now complete. 

2. In paragraph 3 of the discussion on page 77, greater emphasis should be placed the 2. We have added information about off-loading for DFU healing and compression 

importance of offloading and adherence for DFU healing. The largest effect sizes for DFU for VLU (including the suggested references). Thank you for the reference 

healing in the literature are in offloading [1-3] causing leaders to suggest changes to the suggestions. 

methodology for DFU trials.[4] This limitation should also be described on page 26 in the 3. We have added to these sections. Thank you for the reference suggestions. 

quality assessment section. Greater emphasis should also be placed on the importance of 4. We have added absolute risk reduction data to the executive summary. 

compression with VLU trials.[5] 

3. The limitations and recommendations section do not adequately convey the magnitude 

of the problem associated with current industry sponsored trials’ DFU inclusion/exclusion 

criteria. For example, ischemia and infection are either excluded or causes for censoring 

in DFU trials despite being highly prevalent conditions in clinical practice. For example, 

large cohort studies suggested a prevalence of clinically infected DFU’s in 58-61% of 

patients [6, 7]; with up to 49% having peripheral arterial disease.[7] Fife also reports other 

populations that are excluded, including diabetes and significant comorbidities such as renal 

failure, ischemia, sickle cell, tobacco abuse, and steroid dependency [8] that are frequently 

encountered in practice. 

4. In the executive summary, please provide point estimates for effect sizes in the silver, 

NPWT, and HBOT paragraphs on page 5. 
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Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

REVIEWER COMMENT RESPONSE 

1. Armstrong, D.G., et al., Evaluation of Removable and Irremovable Cast Walkers in the 

Healing of Diabetic Foot Wounds: a Randomized Controlled Trial. Diabetes Care, 2005. 

28(3): p. 551-4. 

2. Armstrong, D.G., et al., Off-loading the diabetic foot wound: a randomized clinical trial. 

Diabetes Care, 2001. 24(6): p. 1019-22. 

3. Katz, I.A., et al., A randomized trial of two irremovable off-loading devices in the management 

of plantar neuropathic diabetic foot ulcers. Diabetes Care, 2005. 28(3): p. 555-9. 

4. Boulton, A.J. and D.G. Armstrong, Trials in neuropathic diabetic foot ulceration: time for a 

paradigm shift? Diabetes Care, 2003. 26(9): p. 2689-90. 

5. Mustoe, T.A., K. O’Shaughnessy, and O. Kloeters, Chronic wound pathogenesis and 

current treatment strategies: a unifying hypothesis. Plast Reconstr Surg, 2006. 117(7 Suppl): 

p. 35S-41S. 

6. Lavery, L.A., et al., Validation of the Infectious Diseases Society of America’s diabetic foot 

infection classification system. Clin Infect Dis, 2007. 44(4): p. 562-5. 

7. Prompers, L., et al., High prevalence of ischaemia, infection and serious comorbidity in 

patients with diabetic foot disease in Europe. Baseline results from the Eurodiale study. 

Diabetologia, 2007. 50(1): p. 18-25. 

8. Fife, C., Wound Care in the 21st Century. US Surgery, 2007: p. 63-64. 

I personally found the information related to biological skin equivalents to be most interesting. 

These treatment adjuncts are VERY expensive and it would appear from the report that they 

offer only modest benefit in wound healing compared to standard therapy and no significant 

improvement in shortening the time for ulcer healing. My “take home” message here was that 

these products should be used very judiciously, if at all. 

Thank you. 

5. Are there any clinical performance measures, programs, quality improvement 

measures, patient care services, or conferences that will be directly affected by this 

report? If so, please provide detail. 

Thank you – we will share these suggestions with the people responsible for 

dissemination of the report. 

Yes. The wound clinics, podiatry sections, and possibly plastic surgery and general surgery 

sections if they deal with lower extremity wound care. 

Will likely impact criteria for use 

Yes, as stated above this synthesis will help us develop a guideline for the appropriate use 

of these expensive products using a combination of common sense and the evidence found 

in this study. We will have to resist the temptation to ban the use of products altogether but 

rather to place limits on how and where they are used. We must preserve the clinician’s 

right to practice the art of medicine while recognizing we cannot continue to waste dollars on 

therapies that do not work. One telling point was that despite healing a wound faster or more 

completely there was no difference in all-cause mortality. This speaks to the need to develop 

algorithms that are interdisciplinary and address the systemic diseases as well as the wound. 
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Advanced Wound Care Therapies for Non-Healing Diabetic, 

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REVIEWER COMMENT RESPONSE 

This report has implications for National VA programs such as PACT and NSQIP. Results 

should be disseminated and presented at the VA’s Annual Desert Foot Conference and 

HSR&D meeting. National presentations should also be considered at ADA and SAWC. The 

National PACT program may choose to study current use of advanced modality care in each 

strata using wound healing cameras to measure wound healing rates and appropriate use 

criteria and their effect on patient outcome in a pre & post-design. 

I would hope that the use of collagen products, biological dressings and platelet rich plasma 

would, for the most part, cease in most clinics treating the wounds described in the studies. 

On the other hand, the values of negative pressure wound therapy and hyperbaric oxygen in 

helping with wound healing in selected cases supports my own clinical experience in this area. 

6. Please provide any recommendations on how this report can be revised to more 

directly address or assist implementation needs. 

I worry that efficacy assessments do not always translate to general care of the VA We appreciate this concern and have added the following statement to the 

discussion: “Our review assessed results from randomized controlled trials in 

selected populations and controlled settings. It is not well known how outcomes 

reported in these studies will translate to findings in daily practice settings including 

in Veterans Health Administration facilities. Patients were likely more compliant than 

typical patients and received very close monitoring. Therefore, results from these 

may overestimate benefits and underestimate harms in nonstudy populations.” 

You need to notify Dr. Jeff Robbins, the Chief of Podiatry at the VA central office about this We thank the reviewer for these comments. Dr. Robbins is involved with this 

report. He has a list of whom are most expert in the field within the VA. project. 

As there is a number of factors in treating wounds, the paper must emphasize the difficulty 

in performing studies and coming up with a conclusion on what is best for healing chronic 

wounds. The factors affecting doing a solid, strong study include but not limited to: the type of 

the wound, the host barriers, the host’s associated comorbidities, the host’s associated level 

of nutritional status, compliance with treatment, location of the ulcers (plantar vs. dorsal), 

degree of blood flow (not all small vessel disease act the same!), the host’s medications, ... 

1) This is a long report and while the tables and appendices are important they should 1 and 2) We recognize the length of the report. We believe the information 

probably come at the end and be referenced in the body of the document. included is needed to provide the “interested reader” the full body of evidence we 

2) We could release the executive summary widely and reference the full document. I am considered. We agree clinicians and policy makers are unlikely to read the whole 

concerned that the field clinicians will not read a 178 page document. document. We have tried to highlight the main findings in the executive summary 

3) In addition I am interested in helping in the production of some publications based on and are willing to conduct other dissemination activities including Cyberseminars, 

these findings to share with the scientific community. Management Briefs etc. to further convey the main messages to a wide audience. 

3) We are considering derivative manuscripts from this report. 

There is a growing chasm between operations and research. Those who conduct systematic 

reviews or meta-analyses frequently are not PI’s conducting the studies or actively engaged 

in patient care.[1] A careful compilation of improvement opportunities for study designs 

should be created for both funding agencies (including industry) and PI’s. These should also 

be disseminated to NIH and VA program officers. 

1. Gottrup, F., Controversies in performing a randomized control trial and a systemic review. 

Wound Repair Regen, 2012. 20(4): p. 447-8. 

We have cited several documents detailing recommendations for future research. 

The report is extremely well done and readable as it stands. I have no recommendations for 

improvement. 

Thank you. 
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APPENDIX D. EVIDENCE TABLES 

Table 1. Study Characteristics Table 

Study, Year 

Country 

Funding Source 

Inclusion/Exclusion Criteria Patient Characteristics 

Ulcer Type 

Intervention 

Comparator 

Length of Follow-up 

Study Quality 

Abidia 200349 Inclusion: diabetes; ischemic lower extremity N=16 (of 18 randomized) Intervention (n=9): HBOT; 2.4 ATA Allocation concealment: 

ulcers (>1 cm and <10 cm in maximum Age (years): 71 for 90 minutes on 30 occasions Adequate

United Kingdom 

Funding Source: NR 

Therapy Type: 

Hyperbaric oxygen 

(HBOT) 

diameter); no signs of healing for >6 weeks 

despite optimum medical management; 

occlusive arterial disease confirmed by anklebrachial pressure index <0.8 (or great toe <0.7 if 

calf vessels incompressible) 

Exclusion: planned vascular surgery, 

angioplasty, or thrombolysis 

Gender (% male): 50 

Race/ethnicity: NR 

BMI: NR 

Pre-albumin: NR 

HbA1

c (%): NR 

Smoking: 19% 

# Work days missed: NR 

ABI: <0.8 for inclusion 

Wound location: foot 

over 6 weeks; multi-place chamber 

Control (n=9): sham (hyperbaric 

air) 

ALL: specialized multidisciplinary 

wound management program 

(off-loading, debridement, moist 

dressing) 

Blinding: Patients, 

investigators, outcome 

assessors 

Intention to treat analysis 

(ITT): No, two withdrawals 

not included in analysis 

Withdrawals/dropouts 

Wound type: ischemic diabetic Antibiotic Use: As needed adequately described: Yes 

Wound size, mm2

 (median): HBOT 106; Treatment Duration: 6 weeks 

control 78 Follow-up Duration: 1 year 

Wound grade (Wagner*, %): Grade I 6; Study Withdrawal (%): 20 (n=2) 

II 94 Treatment Compliance: “The 

Wound duration, months: HBOT 6; protocol was strictly followed 

control 9 throughout the study” 

Comorbid conditions (%): 

History of CAD/CVD: (previous bypass 

31, angioplasty 6) 

History of DM: 100 

History of amputation: minor 19 
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Advanced Wound Care Therapies for Non-Healing Diabetic, 

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Study, Year 

Country 

Funding Source 

Inclusion/Exclusion Criteria Patient Characteristics 

Ulcer Type 

Intervention 

Comparator 

Length of Follow-up 

Study Quality 

Agrawal 200928 Inclusion: ≥30 years of age; Wagner stage I, II, N=28 Intervention (n=14): rhPDGF 0.01% Allocation concealment: 

India 

Funding Source: NR 

Therapy Type: 

Platelet-derived 

Growth Factor 

III, or IV ulcers; foot ulcer duration >3 months; 

free of infection; adequate lower-limb blood 

supply (transcutaneous oxygen tension ≥30 

mmHg), no or moderate peripheral vascular 

disease 

Exclusion: active neoplastic disease; diagnosis 

of active infection characterized by warmth, 

erythema, lymphangitis, lymphadenopathy, 

oedema, or pain; received immunosuppressive 

therapy during the preceding three months; 

liver disease, pulmonary tuberculosis, 

thyroid disorder uremia, alcoholism or 

renal insufficiency; undergoing vascular 

reconstruction or receiving steroid or 

anticoagulant therapy 

Age (years): 55 

Gender (% male): 68 

Race/ethnicity: NR 

BMI: 25.7 

Pre-albumin: NR 

HbA1

c (%): 8.8 

Smoking: NR 

# Work days missed: NR 

ABI: NR 

Wound location: foot 

Wound type: diabetic 

Wound size: 41.5 cm2

 (ulcer size 

significantly larger in study group 

p=0.003) 

Wound grade: NR 

Wound duration: NR 

Infection: excluded 

Comorbid conditions (%): 

Diabetes: 100 

gel at 2.2ug/cm2

/day 

Comparator (n=14): placebo gel at 

2.2ug/cm2

/day 

ALL: standard regimen of highquality care (included glycemic 

control, debridement, dressings, 

pressure relief) 

Antibiotic Use: as needed 

Treatment Duration: 12 weeks 

Follow-up Duration: NR 

Study Withdrawal (%): 18 (all from 

control group at week 12) 

Treatment Compliance: NR 

Unclear 

Blinding: Unclear 

Intention to treat analysis 

(ITT): No 

Withdrawals/dropouts 

adequately described: 

Partial – 5 withdrawals 

from the control group 

with no reason for 

withdrawal 

Aminian 200027 Inclusion: chronic non-healing diabetic ulcers N=12 ulcers (7 patients) of 14 ulcers (9 Intervention (n=7 ulcers): Allocation concealment: 

Iran 

Funding Source: 

of at least eight weeks duration; controlled 

blood sugar; normal peripheral blood platelet 

count (>150,000/cu mm); negative history of 

patients) randomized 

Age (years): 60 

Gender (% male): 100 

autologous platelet extract (APE) 

+ silver sulfadiazine dressing 12 

hours on and 12 hours off 

Inadequate 

Blinding: Unclear 

Government 

Therapy Type: 

Platelet-Derived 

Growth Factor 

malignancy 

Exclusion: determined to have non-diabetic 

ulcers 

Race/ethnicity: NR 

BMI: NR 

Pre-albumin: NR 

HbA1

c (%): NR 

Smoking: NR 

# Work days missed: NR 

ABI: NR 

Wound location: foot 

Comparator (n=5 ulcers): saline 

solution and silver sulfadiazine 12 

hours on and 12 hours off 

ALL: supportive, conventional care 

(debridement, blood sugar checked 

weekly, off-loading) 

Intention to treat analysis 

(ITT): No 

Withdrawals/dropouts 

adequately described: Yes 

– 2 patients with 2 ulcers 

excluded after entering 

study (non-compliance, 

Wound type: diabetic ulcer 

Wound size: 5.9 cm2 

Wound grade: NR 

Wound duration: 12.9 wks 

Infection: NR 

Comorbid conditions (%): 

Diabetes: 100 

Antibiotic Use: oral, if needed 

Treatment Duration: 8 weeks 

Follow-up Duration: NR 

Study Withdrawal (%): 22% 

Treatment Compliance: 1/9 pts 

withdrawn for non-compliance 

non-diabetic ulcer) 
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Study, Year 

Country 

Funding Source 

Inclusion/Exclusion Criteria Patient Characteristics 

Ulcer Type 

Intervention 

Comparator 

Length of Follow-up 

Study Quality 

Armstrong 200581 

Apelqvist 200882 

United States (18 

sites) 

Funding Source: 

Industry (not involved 

in analysis or write-up 

of manuscript; did not 

maintain veto power 

over final article) 

Therapy Type: 

Negative Pressure 

Wound Therapy 

Inclusion: age ≥18; wound from diabetic foot 

amputation to transmetatarsal level of foot; 

evidence of adequate perfusion (transcutaneous 

O2 on dorsum of foot ≥30 mmHg or ABI ≥0.7 

and ≤1.2, and toe pressure ≥30 mmHg); 

University of Texas grade 2 or 3 in depth 

Exclusion: active Charcot arthropathy of 

foot; wound from burn, venous insufficiency, 

untreated cellulitis or osteomyelitis, collagen 

vascular disease, malignant disease, or 

uncontrolled hyperglycemia (HbA1

c >12%); 

treated with corticosteroids, immunosuppressive 

drugs, or chemotherapy; VAC therapy in past 

30 days, present or previous (past 30 days) 

treatment with growth factors; normothermic 

therapy, hyperbaric medicine, or bioengineered 

tissue 

N=162 

Age (years): 59 

Gender (% male): 81 

Race/ethnicity (%): Non-Hispanic white: 

48; African-American: 17; MexicanAmerican: 32; Native American: 3 

BMI: 31 

Pre-albumin (g/L): 0.19 

HbA1

c (%): 8.2 

Smoking: 9% 

# Work days missed: NR 

ABI: 1.1 

Wound location: foot 

Wound type: amputation 

Wound size: 20.7 cm2 

Wound grade: U of Texas 2/3 Wound 

duration: 1.5 months 

Comorbid conditions (%): 

History of DM: 100 (90% T2) 

Intervention (n=77): VAC system; 

dressing changes every 48 hrs 

Comparator (n=85): standard 

care (moist wound therapy with 

alginates, hydrocolloids, foams, or 

hydrogels; dressing changes every 

day unless otherwise advised 

ALL: off-loading therapy as 

indicated; sharp debridement at 

randomization and as needed 

Antibiotic Use: NR 

Treatment Duration: wound closure 

or 112 days 

Follow-up Duration: none 

Study Withdrawal (%): 0 

Treatment Compliance: NR 

Allocation concealment: 

Adequate 

Blinding: Partial 

(independently assessed 

and confirmed closure 

with digital planimetry) 

Intention to treat 

analysis (ITT): Yes – no 

withdrawals 

Withdrawals/dropouts 

adequately described: Yes 

– no withdrawals 

Belcaro 201038 

Italy 

Funding Source: NR 

Therapy Type: Silver 

Oxide Ointment 

Inclusion: 

Venous Ulcer (VU) Patients: chronic venous 

ulcers, venous microangiopathy, and perimalleaolar ulcerations 

Diabetic Ulcer (DU) Patients: diabetic 

microangiopathy and plantar ulcers due 

to reduced arterial pressure, diabetic 

microangiopahty and neuropathy, and localized 

infection 

Exclusion: 

Venous Ulcer Patients: venous thrombosis or 

arterial problems in past year; severe ischemia 

and necrosis (based on Doppler detected tibial 

pulse) 

Diabetic Ulcer Patients: none reported 

Venous Ulcer Patients: N=82 

Age (years): 47 

Gender (% male): 46 

Diabetic Ulcer Patients: N=66 

Age (years): 55.9 

Gender (% male): 44 

Both Groups: 

Race/ethnicity: NR 

BMI: NR 

Pre-albumin: NR 

HbA1

c (%): NR 

Smoking: NR 

# Work days missed: NR 

ABI: NR 

Wound location: plantar (DU) 

Wound type: venous, diabetic 

Wound size: VU 3.2 cm2

, DU 2.2 cm2 

Wound grade: NR 

Wound duration: NR 

Comorbid conditions (%): NR 

Intervention (n=44 VU, n=34 

DU): silver ointment around and 

at edges of ulcerated area twice 

daily after noninvasive washing; 

bandage and elastic stocking 

Comparator (n=38 VU, n=32 

DU): cleansing & wound care; 

compression (mild for DU) 

Antibiotic Use: NR 

Treatment Duration: 4 weeks 

Follow-up Duration: No follow-up 

post tx 

Study Withdrawal (%): 0 

Treatment Compliance: NR 

Allocation concealment: 

Unclear 

Blinding: Unclear 

Intention to treat 

analysis (ITT): Yes (no 

withdrawals) 

Withdrawals/dropouts 

adequately described: Yes 

(none) 
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Study, Year 

Country 

Funding Source 

Inclusion/Exclusion Criteria Patient Characteristics 

Ulcer Type 

Intervention 

Comparator 

Length of Follow-up 

Study Quality 

Bhansali 200930 Inclusion: >20 years old with type 1 or 2 N=20 (24 ulcers) Intervention (n=13): 0.01% rh- Allocation concealment: 

India 

Funding Source: 

Industry (provided 

gel) 

Therapy Type: 

Platelet-derived 

Growth Factor 

diabetes; at least one neuropathic plantar ulcer 

of Wagner grade ≥ 2 without X-ray evidence of 

osteomyelitis; ABI>0.9; controlled infection after 

run-in 

Exclusion: none reported 

Age (years): 51 

Gender (% male): 60 

Race/ethnicity: NR 

BMI: 24 

Pre-albumin: NR 

HbA1

c (%): 8.1 

Smoking: NR 

# Work days missed: NR 

ABI: 1.05 

PDGF-BB gel 

Comparator (n=11): standard 

wound care (saline soaked 

dressing) 

ALL: daily dressing changes; offloading (85% total contact cast, 

10% bedridden, 5% special shoe) 

Unclear 

Blinding: No (open label) 

Intention to treat analysis 

(ITT): Yes 

Withdrawals/dropouts 

adequately described: Yes 

(none) 

Wound location: forefoot: 75%; mid: 

20%; hind: 5% 

Wound type: diabetic 

Wound size: 14.6 cm2 

Wound grade: Wagner ≥ 2 

Wound duration: <4 weeks=20%; >4 

weeks=80% 

Infection: 45% 

Comorbid conditions (%): 

History of DM: 100% 

History of amputation: 35% 

Antibiotic Use: As needed 

Treatment Duration: 20 weeks 

Follow-up Duration: NR 

Study Withdrawal (%): 0 

Treatment Compliance: NR 

Bishop 199263 Inclusion: age 21 to 90 years; venous stasis N=86 (of 93 randomized) Intervention (n=29): 0.4% tripeptide Allocation concealment: 

United States (2 

sites) 

Funding Source: 

ulcers of at least 3 months duration; surface 

area 3 cm2

 to 50 cm2; negative pregnancy test 

and using adequate contraceptive (women of 

childbearing age) 

Age (years): 56 

Gender (% male): 50 

Race/ethnicity: white: 62; black: 33; 

other: 6 

copper complex cream 

Comparator (n=28): 1% silver 

sulphadiazine cream 

Unclear 

Blinding: Yes (evaluator) 

Intention to treat analysis 

Industry 

Therapy Type: Silver 

Products 

Exclusion: hypersensitivity to any components 

of test medication; >105

 bacteria/gram 

of tissue in the ulcer; systemic sepsis 

or presence of bone infection; ABI<0.5; 

hypercupremia (Wilson’s disease); systemic 

immunosuppressive or cytotoxic therapy; 

insulin-dependent diabetes mellitus 

BMI: NR 

Pre-albumin: NR 

HbA1

c (%): NR 

Smoking: 33.7% currently 

# Work days missed: NR 

ABI: NR 

Wound location: “lower extremity” 

Wound type: venous stasis 

Wound size: 10.5 cm2 

Wound grade: NR 

Wound duration: 46.4 months 

Comorbid conditions (%): 

History of DM: 9% 

Placebo (n=29): tripeptide vehicle 

ALL: applied daily following saline 

rinse; non-adherent dressing and 

elastic wrap; limb elevated when 

sitting; no standing >2 hrs 

Antibiotic Use: NR 

Treatment Duration: 4 weeks 

Follow-up Duration: 1 year 

Study Withdrawal (%): 7.5 

Treatment Compliance: patient 

diary and medication weighed at 

end of study; results NR 

(ITT): No 

Withdrawals/dropouts 

adequately described: 

Partial (3 were immediate 

dropouts; 4 additional 

patients did not complete 

the trial; reasons not 

provided) 
116 

Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

Study, Year 

Country 

Funding Source 

Inclusion/Exclusion Criteria Patient Characteristics 

Ulcer Type 

Intervention 

Comparator 

Length of Follow-up 

Study Quality 

Blair 198864 

United Kingdom 

Funding Source: NR 

Therapy Type: Silver 

Products 

Inclusion: ulcers up to 10 cm2 

Exclusion: ABI<0.8 

N=60 

Age (years): 69 

Gender (% male): NR 

Race/ethnicity: NR 

BMI: NR 

Pre-albumin: NR 

HbA1

c (%): NR 

Smoking: NR 

# Work days missed: NR 

ABI: NR 

Wound location: NR 

Wound type: venous 

Wound size: 3.4 cm2 

Wound grade: NR 

Wound duration: 26.2 months since 

ulcer was last healed 

Comorbid conditions (%): NR 

Intervention (n=30): silver 

sulphadiazine dressing (Flamazine) 

Comparator (n=30): non-adherent 

and non-occlusive dressing 

ALL: out-patient treatment; 

dressings changed weekly in 

venous ulcer clinic; standard high 

pressure graduated compression 

bandage over the dressing 

Antibiotic Use: NR 

Treatment Duration: 12 weeks 

Follow-up Duration: none 

Study Withdrawal (%): 7% 

Treatment Compliance: NR 

Allocation concealment: 

Adequate 

Blinding: Unclear 

Intention to treat analysis 

(ITT): Yes 

Withdrawals/dropouts 

adequately described: Yes 

Blume 200842 

United States and 

Canada (29 sites) 

Funding Source: 

Industry 

Therapy Type: 

Negative Pressure 

Wound Therapy 

Inclusion: diabetic adults (18+); stage 2 or 3 

(Wagner’s) calcaneal, dorsal, or plantar foot 

ulcer; ≥2 cm2

 after debridement; adequate 

blood circulation (dorsum transcutaneous O2 

test ≥30 mmHg); ABI 0.7-1.2 with toe pressure 

≥30 mmHg or triphasic or biphasic Doppler 

waveforms at ankle 

Exclusion: active Charcot disease; electrical, 

chemical, or radiation burns; collagen 

vascular disease; ulcer malignancy; untreated 

osteomyelitis; cellulitis; uncontrolled 

hyperglycemia; inadequate lower extremity 

perfusion; normothermic or hyperbaric 

oxygen therapy; use of corticosteroids, 

immunosupressants, or chemotherapy; growth 

factor products; skin or dermal substitutes within 

30 days; enzymatic debridement; pregnant or 

nursing 

N=335 (of 341 randomized) 

Age (years): 59 

Gender (% male): 78 

Race/ethnicity (%): African-American: 

15; Caucasian: 58; Hispanic: 24; Native 

American: 2; other: 1 

BMI: NR 

Pre-albumin: 20.5 

HbA1

c (%): 8.2 

Smoking: 19% 

# Work days missed: NR 

ABI: 1.0 

Wound location: calcaneal, dorsal, or 

plantar 

Wound type: diabetic ulcer 

Wound size: 12.3 cm2 

Wound grade: 2 or 3 

Wound duration: 202 days 

Comorbid conditions (%): 

History of DM: 100 

Intervention (n=172): NPWT - 

vacuum-assisted closure therapy; 

dressing changes every 48-72 hrs 

Comparator (n=169): advanced 

moist wound therapy (AMWT) 

Off-load: NPWT 97%; AMWT 98% 

Antibiotic Use: NR (28% treated for 

infection before randomization) 

Treatment Duration: 112 days 

Follow-up Duration: 3 and 9 

months after closure 

Study Withdrawal (%): NPWT: 

32%; AMWT: 25% 

Treatment Compliance: 6/169 

(4%) in NPWT group were noncompliant vs. 0% in AMWT group 

(not defined) 

Allocation concealment: 

Adequate 

Blinding: Patients and 

physicians not blinded; 

unclear if outcome 

assessment was blinded 

Intention to treat analysis 

(ITT): Modified (received 

at least one post-baseline 

treatment) 

Withdrawals/dropouts 

adequately described: Yes 
117 

Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

Study, Year 

Country 

Funding Source 

Inclusion/Exclusion Criteria Patient Characteristics 

Ulcer Type 

Intervention 

Comparator 

Length of Follow-up 

Study Quality 

Blume 201115 Inclusion: type 1 or 2 diabetes; over age 18 yrs; N=52 Intervention (n=33): formulated Allocation concealment: 

United States (22 

sites) 

Funding Source: 

Industry 

Therapy Type: 

Collagen 

Wagner Grade 1 cutaneous lower extremity 

ulcer; 1.5-10.0 cm2

; present ≥6 wks; peripheral 

neuropathy; adequate blood flow (TcpO2 

>40mmHg or toe pressure ≥40mmHg) 

Exclusion: HbA1

c >12%; ulcer on heel; cellulitis; 

biopsy positive for beta hemolytic streptococci 

or total bacterial load >1X106 CFU/g; decrease 

in ulcer size >30% from screening to Tx day 1 

Age (years): 56 

Gender (% male): 77 

Race/ethnicity (%): white 64, black 12, 

Hispanic 23, other 2 

BMI: 34 

Pre-albumin: NR 

HbA1

c (%): 8.0 

Smoking: NR 

# Work days missed: NR 

collagen gel (FCG) (combined 1 

dose and 2 dose groups) 

(NOTE: included 2nd intervention 

arm with non-FDA product) 

Comparator (n=19): standard care 

(debride, moist dressing) 

ALL: debridement; 2 wk standard 

care run-in; off-loading shoe 

Unclear 

Blinding: Investigators 

were blinded; other study 

personnel were not 

Intention to treat analysis 

(ITT): Yes for safety 

analysis; per-protocol for 

other outcomes 

ABI: NR 

Wound location: 89% plantar 

Wound type: diabetic 

Wound size: 2.9 cm2 

Wound duration: 15.1 months 

Comorbid conditions (%): 

History of DM: 100 

Antibiotic Use: NR 

Treatment Duration: 12 weeks 

Follow-up Duration: None 

Study Withdrawal (%): 6/5 (8/124) 

Treatment Compliance: see WD 

Withdrawals/dropouts 

adequately described: Yes 

(including 2 in FCG group 

for non-compliance) 

Brigido 200674 Inclusion: full thickness (Wagner grade II) N=28 Intervention (n=14): Graftjacket Allocation concealment: 

United States 

Funding Source: NR 

chronic wound ≥6 weeks without epidermal 

coverage; non-infected; palpable/ audible pulse 

to the lower extremity 

Age (years): 64 

Gender (% male): NR 

Race/ethnicity: NR 

(single application); mineral oil 

soaked fluff compression dressing 

changed on days 5, 10, and 15 

Unclear 

Blinding: No 

Therapy Type: 

Collagen 

Exclusion: none reported BMI: NR 

Pre-albumin: NR 

HbA1

c (%): 8.0 

Smoking: NR 

# Work days missed: NR 

then weekly assessment 

Comparator (n=14): Curasol 

wound gel; gauze dressing; weekly 

debridement 

Intention to treat analysis 

(ITT): Yes 

Withdrawals/dropouts 

adequately described: Yes 

ABI: NR 

Wound location: leg/foot 

Wound type: mixed 

Wound size: NR 

Wound grade: Wagner grade II 

Wound duration: NR 

Infection: excluded if infected 

Comorbid conditions (%): NR 

ALL: initial sharp debridement; offloading with walking boot 

Antibiotic Use: NR 

Treatment Duration: 16 weeks 

Follow-up Duration: None 

Study Withdrawal (%): 0 

Treatment Compliance: NR 

– all patients completed 

study 
118 

Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

Study, Year 

Country 

Funding Source 

Inclusion/Exclusion Criteria Patient Characteristics 

Ulcer Type 

Intervention 

Comparator 

Length of Follow-up 

Study Quality 

Chang 200073 Inclusion: non-healing foot ulcer or required N=31 Intervention (n=21): meshed Allocation concealment: 

United States 

Funding Source: NR 

partial open foot amputation; ABI <0.5 prior to 

revascularization surgery; underwent bypass or 

angioplasty within 60 days of inclusion 

Age (years): 70 

Gender (% male): 77 

Race/ethnicity (%): NR 

(N=10) or unmeshed (N=11) tissue 

graft (Apligraf); non-adherent 

dressing, Unna boot & ace wrap; 

Unclear 

Blinding: No 

Therapy Type: 

Biological Skin 

Equivalent 

Exclusion: ABI <0.7 after revascularization 

surgery; recent steroid use; chemotherapy; 

previous radiation; wound <2.0 cm2

; infected 

wound, necrotic tissue, exposed bone, or 

exposed tendons 

BMI: NR 

HbA1

c (%): NR 

Smoking: NR 

# Work days missed: NR 

ABI: NR (see inclusion criteria) 

Wound type: previously ischemic 

wounds s/p revascularization surgery 

Wound size: 4.8 cm2 

followed every 5-7 days (or more) 

for 1st month; Unna boot dressing 

changes each visit until graft 

maturation 

Comparator (n=10): moist saline 

gauze sponges with dry cotton 

gauze wrapping; changed 2x/day 

Intention to treat analysis 

(ITT): Unclear 

Withdrawals/dropouts 

adequately described: 

Unclear if any dropouts 

Wound duration: NR 

Infection: excluded 

Comorbid conditions (%): 

History of DM: 58% 

History of amputation: 45% History of 

PVD: 100% 

History of renal failure: 39% 

Antibiotic Use: NR 

Treatment Duration: wound closure 

or ≥ 6 months after randomization 

Follow-up Duration: same 

Study Withdrawal (%): NR 

Treatment Compliance: NR 

d’Hemecourt 199835 Inclusion: ≥19 years old; type 1 or 2 diabetes; at N=172 Intervention (n=30): becaplermin Allocation concealment: 

United States (10 

sites) 

Funding Source: 

Industry 

Therapy Type: 

Platelet-derived 

Growth Factors 

least one full thickness (Stage 3 or 4) diabetic 

ulcer of >8 weeks duration; wound size 1.0-10.0 

cm2

; adequate arterial circulation 

Exclusion: osteomyelitis affecting target ulcer 

area; >3 chronic ulcers present at baseline; nondiabetic wounds; cancer at time of enrollment; 

use of concomitant medications (corticosteroids, 

chemotherapy, immunosuppressive agents); 

pregnant or nursing 

Age (years): 58 

Gender (% male): 74 

Race/ethnicity (%): white: 85; black: 10; 

other: 5 

BMI: NR 

Pre-albumin: NR 

HbA1c (%): NR 

Smoking: NR 

# Work days missed: NR 

ABI: NR 

gel 100ug/g and standard care 

Comparator A (n=70): sodium 

carboxymethylcellulose Gel 

(NaCMC) and standard care 

Comparator B (n=68): standard 

care – sharp debridement, saline 

gauze dressing changes every 12 

hours, off-loading 

Unclear 

Blinding: Yes – patients, 

evaluators 

Intention to treat analysis 

(ITT): Yes 

Withdrawals/dropouts 

adequately described: Yes 

Wound location: right leg: 3%; left leg: 

4%; right foot: 47%; left foot: 47% 

Wound type: diabetic ulcer 

Wound size: 3.2 cm2 

Wound grade: 97% Stage III 

Wound duration: 42.3 weeks 

Infection: NR 

Comorbid conditions (%): 

Diabetes: 100 

Antibiotic Use: systemic control of 

infection if present 

Treatment Duration: 20 weeks 

Follow-up Duration: NR 

Study Withdrawal (%): 24 

Treatment Compliance: NR 
119 

Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

Study, Year 

Country 

Funding Source 

Inclusion/Exclusion Criteria Patient Characteristics 

Ulcer Type 

Intervention 

Comparator 

Length of Follow-up 

Study Quality 

DiDomenico 201126 Inclusion: type 1 or 2 diabetes; Wagner grade 1 N=28 patients (29 wounds) Intervention (n=17 wounds): Allocation concealment: 

United States 

Funding Source: 

Industry 

or University of Texas 1a ulcer; wound duration 

>4 weeks; area 0.5-4 cm2

; HbA1c <12; ABI 

>0.75; palpable pulses on the study foot; able to 

comply with off-loading 

Age (years): NR 

Gender (% male): NR 

Race/ethnicity: NR 

BMI: NR 

Apligraf; up to 5 applications 

Comparator (n=12 wounds): 

Theraskin; up to 5 applications 

Unclear 

Blinding: Unclear 

Intention to treat analysis 

Therapy Type: 

Biological Skin 

Equivalent 

Exclusion: infection or gangrenous tissue or 

abscesses; exposed bone, tendon, or joint 

capsule; non-diabetic etiology; use of topical 

medications that may affect graft material; 

adjuvant therapy such as hyperbaric oxygen; 

wound depth <9 mm 

Pre-albumin: NR 

HbA1

c (%): NR 

Smoking: NR 

# Work days missed: NR 

ABI: NR 

Wound location: NR 

Wound type: diabetic ulcer 

Wound size: 1.9 cm2 

Wound grade: see inclusion 

Wound duration: see inclusion 

Comorbid conditions (%): NR 

ALL: debridement, off-loading; 

dressing changes every other day 

or daily, as needed 

Antibiotic Use: NR 

Treatment Duration: 12 weeks 

Follow-up Duration: to 20 weeks 

Study Withdrawal (%): NR 

Treatment Compliance: NR 

(ITT): Unclear 

Withdrawals/dropouts 

adequately described: Yes 

Dimakakos 200965 Inclusion: leg ulcer classified as exclusively N=42 Intervention (n=21): non-adhesive Allocation concealment: 

Greece 

Funding Source: NR 

Therapy Type: Silver 

Dressing 

infected and venous in origin 

Exclusion: pregnancy; psychiatric disorders; 

diabetes; collagen disease; steroid use; history 

of allergies; ABPI<1 

Age (years): 60 

Gender (% male): 38 

Race/ethnicity: NR 

BMI: NR 

Pre-albumin: NR 

HbA1

c (%): NR 

silver-releasing foam 

Comparator (n=21): non-adhesive 

foam 

ALL: cleansing with sterile water 

and 10% povidone iodine solution; 

Unclear 

Blinding: Unclear 

Intention to treat analysis 

(ITT): No withdrawals/ 

dropouts reported

Smoking: NR 

# Work days missed: NR 

compression bandage Withdrawals/dropouts 

ABI: NR Antibiotic Use: as needed adequately described: 

Wound location: leg Treatment Duration: 9 weeks None reported 

Wound type: venous Follow-up Duration: NR 

Wound size: NR Study Withdrawal (%): NR 

Wound grade: NR Treatment Compliance: NR 

Wound duration: 62% >1 mo 

Infection: excluded 

Comorbid conditions: 0% DM 
120 

Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

Study, Year 

Country 

Funding Source 

Inclusion/Exclusion Criteria Patient Characteristics 

Ulcer Type 

Intervention 

Comparator 

Length of Follow-up 

Study Quality 

Donaghue 199817 Inclusion: >21 years of age; serum albumin N=75 Intervention (n=50): collagen- Allocation concealment: 

United States 

Funding Source: 

Industry 

Therapy Type: 

Collagen 

>2.5 grams/dl; adequate blood flow to lower 

extremity (palpable pulses); foot ulceration of at 

least 1 cm2 

Exclusion: severe renal or liver impairment 

(liver or creatinine tests 2 or more times higher 

than normal); presence of any disorder that 

may interfere with wound healing; evidence of 

osteomyelitis; clinical signs of infection; history 

of drug or alcohol abuse 

Age (years): 59 

Gender (% male): 72 

Race/ethnicity: NR 

BMI: NR 

Pre-albumin: 3.7 

HbA1

c (%): NR 

Smoking: NR 

# Work days missed: NR 

ABI: NR 

Wound location: foot 

alginate 

Comparator (n=25): conventional 

treatment with saline-moistened 

gauze 

ALL: felted foam dressing with 

window at site of ulcer; use of 

healing sandals; patient self 

dressing change as required 

Unclear 

Blinding: No 

Intention to treat analysis 

(ITT): Yes 

Withdrawals/dropouts 

adequately described: Yes 

Wound type: diabetic ulcer 

Wound size: 2.7 cm2 

Wound grade: Wagner I: 12%; II: 75%; 

III: 13% 

Wound duration: 172 days 

Infection: excluded 

Comorbid conditions (%): 

Diabetes: 100 

Antibiotic Use: NR 

Treatment Duration: 8 weeks 

Follow-up Duration: NR 

Study Withdrawal (%): 19 

Treatment Compliance: NR 

Driver 200637 Inclusion: type 1 or 2 diabetes; age 18-95; ulcer N=40 (of 72 randomized) Intervention (n=40): platelet rich Allocation concealment: 

United States (14 

sites including VA 

wound care clinics) 

Funding Source: 

>4 weeks; HbA1

c <12%; index ulcer on plantar, 

medial, or lateral foot; area 0.5-20 cm2; Charcot 

deformity free of acute changes & undergone 

structural consolidation; ulcer free of infection; 

no bone, muscle, ligament, or tendon exposure; 

Age (years): 57 

Gender (% male): 80 

Race/ethnicity: Caucasian: 60; Hispanic: 

30; black: 7.5; other: 2.5 

BMI: NR 

plasma (AutoloGel); applied twice 

weekly 

Comparator (n=32): saline gel 

(Normlgel); applied twice weekly 

Adequate 

Blinding: Yes (patients, 

investigators, outcome 

assessors) 

Industry ≥4 cm from any other wound; adequate Pre-albumin: NR Antibiotic Use: NR Intention to treat analysis 

Therapy Type: 

Platelet Rich Plasma 

perfusion 

Exclusion: investigational drug or device trial 

(30 days); ulcer size decrease ≥50% in 7 day 

run-in; non-diabetic ulcers; serum albumin 

<2.5 g/dL; hemoglobin <10.5 mg/dL; radiation 

or chemotherapy; renal dialysis; immune 

deficiency; known abnormal platelet activation 

disorder; peripheral vascular repair in past 

30 days; known or suspected osteomyelitis; 

surgery required for healing; exposed tendon, 

ligaments, muscle, or bone; disorder that may 

affect compliance; alcohol or drug abuse (past 

year) 

HbA1

c (%): 7.9 

Smoking: NR 

# Work days missed: NR 

ABI: NR 

Wound location (%): right foot: 60; left 

foot: 40; toe: 38; heel: 40 (NR for 9 

patients) 

Wound type: diabetic ulcer 

Wound size: 3.5 cm2 

Wound grade: NR 

Wound duration: NR 

Infection: excluded 

Comorbid conditions (%): 

Diabetes: 100 

Treatment Duration: 12 weeks 

Follow-up Duration: 3 months 

Study Withdrawal (%): 44 

Treatment Compliance: NR 

(ITT): Yes but focused 

on per protocol analysis 

due to protocol violations 

(n=24) and failure to 

complete treatment (n=8) 

Withdrawals/dropouts 

adequately described: Yes 
121 

Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

Study, Year 

Country 

Funding Source 

Inclusion/Exclusion Criteria Patient Characteristics 

Ulcer Type 

Intervention 

Comparator 

Length of Follow-up 

Study Quality 

Duzgun 200847 Inclusion: diabetic; ≥18 years; foot wound N=100 Intervention (n=50): HBOT Allocation concealment: 

Turkey present for ≥4 weeks despite appropriate 

local and systemic wound care; wounds were 

Age (years): 61 

Gender (% male): HBOT 74%; 

administered at maximum working 

pressure of 20 ATA; unichamber 

Inadequate “according 

to a predetermined 

Funding Source: NR categorized according to a modification of Std Care 54%; p<0.05 pressure room; volume of 10m3 sequence wherein 

the Wagner classification; contraindication Race/ethnicity: NR at 2 to 3 ATA for 90 minutes + consecutively enrolled Therapy Type: to hyperbaric oxygen therapy (untreated BMI (>30, %): 63 (HBOT 80% standard therapy; treatment was 2 patients corresponding to Hyperbaric Oxygen pneumothorax, COPD, history of otic surgery, Std Care 46%; p<0.05) sessions/day, then 1 session on the an even random number 

(HBOT) upper respiratory tract infection, febrile state, Pre-albumin: NR following day received ST, and those 

history of idiopathic convulsion, hypoglycemia, 

current corticosteroid, amphetamine, 

catecholamine, or thyroid hormone use) 

HbA1

c (%): 8.4 

Smoking: 56% 

# Work days missed: NR 

Comparator (n=50): standard 

therapy 

corresponding to an odd 

random number received 

ST+HBOT” 

Exclusion: none reported ABI: NR 

Wound location (%): foot 

ALL: daily wound care (dressing 

changes, debridement); amputation Blinding: None reported 

Wound type: diabetic when indicated Intention to treat analysis

Wound size, cm2

: NR 

Wound grade (Wagner) (%): Antibiotic Use: as needed (ITT): Yes 

Grade II 18%; III 37%; IV 45% Treatment Duration: 20 to 30 days Withdrawals/dropouts 

Wound duration, months: NR Follow-up Duration: 92 weeks adequately described: 

Comorbid conditions (%): Study Withdrawal (%): None None reported 

History of DM: 100% reported 

History of HTN: 60% Treatment Compliance: NR 

History of hyperlipidemia: 58% 

Edmonds 200925 Inclusion: diabetes type 1 or 2; 18-80 years N=72 (of 82 randomized) Intervention (n=33): Apligraf (at Allocation concealment: 

Europe, Australia 

(multi-site) 

old; primarily neuropathic origin, not infected; 

present at least 2 weeks; surface area 1-16 

cm2

; adequate vascular supply; able to follow 

Age (years): 59 

Gender (% male): 86 

Race/ethnicity (%): NR 

week 0 and weeks 4 and 8, if 

needed) + Mepitel contact layer 

dressing 

Adequate 

Blinding: No 

Funding Source: NR 

Therapy Type: 

Biological Skin 

Equivalent 

treatment protocol (incl. off-loading) 

Exclusion: active Charcot foot; non-neuropathic 

origin; target ulcer with evidence of skin 

cancer; osteomyelitis at any location requiring 

treatment; infected target ulcer; medical 

condition which could impair healing; pregnant; 

corticosteroid use (current or prior); use of 

immunosuppressive agents; radiation therapy or 

chemotherapy; prior treatment of study wound; 

history of drug or alcohol abuse (in past year) 

BMI: NR 

HbA1

c (%): NR 

Smoking: NR 

# Work days missed: NR 

ABI: NR 

Wound location: plantar, forefoot 

Wound type: diabetic ulcer 

Wound size: 3.0 cm2 

Wound grade: NR 

Wound duration: 1.8 years 

Comorbid Conditions (%): 

Diabetes: 100 

Comparator (n=39): Mepitel 

ALL: weekly debridement if 

needed; saline-moist dressing; offloading 

Antibiotic Use: NR 

Treatment Duration: 12 weeks 

Follow-up Duration: 

24 weeks post-treatment 

Study Withdrawal (%): 12 

Treatment Compliance: NR 

Intention to treat analysis 

(ITT): No 

Withdrawals/dropouts 

adequately described: Yes 
122 

Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

Study, Year 

Country 

Funding Source 

Inclusion/Exclusion Criteria Patient Characteristics 

Ulcer Type 

Intervention 

Comparator 

Length of Follow-up 

Study Quality 

Falanga 199854 Inclusion:18-85 years of age; ulcer due to N=275 (of 309 randomized) Intervention (n=146): human skin Allocation concealment: 

United States (15 

sites) 

venous insufficiency (clinical signs/symptoms); 

no significant arterial insufficiency (ABI>0.65); 

evidence of venous insufficiency (air 

Age (years): 60 

Gender (% male): 52 

Race/ethnicity(%): white 76; black 18; 

equivalent (Apligraf) + elastic 

wrap; applied up to 5 times in first 

3 wks (days 0, 3-5, 7, 14, and/or 

Adequate 

Blinding: No 

Funding Source: plethysmography or photo-plethysmography Asian 1; Hispanic 4 21) until estimated area of graft Intention to treat analysis 

Industry (refilling time <20 seconds) BMI: NR “take” >50%; compression alone (ITT): No 

Therapy Type: 

Biological Skin 

Equivalent 

Exclusion: clinical signs of cellulitis, vasculitis, 

or collagen vascular disease; pregnancy or 

lactation; uncontrolled diabetes; other impaired 

wound healing (renal, hepatic, hematologic, 

neurologic, or immunological disease); received 

corticosteroids, immunosuppressive agents, 

radiation therapy, or chemotherapy in past 

HbA1

c (%): NR 

Smoking: NR 

# Work days missed: NR 

ABI: >0.65 per inclusion 

Wound location: NR 

Wound type: venous 

Wound size: 1.2 cm2 

Wound duration: <6 months: 31%; 6-12 

continued for total of 8 wks 

Comparator (n=129): compression 

therapy reapplied weekly for 8 wks 

Antibiotic Use: NR 

Treatment Duration: 8 weeks 

Follow-up Duration: 6 months 

Study Withdrawal (%): unclear; 

Withdrawals/dropouts 

adequately described: 

Partial – number of 

dropouts (n=72) is 

different than number not 

included in data analysis 

(n=34) 

month months: 21%; 1-2 years: 14%; >2 years: 

35% 

Comorbid conditions (%): NR 

analysis of 275/309 (89%) 

Treatment Compliance: NR 

Falanga 199955 Inclusion: same as above with ulcer duration of N=120 for efficacy analysis Intervention (n=74): same as above Allocation concealment: 

See Falanga199854 

United States (15 

sites) 

>1 year 

Exclusion: same as above 

(demographics from n=122; 2 

extra in treatment group by “double 

randomization”) 

Age (years): 58 

Comparator (n=48): same as above 

Antibiotic Use: NR 

Treatment Duration: 8 weeks 

Not applicable to subset 

Blinding: No 

Intention to treat analysis 

Funding Source: Gender (% male): 61 Follow-up Duration: 6 months (ITT): No 

Industry 

Therapy Type: 

Biological Skin 

Race/ethnicity (%): white 71; black 22; 

Asian 0; Hispanic 6 

Wound size: 1.74 cm2 

Wound duration >1 year: 100% 

Study Withdrawal (%): NR for 

subset of patients 

Treatment Compliance: NR 

Withdrawals/dropouts 

adequately described: No 

– number of dropouts in 

Equivalent Comorbid conditions (%): NR subset not reported 

Fumal 200279 Inclusion: at least 2 similar looking chronic leg N=17 patients (34 ulcers) Intervention (n=17 ulcers): 1% Allocation concealment: 

Belgium 

Funding Source: NR 

Therapy Type: Silver 

Products 

ulcers; minimal size 16 cm2

; no evidence for 

clinical infection 

Exclusion: neurological disorders; arterial 

occlusion; hypertension; diabetes; intake 

of antibiotics or any other drug acting on 

Age (years): 55 

NOTE: no other patient characteristics 

reported 

silver sulfadiazine cream applied 

3x/week 

Comparator (n=17 ulcers): 

standard care 

ALL: saline rinse, hydrocolloid 

NR 

Blinding: No 

Intention to treat analysis 

(ITT): Yes (no withdrawals 

reported) 

microcirculation or blood coagulation dressing, compression bandage 

Antibiotic Use: NR 

Treatment Duration: 6 weeks 

Follow-up Duration: none 

Study Withdrawal (%): NR 

Treatment Compliance: NR 

Withdrawals/dropouts 

adequately described: 

None reported 
123 

Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

Study, Year 

Country 

Funding Source 

Inclusion/Exclusion Criteria Patient Characteristics 

Ulcer Type 

Intervention 

Comparator 

Length of Follow-up 

Study Quality 

Gentzkow 199621 Inclusion: type 1 or 2 diabetes under reasonable N=50 Intervention: Dermagraft Allocation concealment: 

Pilot study for 

Naughton 

control; ulcers on plantar surface or heel; 

full-thickness defect >1 cm2

; wound bed free 

of necrotic debris/infection and suitable for 

Age (years): 61 

Gender (% male): 70 

Race/ethnicity (%): NR 

Group A (n=12): weekly (8 pieces & 

8 applications) 

Group B (n=14): every 2 wks (8 

Adequate 

Blinding: No 

United States (5 skin graft (no exposed tendon, bone, or joint; BMI: NR eight pieces & 4 applications) Intention to treat analysis 

sites) no tunnels or sinus tracts that could not be 

debrided); adequate circulation (clinical signs 

HbA1c (%): 8.4 

Smoking: NR 

Group C (n=11): every 2 wks (4 

pieces & 4 applications) 

(ITT): Yes 

Funding Source: 

Industry 

Therapy Type: 

and ankle-arm index (AAI) >0.75); ability to 

complete 12-week trial 

# Work days missed: NR 

ABI: ankle-arm index 1.0 

Wound location: plantar surface or heel 

Control Group D (n=13): standard 

wound therapy 

Withdrawals/dropouts 

adequately described: No 

Biological Skin Exclusion: >1 hospitalization during previous 6 Wound type: diabetic ulcer ALL: sharp debridement; salineEquivalent months due to hypoglycemia, hyperglycemia or 

ketoacidosis; ulcers of nondiabetic origin; use 

of medications known to interfere with healing 

(e.g., corticosteroids, immunosuppressives, or 

cytotoxic agents); pregnancy 

Wound size: 2.4 cm2 

Wound grade: NR 

Wound duration: 55.6 weeks 

Comorbid conditions (%): NR 

moist gauze; off-loading 

Antibiotic Use: NR 

Treatment Duration: 12 weeks 

Follow-up Duration: mean 14 mos 

Study Withdrawal (%): NR 

Treatment Compliance: NR 

Hammarlund 199472 Inclusion: non-diabetic chronic (> 1 year N=16 Intervention (n=8): HBOT at 2.5 Allocation concealment: 

Sweden 

Funding Source: NR 

duration) leg ulcers; distal blood pressure at 

ankle and first digit within normal range (≥100% 

and ≥70%, respectively, of upper arm blood 

pressure in mmHg) 

Age (years, median): HBOT 71; control 

63 

Gender (% male): 50 

Race/ethnicity: NR 

ATA for 90 minutes 5 days/week; 

multi-place hyperbaric chamber; 

pressurized for total of 30 sessions 

over 6 weeks 

Adequate 

Blinding: Patients, 

investigators 

Therapy Type: 

Hyperbaric Oxygen 

(HBOT) Exclusion: smoking; concomitant chronic 

conditions (e.g., diabetes, collagen disease); 

large vessel disease; ulcers showing tendency 

to heal (by visual inspection) during 2 months 

prior to study 

BMI: NR 

Pre-albumin: NR 

HbA1

c (%): NR 

Smoking: 0% (excluded) 

# Work days missed: NR 

ABI: NR 

Wound location: leg 

Comparator (n=8): placebo 

(hyperbaric air) 

ALL: continued pre-study treatment 

Antibiotic Use: NR 

Treatment Duration: 6 weeks 

Intention to treat analysis 

(ITT): Yes (none) 

Withdrawals/dropouts 

adequately described: Yes 

(none) 

Wound type: venous 

Wound size: 992 mm2 

Wound grade: NR 

Wound duration: NR but >1 yr 

Comorbid conditions (%): 

History of DM: 0% 

Follow-up Duration: 18 weeks (12 

from week 6) 

Study Withdrawal: 0 

Treatment Compliance: 100% 
124 

Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

Study, Year 

Country 

Funding Source 

Inclusion/Exclusion Criteria Patient Characteristics 

Ulcer Type 

Intervention 

Comparator 

Length of Follow-up 

Study Quality 

Hardikar 200529 

India (8 sites) 

Funding Source: NR 

Therapy Type: 

Platelet-derived 

Growth Factor 

Inclusion: type 1 or 2 diabetes; 18-80 years old; 

≥1 full thickness chronic neuropathic ulcer of ≥4 

weeks duration; stage 3 or 4 (Wound, Ostomy 

and Continence Nurses); infection controlled; 

area 1-40 cm2

; adequate perfusion of foot 

(by ultrasonography, pulse, ABI, ankle or toe 

pressure) 

Exclusion: arterial venous ulcers; osteomyelitis 

or burn ulcers; poor nutritional status 

(total proteins <6.5 g/dL); uncontrolled 

hyperglycemia (HbA1

c>12%), persistent 

infection; life threatening concomitant 

diseases; foot deformities; chronic renal 

insufficiency (sCr>3mg/dL); corticosteroid or 

immunosuppressant use; hypersensitivity to 

gel components; childbearing age, pregnant or 

nursing without contraceptive use 

N=113 

Age (years): 55 

Gender (% male): 70 

Race/ethnicity (%): native of India: 100 

BMI: NR 

Pre-albumin: NR 

HbA1

c (%): 7.5 

Smoking: NR 

# Work days missed: NR 

ABI: 1.06 

Wound location: foot 

Wound type: diabetic 

Wound size: 12.8 cm2 

Wound grade: NR 

Wound duration: 22.6 weeks 

Comorbid conditions (%): 

History of DM: 100 

Intervention (n=55): 100ug rhPDGF (0.01%) gel applied daily 

with volume calculated based on 

ulcer size 

Comparator (n=58): placebo gel 

applied daily 

ALL: debridement, daily ulcer 

cleaning and dressing, off-loading 

Antibiotic Use: appropriate use of 

systemic antibiotics advised 

Treatment Duration: 20 weeks 

Follow-up Duration: NR 

Study Withdrawal (%): 18.6 

Treatment Compliance: 97.3% (for 

gel application, dressing changes, 

and off-loading) 

Allocation concealment: 

Unclear 

Blinding: Unclear 

(reported to be doubleblind but not specified) 

Intention to treat analysis 

(ITT): No 

Withdrawals/dropouts 

adequately described: 

Yes 

Harding 200560 

Multinational – 

Belgium, United 

Kingdom, Germany, 

and Poland (21 sites) 

Funding Source: 

Industry 

Therapy Type: 

Keratinocytes 

(LyphoDerm; 

freeze-dried lysate 

from cultured 

allogeneic epidermal 

keratinocytes) 

Inclusion: age 30–85; clinical and documented 

(refilling time <20 sec or duplex ultrasound 

in past 12 months) venous insufficiency; no 

evidence of significant arterial insufficiency 

(ABI>0.8); ulcer duration >6 wks not healed with 

std care; size: 1-20 cm2 

Exclusion: arterial, decubitus, or diabetic 

ulcer; cellulitis or vasculitis; condition that 

impairs healing; systemic corticosteroids, 

immunosuppressive agents, radiation therapy, 

chemotherapy or surgical treatment/sclerotherapy (past 3 months or planned); bed/ 

wheelchair-bound; clinically significant infected 

ulcer; consistently bleeding or excessively 

exudating wound; exposed bone/tendon/fascia; 

treatment with cell- or growth factor-derived 

therapies (past month or planned); DVT; other 

clinical study (past month); allergic to study 

materials; alcohol or drug abuse (past 5 years); 

ulcer margin change >3 mm during 4 wk run-in 

N=194 (of 200 randomized) 

Age (years): 67.5 (median) 

Gender (% male): 39 

Race/ethnicity (%): white: 100 

BMI: 28.9 (median) 

Pre-albumin: NR 

HbA1

c (%): NR 

Smoking: NR 

# Work days missed: NR 

ABI:1.1 (median) 

Wound location: leg (61% on medial 

side) 

Wound type: venous leg ulcers 

Wound size: 5.2 cm2 (median) 

Wound grade: NR 

Wound duration: 43 weeks (median) 

Comorbid conditions (%): 

History of DM: 6 (12/194) 

Intervention (n=95): LyphoDerm 

0.9%; 8 applications (wks 0, 1, 

2, 3, 4, 6, 8, 10) + standard care 

(dressing with hydrocolloid and 

compression therapy) 

Comparator (n=53): vehicle only + 

standard care 

Comparator (n=46): standard care 

ALL: 4 week run-in period with 

alginate, hydrocolloid, foam, 

hydrogel dressings, or petrolatum 

gauze and compression therapy 

Antibiotic Use: NR 

Study Duration: 28 wks (4 wk run 

in, 10 wk tx, 14 wk follow up) 

Study Withdrawal (%): 8.2 (16/194) 

Treatment Compliance: 86.6% had 

no protocol deviation 

Allocation concealment: 

Unclear 

Blinding: No 

Intention to treat analysis 

(ITT): No (excluded 6 

patients who weren’t 

treated then one patient 

from std care group with 

no baseline data); due 

to protocol violations, 

created an “as treated” 

ITT group (n=193) and a 

PP group (n=167) 

Withdrawals/dropouts 

adequately described: Yes 
125 

Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

Study, Year 

Country 

Funding Source 

Inclusion/Exclusion Criteria Patient Characteristics 

Ulcer Type 

Intervention 

Comparator 

Length of Follow-up 

Study Quality 

Harding 201166 Inclusion: ≥18 years; male or female; ABI ≥0.8; N=281 Intervention (n=145): AQUACEL Ag Allocation concealment: 

Europe (43 sites) 

Funding Source: 

Industry (reported 

venous leg ulcer (CEAP classification C6); 

duration <24 months; size 5-40 cm2

; ≥3 of the 

following: pain between dressing changes, 

perilesional skin erythema, edema, foul odor, or 

Age (years): 70 

Gender (% male): 35 

Race/ethnicity: NR 

BMI: 30 

(4 wks); AQUACEL (4 wks) 

Comparator (n=136): Urgotul Silver 

(4 wks); Urgotul (4 wks) 

Adequate 

Blinding: Unclear 

Intention to treat analysis 

that sponsor high levels of exudate Pre-albumin: NR ALL: compression; dressing (ITT): Modified (had at 

designed study and HbA1

c (%): NR changes per clinical condition & least one exposure to 

approved final article; Exclusion: current antibiotics (week before Smoking: NR exudate; cleansing; mechanical treatment) 

authors had full 

control over contents 

of article) 

Therapy Type: Silver 

Products 

inclusion); ulcers clinically infected or 

erysipelas; malignant; recent DVT or venous 

surgery (past 3 months); progressive neoplastic 

lesion treated by radiotherapy or chemotherapy; 

receiving immunosuppressive agents or high 

dose corticosteroids 

# Work days missed: NR 

ABI: 1.04 

Wound location: 2% foot, 47% ankle, 

33% calf, 18% gaiter 

Wound type: venous 

Wound size: NR 

Wound grade: CEAP C6 

debridement if needed 

Antibiotic Use: NR 

Treatment Duration: 8 weeks 

Follow-up Duration: none 

Study Withdrawal (%): 8% 

AQUACEL; 12% Urgotul 

Withdrawals/dropouts 

adequately described: Yes 

Wound duration: 0.76 yr 

Comorbid conditions (%): NR 

Treatment Compliance: NR 

Ieran 199070 Inclusion: skin lesions (ulcers due to idiopathic N=37 (of 44 randomized) Intervention (n=22): EMT stimulator Allocation concealment: 

Italy 

Funding Source: NR 

chronic venous insufficiency or post-phlebitic 

venous insufficiency) present at least for 3 

months 

Age (years): 66 

Gender (% male): 38 

Race/ethnicity: NR 

BMI: NR, Obese 51% 

(single pulse of electrical current 

generating a magnetic field of 2.8 

mT at a frequency of 75 Hz, with 

an impulse width of 1.3 ms for 3-4 

Adequate 

Blinding: Patients, 

investigators 

Therapy Type: 

Electromagnetic 

(EMT) 

Exclusion: patients treated with steroids or 

affected by systemic diseases; concomitant 

arterial occlusive disease 

Pre-albumin: NR 

HbA1

c (%): NR 

Smoking: NR 

# Work days missed: NR 

ABI: NR 

hours daily) 

Comparator (n=22): sham EMT 

ALL: no elastic compression 

Intention to treat analysis 

(ITT): No 

Withdrawals/dropouts 

adequately described: Yes 

Wound location: leg 

Wound type: venous 

Wound size: <15 cm2

 - EMT 54% (mean 

4.8), control 46% (5.0); >15 cm2 - EMT 

36% (mean 34.2), control 64% (39.9) 

Wound duration: 26 months 

Comorbid conditions (%): 

History of DM: 19 

Antibiotic Use: as needed 

Treatment Duration: 90 days or 

until wound healed 

Follow-up Duration: at least one yr 

Study Withdrawal (%): 16% (n=7) 

Treatment Compliance: Average 

stimulator use per day (hours) – 

intervention 3.8, control 3.7 
126 

Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

Study, Year 

Country 

Funding Source 

Inclusion/Exclusion Criteria Patient Characteristics 

Ulcer Type 

Intervention 

Comparator 

Length of Follow-up 

Study Quality 

Jacobs 200839 Inclusion: Wagner grade 1 or 2 ulcerations N=40 Intervention (n=20): Bensal HP Allocation concealment: 

United States 

Funding Source: NR 

Therapy Type: Silver 

Sulfadiazine Cream 

(SSC) 

of the foot; ulcer size 3 cm diameter or less; 

located on plantar aspect of foot; under care for 

diabetes mellitus; demonstration of biphasic or 

triphasic arterial sounds on arterial Doppler; ABI 

of ≥0.75 

Exclusion: HbA1

c greater than 10%; nonpalpable pulses or history of claudication or rest 

pain; clinical evidence of local sepsis (absence 

of malodor, exudates, or erythema extending >1 

cm from the ulceration) 

Age (years): NR 

Gender (% male): NR 

Race/ethnicity: NR 

BMI: NR 

Pre-albumin: NR 

HbA1

c (%): ≤10% for inclusion 

Smoking: NR 

# Work days missed: NR 

ABI: ≥0.75 for inclusion 

Wound location: plantar 

Wound type: diabetic ulcer 

Wound size: 3 cm diameter or less for 

inclusion 

Wound grade: Wagner 1 or 2 

Wound duration: NR 

Comorbid conditions (%): 

History of DM: 100 

applied daily 

Comparator (n=20): SSC applied 

every 12 hours 

ALL: debride; off-loading of weight 

bearing and shoe pressure 

Antibiotic Use: NR 

Treatment Duration: 6 weeks 

Follow-up Duration: none 

Study Withdrawal (%): 0 

Treatment Compliance: NR 

Unclear 

Blinding: Yes 

Intention to treat analysis 

(ITT): Yes 

Withdrawals/dropouts 

adequately described: Yes 

(none) 

Jaiswal 201032 Inclusion: type I or type II diabetes and chronic N=50 Intervention (n=25): topical rhPDGF Allocation concealment: 

India 

Funding Source: NR 

Therapy Type: 

Platelet-derived 

Growth Factors 

ulcers of at least 4 weeks duration; IAET stage 

III and IV 

Exclusion: ankle brachial pressure index (ABI) 

<0.9 

Age (years): 53 

Gender (% male): 84 

Race/ethnicity: NR 

BMI: 22.4 

Pre-albumin: NR 

HbA1

c (%): NR 

Smoking (%): 18 

gel (PLERMIN) applied once daily 

Comparator (n=25): topical KY Jelly 

applied once daily 

ALL: off-loading in patients with 

plantar ulcers 

Adequate 

Blinding: Unclear 

Intention to treat analysis 

(ITT): Yes 

Withdrawals/dropouts 

# Work days missed: NR Antibiotic Use: NR adequately described: Yes 

ABI: NR Treatment Duration: 10 weeks 

Wound location: lower limb Follow-up Duration: NR 

Wound type: diabetic Study Withdrawal (%): NR 

Wound size: 28.2 cm2 Treatment Compliance: NR 

Wound grade: IAET class III – 62%; 

class IV – 38% 

Wound duration (median wks): 

Intervention 5; Control 6 

Infection: NR 

Comorbid conditions (%): 

History of DM: 100 

History of amputation or previous ulcer: 

4% 

History of PVD: 0% 
127 

Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

Study, Year 

Country 

Funding Source 

Inclusion/Exclusion Criteria Patient Characteristics 

Ulcer Type 

Intervention 

Comparator 

Length of Follow-up 

Study Quality 

Jørgensen 200577 Inclusion: chronic venous or mixed venous/ N=129 Intervention (n=65): sustained Allocation concealment: 

Europe and North 

America (7 countries, 

15 sites) 

Funding Source: 

Industry 

arterial leg ulcer with delayed healing process 

(area reduction of ≤0.5 cm in past 4 wks); ABI 

≥0.65; compression therapy for 4 wks prior to 

inclusion; ulcer size ≥2 cm2

; max of 1.5 cm from 

edge of 10X10 cm dressing; at least 1 of 

a) increased exudate (past 4 wks), 

Age (years): 74 (median) 

Gender (% male): 36 

Race/ethnicity: NR 

BMI: NR 

Pre-albumin: NR 

HbA1c (%): NR 

release silver foam dressing 

(Contreet Foam) 

Comparator (n=64): foam dressing 

without added silver (Allevyn 

Hydrocellular) 

Adequate 

Blinding: No (open study) 

Intention to treat 

analysis (ITT): For safety 

outcomes; per-protocol 

Therapy Type: Silver 

Products 

b) increased ulcer area pain (past 4 wks, per 

patient), 

c) discoloration of granulation tissue, 

d) foul odor (per study personnel) 

Exclusion: clinical infection; current use of 

antiseptics/antibiotics (1 wk prior to inclusion 

& through study); HbA1

c >10%, current 

systemic corticosteroids >10mg/d or other 

immunosuppressants from 4 wks prior to 

inclusion; disease that may interfere with 

healing 

Smoking: NR 

# Work days missed: NR 

ABI: 1.0 

Wound location: “leg” 

Wound type: venous or mixed venous/ 

arterial 

Wound size: 6.4 cm2

 (median) 

Wound grade: NR 

Wound duration: 1.05 years (median) 

Comorbid conditions (%): NR 

ALL: compression therapy; 

dressing in place as long as 

clinically possible (max=7 days) 

Antibiotic Use: Excluded 

Treatment Duration: 4 weeks 

Follow-up Duration: none 

Study Withdrawal (%): 15.5% 

Treatment Compliance: NR 

analysis for performance 

outcomes 

Withdrawals/dropouts 

adequately described: Yes 

Jude 200740 Inclusion: type 1 or 2 diabetes with HbA1

c N=134 Intervention (n=67): sterile, non- Allocation concealment: 

United Kingdom, 

France, Germany, 

Sweden (18 sites) 

≤12%; serum creatinine ≤200 μmol/l; Grade 1 or 

2 (Wagner) diabetic foot ulcer of non-ischemic 

etiology 

Age (years): 60 

Gender (% male): 74 

Race/ethnicity: NR 

BMI: NR 

woven sodium carboxymethylcellulose primary ionic silver 

(AQAg, 1.2%) dressing; in place up 

to 7 days or as indicated 

Adequate 

Blinding: No 

Intention to treat analysis 

Funding Source: 

Industry 

Therapy Type: Silver 

Products (dressing) 

Exclusion: allergic to dressing components; 

known or suspected malignancy local to the 

study ulcer; taking systemic antibiotics >7 days 

prior to enrollment; inadequate arterial perfusion 

(ABI<0.8, great toe SBP<40 mmHg, or forefoot 

TcPO2

 <30 mmHg (supine) or <40 mmHg 

Pre-albumin: NR 

HbA1

c (%): 8.0 

Smoking: NR 

# Work days missed: NR 

ABI: 1.8 

Wound location: 68% plantar; 32% nonComparator (n=67): sterile, nonwoven calcium alginate (CA) 

dressing (moistened for use on dry 

wounds, changed daily on infected 

wounds) 

(ITT): No (final wound 

evaluation for 65 of 67 in 

each group) 

Withdrawals/dropouts 

adequately described: Yes 

(sitting)) plantar 

Wound type: 75.5% neuropathic, 24.5% 

neuroischemic 

Wound size: 3.7 cm2 

Wound grade (%): Wagner I 75.5; 

Wagner II 24.5 

Wound duration: 1.3 yrs 

Comorbid conditions (%): 

History of DM: 100% 

ALL: off-load of plantar ulcers 

Antibiotic Use: at clinician’s 

discretion (15.5% at enrollment) 

Treatment Duration: 8 weeks or to 

healing 

Follow-up Duration: none 

Study Withdrawal (%): 16 

Treatment Compliance: NR 
128 

Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

Study, Year 

Country 

Funding Source 

Inclusion/Exclusion Criteria Patient Characteristics 

Ulcer Type 

Intervention 

Comparator 

Length of Follow-up 

Study Quality 

Karatepe 201143 Inclusion: diabetic foot ulcer N=67 Intervention (n=30): Negative Allocation concealment: 

Turkey 

Funding Source: NR 

Therapy Type: 

Negative Pressure 

Wound Therapy 

Exclusion: none reported 

Age (years): 67.3 

Gender (% male): 28 

Race/ethnicity: NR 

BMI: NR 

Pre-albumin: NR 

HbA1

c (%): 85% poor control 

Smoking: NR 

# Work days missed: NR 

ABI: 93% > 0.7 

Wound location: foot 

Pressure Wound Therapy (no 

details provided) 

Comparator (n=37): Standard 

wound care (no details provided) 

Antibiotic Use: NR 

Treatment Duration: NR 

Follow-up Duration: 1 month after 

healing (mean of 4 months) 

Study Withdrawal (%): 0 

Unclear 

Blinding: No 

Intention to treat 

analysis (ITT): Yes – no 

withdrawals 

Withdrawals/dropouts 

adequately described: Yes 

– no withdrawals 

Wound type: diabetic ulcer 

Wound size: 32.4 cm2 

Wound grade: NR 

Wound duration: 9.9 weeks 

Comorbid conditions (%): 

History of DM: 100 

Treatment Compliance: NR 

Kenkre 199671 Inclusion: venous ulcer with unsatisfactory N=19 Intervention 1 (n=5): EMT Allocation concealment: 

United Kingdom 

Funding Source: 

Industry 

Therapy Type: 

Electromagnetic 

(EMT) 

healing for at least the previous 4 weeks 

Exclusion: none reported 

Age (years): 71 (Group 1 (59) 

significantly younger than Group 2 (78) 

& Comp. (73)) 

Gender (% male): 26 

Race/ethnicity: NR 

BMI: NR 

Pre-albumin: NR 

HbA1

c (%): NR 

Smoking: NR 

(Elmedistraal) - 600 Hz electric field 

and 25 mT magnetic field 

Intervention 2 (n=5): EMT 

(Elmedistraal) - 600 Hz electric field 

days 1-5 and 800 Hz days 6-30, 

and 25 mT magnetic field 

Comparator (n=9): sham (placebo) 

Unclear 

Blinding: Patients, 

investigators (reported as 

double-blind) 

Intention to treat analysis 

(ITT): Yes (no dropouts) 

Withdrawals/dropouts 

# Work days missed: NR 

ABI: NR 

Wound location: leg 

Wound type: venous 

Wound size: EMT 600 Hz: 63 mg (6 to 

269) EMT 800 Hz: 81 mg (46 to 197) 

Control: 119 mg (35 to 526) 

Wound duration: 626 weeks 

Antibiotic Use: NR 

Treatment Duration: 30 min week 

days for a total of 30 days 

Follow-up Duration: 4-week 

observation period (dressing 

changes only); final assessment on 

day 50 

Study Withdrawal (%): 0 

adequately described: Yes 

(no dropouts) 

Comorbid conditions (%): NR 
129 

Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

Study, Year 

Country 

Funding Source 

Inclusion/Exclusion Criteria Patient Characteristics 

Ulcer Type 

Intervention 

Comparator 

Length of Follow-up 

Study Quality 

Kessler 200348 Inclusion: type 1 and type 2 diabetes; chronic N=27 (of 28 randomized) Intervention (n=15): HBOT; 2.5 Allocation concealment: 

France 

Funding Source: 

Foundation 

Therapy Type: 

Hyperbaric Oxygen 

(HBOT) 

foot ulcers (Wagner grades I, II, and III) 

Exclusion: gangrenous ulcers, severe 

arteriopathy (TcPo2<30 mmHg), emphysema, 

proliferating retinopathy, claustrophobia 

Age (years): 64 

Gender (% male): 70 

Race/ethnicity: NR 

BMI: 29.5 

Pre-albumin: NR 

HbA1

c (%): 8.8 

Smoking: NR 

# Work days missed: NR 

ATA for two 90-min daily sessions 

of 100% O2

 breathing; multi-place 

hyperbaric chamber pressurized; 5 

days/wk for 2 consecutive wks 

Comparator (n=13): Wound mgmt 

ALL: multi-disciplinary wound 

management program (off-loading, 

Unclear 

Blinding: Outcome 

assessors (surface area 

of the ulcer) 

Intention to treat analysis 

(ITT): No, one withdrawal 

not included in analysis

ABI: NR 

Wound location: heel/sole 61%, toe 

39% 

Wound type: diabetic 

Wound size: 2.6 cm2 

Wound grade: Wagner I–III 

Wound duration: ≥3 months 

Comorbid conditions (%): 

History of CAD/CVD: 22 

History of DM: 100 

metabolic control, antibiotics) 

Antibiotic Use: 63% 

Treatment Duration: 2 weeks 

Follow-up Duration: 4 weeks 

Study Withdrawal (%): 4% (n=1) 

Treatment Compliance: NR; 

hospitalized for first 2 weeks 

Withdrawals/dropouts 

adequately described: Yes 

Krishnamoorthy Inclusion: full thickness venous leg ulcer without N=53 Intervention: compression and Allocation concealment: 

200356 exposure of muscle, tendon or bone; venous Age (years): 69 Group 1 (n=13): 1 piece of Adequate 

Multinational (6 sites) reflux in veins of superficial or deep systems; 

ulcer duration ≥2 months but ≤ 60 months; size 

Gender (% male): 42 

Race/ethnicity (%): Caucasian: 94; 

Dermagraft applied weekly during 

the first 11 weeks (12 applications) Blinding: No 

Funding Source: of 3-25 cm3

; ABPI ≥ 0.7; < 50% healing from black: 4; Asian: 2 Group 2 (n=13): 1 piece of Intention to treat analysis 

Industry screening visit to day of first intervention (with BMI: 30.4 Dermagraft applied at day 0, weeks (ITT): Yes 

Therapy Type: use of multi-layer compression bandage during 

14 day screening period) 

HbA1

c (%): NR 

Smoking: NR 

1, 4 and 8 (4 applications) 

Group 3 (n=14): 1 piece of Withdrawals/dropouts 

Biological Skin # Work days missed: NR Dermagraft applied at day 0 adequately described: No 

Equivalent Exclusion: other causes of ulceration 

(rheumatoid vasculitis, diabetic foot ulcer); 

severe leg edema (could not be controlled with 

ABI: 1.1 

Wound location: leg 

Wound type: venous 

Comparator (n=13): compression 

therapy alone (Profore) 

compression bandages); soft-tissue infections 

that would interfere with wound healing; 

impaired mobility; any underlying medical 

condition (e.g., PVD, renal disease) 

Wound size (median): 7.0 cm2

 Wound 

grade: NR 

Wound duration (median): 47.7 days 

Infection: NR 

Comorbid conditions (%): NR 

Antibiotic Use: as needed 

Treatment Duration: 11 weeks 

Follow-up Duration: NR 

Study Withdrawal (%): 11.3 

Treatment Compliance: NR 
130 

Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

Study, Year 

Country 

Funding Source 

Inclusion/Exclusion Criteria Patient Characteristics 

Ulcer Type 

Intervention 

Comparator 

Length of Follow-up 

Study Quality 

Landsman 200820 Inclusion: ≥18 years, insulin or non-insulin N=26 Intervention (n=13): extracellular Allocation concealment: 

United States (4 

sites) 

Funding Source: NR 

Therapy Type: 

Collagen Compared 

with Biological Skin 

Equivalent 

dependent diabetes; HbA1

c 5.5-12%; diabetic 

ulcer; epidermal ulcers without exposed bone or 

tendon; viable wound bed with granulated tissue 

(bleeding following debridement), ulcer size 

1-16 cm2

; present ≥4 weeks 

Exclusion: malnourished; allergic to porcine 

products; hypersensitivity to Dermagraft; severe 

arterial disease (ABI <0.9); radiation at ulcer 

site; corticosteroids or immune suppressant 

use; immunocompromised; non-diabetic 

ulcer; vasculitis; severe rheumatoid arthritis; 

severe infection at wound site; osteomyelitis, 

necrosis, or avascular ulcer bed; hemodialysis; 

uncontrolled diabetes; active Charcot’s 

neuroarthropathy 

Age (years): 63 

Gender (% male): 69 

Race/ethnicity: NR 

BMI: NR 

Pre-albumin: NR 

HbA1

c (%): NR 

Smoking: NR 

# Work days missed: NR 

ABI: NR 

Wound location: NR 

Wound type: diabetic ulcer 

Wound size: 1.9 cm2 

Wound grade: NR 

Wound duration: NR 

Comorbid conditions (%):NR 

matrix (OASIS); max of 8 

applications 

Comparator (n=13): living skin 

equivalent (Dermagraft); max of 3 

applications with reapplication at 

2 and 4 wks if wound closure not 

achieved 

ALL: debrided and cleansed; saline 

moistened gauze left in place for 1 

wk; off-loading (boot) 

Treatment Duration: 12 weeks 

Follow-up Duration: 8 weeks 

Study Withdrawal (%): NR 

Treatment Compliance: NR 

Adequate 

Blinding: No 

Intention to treat analysis 

(ITT): Yes 

Withdrawals/dropouts 

adequately described: No 

Lindgren 199858 Inclusion: out-patients; venous ulcers over N=27 Intervention (n=15): keratinocyte Allocation concealment: 

Sweden 

Funding Source: 

medial part of the distal third of the legs as 

determined by clinical impression and ABI 

(cutoff not given) 

Age (years): 76 (median) 

Gender (% male): 33.3 

Race/ethnicity: NR 

allograft + dressing (Mepitel) 

Comparator (n=12): dressing only 

Unclear 

Blinding: No 

Industry BMI: NR ALL: CO2 laser debridement; if Intention to treat analysis 

Therapy Type: 

Biological Skin 

Equivalent, 

Cryopreserved 

Exclusion: none reported HbA1c (%): NR 

Smoking: NR 

# Work days missed: NR 

ABI: 1.0 

Wound type: venous 

infection-free ≥1 wk then pneumatic 

compression, treatment & elastic 

compression; inspected on day 3; 

tx weekly; in bed for 24 hrs; feet 

elevated when sitting 

(ITT): Unclear 

Withdrawals/dropouts 

adequately described: No 

Wound size: 6.3 cm2 

Wound duration: 

<2 years: 44.4% 

>2 years: 55.6% 

Comorbid conditions (%): NR 

Antibiotic Use: as needed 

Treatment Duration: 8 weeks 

Follow-up Duration: 8 weeks 

Study Withdrawal (%): 0% 

Treatment Compliance: NR 
131 

Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

Study, Year 

Country 

Funding Source 

Inclusion/Exclusion Criteria Patient Characteristics 

Ulcer Type 

Intervention 

Comparator 

Length of Follow-up 

Study Quality 

Londahl 201046 Inclusion: diabetes; ≥1 full-thickness wound; N=94 Intervention (n=49): HBOT; ATA Allocation concealment: 

Sweden below ankle; >3 months; previously treated 

at diabetes foot clinic for at least 2 months; 

Age (years): 69 

Gender (% male): 81 

of 2.5; multi-place hyperbaric 

chamber; compression of air for 

Unclear (“sealed 

envelopes”) 

Funding Source: 

Foundation 

Therapy Type: 

Hyperbaric Oxygen 

(HBOT) 

adequate distal perfusion or nonreconstructable 

peripheral vascular disease 

Exclusion: contraindications for hyperbaric 

treatment (severe obstructive pulmonary 

disease, malignancy, and untreated 

thyrotoxicosis); current drug or alcohol misuse; 

vascular surgery in the lower limbs within the 

last two months; participation in another study; 

Race/ethnicity: NR 

BMI: NR 

Pre-albumin: NR 

HbA1

c(%): 7.9 

Smoking: 25% current 

# Work days missed: NR 

ABI: NR 

Wound location (%): toe 40; plantar 

forefoot 26; middle 14; malleoli 6; heel 

5 minutes followed by 85-min 

daily (session duration 95 min); 5 

days/wk; 8 weeks (40 treatment 

sessions) 

Comparator (n=45): placebo 

(hyperbaric air); same schedule 

ALL: standard treatment at multidisciplinary diabetes foot clinic 

Blinding: Patients, 

investigators, outcome 

assessments 

Intention to treat analysis 

(ITT): Yes 

Withdrawals/dropouts 

adequately described: Yes 

suspected poor compliance 12; dorsal 1 (debride, off-load, treatment 

Wound type: diabetic of infection, revascularization, 

Wound size: 3.0 cm2 metabolic control)

Wound grade (Wagner) (%): Grade II 

26; III 56; IV 18 Antibiotic Use: Allowed 

Wound duration, months: 9.5 Treatment Duration: 8 weeks 

Comorbid conditions (%): Follow-up Duration: 1 year 

History of CAD/CVD: MI 29%; stroke Study Withdrawal (%): 20 (n=19) 

16% Treatment Compliance: 57% 

History of DM: 100% attended 40 sessions; 80% 

History of amputation: 11% major; 39% attended >35 sessions; compliance 

minor with standard tx NR 

History of HTN: 75% 

History of hyperlipidemia: 88% 
132 

Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

Study, Year 

Country 

Funding Source 

Inclusion/Exclusion Criteria Patient Characteristics 

Ulcer Type 

Intervention 

Comparator 

Length of Follow-up 

Study Quality 

Marston 200323 Inclusion: ≥18 years; type 1 or 2 diabetes; N=245 (ulcer duration >6wks) Intervention (n=130): Dermagraft; Allocation concealment: 

United States (35 

sites) 

Funding Source: 

Industry 

plantar forefoot or heel ulcer present ≥2 weeks; 

1.0-20 cm2

; full thickness but no exposed 

muscle, tendon, bone, or joint capsule; no 

necrotic debris; healthy vascularized tissue 

present; ABI >0.7; adequate circulation to the 

Age (years): 56 

Gender (% male): 74 

Race/ethnicity (%): Caucasian 72; NonCaucasian 28 

BMI: NR 

applied weekly up to 8 times over 

12 week study 

Comparator (n=115): standard 

wound care 

Unclear 

Blinding: Yes 

Intention to treat analysis 

(ITT): Yes 

Therapy Type: 

Biological Skin 

Equivalent 

foot (palpable pulse) 

Exclusion: gangrene on affected foot; underlying 

Charcot deformity; ulcer size changed (+ or 

-) by >50% during 2 wk screening; severe 

malnutrition (albumin <2.0); random blood sugar 

>450 mg/dl; urine ketones present; nearby 

non-study ulcer; on systemic corticosteroids, 

immunosuppressive/cytotoxic agents; AIDS 

or HIV-positive; at-risk for bleeding; cellulitis, 

osteomyelitis, or other infection 

HbA1

c (%): NR 

Smoking: NR 

# Work days missed: NR 

ABI: NR (>0.7 for inclusion) 

Wound location: plantar forefoot (87%) 

or heel (13%) 

Wound type: diabetic ulcers 

Wound size: 2.4 cm2 

Wound duration: 53 wks (41 wks vs. 67 

wks, p=NR) 

Comorbid conditions (%): 

History of DM 100 

ALL: sharp debridement + salinemoistened gauze dressings; 

ambulatory with diabetic footwear 

Antibiotic Use: NR 

Treatment Duration: 12 weeks 

Follow-up Duration: 1 week followup to confirm closure 

Study Withdrawal (%): 19 

Treatment Compliance: NR 

Withdrawals/dropouts 

adequately described: No 

McCallon 200044 Inclusion: diabetes; age 18-75 years; non­ N=10 (pilot study) Intervention (n=5): continuous Allocation concealment: 

United States 

Funding Source: NR 

healing foot ulceration present >1 month 

Exclusion: venous disease; active infection not 

Age (years): 52.8 

Gender (% male): NR 

Race/ethnicity: NR 

pressure (125 mmHg) for 48 hrs; 

dressing change then intermittent 

pressure (125 mmHg); dressing 

Inadequate 

Blinding: No 

Therapy Type: 

Negative Pressure 

Wound Therapy 

resolved by initial debridement; coagulopathy BMI: NR 

Pre-albumin: NR 

HbA1

c (%): NR 

Smoking: NR 

# Work days missed: NR 

change/assessment every 48 hrs 

Comparator (n=5): saline 

moistened gauze; changed every 

12 hrs; assessed 3 times/wk 

Intention to treat 

analysis (ITT): Yes – no 

withdrawals 

Withdrawals/dropouts 

ABI: NR 

Wound location: 9 forefoot, 1 midfoot 

Wound type: diabetic ulcer 

Wound size: NR 

Wound grade: NR 

Wound duration: NR 

Comorbid conditions (%): 

History of DM: 100 

ALL: initial surgical debridement; 

bed rest or strict non-wt bearing 

Antibiotic Use: NR 

Treatment Duration: NR 

Follow-up Duration: Followed until 

delayed primary closure or wound 

healed by secondary intention 

Study Withdrawal (%): 0 

Treatment Compliance: NR 

adequately described: Yes 

– no withdrawals 
133 

Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

Study, Year 

Country 

Funding Source 

Inclusion/Exclusion Criteria Patient Characteristics 

Ulcer Type 

Intervention 

Comparator 

Length of Follow-up 

Study Quality 

Michaels 2009 a,b67,68 Inclusion: active ulceration of lower leg, present N=213 Intervention (n=107): silver- Allocation concealment: 

England (2 locations) 

Funding Source: 

Government 

Therapy Type: Silver 

Products 

for more than 6 weeks 

Exclusion: insulin-controlled diabetes 

mellitus; pregnancy; sensitivity or specific 

contraindications to the use of silver; ABI <0.8 

in affected leg; maximum ulcer diameter <1 cm; 

atypical ulcers (e.g., suspicion of malignancy); 

coexisting skin conditions or vasculitis; receiving 

Age (years): 71 

Gender (% male): 46 

Race/ethnicity: NR 

BMI: NR 

Pre-albumin: NR 

HbA1

c (%): NR 

Smoking: 18.3% 

# Work days missed: NR 

donating dressings (list of 6 

approved for study) 

Comparator (n=106): non-silver 

dressings (any non-antimicrobial 

low-adherence dressing) 

ALL: multilayer compression 

bandage (per local practice); 

Adequate 

Blinding: No 

Intention to treat analysis 

(ITT): No 

Withdrawals/dropouts 

adequately described: Yes 

oral or parenteral antibiotic treatment ABI: NR dressings changed weekly unless

Wound location: leg needed; other interventions used if 

Wound type: venous clinically appropriate

Wound size: 72% <3 cm diam 

Wound grade: NR Antibiotic Use: NR 

Wound duration: 38.5% present for >12 Treatment Duration: 12 weeks 

weeks Follow-up Duration: to 1 year after 

Comorbid conditions (%): entry 

History of CAD/CVD: 14% history of MI Study Withdrawal (%): 2.3% 

or cardiac failure, 8% history of stroke Treatment Compliance: NR 

or TIA 

Miller 201078 Inclusion: lower leg ulcer; ABI ≥0.6; diameter N=266 (of 281 randomized) Intervention (n=140): Acticoat Allocation concealment: 

Australia (2 sites) 

Funding Source 

Foundation, 

≤15 cm; ≥18 years; no topical antiseptic 

treatment in week before and no antibiotics 48 

hrs before recruitment; no systemic steroids; 

no diagnosis of diabetes or malignancy related 

Age (years): 80 

Gender (% male): 41 

Race/ethnicity: NR 

BMI: NR 

(silver); clinician chose dressing 

Comparator (n=141): Iodosorb 

(iodine); clinician chose dressing 

Adequate 

Blinding: No – open label 

Intention to treat analysis 

Government to ulcer; not receiving palliative care; no known Pre-albumin: NR ALL: treated until signs of critical (ITT): No 

Therapy Type: Silver 

Products 

contraindications to treatment products; ≥ 1 

sign of infection or critical colonization (cellulitis, 

suppuration, lymphangitis, sepsis, bacteremia, 

changes in granulation tissue, increased or 

malodorous exudate, new areas of slough or 

wound breakdown, impaired or delayed wound 

healing, increased or new pain) 

Exclusion: none reported 

HbA1

c (%): NR 

Smoking: NR 

# Work days missed: NR 

ABI: NR 

Wound location: lower leg 97% 

Wound type: venous (74%), mixed 

(26.3%) 

Wound size: 705 mm2 

Wound grade: NR 

Wound duration: 54 weeks 

Comorbid conditions (%): 

History of DM: 0 

colonization and infection absent 

1 wk; non-antimicrobial dressing 

if no signs; required adherence to 

compression bandaging 

Antibiotic Use: 21% (55/266) 

Treatment Duration: 12 weeks 

Follow-up Duration: none 

Study Withdrawal (%): 5 

Treatment Compliance: Monitored 

compression bandage adherence 

Withdrawals/dropouts 

adequately described: Yes 
134 

Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

Study, Year 

Country 

Funding Source 

Inclusion/Exclusion Criteria Patient Characteristics 

Ulcer Type 

Intervention 

Comparator 

Length of Follow-up 

Study Quality 

Mostow 200553 Inclusion: chronic venous insufficiency (clinical N=120 Intervention (n=62): OASIS; each Allocation concealment: 

United States, United 

Kingdom, Canada 

(12 Sites) 

presentation, history) and/or positive venous 

reflux; ≥18 years; ulcer >30 days; 1-49 cm2

; 

between knee and ankle; full thickness and 

non-healing; visible wound bed with granulation 

Age (years): 64 

Gender (% male): 42 

Race/ethnicity (%): white 81; black 16; 

Asian 1; other 3 

week to non-epithelialized portion 

Comparator (n=58): standard 

wound care 

Adequate 

Blinding: No 

Intention to treat analysis 

Funding Source: tissue BMI: 31.9 ALL: weekly debride, dressing (ITT): Yes 

Industry 

Therapy Type: 

Biological Dressings 

Exclusion: infected, necrotic, or avascular ulcer 

bed; cellulitis, osteomyelitis, or exposed bone/ 

tendon/fascia; severe RA; uncontrolled CHF 

or diabetes (HbA1

c >12%); ABI <0.8; history 

of local radiation; corticosteroids or immune 

suppressives; known allergy or hypersensitivity 

to products; sickle cell disease; hemodialysis; 

malnutrition (albumin <2.5 g/dL); investigational 

drug or device treatment in last 30 days 

HbA1

c (%): NR 

Smoking: NR 

# Work days missed: NR 

ABI: NR, all >0.8 by exclusion 

Wound type: venous 

Wound size: 11.1 cm2 

Wound duration: 1-3 months: 34.2%; 

4-6 months: 15.8%; 7-12 months: 

10.0%; >12 months: 36.7%; not 

specified: 3.3% 

Comorbid conditions (%): NR 

changes; non-adherent dressing + 

4 layer compression bandaging 

Antibiotic Use: NR 

Treatment Duration: 12 weeks; 

control group offered cross-over 

to OASIS if not healed; treated for 

4 weeks; continued for total of 12 

weeks if initial improvement seen 

Follow-up Duration: 6 months; 

(retained 45% of ITT population) 

Study Withdrawal (%): 20 

Treatment Compliance: NR 

Withdrawals/dropouts 

adequately described: Yes 

Naughton 199722 Inclusion: diabetes; neuropathic full-thickness N=235 (of 281 randomized) Intervention (n=109): Dermagraft; Allocation concealment: 

United States (20 

sites) 

Funding Source: 

plantar surface foot ulcers of the forefoot or 

heel; ulcer size >1.0 cm2 

Exclusion: initial rapid healing in response to 

Age (years): NR 

Gender (% male): NR 

Race/ethnicity (%): NR 

BMI: NR 

day 0 and weeks 1-7 (8 total) 

Comparator (n=126): standard 

wound care 

Unclear 

Blinding: “Single-blinded” 

Intention to treat analysis 

Industry standard care during a screening period HbA1

c (%): NR ALL: debridement, infection control, (ITT): No 

Therapy Type: 

Biological Skin 

Smoking: NR 

# Work days missed: NR 

ABI: NR 

saline-moistened gauze dressings, 

and off-weighting Withdrawals/dropouts 

adequately described: No 

Equivalent – Wound location: plantar forefoot or heel Antibiotic Use: NR 

Dermagraft Wound type: Diabetic ulcer 

Wound size: NR 

Wound duration: NR 

Comorbid conditions (%): 

History of DM: 100 

Treatment Duration: 12 weeks (8 

week intervention) 

Follow-up Duration: to 32 weeks 

Study Withdrawal (%): 16.4 

Treatment Compliance: NR 
135 

Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

Study, Year 

Country 

Funding Source 

Inclusion/Exclusion Criteria Patient Characteristics 

Ulcer Type 

Intervention 

Comparator 

Length of Follow-up 

Study Quality 

Navratilova 200459 Inclusion: venous ulcer diagnosed by N=50 Intervention (n=25): single Allocation concealment: 

Czech Republic 

Funding Source: 

history, physical examination, and Doppler 

ultrasonography 

Age (years): 63 

Gender (% male): 36 

Race/ethnicity: NR 

application of cryopreserved 

cultured epidermal keratinocytes; 

nonadherent silicone dressing 

No 

Blinding: No 

Government Exclusion: arterial ulcer; ulcer size <2 cm2

; BMI: 30.1 and gauze bandages; dressings Intention to treat analysis 

Therapy Type: 

Biological Skin 

Equivalent, 

cryopreserved 

versus lyophilized 

allografts 

duration <3months; uncompensated diabetes 

mellitus; pronounced anemia (hg <10.0g/dL); 

uncompensated heart insufficiency; pronounced 

hypoproteinemia (albumin <3.5g/dL); ABI 

<0.8; metastatic malignant tumor; systemic 

immunosuppressive therapy 

HbA1

c (%): NR 

Smoking: NR 

# Work days missed: NR 

ABI: NR, >0.8 per exclusion 

Wound location: leg 

Wound type: venous ulcer 

Wound size: 10.7 cm2

 (cryopreserved 

removed after 5 days then 

changed every 3 days 

Comparator (n=25): same except 

allografts of lyophilized cultured 

epidermal keratinocytes 

ALL: debride and dressings until 

(ITT): Yes 

Withdrawals/dropouts 

adequately described: 

None reported 

12.4 cm2, lyophilized 9.0 cm2) 

Wound duration: 23.7 months 

(cryopreserved 21 months, lyophilized 

17 months) 

Comorbid conditions (%): NR 

clean & granulating wound base 

achieved; wet saline dressings 1-3 

days before graft; hospitalized for 

graft; bed rest and limb elevation 

for 48 h after grafting 

Antibiotic Use: systemic; 1 day 

before allografts if infection 

Treatment Duration: single 

application 

Follow-up Duration: 3 months 

Study Withdrawal (%): 0% 

Treatment Compliance: NR 
136 

Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

Study, Year 

Country 

Funding Source 

Inclusion/Exclusion Criteria Patient Characteristics 

Ulcer Type 

Intervention 

Comparator 

Length of Follow-up 

Study Quality 

Niezgoda 200519 

United States and 

Canada (9 Sites) 

Funding Source: 

Industry (provided 

study supplies) 

Therapy Type: 

Biological Dressings 

Compared to 

Platelet-derived 

Growth Factors 

Inclusion: ≥18 years; type 1 or 2 diabetes; nonhealing diabetic ulcer of >30 days; ulcer full 

thickness with size of 1-49 cm2

; visible wound 

bed with granulation tissue; Grade I, Stage A 

(UT classification) 

Exclusion: ulcer of non-diabetic etiology; 

uncontrolled diabetes ( A1C >12%); 

documented severe arterial disease or low 

blood supply (TcPO2 <30 mmHg or toe-brachial 

index <0.70); on corticosteroids or immune 

suppressives; infected, necrotic, or avascular 

ulcer bed; cellulitis, osteomyelitis, or exposed 

bone/tendon/fascia; active Charcot or sickle cell 

disease; hemodialysis, malnutrition (albumin 

<2.5 g/dL); known allergy/hypersensitivity 

to products; treatment with any other 

investigational drug or device (past 30 days) 

N=73 (of 98 randomized) 

Age (years): 58 

Gender (% male): 60 

Race/ethnicity %: NR 

BMI: 32.5 

Pre-albumin: NR 

HbA1

c (%): 8.3 

Smoking: NR 

# Work days missed: NR 

ABI: NR 

Wound location: 65% plantar 

Wound type: diabetic ulcer 

Wound size: 4.1 cm2 

Wound duration (%): 1-3 months: 49; 

4-6 months: 16; 7-12 months: 15 >12 

months: 19 

Comorbid conditions (%): 

History of DM: 100% 

Type 1 - 49% OASIS, 22% PDGF 

Type 2 - 51% OASIS, 78% PDGF 

History of PVD: 0% severe 

Intervention (n=37): OASIS; saline 

and secondary dressing; reapplied weekly as needed 

Comparator (n=36): PDGF 

(becaplermin/Regranex); patients 

applied daily; saline-moistened 

gauze dressing for 12 hrs then 

rinsed and covered 

ALL: off-loading; clean and debride 

weekly 

Antibiotic Use: NR 

Treatment Duration: 12 weeks; if 

not healed, crossover tx offered; 

treated for 4 weeks; continued 

for total of 12 weeks if initial 

improvement seen 

Follow-up Duration: 6 months (only 

50% of per protocol sample) 

Study Withdrawal (%): 26 

Treatment Compliance: NR 

Allocation concealment: 

Adequate 

Blinding: Unclear 

Intention to treat analysis 

(ITT): No 

Withdrawals/dropouts 

adequately described: 

Yes 

Omar 200457 

United Kingdom 

Funding Source: 

Unclear (“statistical 

advice and 

guidance” from 

industry) 

Therapy Type: 

Biological Skin 

Equivalent, 

Dermagraft 

Inclusion: chronic venous leg ulcers (based on 

clinical examination, duplex finding of venous 

dysfunction [all had evidence of superficial 

reflux, but no deep venous reflux or DVT]; and 

exclusion of other causes [especially arterial 

insufficiency, ABPI >0.9]); duration >12 wks; 

ulcer area 3–25 cm2

, clean ulcer bed with 

healthy granulation tissue 

Exclusion: none reported 

N=18 

Age (years): 60 

Gender (% male): 61 

Race/ethnicity: NR 

BMI: NR 

HbA1c (%): NR 

Smoking: NR 

# Work days missed: NR 

ABI: 1.06 

Wound type: venous leg ulcer 

Wound size: 10.7 cm2 

Wound duration: 119.3 weeks 

Comorbid conditions (%): NR 

Intervention (n=10): Dermagraft at 

weeks 0, 1, 4 & 8 

Comparator (n=8): non-adherent 

dressing 

ALL: cleaning, debridement, fourlayer compression bandaging 

Antibiotic Use: NR 

Treatment Duration: 12 weeks 

Follow-up Duration: none 

Study Withdrawal (%): NR 

Treatment Compliance: NR 

Allocation concealment: 

Unclear (“computergenerated code based on 

the order of admittance to 

the study”) 

Blinding: Yes (ulcer 

measurement) 

Intention to treat analysis 

(ITT): Unclear 

Withdrawals/dropouts 

adequately described: 

None reported 
137 

Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

Study, Year 

Country 

Funding Source 

Inclusion/Exclusion Criteria Patient Characteristics 

Ulcer Type 

Intervention 

Comparator 

Length of Follow-up 

Study Quality 

Reyzelman 200918 Inclusion: ≥18 years; type 1 or 2 diabetes; N=85 (of 86 randomized) Intervention (n=47): single Allocation concealment: 

United States (11 

sites) 

diabetic foot ulcer; 1-25 cm2

; absence of 

infection; adequate circulation to affected 

extremity (TcPO2 >30 mmHg, ABI 0.70–1.2, or 

Age (years): 57 

Gender (% male): NR 

Race/ethnicity (%): NR 

application - 4x4 cm 

human acellular dermal 

regenerative tissue matrix graft 

Unclear 

Blinding: No 

Funding biphasic Doppler waveforms in arteries of lower BMI: 33.8 (based on n=83) (GRAFTJACKET); sutured or Intention to treat analysis 

Source: Industry extremity) HbA1

c (%): 7.9 stapled in place; silver-based (ITT): Yes (included all 

(compensation to Smoking: NR non-adherent dressing (Silverlon) but one intervention 

study personnel and 

consultants involved 

Exclusion: poor glycemic control (HbA1

c >12%); 

serum Cr >3.0 mg/dl; sensitivity to antibiotics 

# Work days missed: NR 

ABI: NR 

applied; secondary dressings as 

determined by investigator 

group patient who 

was removed from 

in data interpretation 

and writing; therapy 

provided at no 

charge) 

Therapy Type: 

Collagen 

used in preparation of cellular matrix; non 

revascularable surgical sites; ulcers probing to 

bone; wound recently treated with biomedical 

or topical growth factors 

Wound location (%): toe 28; foot 44; 

heel 17; other 11 

Wound type: diabetic ulcer 

Wound size: 4.3 cm2 

Wound duration: 23.1 weeks

 (Note: range=0-139 weeks) 

Comorbid conditions (%): 

Comparator (n=39): standard 

care (moist-wound therapy with 

alginates, foams, hydrocolloids 

or hydrogels at discretion of 

physician); dressing changes daily 

or per treating physician 

participation due to noncompliance) 

Withdrawals/dropouts 

adequately described: 

Yes 

History of DM: 100; Type 1 – 8.2; Type 

2 – 91.8 

ALL: surgical site prep. before tx; 

off-load (removable cast walker) 

Antibiotic Use: if infection present 

Treatment Duration: 12 weeks 

Follow-up Duration: none 

Study Withdrawal (%): 8% 

Treatment Compliance: NR 

Romanelli 200775 Inclusion: >18 years; mixed A/V leg ulcer by N=54 Intervention (n=27): OASIS Allocation concealment: 

Italy clinical and instrumental assessment; venous 

reflux by Doppler flow studies; ABPI >0.6 and 

Age (years): 63 

Gender (% male): 48 Comparator (n=27): Hyaloskin Inadequate (every other 

patient that was selected 

Funding Source: <0.8; ulcer duration >6 weeks; 2.5-10 cm2

; Race/ethnicity (%): NR ALL: saline + secondary dressing; by clinician for study) 

Industry 

Therapy Type: 

Biological Dressing 

>50% granulation tissue on wound bed 

Exclusion: diabetes; current smoker; ABPI <0.6; 

clinical signs of wound infection; necrotic tissue 

on wound bed; known allergy to treatment 

products; unable to follow protocol 

BMI: NR 

HbA1

c (%): NR (DM excluded) 

Smoking: 0 (excluded) 

# Work days missed: NR 

ABI: 0.6 to 0.8 

Wound type: mixed A/V ulcers 

Wound size: 6 cm2 

no compression; observed 2x/wk; 

dressing change as needed (approx. 

1x/wk); all dressings applied in clinic 

Antibiotic Use: NR 

Treatment Duration: 16 weeks 

Follow-up Duration: none 

Blinding: No 

Intention to treat analysis 

(ITT): No 

Withdrawals/dropouts 

adequately described: 

Wound duration: 7.8 weeks 

Comorbid conditions (%): 

History of DM: 0 

History of PVD: 100 

Study Withdrawal (%): 7.4 (4/54) 

Treatment Compliance: NR 

Yes 
138 

Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

Study, Year 

Country 

Funding Source 

Inclusion/Exclusion Criteria Patient Characteristics 

Ulcer Type 

Intervention 

Comparator 

Length of Follow-up 

Study Quality 

Romanelli 201076 Inclusion: venous or mixed A/V leg ulcer; ABI N=50 Intervention (n=25): OASIS Allocation concealment: 

Italy 

Funding Source: 

0.6-0.8; duration >6 months; size >2.5 cm2

; 

50% granulation tissue on wound bed 

Age (years): NR 

Gender (% male): 48 

Race/ethnicity (%): NR 

Comparator (n=25): petroleumimpregnated gauze 

Unclear 

Blinding: Unclear 

Industry Exclusion: clinical signs of infection; ABI <0.6; BMI: NR ALL: moistened with saline + Intention to treat analysis 

Therapy Type: 

Biological dressing 

necrotic tissue on wound bed; known allergy to 

treatment products; unable to follow protocol 

HbA1

c (%): NR 

Smoking: NR 

# Work days missed: NR 

ABI: NR but for inclusion 0.6-0.8 

Wound location: leg 

secondary nonadherent dressing; 

assessed weekly for up to 8 wks; 

patients changed secondary 

dressing at home 

(ITT): No 

Withdrawals/dropouts 

adequately described: 

Yes 

Wound type: venous or mixed A/V ulcer 

Wound size: 24.4 cm2 

Wound duration: 7.1 weeks 

Comorbid conditions (%): NR 

Antibiotic Use: NR 

Treatment Duration: 8 weeks 

Follow-up Duration: stated monthly 

follow-up for 6 months (results not 

reported) 

Study Withdrawal (%): 4% (2/50) 

Treatment Compliance: NR 

Saad Setta 201136 Inclusion: age 40-60 yrs; type 1 or 2 diabetes; N=24 Intervention (n=12): platelet rich Allocation concealment: 

Egypt 

Funding Sources: 

NR 

Therapy Type: 

Platelet Rich Plasma 

normal peripheral platelet count (>150,000 

mm3

) 

Exclusion: receiving or had received chemo or 

radiation therapy in past 3 months; screening 

serum albumin <2.5 ml/dl or hemoglobin <10.5 

mg/dl or platelet count <100x109

/l; peripheral 

vascular disease; bacteria count (study ulcer) 

>105 organisms/gram tissue;, exposed tendons, 

ligaments or bone 

Age (years): NR 

Gender (% male): NR 

Race/ethnicity: NR 

BMI: NR 

Pre-albumin: NR 

HbA1

c (%): NR 

Smoking: 33.3% 

# Work days missed: NR 

ABI: NR 

Wound location: foot 

Wound type: diabetic 

plasma applied twice weekly 

(intervals of 3-4 days) 

Comparator (n=12): platelet poor 

plasma (same schedule) 

ALL: off-loading of ulcer area 

Antibiotic Use: NR 

Treatment Duration: 20 weeks 

Follow-up Duration: none 

Study Withdrawal (%): NR 

Unclear 

Blinding: No 

Intention to treat analysis 

(ITT): Unclear 

Withdrawals/dropouts 

adequately described: No 

(not reported) 

Wound size: 9.4 cm2 

Wound grade: NR 

Wound duration: ≥12 weeks 

Infection: NR 

Comorbid conditions (%): 

History of HTN: 70 

Treatment Compliance: NR 
139 

Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

Study, Year 

Country 

Funding Source 

Inclusion/Exclusion Criteria Patient Characteristics 

Ulcer Type 

Intervention 

Comparator 

Length of Follow-up 

Study Quality 

Schuler 199669 Inclusion: age >18 years old; ulcers <50 cm2

; N=54 Intervention (n=28): below-knee Allocation concealment: 

United States 

Funding Source: 

ulcers <2 years old 

Exclusion: ABI <0.9; cancer; massive leg 

Age (years): 57 

Gender (% male): 46 

Race/ethnicity: NR 

gradient compression elastic 

stocking + external pneumatic 

compression; applied daily (1 hour 

Unclear 

Blinding: No 

Industry edema due to congestive heart failure; cellulitis; BMI: 33 in morning + 2 hours in evening) Intention to treat analysis 

Therapy Type: 

Intermittent 

Pneumatic 

Compression 

osteomyelitis; sickle cell disease; use of 

steroids or vasoconstrictive medications; DVT 

or pulmonary embolism in previous 6 months; 

vein ligation or injection sclerotherapy in 

previous year 

Pre-albumin: NR 

HbA1

c (%): NR 

Smoking (%): 31 

# Work days missed: NR 

ABI: 1.1 

Wound location: NR 

Comparator (n=26): Unna’s boot 

ALL: leg elevation 2X/day 

Antibiotic Use: NR 

Treatment Duration: 6 months 

(ITT): No 

Withdrawals/dropouts 

adequately described: 

Yes 

Wound type: venous ulcer 

Wound size: 9.9 cm2 

Wound grade: NR 

Wound duration: 306 days 

Comorbid conditions (%): NR 

Follow-up Duration: NR 

Study Withdrawal (%): 13 

Treatment Compliance: 93% (4 

total dropped for non-compliance) 

Stacey 200062 Inclusion: venous ulceration based on ABI >0.9, N=86 Intervention (n=42): bandage Allocation concealment: 

Australia 

Funding Source: 

Government, 

Industry 

venous refilling time < 25 seconds, blood tests 

negative for other causes of ulceration 

Exclusion: none reported 

Age (years): 71 

Gender (% male): 42 

Race/ethnicity: NR 

BMI: NR 

Pre-albumin: NR 

soaked in platelet lysate in 

phosphate buffered saline (PBS) 

Comparator (n=44): placebo (PBS) 

soaked bandage 

Adequate 

Blinding: Unclear 

Intention to treat analysis 

(ITT): Unclear 

Therapy Type: 

Platelet Rich Plasma 

HbA1

c (%): NR 

Smoking: NR 

# Work days missed: NR 

ABI: NR 

Wound location: leg 

Wound type: venous ulcer 

Wound size: 4.9 cm2 

Wound grade: NR 

Wound duration: 12 weeks 

Comorbid conditions (%): NR 

ALL: compression bandaging; 

dressings/bandages applied twice 

weekly 

Antibiotic Use: NR 

Treatment Duration: 9 months 

Follow-up Duration: NR 

Study Withdrawal (%): 9 

Treatment Compliance: NR 

Withdrawals/dropouts 

adequately described: 

Yes 
140 

Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

Study, Year 

Country 

Funding Source 

Inclusion/Exclusion Criteria Patient Characteristics 

Ulcer Type 

Intervention 

Comparator 

Length of Follow-up 

Study Quality 

Steed 1995, 200633,34 

United States 

Funding Source: 

Industry (responsible 

for conduct of trial 

and all analyses) 

Therapy Type: 

Platelet-derived 

Growth Factors 

Inclusion: ≥19 years; ulcer area 1-100 cm2

; 

chronic (≥8 weeks duration) non-healing; fullthickness; lower extremity ulcer resulting from 

diabetes; free of infection; adequate arterial 

blood supply 

Exclusion: nursing, pregnant, or of childbearing 

potential; hypersensitivity to study gel; >3 

ulcers; ulcers from large-vessel arterial 

ischemia, venous insufficiency, pressure, 

or necrobiosis lipoidica diabeticorum; 

osteomyelitis; malignant or terminal disease; 

alcohol or substance abuse; thermal, electrical, 

or radiation burn wounds at site of target ulcer; 

receiving corticosteroids, immunosuppressive 

agents, radiation therapy, or chemotherapy 

N=118 

Age (years): 61 

Gender (% male): 75 

Race/ethnicity (%): white: 86; other: 14 

BMI: NR 

Pre-albumin: NR 

HbA1c (%): NR 

Smoking: NR 

# Work days missed: NR 

ABI: NR 

Wound location: foot 

Wound type: diabetic ulcer 

Wound size: 7.2 cm2 

Wound grade: NR 

Wound duration: 78 weeks 

Infection: NR 

Infection: Excluded 

Comorbid conditions (%): NR 

Intervention (n=61): plateletderived growth factor (PDGF-BB 

100ug/g gel) applied once/day by 

patient or patient caregiver 

Comparator (n=57): placebo gel 

applied as above 

ALL: debridement as needed; 

instructed on off-loading 

Antibiotic Use: NR 

Treatment Duration: 20 weeks 

Follow-up Duration: NR 

Study Withdrawal (%): 27 

Treatment Compliance: 98% 

(weight of gel tube, diary of 

dressing changes) 

Allocation concealment: 

Adequate 

Blinding: Unclear 

Intention to treat analysis 

(ITT): Yes 

Withdrawals/dropouts 

adequately described: 

Yes 
141 

Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

Study, Year 

Country 

Funding Source 

Inclusion/Exclusion Criteria Patient Characteristics 

Ulcer Type 

Intervention 

Comparator 

Length of Follow-up 

Study Quality 

Vanscheidt 200761 Inclusion: age 18-90; chronic venous leg ulcers N=225 Intervention (n=116): 2 wks before Allocation concealment: 

Europe (Hungary, 

Czech Republic, 

Germany) 

(>3-month duration); area 2-50 cm2

 after sharp 

debridement (±5%); venous insufficiency (by 

Doppler sonography with reflux in superficial 

and/or deep veins, venous refilling time <20 

Age (years): 67 

Gender (% male): 37 

Race/ethnicity: NR 

BMI: 28.6 

Day 0 – skin biopsy to collect and 

cultivate autologous keratinocytes 

Day 0 – debride, disinfect & rinse; 

applied autologous keratinocytes 

Unclear 

Blinding: No 

Intention to treat analysis 

Funding Source: NR seconds, duplex sonography, or phlebography); Pre-albumin: NR within fibrin sealant; pressure (ITT): Yes 

Therapy Type: ulcer located below knee joint excluding ulcers 

of distal metatarsal area 

HbA1c (%): NR 

Smoking: 19.1% 

dressing; compression therapy; 

repeated up to 3X in first 3 mos; Withdrawals/dropouts 

Keratinocytes # Work days missed: NR further applications allowed if >2 adequately described: No 

(autologous 

keratinocytes 

combined with fibrin 

sealant: BioSeed-S) 

Exclusion: not able to get/apply compression 

therapy; ABI <0.8; vasculitis, severe rheumatoid 

arthritis, or other connective tissue diseases; 

previous surgery on venous system or 

sclerotherapy, phlebitis, or DVT in past 3 

months; significant medical conditions that 

impair wound healing (e.g., renal and hepatic 

insufficiency or uncontrolled diabetes); known 

ABI: NR, but all >0.8 by criteria 

Wound location: below knee 

Wound type: venous leg 

Wound size: 

2-10 cm2: 60.4% (136/225) 

>10 cm2

: 38.7% (87/225) 

Wound grade: NR 

Wound duration: 

wks apart; compression therapy 

maintained throughout 6 months 

Comparator (n=109): Day 0 – 

Same except non-adherent gauze; 

continuous compression therapy; 

sharp debridement and paraffin 

gauze as needed 

hypersensitivity to bovine proteins or other 

constituents of BioSeed-S (if randomized to 

that group); pregnant or breast-feeding women, 

or of childbearing age not using contraception 

during treatment phase 

3-12 months: 59.1%(133/225) 

>12 months: 40.9% (92/225) 

Comorbid conditions (%): NR 

ALL: debrided, routine dressings 

and compression for 4 weeks 

prior to Day 0 (not randomized if 

responsive to std care after 2 wks) 

Antibiotic Use: NR 

Treatment Duration: up to 3 mos 

Follow-up Duration: 6 mos 

Study Withdrawal (%): NR 

Treatment Compliance: NR 
142 

Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

Study, Year 

Country 

Funding Source 

Inclusion/Exclusion Criteria Patient Characteristics 

Ulcer Type 

Intervention 

Comparator 

Length of Follow-up 

Study Quality 

Veves 200124 Inclusion: type 1 or 2 diabetes; age 18-80 N=208 (of 277 randomized) Intervention (n=112): Graftskin Allocation concealment: 

United States (24 

sites) 

years; HbA1

c 6-12%; full thickness neuropathic 

ulcers ≥2 weeks in duration (excluded dorsum 

of foot and calcaneous); ulcer size 1-16 cm2

; 

Age (years): 57 

Gender (% male): 78 

Race/ethnicity: white: 69; African 

(Apligraft); at baseline then weekly, 

if needed, for maximum of 4 weeks 

(max of 5 application) 

AdequateBlinding: No 

Funding Source: 

Industry 

Therapy Type: 

Biological Skin 

Equivalent 

dorsalis pedis and posterior tibial pulses 

audible by Doppler 

Exclusion: clinical infection at ulcer site; 

significant lower extremity ischemia; active 

Charcot’s disease; ulcer of non-diabetic 

pathophysiology; significant medical conditions 

that would impair healing 

American: 16; Hispanic: 13 

BMI: 32 

HbA1

c (%): 8.6 

Smoking: NR 

Alcohol: NR 

# Work days missed: NR 

ABI: >1.0 54%; <0.8 10% 

Wound Type: neuropathic diabetic foot 

ulcer 

Wound size: 2.9 cm2 

Wound Duration: 11.3 months 

Comorbid Conditions (%): NR 

Comparator (n=96): saline 

moistened gauze 

ALL: scheduled dressing changes; 

off-loading 

Antibiotic Use: NR 

Treatment Duration: maximum of 

4 weeks 

Follow-up Duration: 12 weeks with 

safety evaluation to 3 months 

Study Withdrawal (%): 21 

Treatment Compliance: 98% 

Intention to treat analysis 

(ITT): Modified (excluded 

69 patients during 1 week 

run-in) 

Withdrawals/dropouts 

adequately described: 

Yes 

Veves 200216 Inclusion: ≥18 years of age; diabetic foot ulcer; N=276 Intervention (n=138): collagen & Allocation concealment: 

United States 

(11 sites) 

≥30 days duration; Wagner grade 1 or 2; area 

≥1 cm3

; adequate circulation 

Age (years): 58.5 

Gender (% male): 74 

Race/ethnicity (%): white 63, African 

oxidized regenerated cellulose 

dressing (Promogran); application 

frequency at clinicians’ discretion 

Unclear 

Blinding: No 

Funding Source: 

Industry 

Therapy Type: 

Collagen 

Exclusion: clinical signs of infection; exposed 

bone; concurrent condition that may interfere 

with healing; known alcohol or drug abuse; 

dialysis; corticosteroids; immunosuppressive 

agents; radiation or chemotherapy; 

hypersensitivity to dressing components; 

American 10; Hispanic 16; Native 

American 12 

BMI: NR 

Pre-albumin: NR 

HbA1

c (%): 8.6 

Smoking: NR 

Comparator (n=138): isotonic 

sodium chloride solutionmoistened gauze 

ALL: surgical debridement at all 

study visits; dressing changes 

Intention to treat analysis 

(ITT): Yes 

Withdrawals/dropouts 

adequately described: 

Yes 

inability to be fitted with off-loading device; 

multiple ulcers on same foot 

# Work days missed: NR 

ABI: NR 

Wound location: foot 

Wound type: diabetic ulcer 

Wound size: 2.8 cm2 

Wound grade: NR 

Wound duration: 3 months (median) 

Infection: NR 

Comorbid conditions (%): NR 

according to good clinical practice; 

off-loading 

Antibiotic Use: NR 

Treatment Duration: 12 weeks 

Follow-up Duration: NR 

Study Withdrawal (%): 32 

Treatment Compliance: >90% 

(both groups; tx, dressing change) 
143 

Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

Study, Year 

Country 

Funding Source 

Inclusion/Exclusion Criteria Patient Characteristics 

Ulcer Type 

Intervention 

Comparator 

Length of Follow-up 

Study Quality 

Vin 200252 Inclusion: venous leg ulcers; free of infection; N=73 Intervention (n=37): Promogran Allocation concealment: 

France (14 sites) 

Funding Source: 

Industry 

Therapy Type: 

Collagen 

≥30 days duration; ABPI ≥0.8; 2 cm-10 cm in 

any one dimension(if multiple ulcers largest 

was selected if ≥3 cm away from any other 

ulcer) 

Exclusion: unwilling to wear compression 

bandage continuously; immobile and unable 

to care for themselves; medical condition that 

may interfere with healing including carcinoma, 

vasculitis, connective tissue disease, and 

immune system disorders; received topical 

corticosteroids, immunosuppressive agents, 

radiation therapy, or chemotherapy in 30 days 

before study entry 

Age (years): 73 

Gender (% male): 35 

Race/ethnicity: NR 

BMI: 28 

Pre-albumin: NR 

HbA1

c (%): NR 

Smoking (%): 8 

# Work days missed: NR 

ABI: 1.1 

Wound location: leg 

Wound type: venous ulcer 

Wound size: 8.2 cm2 

Wound grade: NR 

Wound duration: 9.2 months 

Comorbid conditions (%): 

History of CAD: 11; History of DM: 14; 

History of HTN: 49 

dressing + Adaptec (petrolatumimpregnated dressing) 

Comparator (n=36): Adaptec only 

ALL: compression bandages; 

dressing changes 2x/wk or more 

Antibiotic Use: NR 

Treatment Duration: to 12 weeks 

Follow-up Duration (mean): 

Promogran=65.9 days 

Adaptec=63.8 days 

Study Withdrawal (%): 26 

Treatment Compliance: NR 

Unclear 

Blinding: Partial 

(investigator assessment 

validated by 2 clinicians) 

Intention to treat analysis 

(ITT): Yes 

Withdrawals/dropouts 

adequately described: 

Yes 

Viswanathan 201141 Inclusion: type 2 diabetes; Wagner Grade I, II, N=38 (of 40 randomized) Intervention (n=20): diabetic Allocation concealment: 

India 

Funding Source: 

Industry 

Therapy Type: Silver 

Products 

or III ulcer 

Exclusion: clinical signs of severe infection; 

exposed bone; unwilling to participate in study 

Age (years): 59 

Gender (% male): NR 

Race/ethnicity: NR 

Pre-albumin: NR 

HbA1

c (%): 10.7 

Smoking: NR 

# Work days missed: NR 

ABI: NR 

wound cream (polyherbal 

formulation) 

Comparator (n=20): silver 

sulphadiazine cream 

ALL: daily dressing changes 

(saline wash, cream applied) 

Unclear 

Blinding: Unclear 

Intention to treat analysis: 

No 

Withdrawals/dropouts 

adequately described: 

Wound location: plantar (66% fore, 24% 

mid, 11% hind) 

Wound type: diabetic ulcer 

Wound size: 4.6 X 3.3 cm 

Wound grade: 29.0% I, 31.6% II, 39.5% 

III 

Wound duration: 14.5 days 

Comorbid conditions (%): 

History of DM: 100 

History of PAD: 23.7 

Antibiotic Use: If ulcers showed 

clinical signs of infection 

Treatment Duration: unclear 

Follow-up Duration: 5 months 

Study Withdrawal (%): 5 

Treatment Compliance: NR 

Yes 
144 

Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

Study, Year 

Country 

Funding Source 

Inclusion/Exclusion Criteria Patient Characteristics 

Ulcer Type 

Intervention 

Comparator 

Length of Follow-up 

Study Quality 

Vuerstack 200680 

Netherlands (2 sites) 

Funding Source: 

Industry (no 

influence on data 

analysis, data 

interpretation, 

writing of report, 

or manuscript 

submission) 

Therapy Type: 

Negative Pressure 

Wound Therapy 

Inclusion: hospitalized with chronic 

venous, combined venous and arterial, or 

microangiopathic leg ulcers (>6 months 

duration); ambulatory; failed conservative local 

treatment for ≥6 months 

Exclusion: age >85 years; use of immune 

suppression; allergy to wound therapies; 

malignant or vasculitis origin; ABI <0.6 

N=60 

Age (years): 72 (median) 

Gender (% male): 23 

Race/ethnicity: NR 

BMI: NR 

Pre-albumin: NR 

HbA1

c (%): NR 

Smoking: 26% 

# Work days missed: NR 

ABI: 100 (median) 

Wound location: leg 

Wound type: venous (43%), combined 

arterial/venous (13%), arteriolosclerotic 

(46%) 

Wound size: 38 cm2 

Wound grade: NR 

Wound duration: 7.5 months 

Comorbid conditions (%): 

History of DM: 17% (type 2) 

History of HTN: 43% 

Immobility: 42% 

Intervention (n=30; 28 received 

tx): vacuum-assisted; permanent 

negative pressure (125 mmHg) 

until skin graft + 4 days after graft 

Comparator (n=30; 26 received 

tx): daily local wound care and 

compression therapy until skin 

graft; standard care after graft 

ALL: initial necrosectomy; fullthickness punch skin graft when 

100% granulation tissue on surface 

and wound secretion minimal; only 

toilet and basic hygiene mobility 

during treatment 

Antibiotic Use: 3.5% at baseline 

Treatment Duration: to closure 

Follow-up Duration: 12 months 

Study Withdrawal (%): 10 

Treatment Compliance: Inpatients 

Allocation concealment: 

Adequate 

Blinding: No 

Intention to treat analysis 

(ITT): Unclear (ITT 

for adverse events 

but unclear for other 

outcomes) 

Withdrawals/dropouts 

adequately described: 

Yes 
145 

Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

Study, Year 

Country 

Funding Source 

Inclusion/Exclusion Criteria Patient Characteristics 

Ulcer Type 

Intervention 

Comparator 

Length of Follow-up 

Study Quality 

Wainstein 201150 

Israel 

Funding Source: NR, 

device supplied by 

manufacturer 

Therapy Type: 

Ozone-oxygen 

Therapy 

Inclusion: adult (age ≥18 years); type 2 or type 

1 diabetes; Wagner classification stage 2 or 3 

or post-debridement stage 4 foot ulcer 

Exclusion: gangrenous foot ulcer; active 

osteomyelitis; history of collagen diseases; 

hyperthyroidism; pregnancy or nursing; HbA1

c 

>10.5%; ABI <0.65; hemoglobin <8 g/dL; liver 

function tests (alanine transaminase, aspartate 

transaminase, or c-glutamyl transpeptidase) 

elevated to more than three times the upper 

normal limit; serum creatinine >2.5 mg/dL or 

dialysis; known allergy to ozone 

N=61 

Age (years): 63 

Gender (% male): 62 

Race/ethnicity: NR 

BMI: NR 

Pre-albumin: NR 

HbA1

c (%): 8.6 

Smoking: 8% current 

# Work days missed: NR 

ABI: 26% 0.65-0.8; 23% 0.8-1.0; 46% 

>1.0 

Wound location: foot 

Wound type: diabetic 

Wound size (cm2

): ozone 4.9, sham 3.5 

Wound grade: Wagner 2-4 

Wound duration: 15.8 years 

Comorbid conditions (%): 

History of DM: 100% 

Intervention (n=31): ozoneoxygen; Phase I – tx sessions 

4x/wk for 4 wks or granulation in 

50% of wound area; max of 1 day 

between txs (5 day week); gas 

concentration: 96% oxygen & 4% 

(80 lg/ mL) ozone; Phase II – tx 

sessions 2x/wk to complete 12 wk 

tx; gas concentration: 98% oxygen 

& 2% (40 lg/mL) ozone 

Comparator (n=30); sham tx; 

device circulated room air only 

ALL: debridement; daily wound 

dressings as needed; tx 

sessions=26 min 

Antibiotic Use: as needed 

Treatment Duration: 12 weeks 

Follow-up Duration: none 

Study Withdrawal (%): 44 (27/61) 

Treatment Compliance: NR 

Allocation concealment: 

Unclear 

Blinding: Double (patient 

and investigator) 

Intention to treat analysis 

(ITT): Yes, all randomized 

included 

Withdrawals/dropouts 

adequately described: 

Yes 
146 

Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

Study, Year 

Country 

Funding Source 

Inclusion/Exclusion Criteria Patient Characteristics 

Ulcer Type 

Intervention 

Comparator 

Length of Follow-up 

Study Quality 

Wang 201145 Inclusion: chronic non-healing foot ulcers of N=77 (of 86 randomized) Intervention: HBOT (n=45, 2 with Allocation concealment: 

Taiwan 

Funding Source: 

Research Fund 

through a University 

Therapy Type: 

Hyperbaric Oxygen 

(HBOT) 

more than 3 months duration 

Exclusion: cardiac arrhythmia or pacemaker; 

pregnancy; skeletal immaturity; malignancy 

Age (years): 62 

Gender (% male): NR 

Race/ethnicity: Asian 

BMI: NR 

Pre-albumin: NR 

HbA1

c(%): 8.4 

Smoking: NR 

# Work days missed: NR 

ABI: 0.99 (HBOT 0.91, control 1.07; 

p=0.06 between groups) 

Wound location (%): plantar foot 71; 

dorsal foot 29 

Wound type: diabetic 

bilateral ulcers); ATA of 2.5; 90 min 

5 days/wk for 4 wks (20 sessions); 

multi-place hyperbaric chamber + 

standard treatment 

Comparator: extracorporeal 

shockwave therapy (dermaPACE 

device) (n=41, 5 with bilateral 

ulcers); dosage dependent on 

ulcer size – min of 500 impulses 

at E2 (0.23mJ/ mm2

 energy flux 

density) at 4 shocks/sec; 2 times/ 

wk for 3 wks (6 sessions) 

Inadequate (odd-even) 

Blinding: No 

Intention to treat analysis 

(ITT): No 

Withdrawals/dropouts 

adequately described: 

Yes 

Wound size, cm2 (median): HBOT 7; 

control 4 (p=0.06) 

Wound grade (Wagner) (%): NR 

Wound duration, months (median): 

HBOT 6; control 6 

Comorbid conditions (%): 

History of DM: 100% 

Antibiotic Use: per physician 

Treatment Duration: 3-4 weeks 

depending on therapy; some 

subjects received 2nd course 

Follow-up Duration: none 

Study Withdrawal (%): 10 (n=9) 

Treatment Compliance: NR 

Wieman 199831 Inclusion: type I or II diabetes; ≥1 full thickness N=382 Intervention: becaplermin gel# Allocation concealment: 

United States (23 

sites) 

Funding Source: 

Industry 

Therapy Type: 

Platelet-derived 

Growth Factors 

(IAET stage III or IV) wound of lower extremity 

present for ≥8 weeks; transcutaneous oxygen 

tension (TcPo2

) ≥30 mmHg 

Exclusion: osteomyelitis affecting target 

ulcer; post-debridement ulcer size exceeding 

100 cm2

; non-diabetic ulcers; cancer; other 

concomitant diseases; receiving treatment or 

medication (radiation therapy, corticosteroids, 

chemotherapy, or immunosuppressive agents); 

nursing, pregnant, or of childbearing potential 

not using contraception 

Age (years): 58 

Gender (% male): 67 

Race/ethnicity: white: 81; black: 12; 

Asian: 0.3; Hispanic: 6.3; other: 0.3 

BMI: NR 

Pre-albumin: NR 

HbA1

c (%): NR 

Smoking: NR 

# Work days missed: NR 

ABI: NR 

Wound location: 55% foot dorsum 

Wound type: diabetic 

Wound size: 2.7 cm2 

Wound grade: IAET stage III/IV 

Wound duration: 49 weeks 

Infection: NR 

Comorbid conditions (%): NR 

A) 30ug/g (n=132): amount 

determined weekly at study visits 

B) 100ug/g (n=123): amount 

determined weekly at study visits 

Comparator (n=127): placebo 

ALL: daily treatment with gel, 

sharp debridement; moist saline 

dressings (2x/day), off-loading 

Antibiotic Use: as needed 

Treatment Duration: 20 weeks 

Follow-up Duration: 3 months 

Study Withdrawal (%): 19 

Treatment Compliance: 97.4% (no 

details provided) 

#

Regranex 0.01% 

Unclear 

Blinding: Unclear 

(reported to be doubleblind but not specified) 

Intention to treat analysis 

(ITT): No 

Withdrawals/dropouts 

adequately described: 

Yes 

NR=Not Reported; HbA1c=Hemoglobin A1c; DM=Diabetes Mellitus; HTN=Hypertension; CAD/CVD=Coronary Artery Disease/Cardiovascular Disease; PVD=Peripheral Vascular Disease; ITT=Intention to 

Treat Analysis; BMI=Body Mass Index; PRP=Platelet Rich Plasma; rhPDGF=recombinant human Platelet-derived Growth Factor; IAET=International Association of Enterostomal Therapy; IPC=Intermittent 

Pneumatic Compression; ABI=Ankle Brachial Index; NPWT=Negative Pressure Wound Therapy; HBOT=Hyperbaric Oxygen Therapy 

*The Wagner grade system is a classification based on 6 wound grades (scored 0 to 5) to assess ulcer depth 
Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

Table 2. Primary Outcomes 

Study, year 

Time of 

assessment 

(weeks) 

Healed ulcers* 

% (n/N) 

Mean time (± SD or SE)** to 

ulcer healing 

Global assessment Return to daily activities 

% (n/N) 

Treatment Control Treatment Control Treatment Control Treatment Control 

DIABETIC ULCERS 

Collagen 

Blume 201115 

(Formulated Collagen 

Gel) 

12 45 (14/31) 

(p=ns) 

31 (5/16) 

Reyzelman 200918 

(Graftskin) 

12 69.6 (32/46) 

(p=0.03) 

46.2 (18/39) 5.7 ± 3.5 

weeks (n=32) 

(p=ns) 

6.8 ± 3.3 weeks 

(n=18) 

Veves 200216 

(Promogran) 

12 37 (51/138) 

(p=ns) 

Wound duration <6 

months: 

45 (43/95); 

(p=0.056) 

duration >6 months: 

19 (8/43) 

(p=0.83) 

Wagner grade 1 

or grade 2 – no 

difference 

Ulcer size <10 cm2 

or ≥10 cm2

 – no 

difference 

28 (39/138) 

Wound duration 

<6 months: 

33 (29/89) 

duration >6 

months: 

20 (10/49) 

7.0 ± 0.4 

weeks 

(p<0.0001) 

5.8 ± 0.4 weeks 

Donaghue 199817 

(Fibracol) 

8 48 (24/50) 

(p=ns) 

36 (9/25) 6.2 weeks 

(p=ns) 

5.8 weeks 

Biological Dressings 

Niezgoda 200519 

(OASIS vs PDGF) 

12 49 (18/37) 

(p=0.06) 

28 (10/36) 67 days 

p=0.25 

73 days 

Landsman 200820 

(OASIS vs. BSE 

[Dermagraft]) 

12 76.9 (10/13) 

(p=ns) 

84.6 (11/13) 35.7 ± 41.5 

days 

(p=0.73) 

40.9 ± 32.3 days 

Biological Skin Equivalents 

Gentzkow 199621 

(Dermagraft) 

12 Group A: 50.0 

(6/12) (p=0.03; A 

versus D) 

Group B: 21.4 

(3/14) 

Group C: 18.2 

(2/11) 

Group D: 

7.7 

(1/13) 

Group A: 12 

weeks 

Group B: >12 

weeks 

Group C: >12 

weeks 

(medians) 

Group D: >12 

weeks 

p=0.056 when 

comparing 

groups A and D 

(medians) 

147 
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Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Study, year 

Time of 

assessment 

(weeks) 

Healed ulcers* 

% (n/N) 

Mean time (± SD or SE)** to 

ulcer healing 

Global assessment Return to daily activities 

% (n/N) 

Treatment Control Treatment Control Treatment Control Treatment Control 

Naughton 199722 

(Dermagraft) 

12 (then 

followed to 

32 weeks) 

38.5 

(42/109) 

(p=0.14) 

Received 

Metabolically active 

Dermagraft: 

48.7 (37/76) 

(p=0.008) 

31.7 

(40/126) 

13 weeks 

(median) 

28 weeks 

(median) 

Marston 200323 

(Dermagraft) 

12 30 (39/130) 

(p=0.049) 

18 (21/115) Reported that treatment group 

healed faster (p=0.04) 

Veves 200124 

(Apligraf) 

12 56 (63/112) 

(p=0.004) 

38 (36/96) 65 days 

(median) 

p=0.003 

90 days 

(median) 

Edmonds 200925 

(Apligraf) 

12 51.5 (17/33) 

(p=0.049) 

26.3 (10/38) 84 days 

(median) 

Not estimated 

since <50% had 

full closure 

DiDomenico 201126 

(Apligraf vs. 

Theraskin) 

12 

20 

41.3 (7/17) 

(p=ns) 

47.1 (8/17) 

(p=ns) 

66.7 (8/12) 

66.7 (8/12) 

6.9 ± 4.1 

weeks (n=8) 

(p=ns) 

5.0 ± 3.4 weeks 

(n=8) 

Platelet-derived Growth Factor 

Aminian 200027 

(rhPDGF) 

8 57 (4/7) 

Ulcers 

(p=0.08) 

0 (0/5) 

Ulcers 

6.5 +/- 3.7 

weeks 

No complete 

healing 

Agrawal 200928 

(PDGF) 

12 64 (9/14) 

(p<0.001) 

21 (3/14) NR NR 

Hardikar 200529 

(rhPDGF) 

10 

20 

71(39/55) 

(p<0.001) 

85 (47/55) 

(p<0.05β) 

31 (18/58) 

53 (31/58) 

46 days 

(p<0.001) 

57 days 

(p<0.01) 

61 days 

96 days 

Bhansali 200930 

(rhPDGF) 

20 100 (13/13) 

(p=ns) 

100 (11/11) 50.1 +/- 23.4 

days 

(p=0.02) 

86.1 +/- 30.7 

days 

Wieman 199831 

(rhPDGF – 

Bercaplermin gel) 

20 100μg/g: 

50 (61/123) 

(p=0.007) 

30μg/g: 

36 (48/132) 

(p=ns vs. placebo 

gel) 

35 (44/127) 100μg/g: 

86 days 

(p=0.01) 

30μg/g: 

NR 

127 days 

148 
Advanced Wound Care Therapies for Non-Healing Diabetic, 

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Study, year 

Time of 

assessment 

(weeks) 

Healed ulcers* 

% (n/N) 

Mean time (± SD or SE)** to 

ulcer healing 

Global assessment Return to daily activities 

% (n/N) 

Treatment Control Treatment Control Treatment Control Treatment Control 

Jaiswal 201032 

(rhPDGF) 

10 60 (15/25) 

(p=ns) 

72 (18/25) 

Steed1995 200633,34 

(rhPDGF) 

20 48 (29/61) 

(p=0.01) 

25 (14/57) 30 to 40 days 

shorter than 

control group 

(p=0.01) 

d’Hemecourt 199835 

(PDGF [Bercaplermin 

gel) vs. NaCMC or 

Std care) 

20 Gel: 

44 (15/34) 

(p=0.04 vs. std care, 

p=ns vs. NaCMC) 

NaCMC 

36 (25/70) 

Std care: 

22 (15/68) 

Gel 

85 days 

(p=ns vs. 

NaCMC or std 

care) 

NaCMC: 98 

days 

Std care: 

141 days 

Platelet Rich Plasma 

Saad Setta 201136 20 100 (12/12) 

(p=ns) 

75 (9/12) 11.5 weeks 

(p<0.005) 

17.0 weeks 

Driver 200637 12 ITT: 33 (13/40) 

(p=ns) 

PP: 68 (13/19) 

(p=ns) 

ITT: 28 (9/32) 

PP: 43 (9/21) 

PP: 43 days 

(mean); 45 

days (median) 

(p=ns) 

PP: 47 days 

(mean); 85 days 

(median) 

Silver Products 

Belcaro 201038 

(Silver Ointment) 

4 39 (13/34) 

(p<0.05) 

16 (5/32) 

Jacobs 201039 

(Silver Cream (control 

tx)) 

6 40 (8/20) 

(p=ns) 

30 (6/20) 

(Silver) 

Jude 200840 

(Silver Dressing) 

8 or 

healing 

31 (21/67) 

(p=ns) 

22 (15/67) 53 ± 1.8 days 

(p=ns) 

58 ± 1.7 days (all p=ns except as 

noted) 

Healed or 

Improved: 

87.7% 

Plantar: 81.4% 

Non-plantar: 100% 

Baseline 

antibiotics: 91.7% 

(p=0.02) 

None: 86.8% 

Neuro: 91.2% 

Neuro-ischemic: 

77.0% 

70.8% 

Plantar: 69.6% 

Non-plantar: 

73.7% 

Baseline 

antibiotics: 

50.0% 

None: 73.8% 

Neuro: 71.7% 

Neuro-ischemic: 

68.4% 

Viswanathan 201141 

(Silver Cream (control 

tx)) 

20 

(5 months) 

43 ± 26.8 days 

(p=ns) 

44 ± 30.7 days 

(Silver) 

149 
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Study, year 

Time of 

assessment 

(weeks) 

Healed ulcers* 

% (n/N) 

Mean time (± SD or SE)** to 

ulcer healing 

Global assessment Return to daily activities 

% (n/N) 

Treatment Control Treatment Control Treatment Control Treatment Control 

Negative Pressure Wound Therapy 

Blume 200842 Ulcer 

closure or 

112 days 

43 (73/169) 

(p=0.007) 

29 (48/166) 96 days 

(median) 

Could not be 

estimated 

Karatepe 201143 Reepithelization 

4 (1.9) weeks 

(p<0.05) 

5 (1.4) weeks 

McCallon 200044 Satisfactory 

healing 

Patients remained in study until 

satisfactory healing 

23 ± 17.4 days 

(n=5) 

(p=ns) 

43 ± 32.5 days 

(n=5) 

Hyperbaric Oxygen Therapy 

Wang 201145 

(vs. extracorporeal 

shock wave therapy) 

4 First course of 

treatment 

25 (10/40) 

(p=0.008) 

Second course 

6 (1/17) 

(p=0.01) 

First course of 

treatment 

55 (24/44) 

Second course 

50 (7/14) 

Löndahl 201046 

(vs. sham) 

52 52 (25/48) 

(p=0.03) 

29 (12/42) 

Duzgun 200847 

(vs. standard/ 

multi-disciplinary 

wound therapy) 

92 66 (33/50) 

(p<0.001) 

0/50 

Wagner 2 

100 (6/6) 

(p<0.001) 

Wagner 2 

0/12 

Wagner 3 

68 (13/19) 

(p<0.001) 

Wagner 3 

0/18 

Wagner 4 

56 (14/25) 

(p<0.001) 

Wagner 4 

0/20 

Kessler 200348 

(vs. standard/ 

multi-disciplinary 

wound therapy) 

4 14 (2/14) 

(p=ns) 

0/13 

150 
Advanced Wound Care Therapies for Non-Healing Diabetic, 

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Study, year 

Time of 

assessment 

(weeks) 

Healed ulcers* 

% (n/N) 

Mean time (± SD or SE)** to 

ulcer healing 

Global assessment Return to daily activities 

% (n/N) 

Treatment Control Treatment Control Treatment Control Treatment Control 

Abidia 200349 

(vs. sham) 

6 62.5 (5/8) 

(p=0.12) 

12.5 (1/8) 

26 62.5 (5/8) 

(p=0.31) 

25 (2/8) 

52 62.5 (5/8) 

(p=0.03) 

0 (0/8) 

Ozone-Oxygen Therapy 

Wainstein 201150 24 40.6 

(13/32) 

reported as 33% 

n unclear 

VENOUS ULCERS 

Collagen 

Vin 200252 

(Promogran) 

12 ITT: 49 (18/37) 

(p=ns) 

PP: 41% 

(p=ns) 

ITT: 33 (12/36) 

PP: 31% 

Biological Dressings (BD) 

Mostow 200553 

(OASIS) 

12 weeks 

6 months 

55 (34/62) 

(p=0.02) 

6 months 

67 (20/30) 

(p=ns) 

34 (20/58) 

6 months 

46 (11/24) 

Biological Skin Equivalents 

Falanga 199854 

Falanga 199955 

(Apligraf) 

6 months 63 

(92/146) 

(p=0.02) 

Wound duration 

>1 yr 

47 (34/72) 

(p<0.005) 

49 (63/129) 

19 (9/48) 

61 days 

(median) 

(p=0.003) 

Duration 

>1 yr 

181 days 

p < 0.005 

181 days 

(median) 

Could not be 

determined 

Krishnamoorthy 

200356 

(Dermagraft) 

12 Group 1: 38 (5/13) 

(p=ns) 

Group 2: 38 (5/13) 

(p=ns) 

Group 3: 7 (1/14) 

(p=ns) 

Group 4: 15 

(2/13) 

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Advanced Wound Care Therapies for Non-Healing Diabetic, 

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Study, year 

Time of 

assessment 

(weeks) 

Healed ulcers* 

% (n/N) 

Mean time (± SD or SE)** to 

ulcer healing 

Global assessment Return to daily activities 

% (n/N) 

Treatment Control Treatment Control Treatment Control Treatment Control 

Omar 200457 

(Dermagraft) 

12 50 (5/10) 

(p=0.15) 

12 (1/8) 

Keratinocytes 

Lindgren 199858 

(Cryopreserved, 

allogeneic cells) 

8 13 

(2/15) 

(p=ns) 

17 

(2/12) 

Navratilova 200459 

(Cryopreserved vs. 

lyophilized) 

12 Cryo-preserved 

84 (21/25) (p=ns) 

Lyophilized 

80 (20/25) 

Cryopreserved 

32 days 

(p=ns) 

Lyophilized 

27 days 

Harding 200560 

(Lyophilized, 

allogeneic) 

NOTE: Control group 

is combined standard 

care and standard 

care + vehicle groups 

24 “As treated ITT 

cohort” 38 

(36/95) 

(p=0.11) 

“As randomized ITT 

cohort” 

37 (36/98) 

(p=0.14) 

“As treated 

ITT cohort” 27 

(26/98) 

“As randomized 

ITT cohort” 

27 (26/95) 

139.7 ± 5.6 

days 

(p=0.20) 

148.5 ± 5.6 days 

Vanscheidt 200761 

(Autologous, in fibrin 

sealant) 

6 months 38 (44/116) 

(p=0.01) 

22 (24/109) 176 days 

(median) 

(p<0.0001) 

Median not 

reached (>201 

days) 

Platelet Rich Plasma 

Stacey 200062 

(PRP) 

39 79 (33/42) 

(p=ns) 

77 (34/44) 

Silver 

Belcaro 201038 

(Silver Ointment) 

4 42 (19/44) 

(p<0.05) 

22 (8/38) 

Bishop 199263 

(Silver Cream (control 

tx)) 

4 0/29 

Tripeptide (p=0.01 

vs. Silver; p=ns vs. 

placebo) 

21 (6/28) 

(Silver) 

3 (1/29) 

Tripeptide 

placebo 

5.0‡

 (Tripeptide) 

(p<0.0001 vs. 

other txs) 

3.7 

(Silver) 

5.0 Tripeptide 

placebo 

Blair 198864 

(Silver Dressing) 

12 63 (19/30) 

(p=ns) 

80 (24/30) 

Dimakakos 200865 

(Silver Dressing) 

9 81 (17/21) 

(p=0.02) 

48 (10/21) 6.1 weeks 

(p=NR) 

6.4 weeks 

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Advanced Wound Care Therapies for Non-Healing Diabetic, 

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Study, year 

Time of 

assessment 

(weeks) 

Healed ulcers* 

% (n/N) 

Mean time (± SD or SE)** to 

ulcer healing 

Global assessment Return to daily activities 

% (n/N) 

Treatment Control Treatment Control Treatment Control Treatment Control 

Harding 201166 

(2 Silver Dressings) 

8 (4 with 

silver, 4 

without) 

17 (24/145) 

AQUACEL (p=0.09) 

15 (21/136) 

Urgotul 

67 (97/145)† 

AQUACEL 

(p=0.01) 

52 (69/136) 

Urgotul 

Michaels 2009 a,b67,68 

(Silver Dressing) 

12 weeks 

and 1 year 

12 weeks 

60 (62/104) 

1 year 

96 (95/99) 

(both p=ns) 

57 (59/104) 

96 (90/94) 

67 days 

(median) 

(p=ns) 

58 days 

(median) 

Intermittent Pneumatic Compression 

Schuler 199669 26 71 (20/28) 

(p=ns) 

60 (15/25) 

Electromagnetic Therapy 

Ieran 199070 12.9 (day 

90) 

67 (12/18) 

(p=0.05) 

32 (6/19) 71 days 76 days Excellent#

28 (5/18) 

Excellent and 

good#

83 (15/18) 

(both p=ns) 

Excellent#

11 (2/19) 

Excellent and 

good#

53 (10/19) 

Patient not 

restricted in 

activity 

44 (8/18) 

Activity 

lasted <6 h 

39 (7/18) 

(both p=ns) 

Patient not 

restricted in 

activity 

58 (11/19) 

Activity lasted 

<6 h 

11 (2/19) 

52 89 (16/18) 

(p=0.005) 

42 (8/19) 

1 year 

followup from 

healing 

67 (12/18) 

(p=0.008) 

21 (4/19) 

Kenkre 199671 Day 30 0/10 

(p=ns) 

11 (1/9) -Groups A and B2 improved 

ability to walk up flight of 

stairs following tx 

-All groups improved in 

walking a distance of a block 

of houses 

-Baseline: “went out for 

entertainment less often” 

58% (11/19); “less sociable 

to friends and neighbors” 

37% (7/19); “went out 

visiting less frequently” 63% 

(12/19) 

-Day 30: 42% (8/19), 16% 

(3/19), and 37% (7/19), 

respectively 

Day 50 All EMT 

20 (2/10) 

EMT Group 1 

20 (1/5) 

EMT Group 2 

20 (1/5) 

(all p=ns) 

22 (2/9) 

Hyperbaric Oxygen Therapy 

Hammarlund 199472 18 25 (2/8) 

(p=ns) 

0/8 

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Advanced Wound Care Therapies for Non-Healing Diabetic, 

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Study, year 

Time of 

assessment 

(weeks) 

Healed ulcers* 

% (n/N) 

Mean time (± SD or SE)** to 

ulcer healing 

Global assessment Return to daily activities 

% (n/N) 

Treatment Control Treatment Control Treatment Control Treatment Control 

ARTERIAL ULCERS 

Chang 200073 

(Biologic Skin 

Equivalent – Apligraf) 

24 4 weeks 

32 (7/21) 

8 weeks 

62 (13/21) 

12 weeks 

86 (18/21) 

24 weeks 

100 (21/21) 

(p<0.01 at all time 

points) 

4 weeks 

0/10 

8 weeks 

0/10 

12 weeks 

40 (4/10) 

24 weeks 

Reported to 

be 75% (of 10 

patients) 

7 weeks 

(median) 

(p=0.002) 

15 weeks 

(median) 

MIXED LOWER EXTREMITY ULCERS 

Brigido 200674 

(Collagen) 

16 86 (12/14) 

(p=0.01) 

29 (4/14) 11.9 weeks 13.5 weeks 

Romanelli 200775 

(Biological Dressing -

OASIS) 

16 81 (21/26) 

(p<0.001) 

46 (11/24) 

Romanelli 201076 

(Biological Dressing) 

8 80 (20/25) 

(p<0.05) 

65 (15/23) 5.4 weeks 

(p=0.02) 

8.3 weeks 

Jørgensen 200577 

(Silver-releasing 

Dressing) 

4 10 (5/52) 

(p=ns) 

9 (5/57) 

Miller 201078 

(Silver Dressing) 

12 64 (85/133) 

(p=ns) 

63 (84/133) Reported no 

significant 

difference in 

days to heal 

Fumal 200279 

(Silver Cream) 

NR 15 weeks 

(p=ns) 

16 weeks 

Vuerstaek 200680 

(NPWT) 

At 

discharge 

(complete 

healing) 

96 (27/28) 

(p=ns) 

96 (25/26) 29 days 

(median) 

(p=0.0001) 

45 days 

(median) 

AMPUTATION ULCERS 

Armstrong 200581 

(NPWT) 

Wound 

closure or 

112 days 

56 (43/77) 

(p=0.04) 

39 (33/85) 56 days 

(median) 

(p=0.005) 

77 days 

(median) 

SD=Standard deviation; SE=Standard error; tx=Treatment; Neuro=Neuropathic; ITT=Intention to treat population; PP=Per protocol population; NaCMC=sodium carboxymethylcellulose; PDGF=Plateletderived growth factors; PRP=Platelet rich plasma; BSE=Biological skin equivalent; NPWT=Negative pressure wound therapy 

154 
155 

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

*Complete healing was defined as follows: 

Aminian 2000: 100% epithelialization 

Brigido 2006: Complete epithelialization without drainage 

Landsman 2008: Full epithelialization without drainage or bleeding 

Hardikar 2005: Wound closure with full epithelization and no drainage or scab 

Schuler 1996: Complete re-epithelialization of the entire wound bed 

Vin 2002: 100% reduction in surface area, confirmed by planimetry and the investigator 

Blume 2008: Skin closure (100% re-epithelization) without drainage or dressing requirements 

Armstrong 2005: 100% re-epithelialization without drainage 

Vuerstaek 2006: 2 stage procedure – preparation of wound for skin grafts (granulation tissue covered 100% of surface and secretion minimal) then transplantation of skin grafts with goal of complete 

healing; data are provided for complete healing 

Wang 2011: Not reported 

Löndahl 2010: Completely covered by epithelial regeneration and remained so until the next visit in the study. Wagner grade 4 ulcers were considered healed when the gangrene had separated and 

the ulcer below was completely covered by epithelial regeneration 

Duzgun 2008: Total closure of the wound without the need for surgical intervention in the operating room (complete cure with bedside debridement) 

Abidia 2003: Complete epithelialization 

Kessler 2003: Not reported 

Hammarlund 1994: Not reported 

Ieran 1990: Completed epithelialization 

Belcaro: Complete closure 

Jacobs: Data are ulcers reported as “resolved” at end of 6 week study – primary outcome in study was wound size reduction so no definition of healed ulcers 

Jude, Miller: 100% re-epithelialization 

Viswanathan: Complete epithelialization either by secondary intention or by split skin graft 

Bishop: “Total healing” 

Blair: Not reported 

Harding: “Healed” 

Michaels: Complete epithelialization of the ulcer with no scab 

Jørgensen: “Closed” 

**Some studies reported median time (as noted) 

βSeveral covariates were seen as important to the increased healing witnessed in the rhPDGF group: overall baseline ulcer size (p<0.001), use of antibiotics increased healing in the treatment group from 

59% to 78% and placebo group from 22.7% to 36% leading to a significant relationship between antibiotic use and the efficacy of treatment drug (p<0.05) 

#

Rated by three different physicians unaware of the experimental condition 

‡

Composite score based on erythema, exudation, and granulation (0 to 9+ with lower scores indicating better physical state) 

†

Composite endpoint: wound volume reduction and final wound assessment of improvement 
Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

Table 3. Secondary Outcomes – Part A 

Study, year 

(Treatment) 

Ulcers infected during 

treatment 

% (n/N) 

Amputation 

% (n/N) 

Revascularization/ 

surgery 

% (n/N) 

Recurrence 

% (n/N) 

Recurrence, mean or 

median time to 

(± SD or SE) 

Pain/discomfort 

% (n/N) 

Treatment Control Treatment Control Treatment Control Treatment Control Treatment Control Treatment Control 

DIABETIC ULCERS 

Collagen 

Reyzelman 

200918 

(Graftskin) 

NR* NR* 2 (1/46) 

(p=ns) 

3 (1/39) 2 (1/46) 

(p=ns) 

0/39 

Veves 200216 

(Promogran) 

12 (17/138) 

(p=ns) 

19 

(26/138) 

Donaghue 

199817 

(Fibracol) 

Reported no difference 

in number of infections 

between groups 

Biological Dressings 

Niezgoda 

200519 

(OASIS vs. 

PDGF) 

18 (9/50) 

(p=ns) 

6 (3/48) 25% 

(2/8 at 6 

months) 

(p=ns) 

33% 

(2/6 at 6 

months) 

2 events 

(# pts not 

reported) 

1 event 

Biological Skin Equivalents 

Gentzkow 

199621 

(Dermagraft) 

Group A: 

17 (2/12) 

Group B: 

29 (4/14) 

Group C: 

27 (3/11) 

(all p=ns) 

Group D: 

23 (3/13) 

Groups A, 

B, and C: 0 

(of 11 

healed) 

(p=ns) 

Group 

D: 0 

(of 1 

healed) 

Naughton 

199722 

(Dermagraft) 

Reported no difference 

between groups in 

occurrence of ulcer 

infections 

Reported recurrence in 

a “comparable minority” 

in both groups 

12 weeks 7 weeks 

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Study, year 

(Treatment) 

Ulcers infected during 

treatment 

% (n/N) 

Amputation 

% (n/N) 

Revascularization/ 

surgery 

% (n/N) 

Recurrence 

% (n/N) 

Recurrence, mean or 

median time to 

(± SD or SE) 

Pain/discomfort 

% (n/N) 

Treatment Control Treatment Control Treatment Control Treatment Control Treatment Control Treatment Control 

Marston 200323 

(Dermagraft) 

Infection 

10.4 (17/163) 

(p=ns) 

Osteo-myelitis 

8.6 (14/163) 

(p=ns) 

Cellulitis 

7.4 (12/163) 

(p=ns) 

Overall 

19.0 (31/163) 

(p=0.007) 

Infection 

17.9 

(27/151) 

Osteomyelitis 

8.6 

(13/151) 

Cellulitis 

9.3 

(14/151) 

Overall 

32.5 

(49/151) 

8 (13/163) 

had 

surgical 

procedure 

(p=ns) 

15 

(22/ 

151) 

Veves 200124 

(Apligraf) 

Infection 

10.7 (12/112) 

(p=0.67) 

Osteo-myelitis 

2.7 (3/112) 

(p=0.04) 

Cellulitis 8.9 

(10/112) 

(p=ns) 

Infection 

13.5 

(13/96) 

Osteomyelitis 

10.4 

(10/96) 

Cellulitis 

8.3 (8/96) 

6.3 (7/112) 

(p=0.03) 

15.6 

(15/96) 

5.9 (3/112) 

(p=0.42) 

12.9 

(4/96) 

Edmonds 200925 

(Apligraf) 

3 (1/33)β

(p=ns) 

0/39 0/33 

(p=ns) 

2.6 

(1/39) 

7 (1/15) 

(p=ns) 

10 (1/10) 

Platelet-derived Growth Factor 

Wieman 199831 

(rhPDGF) 

100μg/g: 29 

(36/123) 

(p=ns) 

30μg/g: 

23 (30/132) 

(p=ns) 

31 

(39/127) 

NR Reported to be 

approximately 30% in 

all treatment groups 

at 3 month follow-up; 

number with follow-up 

data not reported 

100μg/g: 

6 (7/123) 

(p=ns) 

30μg/g: 

6 (8/132) 

(p=ns) 

2 (2/127) 

Steed 2006 

199533,34 

(rhPDGF) 

Infection 

11 (7/61) 

(p=ns) 

Cellulitis 

5 (3/61) 

(p=ns) 

Overall 

11.4% 

(p=ns) 

Infection 

16 (9/57) 

Cellulitis 

12 (7/57) 

Overall 

26.3% 

26% 

(p=ns) 

46% 8.6 

weeks 

8.5 

weeks 

7 (4/61) 

(p=ns) 

11 (6/57) 

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Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

Study, year 

(Treatment) 

Ulcers infected during 

treatment 

% (n/N) 

Amputation 

% (n/N) 

Revascularization/ 

surgery 

% (n/N) 

Recurrence 

% (n/N) 

Recurrence, mean or 

median time to 

(± SD or SE) 

Pain/discomfort 

% (n/N) 

Treatment Control Treatment Control Treatment Control Treatment Control Treatment Control Treatment Control 

d’Hemecourt 

199835 

(rhPDGF – 

Bercaplermin 

gel versis 

NaCMC gel or 

Std Care) 

Gel 

Cellulitis: 

3 (1/34) 

Osteomyelitis: 

9 (3/34) 

Infection: 21 

(7/34) 

(all p=ns) 

NaCMC 

Cellulitis: 

10 (7/70) 

Osteomyelitis: 

10 (7/70) 

Infection: 

30 (21/70) 

Std 

Cellulitis: 

15 (10/68) 

Osteomyelitis: 

13 (9/68) 

Infection: 

28(19/68) 

Gel

 6 (3/34) 

(all p=ns) 

NaCMC15 

(11/70) 

Std 

15 (10/68) 

Platelet Rich Plasma 

Driver 200637 PP: 5 

(1/13) 

(p=ns) at 

12 weeks 

PP: 0 

Silver Products 

Jude 200840 

(Silver 

Ointment) 

16 (11/67) 

(p=ns) 

12 (8/67) 

Viswanathan 

201141 

Silver Cream 

(control tx) 

5 (1/20) 

(p=ns) 

0/20 47 (9/19) 

(p=ns) 

42 (8/19) 

Negative Pressure Wound Therapy 

Blume 200842 2.4 (4/169) 

(p=ns) 

0.6 

(1/166) 

4.1 (7/169) 

(p=0.04) 

10.2 

(17/166) 

Hyperbaric Oxygen (HBOT) 

Löndahl 201046 Major 

6.1 

(3/49) 

(p=ns) 

Major 

2.2 

(1/45) 

Open 0% 

PTA 

12.2 (6/49) 

(p=ns) 

Open 

0% 

PTA 

8.9 

(4/45) 

158 
Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

Study, year 

(Treatment) 

Ulcers infected during 

treatment 

% (n/N) 

Amputation 

% (n/N) 

Revascularization/ 

surgery 

% (n/N) 

Recurrence 

% (n/N) 

Recurrence, mean or 

median time to 

(± SD or SE) 

Pain/discomfort 

% (n/N) 

Treatment Control Treatment Control Treatment Control Treatment Control Treatment Control Treatment Control 

Duzgun 200847 Minor-distal 

8.0b 

(4/50) 

(p<0.01) 

Minorproximal 

0/50 

(p<0.01) 

Minordistal 

48.0c 

(24/50) 

Minorproximal 

34.0† 

(17/50) 

Debridement† 

0/50 

(p=0.003) 

Debridement† 

18.0 

(9/50) 

[Ulcer 

grade 

2=8 

Ulcer 

grade 

3=1] 

Abidia 200349 37.5 (3/8) 

(p=ns) 

25 (2/8) Major 

12.5 (1/8) 

Minor 

12.5 (1/8) 

(both p=ns) 

Major 

12.5 

(1/8) 

0/9 

(p=ns) 

11.1 

(1/9) †† 

Ozone-Oxygen Therapy 

Wainstein 

201150 

“wound 

infection” 

3.1 

(1/32) 

“infection” 

3.4 

(1/29) 

0/32 3.4 

(1/29) 

VENOUS ULCERS 

Collagen 

Vin 200252 

(Adaptec) 

0 (0/37) 

(p=0.03) 

14 (5/36) 19 (7/37) 

(p=ns) 

11 (4/36) 

Biological Dressings (BD) 

Mostow 200553 

(OASIS) 

1.6 (1/62) 

(p=0.11) 

8.6 (5/58) 0 

(0 of 19 

healed 

ulcers at 6 

months) 

(p=0.03) 

30 

(3 of 10 

healed 

ulcers at 

6 months) 

159 
Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

Study, year 

(Treatment) 

Ulcers infected during 

treatment 

% (n/N) 

Amputation 

% (n/N) 

Revascularization/ 

surgery 

% (n/N) 

Recurrence 

% (n/N) 

Recurrence, mean or 

median time to 

(± SD or SE) 

Pain/discomfort 

% (n/N) 

Treatment Control Treatment Control Treatment Control Treatment Control Treatment Control Treatment Control 

Biological Skin Equivalents 

Falanga 199854 

Falanga 199955 

(Apligraf) 

Cellulitis: 

8 (12/146) 

(p=ns) 

Infection: 

Reported no 

difference 

between 

groups 

Cellulitis: 

8 (10/129) 

12 (11/92)a 

(p=0.48) 

Wound 

duration 

>1 yr 

18 (13/72) 

(p=ns) 

16 

(10/63)a 

22 

(12/54) 

Reported no difference in 

pain between treatment 

groups 

Krishnamoorthy 200356 

(Dermagraft) 

Reported no differences 

in incidence of infection 

between groups 

Keratinocytes 

Navratilova 

200459 

(Cryo-preserved 

vs lyophilized 

allografts) 

Reported pain significantly 

reduced (p<0.001) during 

1st week after application in 

both groups 

Harding 200560 

(Lyophilized, 

allogeneic ) 

NOTE: 

Control group 

is combined 

standard care 

and standard 

care + vehicle 

group 

14 (13/95) 

(p=ns) 

11 (11/99) 22 (8/36) 

(p=0.78) 

19 (5/26) Tx Period: 

4 (4/95) 

(p=ns) 

Follow-up 

Period: 

2 (2/89) 

(p=ns) 

2 (2/99) 

0/91 

Silver Products 

Bishop 199263 

(Silver Cream 

(control tx) 

No healed 

ulcers 

At 1 yr 

17 (1/6) 

(Silver) 

0/1 (Tripeptide 

placebo) 

(p=ns) 

160 
Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

Study, year 

(Treatment) 

Ulcers infected during 

treatment 

% (n/N) 

Amputation 

% (n/N) 

Revascularization/ 

surgery 

% (n/N) 

Recurrence 

% (n/N) 

Recurrence, mean or 

median time to 

(± SD or SE) 

Pain/discomfort 

% (n/N) 

Treatment Control Treatment Control Treatment Control Treatment Control Treatment Control Treatment Control 

Dimakakos 

200965 

(Silver Dressing) 

100% painfree at 8 wks 62% pain-free 

at 9 wks 

Harding 201166 

(Silver 

Dressing) 

11 (16/145)*** 

AQUACEL 

(p=ns) 

9 (12/136) 

Urgotul 

Michaels 

2009a,b67,68 

(Silver 

Dressing) 

Of ulcers 

healed in 

1st year 

12 (11/95) 

(p=ns) 

14 

(13/90) 

Intermittent Pneumatic Compression 

Schuler 199669 VAS score: 

2.0 ± 1.4 

(p=ns) 

VAS score: 

3.1 ± 2.3 

Electromagnetic Therapy 

Ieran 199070 Day 90 

3 ulcers 11 ulcers 

Among 

healed ≤90

days: 2 

patients 

Among 

healed >90 

days: 2 

patients 

25 (4 of 

16 healed) 

(p=ns) 

Among 

healed 

≤90 days:

3 patients 

Among 

healed 

>90 days: 

1 patient 

50 

(4 of 8 

healed) 

0.7 cm (from 

baseline 

5.1 cm, 

based on 11 

cm analog 

scale 

(p=ns) 

1.4 cm (from 

baseline 

5.3 cm, 

based on 11 

cm analog 

scale 

161
 
Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

Study, year 

(Treatment) 

Ulcers infected during 

treatment 

% (n/N) 

Amputation 

% (n/N) 

Revascularization/ 

surgery 

% (n/N) 

Recurrence 

% (n/N) 

Recurrence, mean or 

median time to 

(± SD or SE) 

Pain/discomfort 

% (n/N) 

Treatment Control Treatment Control Treatment Control Treatment Control Treatment Control Treatment Control 

Kenkre 199671 Day 50 

0/10 

(p=ns) 

Day 50 

22.2 (2/9) 

Pain in 

analog 

scale, mm 

(range) 

Day1 600Hz 

60 

(37-76) 

Day 30 

17 

(0-44), 

(p<0.05 from 

day 1) 

Day1 800Hz 

62 

(29-90) 

Day 30 

36 

(0-84), 

(p<0.05 from 

day 1) 

Pain in 

analog scale, 

mm (range) 

Day 1 

47 

(0-68) 

Day 30 

41 

(0-88) 

ARTERIAL ULCERS 

Chang 200073 

(Apligraf) 

14.3 (3/21) 

(p=ns) 

0 (0/10) 4.8 (1/21) 

(p=ns) 

0 (0/10) 

MIXED LOwER EXTREMITy ULCERS 

Brigido 200674 

(Collagen)) 

21 

(3/14) 

(p=ns) 

36 (5/14)↑

Romanelli 

200775 

(Biological 

Dressing -

OASIS) 

3.7** 

(p<0.05) 

6.2** 

Romanelli 

201076 

(Biological 

Dressing -

OASIS) 

0/25 

(p=ns) 

0/25 0/25 

(p=ns) 

0/25 

162 
Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

Study, year 

(Treatment) 

Ulcers infected during 

treatment 

% (n/N) 

Amputation 

% (n/N) 

Revascularization/ 

surgery 

% (n/N) 

Recurrence 

% (n/N) 

Recurrence, mean or 

median time to 

(± SD or SE) 

Pain/discomfort 

% (n/N) 

Treatment Control Treatment Control Treatment Control Treatment Control Treatment Control Treatment Control 

Jørgensen Both groups 

200577 reported 

(Silver­ de-creased 

releasing pain during 

Dressing) treatment 

Vuerstack 

200680 

(NPWT) 

0 

(p=ns) 

3 (1/30) 52 (12/23) 

(p=ns) 

42 

(10/24) 

4th month 

(median) 

(p=ns) 

2nd 

month 

(median) 

Pain as AE: 

10 (3/30) 

(p=ns) 

SF-MPQd 

Baseline: 

9 (4) 

8 weeks: 1 

(1) 

PPIe 

Baseline: 

2.5 (1) 

8 weeks: 

0.2 (0.7) 

(both 

p<0.05) 

3 (1/30) 

10 (3) 

1 (1) 

3.1 (1) 

0.4 (0.6) 

AMPUTATION ULCERS 

Armstrong 17 (13/77) 6 (5/85) 3 (2/77) 11 (9/85) 

200581 (p=0.04) (p=0.06) 

(NPWT) 

NR=Not Reported, NPWT=Negative Pressure Wound Therapy; PTA=Percutaneous Transluminal Angioplasty; VAS=Visual Analog Scale for pain (0-100 mm); NaCMC=sodium carboxymethylcellulose; 

PDGF=Platelet-derived growth factors; PRP=Platelet rich plasma; BSE=Biological skin equivalent; NPWT=Negative pressure wound therapy 

↑

No patient required antibiotic treatment or hospital stay. Numbers include infection at the wound site such as periwound erythema or local cellulitis
 

*Any infections were treated and not otherwise reported unless leading to a further adverse event
 

**Pain at end of treatment (VAS with 0=none, 10=severe)
 βOne patient reported as having multiple infections (osteomyelitis during treatment, and cellulitis during follow-up)
 

†Debridement=operative surgical debridement of the wound was all that was required to achieve closure
 

††Required an “urgent vascular intervention”
 

***Infection and infestation
 a

Measured as recurrence at 12 months in those with complete wound closure at 6 months
 b

HBOT: distal wounds Wagner 3=1; Wagner 4=3
 c

Control: distal wounds Wagner 2=4; Wagner 3=17; Wagner 4=3. Proximal wounds Wagner 4=17
 d

Short Form-McGill Pain Questionnaire (SF-MPQ: 0-45, with 45 reflecting maximum sensory and affective score ); mean (SD); significant decrease over time e

Present Pain Intensity (PPI: 1-5, mild to excruciating); mean (SD);significant decrease over time and significantly lower in VAC group at baseline and 8 weeks

163
 
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Table 4. Secondary Outcomes – Part B 

Study, year 

(Treatment) 

Hospitalization 

% (n/N) 

Required home care 

% (n/N) 

Quality of life 

Mean/median (±SD/SE) 

Other (note) 

% (n/N) 

Other (note) 

% (n/N) 

Treatment Control Treatment Control Treatment Control Treatment Control Treatment Control 

DIABETIC ULCERS 

Biological Skin Equivalents 

Marston 200323 

(Dermagraft) 

Surgical 

procedure 

related to 

study ulcer: 

8 (13/163) 

(p=0.07) 

15 (22/151) 

Negative Pressure Wound Therapy 

Karatepe 201143 Reported positive 

effect of NPWT on 

mental (p=0.03) 

& physical 

(p=0.004) 

health (SF=36) 

compared 

to standard 

treatment 

McCallon 

200044 

Delayed 

primary 

closure 

80 (4/5) (p=ns) 

Delayed 

primary 

closure 

40 (2/5) 

Hyperbaric Oxygen Therapy 

Löndahl 201046 Leading to study 

withdrawal 

6.1 (3/49) 

(p=ns) 4.4 (2/45) 

VENOUS ULCERS 

Biological Dressings 

Mostow 200553 

(OASIS) 

Hospitalization 

resulting in failing 

to complete study 

3 (2/62) (p=ns) 

0/58 

164 
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Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Study, year 

(Treatment) 

Hospitalization 

% (n/N) 

Required home care 

% (n/N) 

Quality of life 

Mean/median (±SD/SE) 

Other (note) 

% (n/N) 

Other (note) 

% (n/N) 

Treatment Control Treatment Control Treatment Control Treatment Control Treatment Control 

Keratinocytes 

Harding 200560 

(Lyophilized, 

allogeneic) 

NOTE: Control 

group is 

combined 

standard care 

and standard 

care + vehicle 

group 

2 (2/95) 

(p=ns) 

1 (1/99) 

Platelet Rich Plasma (PRP) 

Stacey 200062 Reported 2 hospitalizations 

leading to withdrawal but group 

not reported 

Silver Products 

Michaels 

2009a,b67,68 

(Silver 

Dressing) 

EQ-5D 

12 weeks 

0.73 (n=81) 

1 year 

0.75 

(n=61) 

SF-6D 

12 weeks 

0.69 (n=73) 

1 year 

0.71 (n=55) 

(all p=ns) 

12 weeks 

0.70 (n=76) 

1 year 

0.668 

(n=58) 

12 weeks 

0.70 (n=68) 

1 year 

0.67 (n=53) 

MIXED LOwER EXTREMITy ULCERS 

Romanelli 

200775 

(OASIS) 

Mean time 

to dressing 

change 

6.4 ±1.4 days 

2.4 ±1.6) 

(p<0.05) 

Comfort w/ 

treatment 2.5 

(p<0.01) 

(0=excellent, 

10=critical) 

6.7 

165 
Advanced Wound Care Therapies for Non-Healing Diabetic, 

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Study, year 

(Treatment) 

Hospitalization 

% (n/N) 

Required home care 

% (n/N) 

Quality of life 

Mean/median (±SD/SE) 

Other (note) 

% (n/N) 

Other (note) 

% (n/N) 

Treatment Control Treatment Control Treatment Control Treatment Control Treatment Control 

Jørgensen, 

200577 

(Silver-releasing 

Dressing) 

EQ-5D 

0.79 

(p=ns) 

(1=perfect 

health, 

0=death) 

0.79 

Odor present 

19 (10/52) of 

ulcers 

(p=0.03) 

39 (22.57) 

Dressing 

changes 

associated 

with leakage 

19 (10/52) 

(p=0.002) 

49 (28/57) 

Vuerstack 

200680 

(NPWT) 

EQ-DSIa 

Baseline 

40 (13) 

8 weeks 

76 (17) 

Baseline 

45 (19) 

8 weeks 

77 (14) 

Wound bed 

prep time 

(median): 

7 days 

(p=0.005) 

17 days Skin graft 

survival: 

83% 

(p=0.01) 

70% 

AMPUTATION ULCERS 

Armstrong 

200581 Apelqvist 

200882 

NPWT 

Inpatient stay, 

mean days: 

10.6 

(p=ns) 

9.9 

Overall 

procedures, 

mean #: 

43 

(p<0.001) 120 

Clinic visits, 

mean #: 

4 

(p<0.05) 

11 

NPWT=Negative pressure wound therapy; EQ-5D=EuroQol 5D; SF-6D=Single index measure generated from SF-36 data; SF-36=Short-Form 36 

a

EuroQol Derived Single Index (EQ-DSI) with higher score reflecting better health status; significant increase over time (both groups) 

166
 
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Table 5. Secondary Outcomes – Part C 

Study, year 

(Treatment) 

Withdrawals due to 

adverse events 

% (n/N) 

Patients with ≥1 

adverse event 

(%) n/N 

All-cause mortality 

% (n/N) 

Allergic reactions to 

treatment 

% (n/N) 

Treatment specific 

adverse events 

% (n/N) 

Treatment specific 

adverse events 

% (n/N) 

Treatment Control Treatment Control Treatment Control Treatment Control Treatment Control Treatment Control 

DIABETIC ULCERS 

Collagen 

Blume 201115 

(Formulated 

Collagen Gel) 

6 (2/33) 

(p=ns) 

0 

Reyzelman 

200918 

(Graftskin) 

6 (3/47) 

(p=ns) 

5 (2/39) Same as WD 

due to AE 

Same as 

WD due 

to AE 

0/47 

(p=ns) 

0/39 

Veves 200216 

(Promogran) 

Non-serious 

AE: 27 

(37/138) 

Serious AE: 

18 (25/138) 

(both p=ns) 

Nonserious 

AE: 25 

(34/138) 

Serious 

AE: 25 

(35/138) 

1.4 (2/138) 

(p=ns) 

4.3 

(6/138) 

Donaghue 

199817 

(Fibracol) 

Reported that overall 

7% (5/75) patients 

withdrew due to AE; 

no difference between 

groups 

Biological Dressings 

Niezgoda 200519 

(OASIS vs. 

PDGF) 

Reported no difference in 

proportion of patients with 

complications or AEs 

2 (1/50) 

(p=ns) 

0/48 

Biological Skin Equivalents (BSE) 

Gentzkow 199621 

(Dermagraft) 

Reported no adverse 

device effects 

Naughton 199722 

(Dermagraft) 

Reported no difference 

between groups in 

occurrence of intercurrent 

events 

Marston 200323 

(Dermagraft) 

67 (87/130) 

(p=ns) 

73 

(84/115) 

167 
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Study, year 

(Treatment) 

Withdrawals due to 

adverse events 

% (n/N) 

Patients with ≥1 

adverse event 

(%) n/N 

All-cause mortality 

% (n/N) 

Allergic reactions to 

treatment 

% (n/N) 

Treatment specific 

adverse events 

% (n/N) 

Treatment specific 

adverse events 

% (n/N) 

Treatment Control Treatment Control Treatment Control Treatment Control Treatment Control Treatment Control 

Veves 200124 

(Apligraf) 

5.4 (6/112) 

(p=ns) 

9.4 

(9/96) 

1/208; treatment group not 

specified 

Edmonds 200925 

(Apligraf) 

3 (1/33) 

(p=ns) 

10 (4/39) Serious AE 

(Tx phase) 

12 (4/33) 

(p=ns) 

13 (5/39) 3 (1/33) 

(p=ns) 

0 (0/39) 0 (0/33) 

(p=ns) 

0 (0/39) 

DiDomenico 

201126 

(Apligraf vs. 

Theraskin) 

29 (5/17) 

(p=ns) 

25 (3/12) 

Platelet-derived Growth Factor 

Agrawal 200928 

(PDGF) 

7 (1/14) 

(p=ns) 

0 (0/14) 

Hardikar 200529 

(rhPDGF) 

4 (2/55) 

(p=ns) 

5 (3/58) 0/55 

(p=ns) 

0/58 

Bhansali 200930 

(rhPDGF) 

Reported no adverse 

events in either group 

Wieman 199831 

(rhPDGF – 

Bercaplermin 

gel) 

100μg/g: 

11 (13/123) 

30μg/g: 

13 (17/132) 

(both p=ns) 

10 

(13/127) 

100μg/g: 

1 (1/123) 

30μg/g: 

2 (3/132) 

(both p=ns) 

2 (3/127) 

Jaiswal 201032 

(rhPDGF) 

Reported no local or 

systemic side-effects in 

either group 

Steed 2006 

199533,34 

(rhPDGF) 

Overall 51 

(31/61) 

(p=ns) 

Tx Related 

16 (10/61) 

(p=ns) 

Overall 60 

(34/57) 

Tx 

Related 

18 (10/57) 

0 

(p=ns) 

4 (2/57) 

168 
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Study, year 

(Treatment) 

Withdrawals due to 

adverse events 

% (n/N) 

Patients with ≥1 

adverse event 

(%) n/N 

All-cause mortality 

% (n/N) 

Allergic reactions to 

treatment 

% (n/N) 

Treatment specific 

adverse events 

% (n/N) 

Treatment specific 

adverse events 

% (n/N) 

Treatment Control Treatment Control Treatment Control Treatment Control Treatment Control Treatment Control 

d’Hemecourt 

199835 

(PDGF 

[Bercaplermin 

gel] versus 

NaCMC or Std 

Care) 

Gel 

15 (5/34) 

(p=ns 

vs. both 

controls) 

NaCMC 

11 (8/70) 

Std 

24 

(16/68) 

Gel 

65 (22/34) 

(p=ns vs. 

both controls) 

NaCMC 

81 (57/70) 

Std 

71 (48/68) 

Gel 

3 (1/34) 

(p=ns vs. both 

controls) 

NaCMC 

1 (1/70) 

Std 

3 (2/68) 

Woundrelated 

events: 

Gel 

21 (7/34) 

(p=ns 

vs. both 

controls) 

NaCMC 

27 (19/70) 

Std 

37 (25/68) 

Platelet Rich Plasma 

Driver 200637 Total of 122 events, 60 

(49%) in PRP group, 62 

(51%) in control group 

(p=ns) 

3 (1/40) 

(p=ns) 

3 (1/32) 

Silver Products 

Belcaro 201038 

(Silver Ointment) 

0/34 

(p=ns) 

0/32 0/34 

(p=ns) 

0/32 0/34 

(p=ns) 

0/32 

Jacobs 201039 

(Silver Cream 

(control tx)) 

0/20 

(p=ns) 

0/20 0/20 

(p=ns) 

0/20 0/20 

(p=ns) 

0/20 

Jude 200740 

(Silver Dressing) 

12 (8/67) 

(p=ns) 

19 

(13/67) 

37 (25/67) 

(p=ns) 

39 (26/67) 1.5 (1/67) 

(p=ns) 

1.5 (1/67) Studyrelated 

events 16 

(11/67) 

(p=ns) 

13 (9/67) 

Viswanathan 

201141 

(Silver Cream 

(control tx)) 

5 (1/20) 

(p=ns) 

0/20 0/19 (Perprotocol) 0/19 0/20 

(p=ns) 

5 (1/20) 

Negative Pressure Wound Therapy 

Blume 200842 11.2 

(19/169) 

(p=ns) 

9.0 

(15/166) 

1.8 (3/169) 

(p=ns) 

1.8 

(3/166) 

McCallon 200044 0/5 

(p=ns) 

0/5 0/5 

(p=ns) 

0/5 

169 
Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

Study, year 

(Treatment) 

Withdrawals due to 

adverse events 

% (n/N) 

Patients with ≥1 

adverse event 

(%) n/N 

All-cause mortality 

% (n/N) 

Allergic reactions to 

treatment 

% (n/N) 

Treatment specific 

adverse events 

% (n/N) 

Treatment specific 

adverse events 

% (n/N) 

Treatment Control Treatment Control Treatment Control Treatment Control Treatment Control Treatment Control 

Hyperbaric Oxygen Therapy 

Löndahl 201046 2.0 (1/49) 

(p=ns) 

6.7 

(3/45) 

2.0 (1/49) 

(p=ns) 

6.7 (3/45) Oxygen 

toxicity 

0/49 

(p=ns) 

0/45 Barotraumatic 

otitis 

2.0 (1/49)‡ 

(p=ns) 

0/45‡

* Dizziness 

2.0 (1/49) 

Worsen 

cataract 

2.0 (1/49) 

Minor 

head 

injury 

2.2 

(1/45) 

Duzgun 200847 0/50 

(p=ns) 

0/50 

Kessler 200348 6.7 (1/15) 

(p=ns) 

0/13 6.7 (1/15) 

(p=ns) 

0/13 0/15 

(p=ns) 

0/13 Barotraumatic 

otitis 

6.7 (1/15) 

(p=ns) 

0/13 

Abidia 200349 0/9 

(p=ns) 

11.1 

(1/9)* 

0/9 

(p=ns) 

11.1 

(1/9)* 

0/9 

(p=ns) 

0/9 

VENOUS ULCERS 

Collagen (COL) 

Vin 200252 

(Promogran) 

14 (5/37) 

(p=ns) 

14 (5/36) 14 (5/37) 

(p=ns) 

14 (5/36) 

Biological Dressings (BD) 

Mostow 200553 

(OASIS) 

9.6 (6/62) 

(p=ns) 

10.3 

(6/58) 

Reported no difference 

in proportions of patients 

with AEs between groups 

(8 events in OASIS 

group, 15 in control) 

1.6 (1/62) 

(p=ns) 

0/58 3 events in 

62 patients 

3 events 

in 58 

patients 

Biological Skin Equivalents 

Falanga 199854 

Falanga 199955 

(Apligraf) 

2.1 (3/146) 

(p=ns) 

5.4 

(7/129) 

3.4 (5/146) 

(p=ns) 

3.1 

(4/129) 

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Study, year 

(Treatment) 

Withdrawals due to 

adverse events 

% (n/N) 

Patients with ≥1 

adverse event 

(%) n/N 

All-cause mortality 

% (n/N) 

Allergic reactions to 

treatment 

% (n/N) 

Treatment specific 

adverse events 

% (n/N) 

Treatment specific 

adverse events 

% (n/N) 

Treatment Control Treatment Control Treatment Control Treatment Control Treatment Control Treatment Control 

Krishnamoorthy Group 1: Group 4: Group 1: Group 4: No deaths 

200356 0/13 0/13 18 AE’s, 1 17 AE’s, 0 

(Dermagraft) Group 2: serious serious 

1/13 Group 2: 

Group 3: 15 AE’s, 1 

Unclear† serious 

(all p=ns) Group 3: 

15 AE’s, 4 

serious 

Keratinocytes 

Harding 200560 

(Lyophilized, 

Local AE: 

Tx phase 

1 (1/95) 

(p=ns) 

0/99 Reported no 

differences between 

allogeneic) 

NOTE: Control 

22 (21/95) 

Follow-up 

23 (23/99) treatment groups in 

“sensations such as 

group is 

combined 

standard care 

8 (7/89) 

General AE: 

Tx phase 

5.5 (5/91) burning, stinging, pain, 

or itching” 

and standard 

care + vehicle 

25 (24/95) 

Follow-up 

23 (23/99) 

group 16 (14/89) 

(all p=ns) 

14 (13/91) 

Vanscheidt 33 (38/116) 25 0.9 (1/116) 0.9 

200761 (63 events) (27/109) (p=ns)^ (1/109) 

(Autologous, in (p=ns for (51 

fibrin sealant) patients) 

Serious AEs: 

10 (12/116) 

(12 events) 

events) 

10 

(11/109) 

(14 

events) 

Platelet Rich Plasma 

Stacey 200062 5 patients withdrew 

from study w/ allergy to 

paste bandage and 1 

w/ trauma on leg from 

bandages; not detailed 

by group 

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Study, year 

(Treatment) 

Withdrawals due to 

adverse events 

% (n/N) 

Patients with ≥1 

adverse event 

(%) n/N 

All-cause mortality 

% (n/N) 

Allergic reactions to 

treatment 

% (n/N) 

Treatment specific 

adverse events 

% (n/N) 

Treatment specific 

adverse events 

% (n/N) 

Treatment Control Treatment Control Treatment Control Treatment Control Treatment Control Treatment Control 

Silver Products 

Belcaro 201038 

(Silver Ointment) 

0/44 

(p=ns) 

0/38 0/44 0/38 

(p=ns) 

0/44 

(p=ns) 

0/38 

Bishop 199263 

(Silver Cream -

control tx) 

Reported no statistical 

differences among 

treatment groups 

Blair 198864 

(Silver Dressing) 

13 (4/30) 

(p=ns) 

0/30 Deterioration due 

to cellulitis 

7 (2/30) 

(p=ns) 

3 (1/30) 

Dimakakos 

200965 

(Silver Dressing) 

0 (0/21) due 

to tx 

0 (0/21) due 

to tx 

Harding 201166 

(Silver Dressing) 

6 (9/145) 

AQUACEL 

(p=ns) 

9 

(12/136) 

Urgotul 

Any AE 

50 (72/145) 

Related AE 

23 (33/145) 

(both p=ns) 

42 

(57/126) 

18 

(24/136) 

0/145 

(p=ns) 

1.4 

(2/136) 

Michaels 

2009ab67,68 

(Silver Dressing) 

1 (1/107) 

(p=ns) 

0/106 12 week tx 

0/107 

(p=ns) 

1st year 

4 (4/107) 

(p=ns) 

0/106 

4 (4/106) 

Intermittent Pneumatic Compression 

Schuler 199669 4 (1/28) 

(p=ns) 

7.7 

(2/26) 

0 (0/28) 

(p=ns) 

3.8 

(1/26) 

Electromagnetic Therapy 

Ieran 199070 9.1 (2/22)# 

(p=ns) 

0/22 0/22 

(p=ns) 

0/22 

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Study, year 

(Treatment) 

Withdrawals due to 

adverse events 

% (n/N) 

Patients with ≥1 

adverse event 

(%) n/N 

All-cause mortality 

% (n/N) 

Allergic reactions to 

treatment 

% (n/N) 

Treatment specific 

adverse events 

% (n/N) 

Treatment specific 

adverse events 

% (n/N) 

Treatment Control Treatment Control Treatment Control Treatment Control Treatment Control Treatment Control 

Kenkre 199671 0/10 

(p=ns) 

0/9 68 (13/19) 

Results not reported by 

treatment arm 

0 NR Moderate/ 

severe 

headache 

20 (2/10) 

Sense 

of heat, 

tingling, 

and 

“needles 

and pins” 

in limbs 

30 (3/10) 

0/9 

33 (3/9) 

ARTERIAL ULCERS 

Chang 200073 

(Biologic Skin 

Equivalent -

Apligraf) 

0/21 

(p=ns) 

0/10 14.3 (3/21) 

(p=ns) 

0/10 4.8 (1/21) 

(p=ns) 

(after ulcer 

had healed) 

0/10 

MIXED LowER EXTREMITy ULCERS 

Brigido 200674 

(Collagen) 

AEs were comparable 

between treatment arms 

Romanelli 200775 

(Biological 

Dressing – 

OASIS) 

0/27 

(p=ns) 

0/27 0/27 

(p=ns) 

0/27 0/27 

(p=ns) 

0/27 

Romanelli 201076 

(Biological 

Dressing – 

OASIS) 

0/25 

(p=ns) 

0/25 0/25 

(p=ns) 

0/25 0/25 

(p=ns) 

0/25 

Jørgensen 

200577 

(Silver-releasing 

Dressing) 

Devicerelated AEs 

6 (4/65) 

(p=ns) 5 (3/64) 

↑ ulcer size 

14 (9/65) 

(p=ns) 

25 (16/64) 

Miller 201078 

(Silver Dressing) 

8 (13/140) 

(p=ns) 

Vuerstack 200680 

(NPWT) 

40% (p=ns) 23% 13 (4/30) 

(p=ns) 

7 (2/30) 

173
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Study, year 

(Treatment) 

Withdrawals due to 

adverse events 

% (n/N) 

Patients with ≥1 

adverse event 

(%) n/N 

All-cause mortality 

% (n/N) 

Allergic reactions to 

treatment 

% (n/N) 

Treatment specific 

adverse events 

% (n/N) 

Treatment specific 

adverse events 

% (n/N) 

Treatment Control Treatment Control Treatment Control Treatment Control Treatment Control Treatment Control 

AMPUTATIoN ULCERS 

Armstrong 

200581 

(NPWT) 

52 (40/77) 

(p=ns) 

54 (46/85) 

AE=Adverse event; PP=Per protocol population; NaCMC=sodium carboxymethylcellulose; PDGF=Platelet-derived growth factors; PRP=Platelet rich plasma; BSE=Biological skin equivalent; 

NPWT=Negative pressure wound therapy 

‡

2 patients in each group required myringotomy with tube placement due to pain caused by the inability to equilibrate air pressure through the eustachion tube 

#

allergic reaction to drugs, diagnosed as having rheumatoid arthritis 

†

3 withdrawals reported in text; 2 withdrawals reported in Figure 1 in article; Table 1 in article includes >1 serious adverse event only in Group 3 

^1 additional death in screening phase; treatment group not reported 
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APPENDIX E. CommoN mEthoDologICAl Errors AND 

rECommENDAtIoNs for futurE ClINICAl trIAls of 

WouND hEAlINg 

1. Common methodological Errors in studies of Wound Care 

Source: 

European Wound Management Association 

Gottrup F, Apelqvist J, Price P. Outcomes in controlled and comparative studies on 

non-healing wounds: recommendations to improve the quality of evidence in wound 

management. J Wound Care. 2010;19:239-68. 

•	 Lack of validation of subjective assessments 

•	 Lack of description of objective or subjective measures 

•	 Lack of comparable baselines for patient groups 

•	 Lack of blinding for the evaluation of primary outcomes 

•	 Incorrect randomization methods 

•	 Poor definition of primary and secondary objectives 

•	 Number of patients not based on a priori sample size calculation 

•	 Randomization method poorly/not described 

•	 Time to wound healing not a primary objective 

•	 Intention-to-treat analysis not used 

•	 Heterogeneous study population 

•	 Number of and reason for dropouts not stated 

•	 No specification of adjuvant treatments 

•	 Small sample size combined with multiple outcome measures 

•	 Reporting of multiple outcomes over multiple time points (increased chance of type 1 error) 

•	 Poor overall study reporting 

2. recommendations for Clinical trials of Wound healing 

Sources: 

Center for Medical Technology Policy 

Center for Medical Technology Policy. Effectiveness Guidance Document: 

Methodological Recommendations for Comparative Effectiveness Research on the 

Treatment of Chronic Wounds. Version 2.0, October 1, 2012. Available at: http://www. 

cmtpnet.org/effectiveness-guidance-documents/negative-pressure-wound-therapy-egd/. 

Accessed October 2012. 

European Wound Management Association 

Gottrup F, Apelqvist J, Price P. Outcomes in controlled and comparative studies on 

non-healing wounds: recommendations to improve the quality of evidence in wound 

management. J Wound Care. 2010;19:239-68. 
176 

Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

Panel on Wound Care Evidence-Based Research 

Serena T, Bates-Jensen B, Carter MJ, et al. Consensus principles for wound care research 

obtained using a Delphi process. Wound Repair Regen. 2012;20:284-93. 

US Food and Drug Administration 

FDA. Guidance for Industry: Chronic Cutaneous Ulcer and Burn Wounds-Developing 

Products for Treatment. 2006. Available at: http://www.fda.gov/downloads/Drugs/ 

GuidanceComplianceRegulatoryInformation/Guidances/UCM071324.pdf. Accessed 

September 2012. 

1.		 “Chronic” needs to be defined or replaced with “non-healing.” 

2.	 Studies should be multi-center to include a range of settings. 

3.		 Studies should focus on one wound type with stratification by risk factors for not healing. 

4.	 Exclusion criteria should be minimal to increase generalizability; rationale for inclusion 

and exclusion criteria should match the goals of the study. 

5.	 Randomization is critical; baseline wound characteristics have a major effect on 

outcomes. Non-randomized trials should be considered only when there are barriers to 

conducting randomized trials that can be identified and explained. 

6.	 Interventions should be clearly described and consistent across all patients. 

7.	 Simultaneous and/or sequential interventions should be evaluated when appropriate. 

8.		 Standard care should be clearly defined and consistent across study sites or balanced 

using stratification of study sites for multi-site studies; large cohort studies with each 

wound type should establish outcomes achieved with standard care. 

9.	 Protocols for pain management and treatment of comorbid conditions should be 

standardized in all study arms. 

10. Comparator arms in studies of dressings, medications, etc. should be a “vehicle control 

arm” with the same components except for the active agent; if the effect of the “vehicle” 

is not known, there should also be a standard care group only. 

11. Blinding of subjects and investigators should be employed if feasible; blinded assessment 

by a third-party evaluator should be considered if blinding of investigators and patients 

isn’t possible. 

12. Outcome assessment tools should be pre-specified and protocols standardized across 

patients and across study sites for multi-site studies. 

13. The patient population should be appropriate for the treatment and type of wound to be 

studied. 

14. A substantial proportion of patients should be drawn from clinical settings where wound 

care is delivered. 

15. Chronic ulcers might heal because patients become more compliant with standard 

therapy when enrolled in a trial; studies should include a run-in period of standard care 

(1-2 weeks) with entry criterion based on change in ulcer size during the run-in phase to 

exclude those healing because of compliance. 

16. Endpoints should be chosen based on the purpose of the intervention; important outcomes 

include: 

a.		 incidence of complete closure (defined as skin re-epithelialization without drainage 

or dressing requirements confirmed at two consecutive study visits 2 weeks apart); 

closure should be confirmed by an independent source; trial should include at least 
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Advanced Wound Care Therapies for Non-Healing Diabetic, 

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3 months follow-up following closure to distinguish actual healing from transient 

wound coverage; partial healing should not be a primary endpoint except partial 

healing to facilitate surgical wound closure; if purpose of intervention is something 

other than healing, endpoints should be pre-defined and validated scoring systems 

used, 

b.	 accelerated wound closure (decreased time to healing); monitoring intervals should be 

sufficiently short to detect meaningful difference in time to closure between treatment 

groups; ideally all patients would be followed until healing is achieved, 

c.	 quality of healing (e.g., scarring, contour and feel of healed skin, normalization of 

skin markings or pigmentation), 

d.	 quality of wound care (e.g., prevention or cure of infection, reduced pain and/or 

decreased blood loss with debridement, pain), and 

e.	 activities of daily living, quality of life, limb salvage, dressing performance. 

17. Potential sources of bias include: 

a.	 selection bias – allocation concealment is important, 

b.		 performance bias – clearly define standard care; blind outcome assessment; include 

independent assessment of outcomes, 

c.	 attrition bias – document reasons for drop-out; plan for drop-outs, including 

withdrawals due to wound deterioration,
 

d.		 detection bias – define outcomes; follow-up to detect recurrence, and 

e.	 publication bias – trials may not be published or available in indexed journals. 

18. National or formal wound registries should be developed.