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Advanced Wound Care Therapies for Nonhealing Diabetic, Venous, and Arterial Ulcers: A Systematic Review FREE

Nancy Greer, PhD; Neal A. Foman, MD, MS; Roderick MacDonald, MS; James Dorrian, MD; Patrick Fitzgerald, MPH; Indulis Rutks, BS; and Timothy J. Wilt, MD, MPH
[+] Article and Author Information

From Minneapolis Veterans Affairs Health Care System and University of Minnesota, Minneapolis, Minnesota.

Disclaimer: The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the U.S. government.

Financial Support: This article is based on research conducted by the Minneapolis Evidence-based Synthesis Program and was supported by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Quality Enhancement Research Initiative.

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M13-1027.

Requests for Single Reprints: Nancy Greer, PhD, Minneapolis Veterans Affairs Health Care System, One Veterans Drive, Mail Code 152, Minneapolis, MN 55417; e-mail, nancy.greer@va.gov.

Current Author Addresses: Drs. Greer and Wilt, Mr. MacDonald, Mr. Fitzgerald, and Mr. Rutks: Center for Chronic Disease Outcomes Research, Minneapolis Veterans Affairs Health Care System, One Veterans Drive, Mail Code 152, Minneapolis, MN 55417.

Drs. Foman and Dorrian: Dermatology Service, Minneapolis Veterans Affairs Health Care System, One Veterans Drive, Mail Code 111K, Minneapolis, MN 55417.

Author Contributions: Conception and design: N. Greer, N.A. Foman, T.J. Wilt.

Analysis and interpretation of the data: N. Greer, N.A. Foman, R. MacDonald, J. Dorrian, P. Fitzgerald, T.J. Wilt.

Drafting of the article: N. Greer, N.A. Foman, R. MacDonald, J. Dorrian, T.J. Wilt.

Critical revision of the article for important intellectual content: N. Greer, N.A. Foman, J. Dorrian, T.J. Wilt.

Final approval of the article: N. Greer, N.A. Foman, R. MacDonald, I. Rutks, T.J. Wilt.

Provision of study materials or patients: I. Rutks.

Statistical expertise: R. MacDonald, T.J. Wilt.

Obtaining of funding: T.J. Wilt.

Administrative, technical, or logistic support: N. Greer, P. Fitzgerald, I. Rutks, T.J. Wilt.

Collection and assembly of data: N. Greer, R. MacDonald, J. Dorrian, P. Fitzgerald, I. Rutks, T.J. Wilt.


Ann Intern Med. 2013;159(8): 532-542. doi:10.7326/0003-4819-159-8-201310150-00006
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Background: Nonhealing ulcers affect patient quality of life and impose a substantial financial burden on the health care system.

Purpose: To systematically evaluate benefits and harms of advanced wound care therapies for nonhealing diabetic, venous, and arterial ulcers.

Data Sources: MEDLINE (1995 to June 2013), the Cochrane Library, and reference lists.

Study Selection: English-language randomized trials reporting ulcer healing or time to complete healing in adults with nonhealing ulcers treated with advanced therapies.

Data Extraction: Study characteristics, outcomes, adverse events, study quality, and strength of evidence were extracted by trained researchers and confirmed by the principal investigator.

Data Synthesis: For diabetic ulcers, 35 trials (9 therapies) met eligibility criteria. There was moderate-strength evidence for improved healing with a biological skin equivalent (relative risk [RR], 1.58 [95% CI, 1.20 to 2.08]) and negative pressure wound therapy (RR, 1.49 [CI, 1.11 to 2.01]) compared with standard care and low-strength evidence for platelet-derived growth factors and silver cream compared with standard care. For venous ulcers, 20 trials (9 therapies) met eligibility criteria. There was moderate-strength evidence for improved healing with keratinocyte therapy (RR, 1.57 [CI, 1.16 to 2.11]) compared with standard care and low-strength evidence for biological dressing and a biological skin equivalent compared with standard care. One small trial of arterial ulcers reported improved healing with a biological skin equivalent compared with standard care. Overall, strength of evidence was low for ulcer healing and low or insufficient for time to complete healing.

Limitations: Only studies of products approved by the U.S. Food and Drug Administration were reviewed. Studies were predominantly of fair or poor quality. Few trials compared 2 advanced therapies.

Conclusion: Compared with standard care, some advanced wound care therapies may improve the proportion of ulcers healed and reduce time to healing, although evidence is limited.

Primary Funding Source: Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Quality Enhancement Research Initiative.


Nonhealing ulcers (those that are unresponsive to initial therapy or persist despite appropriate care) affect patient quality of life and productivity and represent a substantial financial burden on the health care system (13). More than 6 million persons in the United States are affected, and this number is expected to increase as the population ages and more people develop diabetes (1). Identifying ulcer cause is an important factor in determining appropriate wound care interventions (4). Nonhealing ulcers are typically categorized as diabetic, venous, or arterial.

Standard treatment for ulcers may include debridement of necrotic tissue, revascularization surgery, infection control, mechanical offloading, management of blood glucose, foot care education, mechanical compression, or limb elevation (46). If ulcers do not adequately heal with standard treatment, “advanced wound care therapies” (therapies used when standard treatments have failed) are considered. Although a large and growing array of advanced therapies exists, their efficacy, comparative effectiveness, and harms are not well-established. The purpose of this review was to systematically evaluate randomized, controlled trials of the efficacy and harms of advanced wound care therapies compared with either usual care or another advanced therapy for lower-extremity, nonhealing, diabetic, venous, and arterial ulcers in adult patients.

This report is part of a Department of Veterans Affairs Evidence-based Synthesis Program review, which is available at www.hsrd.research.va.gov/publications/esp/wound-care.cfm.

Data Sources and Searches

We searched MEDLINE (Ovid interface) for randomized, controlled trials published from 1995 through June 2013 (see the search strategy in Appendix Table 1). We limited the search to English-language studies involving adults aged 18 years or older. We obtained additional references from a search of the Cochrane Library, existing systematic reviews, and reference lists of pertinent studies.

Table Jump PlaceholderAppendix Table 1. Search Strategy 
Study Selection

Investigators and research associates reviewed abstracts identified from the literature search for relevance. We included randomized, controlled studies of adults with nonhealing diabetic, venous, or arterial ulcers receiving treatment with an advanced wound care therapy of interest as identified by an expert advisory panel. We included studies that compared these therapies with standard wound care as well as with other advanced therapies and reported either percentage of ulcers healed at study completion or time to complete ulcer healing.

Data Extraction and Quality Assessment

Study, patient, ulcer, and treatment characteristics; outcomes; and adverse events were extracted from the full text of eligible articles by a trained research associate and verified by a second research associate. The principal investigator confirmed key characteristic and outcome data. Our primary outcome of interest was the percentage of ulcers healed at study completion. Additional outcomes of interest included time to complete ulcer healing, patient global assessment, and return to daily activities. We also assessed pain, ulcer infection, amputation, revascularization surgery, ulcer recurrence, time to ulcer recurrence, hospitalization, all-cause mortality, adverse events, and adverse reactions to treatment.

The quality of individual studies was rated as good, fair, or poor using a modification of the Cochrane approach to determining risk of bias (7), which involved evaluation of established criteria for randomized, controlled trials: allocation concealment, blinding, analysis approach, and description of withdrawals. We attempted to minimize publication bias through a comprehensive literature search, hand-searching of reference lists, and input from content experts. Funnel plots were not possible because of the small number of trials for each intervention and outcome.

Data Synthesis and Analysis

Results are summarized according to ulcer cause (arterial, venous, or diabetic) as defined by study authors. When feasible, data were analyzed in Review Manager, version 5.1 (The Nordic Cochrane Centre, Copenhagen, Denmark). Random-effects models were used to generate pooled estimates of relative risks (RRs) with 95% CIs for outcomes from studies of equivalent therapies used to treat similar ulcer types. We evaluated statistical heterogeneity using a chi-square test and the I2 statistic (with cutoffs of 25.0%, 50.0%, and 75.0% for low, moderate, and substantial heterogeneity, respectively) (8). We calculated absolute risk differences (ARDs) with 95% CIs for the primary outcome of ulcers healed. All other data are narratively summarized. Strength of evidence was determined for the percentage of ulcers healed and time to complete ulcer healing. We rated the overall strength of the evidence as high, moderate, low, or insufficient (9). Rating of study quality and strength of evidence was done by a research associate and verified by the principal investigator.

Role of the Funding Source

The funding source (Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Quality Enhancement Research Initiative) assigned the topic and reviewed the key questions but was not involved in data collection or analysis or manuscript preparation or submission.

We screened 1322 titles and abstracts, excluded 1135, and performed a detailed review of the remaining 187 articles. From these, 59 articles representing 56 randomized, controlled trials (35 involving patients with diabetic ulcers, 20 involving those with venous ulcers, and 1 involving those with arterial ulcers) were eligible for inclusion (Appendix Figure 1). Most studies compared advanced wound care therapies with standard care or placebo. Direct comparison of one advanced therapy with another was done in 10 studies (29%) of diabetic ulcers and 4 studies (20%) of venous ulcers.

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Appendix Figure 1.

Summary of evidence search and selection.

* One article provided outcomes for both diabetic and venous ulcers.

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Diabetic Ulcers

We identified 35 eligible trials of 9 advanced wound care therapies for diabetic ulcers (1045). Appendix Table 2 summarizes baseline patient and wound characteristics. Enrollees were generally middle-aged, and most were white men. Sample size ranged from 9 to 382, and treatment duration ranged from 4 to 20 weeks.

Table Jump PlaceholderAppendix Table 2. Baseline Characteristics: Diabetic Ulcer Studies 

Mean ulcer size ranged from 1.9 to 41.5 cm2, although it was greater than 10 cm2 in only 6 of 30 studies that reported ulcer size. Mean ulcer duration ranged from 2 to 94 weeks. Complete study characteristics, including the risk-of-bias assessment, are presented in Table 1 of the Supplement.

The ulcer was described as a “foot” ulcer in 26 trials (1113, 1521, 23, 25, 3143, 45), a “lower-extremity” ulcer in 7 trials (10, 24, 2630, 44), and a “diabetic” ulcer in 2 trials (14, 22). The ulcer type was further described as neuropathic in 11 trials (10, 17, 1920, 2426, 2829, 31, 33, 36), ischemic in 1 trial (44), neuroischemic in 1 trial (23), and mixed in 3 trials (3435, 38). Of the remaining trials, 16 had inclusion or exclusion criteria related to circulation or severe arterial disease (1117, 21, 27, 30, 32, 37, 39, 41, 43, 45) and 3 did not specify criteria related to circulation (22, 40, 42).

Findings for our primary outcome of interest—proportion of healed ulcers at study conclusion—are presented in Figure 1and Table 1 . In Figure 1, results are depicted according to the sample size of the individual studies and whether results significantly (P < 0.05) favored the listed advanced wound therapy versus standard care or another advanced wound care product. Table 1 provides ARDs and RRs with 95% CIs.

Table Jump PlaceholderTable 1. ARDs and RRs for Percentages of Healed Ulcers: Diabetic Ulcer Studies 
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Figure 1.

Healed diabetic ulcers.

Each dot represents 1 trial. Shaded rows indicate therapies for which meta-analyses were possible (see Figure 2 and Appendix Figure 2). BSE = biological skin equivalent; HBOT = hyperbaric oxygen therapy; NPWT = negative pressure wound therapy; PDGF = platelet-derived growth factor; PRP = platelet-rich plasma.

* Shire Regenerative Medicine, San Diego, California.

† Organogenesis, Canton, Massachusetts.

‡ Compared biological dressing with BSE (Dermagraft) and found no significant difference (15).

§ Compared biological dressing with PDGF and found no significant difference (14).

∥ A second study of silver cream did not report the proportion of healed ulcers (36).

¶ Found extracorporeal shock wave therapy to be more effective than HBOT (40).

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Ulcers Healed: Advanced Wound Care Versus Standard Care

Overall, the strength of evidence favoring advanced therapies over standard care was low for 7 therapies and moderate for 2 therapies (Figure 1 and Appendix Table 3). Study design (for example, duration of intervention and time of final outcome assessment) and clinical heterogeneity (for example, ulcer size, duration, and location and comorbid conditions) precluded meta-analyses of results in many situations.

Table Jump PlaceholderAppendix Table 3. Strength of Evidence for Advanced Wound Care Therapies: Diabetic Ulcers 

We were able to combine results from trials comparing 3 advanced therapies with standard care (Figure 1; Table 1; and Appendix Figure 2). Although effect sizes were similar for all 3 therapies, the findings were statistically significant for only 2. We found moderate-strength evidence for improved healing with the biological skin equivalent Apligraf (Organogenesis, Canton, Massachusetts) (2 fair-quality trials; ARD, 21% [95% CI, 9% to 32%]; RR, 1.58 [CI, 1.20 to 2.08]; I2 = 0%) (1920) and low-strength evidence for improved healing with platelet-derived growth factors (2 good-quality and 5 fair-quality trials; ARD, 21% [CI, 14% to 29%]; RR, 1.45 [CI, 1.03 to 2.05]; I2 = 85%) (2330). The rating of low strength of evidence for the platelet-derived growth factor trials was based on high heterogeneity (inconsistent results) in trials of predominantly fair quality and concerns about lack of directness (probable enrollment of a highly selected population). Low-strength evidence suggested no statistically significant effect with the biological skin equivalent Dermagraft (Shire Regenerative Medicine, San Diego, California) (3 fair-quality trials; ARD, 10% [CI, 2% to 18%]; RR, 1.49 [CI, 0.96 to 2.32]; I2 = 43%) (1618).

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Appendix Figure 2.

Meta-analyses of the proportion of diabetic ulcers healed.

BSE = biological skin equivalent; M–H = Mantel–Haenszel; PDGF = platelet-derived growth factor.

* Shire Regenerative Medicine, San Diego, California. † Organogenesis, Canton, Massachusetts.

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We found moderate-strength evidence of improved healing with negative pressure wound therapy (1 good-quality trial; ARD, 14% [CI, 4% to 24%]; RR, 1.49 [CI, 1.11 to 2.01]) (37) and low-strength evidence of improved healing with silver cream (1 fair-quality trial; ARD, 23% [CI, 2% to 43%]; RR, 2.45 [CI, 0.98 to 6.09]) (33).

For the remaining therapies, either no difference was observed between the advanced therapy (platelet-rich plasma or ozone–oxygen therapy) and standard care or results from multiple trials of the same therapy were mixed (collagen, biological skin equivalent [Dermagraft], platelet-derived growth factor, or hyperbaric oxygen therapy). Absolute risk differences typically ranged from 4% to 30% (Table 1). Strength of evidence was low (Appendix Table 3).

Ulcers Healed: Comparative Effectiveness of Advanced Wound Care Products

In 9 trials comparing one advanced therapy with another (Figure 1 and Table 1), ARDs ranged from 8% to 30%. One poor-quality study found that extracorporeal shock wave therapy statistically significantly improved ulcer healing compared with hyperbaric oxygen therapy (ARD, 30% [CI, 10% to 49%]) (40). Strength of evidence was low for the effect on the proportion of healed ulcers when one advanced therapy was compared with another. For 6 of the 8 comparisons, data were available from only 1 trial.

Other Outcomes

No studies reported a statistically significant improvement in time to ulcer healing for collagen (1213), biological dressings (1415), or silver products (3536) compared with standard care or another advanced therapy. Results were mixed but generally negative for biological skin equivalents compared with standard care or another advanced therapy (16, 1820), platelet-derived growth factor compared with standard care or another advanced therapy (14, 2426, 2830), platelet-rich plasma compared with standard care or another advanced therapy (3132), and negative pressure wound therapy compared with standard care (3839). Strength of evidence was low or insufficient for all findings related to time to ulcer healing (Appendix Table 3). One study of silver versus calcium dressings reported no difference between groups for a global outcome of healed or improved ulcers (35). No studies reported on return to daily activities.

No studies reported a statistically significant difference in ulcers infected during treatment or ulcer recurrence for any of the reviewed advanced therapies compared with standard care or another advanced therapy. Fewer amputations were reported in the advanced therapy group in 3 studies (1 each of a biological skin equivalent [19], negative pressure wound therapy [37], and hyperbaric oxygen therapy [42], all compared with standard care), and 5 studies reported no difference (13, 20, 41, 4445). Few studies reported on the need for revascularization or hospitalization. Overall, few deaths were reported and the results did not show a statistically significant benefit of advanced therapies in reducing all-cause mortality (reported in 16 studies) (11, 1314, 20, 24, 26, 2830, 32, 3537, 39, 41, 4344). Similarly, there were no observed reductions in pain, withdrawals due to adverse events, or allergic reactions to treatment (Tables 2 to 4 of the Supplement). Studies lacked adequate power to assess the effect of an advanced therapy on these outcomes.

Venous Ulcers

We identified 20 eligible trials of 9 advanced therapies for venous ulcers (33, 4666). A summary of baseline characteristics is presented in Appendix Table 4. Enrollees were predominately older white women. Studies enrolled 16 to 309 patients, and treatment duration ranged from 4 to 26 weeks. Mean ulcer size ranged from 1.2 to 11.1 cm2, with mean ulcer sizes of greater than 10 cm2 in 4 of the 12 studies reporting. Mean ulcer duration ranged from 12 to 207 weeks. Complete study characteristics, including the risk-of-bias assessment, are presented in Table 1 of the Supplement.

Table Jump PlaceholderAppendix Table 4. Baseline Characteristics: Venous Ulcer Studies 

The ulcer was described as a “leg” ulcer in 14 trials (4647, 5051, 5356, 5859, 6162, 6466) and a “lower-extremity” ulcer in 3 trials (52, 57, 60), whereas 3 trials did not report the ulcer location but described it only as a “venous” ulcer (33, 48, 63). In 12 trials, diagnosis of a venous ulcer was based on clinical signs or symptoms of venous insufficiency (4648, 5156, 6365). The remaining 8 trials required patients to have adequate arterial circulation or excluded patients with known arterial insufficiency (33, 50, 5762, 66).

Ulcers Healed: Advanced Wound Care Products Versus Standard Care

Findings for our primary outcome of interest—proportion of healed ulcers—are presented in Figure 2,Table 2, and Appendix Table 5. Meta-analyses (Appendix Figure 3) showed an overall benefit of keratinocyte therapy compared with standard care (2 fair-quality trials; ARD, 14% [CI, 5% to 23%]; RR, 1.57 [CI, 1.16 to 2.11]; I2 = 0%), with moderate strength of evidence (5455). Data from 3 studies of silver cream versus standard care (1 good-quality and 2 fair-quality studies; ARD, 9% [CI, −4% to 23%]; RR, 1.65 [CI, 0.54 to 5.03]; I2 = 84%) (33, 5758) and 2 studies of silver dressing versus nonsilver dressing (both of fair quality; ARD, 8% [CI, −4% to 20%]; RR, 1.27 [CI, 0.80 to 2.01]; I2 = 67%) (59, 6162) showed no overall benefit of silver products. In single trials, there was low-strength evidence of improved ulcer healing with biological dressing (1 fair-quality trial; ARD, 20% [CI, 3% to 38%]) (47) and the biological skin equivalent Apligraf (1 fair-quality trial; ARD, 14% [CI, 3% to 26%]) (48) compared with placebo or standard care (Figure 2 and Table 2). Absolute risk differences in ulcer healing ranged from 1% to 38% for collagen (46), the biological skin equivalent Dermagraft (5051), platelet-rich plasma (56), hyperbaric oxygen therapy (66), or intermittent pneumatic compression therapy (63) compared with placebo or standard care (Table 2). Results for electromagnetic therapy were mixed (6465). Strength of evidence was low (Appendix Table 5).

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Figure 2.

Healed venous ulcers.

Each dot represents 1 trial. Shaded rows indicate therapies for which meta-analyses were possible (see Appendix Figure 3). BSE = biological skin equivalent; EMT = electromagnetic therapy; HBOT = hyperbaric oxygen therapy; IPC = intermittent pneumatic compression; PRP = platelet-rich plasma.

* Shire Regenerative Medicine, San Diego, California.

† Organogenesis, Canton, Massachusetts.

‡ Found silver cream to be more effective than tripeptide copper cream (57).

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Table Jump PlaceholderTable 2. ARDs and RRs for Percentages of Healed Ulcers: Venous Ulcer Studies 
Table Jump PlaceholderAppendix Table 5. Strength of Evidence for Advanced Wound Care Therapies: Venous Ulcers 
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Appendix Figure 3.

Meta-analyses of the proportion of venous ulcers healed.

M–H = Mantel–Haenszel.

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Ulcers Healed: Comparative Effectiveness of Advanced Wound Care Products

Only 4 studies compared one advanced therapy with another (5253, 57, 60). Strength of evidence was low for the effect on the proportion of healed ulcers (Figure 2 and Appendix Table 5). In 1 moderate-size, fair-quality trial, use of a silver cream resulted in a greater proportion of healed ulcers (ARD, 21% [CI, 6% to 37%]) than a copper-based cream (57). We found no differences in proportion of healed ulcers between 2 forms of keratinocyte therapy (1 moderate-size, poor-quality trial) (53), keratinocyte therapy compared with pneumatic compression therapy (1 small, fair-quality trial) (52), or 2 forms of silver dressing (1 large, fair-quality trial) (60). The magnitude of the differences between treatment groups ranged from 1% to 4% (Table 2).

Other Outcomes

Few studies reported time to ulcer healing. One study of the biological skin equivalent Apligraf found shorter time to ulcer healing than with standard care (48), as did a study comparing a keratinocyte product with standard care (55). No other studies reported a significant difference (5354, 6162). Strength of evidence was low for these comparisons (Appendix Table 4). Two studies that compared silver products with other active treatments reported higher global assessment outcomes in the silver groups (57, 60), whereas a study that compared electromagnetic therapy with sham treatment reported no difference between groups (64).

Advanced wound care products did not consistently improve ulcer infection rate, ulcer recurrence, or pain, although these were not primary outcomes in the studies (Tables 2 to 4 of the Supplement). Of 8 studies reporting ulcer infection during treatment, only 1, a collagen study, found fewer infected ulcers in the collagen group than in the standard care group (46). Similarly, of 7 studies reporting ulcer recurrence, only 1, a biological dressing study, saw fewer recurring ulcers in the active treatment group than in the standard care group (47). One study of electromagnetic therapy noted a significant reduction in pain from baseline to 30 days in patients receiving electromagnetic therapy compared with sham treatment (65). However, 9 other studies reported no difference in pain between an advanced therapy and standard care or between 2 advanced therapies.

No studies reported amputation, revascularization or other surgery, time to recurrence, or need for home care. Two studies reported hospitalization (47, 54) and 1 reported quality of life (6162) and found no difference between advanced therapy and standard care. No significant differences were seen in all-cause mortality, study withdrawals due to adverse events, or allergic reactions to treatment, although there were few events and studies were not adequately powered to assess these outcomes.

Arterial Ulcers

We identified 1 small (n = 31), fair-quality study that enrolled patients specifically identified as having arterial ulcers (67). Mean age of the patients was 70 years, and 75% were men. Mean ulcer size was 4.8 cm2; ulcer duration was not reported. There were significant differences in ulcer healing (ARD, 46% [CI, 12% to 80%]) and time to healing, suggesting that a biological skin equivalent may be more effective than standard care when used on ischemic foot ulcers or partial open-foot amputations after revascularization surgery. Other outcomes did not differ significantly compared with standard care.

We found moderate-strength evidence for improved healing compared with standard care in patients with diabetic ulcers treated with the biological skin equivalent Apligraf or negative pressure wound therapy. There was also moderate-strength evidence for improved healing in patients with venous ulcers treated with keratinocyte therapy compared with standard care. Strength of evidence was low for all treatment comparisons reporting time to ulcer healing, but a few therapies were associated with significant improvement. No studies reported a significant difference in adverse events for any treatment comparison.

Although a wide range of patients were enrolled in studies, many were older than 60 years, male, and white and were probably adherent to treatment protocols and had ulcers with relatively small surface areas. Most studies excluded patients with infected ulcers, and few monitored adherence to standard care or intervention components. Study authors rarely reported outcomes by patient demographic, comorbidity, adherence, or ulcer characteristics. Therefore, we found insufficient evidence about whether efficacy differs according to these factors.

The overall low strength of evidence reflects methodological flaws; the small number of trials; and heterogeneity of the comparators, study durations, and how outcomes were assessed. For each ulcer type (diabetic, venous, or arterial), specific advanced wound care therapies were evaluated in only a few studies, often in highly selected populations and frequently with conflicting findings. Several types of interventions were used within each category of wound care therapy, making it difficult to determine whether results were replicable in other studies or generalizable to broader clinical settings.

The quality of the individual studies reviewed was predominantly fair or poor. Common factors limiting study quality were inadequate allocation concealment, lack of blinding (including blinding of outcome assessment), failure to use intention-to-treat analysis methods, and failure to adequately describe study dropouts and withdrawals.

Most studies compared advanced therapies with standard care or placebo; little comparative effectiveness research has evaluated one advanced therapy against another. Despite the clinical importance of arterial ulcers, we identified only 1 study of an advanced therapy (which was compared with standard care) for this type of ulcer. Patients with arterial disease may have been included in the studies of diabetic ulcers or venous ulcers (that is, mixed cause).

Our literature search identified recent systematic reviews on many of the advanced therapies included in our review. Although we were able to use these reviews to identify references our search may have missed, direct comparisons of the findings from existing reviews and those from our review are difficult. Many of the reviews included studies of ulcers that were not diabetic, venous, or arterial; many allowed studies with any outcome that reflected healing (including changes in area or volume); and some were not limited to randomized, controlled trials.

We identified methodological limitations. Few studies provided a run-in period with carefully monitored standard care to exclude patients for whom this would obviate the need for advanced therapy. Although failure to exclude these patients may bias the study of the advanced therapy, it may, in fact, represent a more clinically relevant situation. Much of the existing research on advanced wound care therapies has attempted to minimize the influence of ulcer area, depth, duration, and location; patient comorbid conditions; and patient adherence to the treatment protocol through strict inclusion and exclusion criteria. The broader applicability to patients seen in many clinical settings is not clear (6869). Results from our included studies may overestimate benefits and underestimate harms in nonstudy populations. More than half of the trials in our review were industry-sponsored, and the role of the sponsor in study design and analysis was typically not stated. To minimize the potential for selective outcome reporting, we excluded studies that reported changes in ulcer size without providing data on complete healing. Although we attempted to minimize publication bias, the possibility of missed publications and unreported data exists. Definitions of “chronic” ulcers varied widely, and few studies were of sufficient duration to assess whether healing was maintained (6970).

We limited our review to studies of products approved by the U.S. Food and Drug Administration. We excluded studies with wounds of multiple causes (for example, vascular, pressure, trauma, or surgery) if they did not report results by cause. We also excluded studies if they did not report 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.

Our review highlights future research needs. Although additional randomized trials that compare advanced wound care therapies with 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 therapies. In both effectiveness and comparative effectiveness research, the sample sizes should be adequate for outcome reporting according to key patient and ulcer characteristics, including age; race; sex; and ulcer size, location, and depth. In addition, patients should be followed for sufficient time to assess whether healing has been maintained.

Cost-effectiveness analyses are needed to assess whether and for whom advanced wound care products are high-value care. Advanced wound care products are expensive. They may be cost-effective or even cost-saving in appropriate patients and ulcers when their effect on medical complications and other ulcer-related costs is considered. However, a substantial proportion (generally a third or more) of patients with nonhealing ulcers who were randomly assigned to standard care had complete wound healing with this approach over study durations of 4 to 12 weeks. These findings suggest that a more rigorous “standard care approach” than might occur in clinical practice may be beneficial in many patients.

We conclude, on the basis of our findings from published randomized, controlled trials, that in highly controlled settings, advanced wound care therapies may improve the proportion of healed diabetic and venous ulcers compared with standard care in adults with nonhealing ulcers. A few therapies may reduce the time to ulcer healing, but evidence is limited. Limitations in the quality of evidence and the number of studies directly comparing different advanced therapies decrease the strength and generalizability of our findings.

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Gentzkow GD, Iwasaki SD, Hershon KS, Mengel M, Prendergast JJ, Ricotta JJ, et al. Use of Dermagraft, a cultured human dermis, to treat diabetic foot ulcers. Diabetes Care. 1996; 19:350-4.
PubMed
CrossRef
 
Naughton G, Mansbridge J, Gentzkow G. A metabolically active human dermal replacement for the treatment of diabetic foot ulcers. Artif Organs. 1997; 21:1203-10.
PubMed
 
Marston WA, Hanft J, Norwood P, Pollak R, Dermagraft Diabetic Foot Ulcer Study Group. The efficacy and safety of Dermagraft in improving the healing of chronic diabetic foot ulcers: results of a prospective randomized trial. Diabetes Care. 2003; 26:1701-5.
PubMed
CrossRef
 
Veves A, Falanga V, Armstrong DG, Sabolinski ML, Apligraf Diabetic Foot Ulcer Study. Graftskin, a human skin equivalent, is effective in the management of noninfected neuropathic diabetic foot ulcers: a prospective randomized multicenter clinical trial. Diabetes Care. 2001; 24:290-5.
PubMed
CrossRef
 
Edmonds M, European and Australian Apligraf Diabetic Foot Ulcer Study Group. Apligraf in the treatment of neuropathic diabetic foot ulcers. Int J Low Extrem Wounds. 2009; 8:11-8.
PubMed
 
DiDomenico L, Emch KJ, Landsman AR, Landsman A. A prospective comparison of diabetic foot ulcers treated with either a cryopreserved skin allograft or a bioengineered skin substitute. Wounds. 2011; 23:184-9.
 
Aminian B, Shams M, Soveyd M, Omrani GR. Topical autologous platelet-derived growth factors in the treatment of chronic diabetic ulcers. Arch Iran Med. 2000; 3:55-9.
 
Agrawal RP, Jhajharia A, Mohta N, Dogra R, Chaudhari V, Nayak KC. Use of a platelet-derived growth factor gel in chronic diabetic foot ulcers. Diabetic Foot Journal. 2009; 12:80-8.
 
Hardikar JV, Reddy YC, Bung DD, Varma N, Shilotri PP, Prasad ED, et al. Efficacy of recombinant human platelet-derived growth factor (rhPDGF) based gel in diabetic foot ulcers: a randomized, multicenter, double-blind, placebo-controlled study in India. Wounds. 2005; 17:141-52.
 
Bhansali A, Venkatesh S, Dutta P, Dhillon MS, Das S, Agrawal A. Which is the better option: recombinant human PDGF-BB 0.01% gel or standard wound care, in diabetic neuropathic large plantar ulcers off-loaded by a customized contact cast? Diabetes Res Clin Pract. 2009; 83:13-6.
PubMed
CrossRef
 
Wieman TJ, Smiell JM, Su Y. Efficacy and safety of a topical gel formulation of recombinant human platelet-derived growth factor-BB (becaplermin) in patients with chronic neuropathic diabetic ulcers. A phase III randomized placebo-controlled double-blind study. Diabetes Care. 1998; 21:822-7.
PubMed
CrossRef
 
Jaiswal SS, Gambhir RP, Agrawal A, Harish S. Efficacy of topical recombinant human platelet derived growth factor on wound healing in patients with chronic diabetic lower limb ulcers. Indian J Surg. 2010; 72:27-31.
PubMed
CrossRef
 
Steed DL. Clinical evaluation of recombinant human platelet-derived growth factor for the treatment of lower extremity diabetic ulcers. Diabetic Ulcer Study Group. J Vasc Surg. 1995; 21:71-8.
PubMed
CrossRef
 
Steed DL. Clinical evaluation of recombinant human platelet-derived growth factor for the treatment of lower extremity ulcers. Plast Reconstr Surg. 2006; 117:143S-149S.
PubMed
CrossRef
 
d'Hemecourt PA, Smiell JM, Karim MR. Sodium carboxymethylcellulose aqueous-based gel vs becaplermin gel in patients with nonhealing lower extremity diabetic ulcers. Wounds. 1998; 10:69-75.
 
Saad Setta H, Elshahat A, Elsherbiny K, Massoud K, Safe I. Platelet-rich plasma versus platelet-poor plasma in the management of chronic diabetic foot ulcers: a comparative study. Int Wound J. 2011; 8:307-12.
PubMed
CrossRef
 
Driver VR, Hanft J, Fylling CP, Beriou JM, Autologel Diabetic Foot Ulcer Study Group. A prospective, randomized, controlled trial of autologous platelet-rich plasma gel for the treatment of diabetic foot ulcers. Ostomy Wound Manage. 2006; 52:68-70, 72, 74 passim.
PubMed
 
Belcaro G, Cesarone MR, Errichi BM, Ricci A, Dugall M, Pellegrini L, et al. Venous and diabetic ulcerations: management with topical multivalent silver oxide ointment. Panminerva Med. 2010; 52:37-42.
PubMed
 
Jacobs AM, Tomczak R. Evaluation of Bensal HP for the treatment of diabetic foot ulcers. Adv Skin Wound Care. 2008; 21:461-5.
PubMed
CrossRef
 
Jude EB, Apelqvist J, Spraul M, Martini J, Silver Dressing Study Group. Prospective randomized controlled study of Hydrofiber dressing containing ionic silver or calcium alginate dressings in non-ischaemic diabetic foot ulcers. Diabet Med. 2007; 24:280-8.
PubMed
CrossRef
 
Viswanathan V, Kesavan R, Kavitha KV, Kumpatla S. A pilot study on the effects of a polyherbal formulation cream on diabetic foot ulcers. Indian J Med Res. 2011; 134:168-73.
PubMed
 
Blume PA, Walters J, Payne W, Ayala J, Lantis J. Comparison of negative pressure wound therapy using vacuum-assisted closure with advanced moist wound therapy in the treatment of diabetic foot ulcers: a multicenter randomized controlled trial. Diabetes Care. 2008; 31:631-6.
PubMed
CrossRef
 
Karatepe O, Eken I, Acet E, Unal O, Mert M, Koc B, et al. Vacuum assisted closure improves the quality of life in patients with diabetic foot. Acta Chir Belg. 2011; 111:298-302.
PubMed
 
McCallon SK, Knight CA, Valiulus JP, Cunningham MW, McCulloch JM, Farinas LP. Vacuum-assisted closure versus saline-moistened gauze in the healing of postoperative diabetic foot wounds. Ostomy Wound Manage. 2000; 46:28-32, 34.
PubMed
 
Wang CJ, Wu RW, Yang YJ. Treatment of diabetic foot ulcers: a comparative study of extracorporeal shockwave therapy and hyperbaric oxygen therapy. Diabetes Res Clin Pract. 2011; 92:187-93.
PubMed
CrossRef
 
Löndahl M, Katzman P, Nilsson A, Hammarlund C. Hyperbaric oxygen therapy facilitates healing of chronic foot ulcers in patients with diabetes. Diabetes Care. 2010; 33:998-1003.
PubMed
CrossRef
 
Duzgun AP, Satir HZ, Ozozan O, Saylam B, Kulah B, Coskun F. Effect of hyperbaric oxygen therapy on healing of diabetic foot ulcers. J Foot Ankle Surg. 2008; 47:515-9.
PubMed
 
Kessler L, Bilbault P, Ortéga F, Grasso C, Passemard R, Stephan D, et al. Hyperbaric oxygenation accelerates the healing rate of nonischemic chronic diabetic foot ulcers: a prospective randomized study. Diabetes Care. 2003; 26:2378-82.
PubMed
CrossRef
 
Abidia A, Laden G, Kuhan G, Johnson BF, Wilkinson AR, Renwick PM, et al. The role of hyperbaric oxygen therapy in ischaemic diabetic lower extremity ulcers: a double-blind randomised-controlled trial. Eur J Vasc Endovasc Surg. 2003; 25:513-8.
PubMed
CrossRef
 
Wainstein J, Feldbrin Z, Boaz M, Harman-Boehm I. Efficacy of ozone-oxygen therapy for the treatment of diabetic foot ulcers. Diabetes Technol Ther. 2011; 13:1255-60.
PubMed
CrossRef
 
Vin F, Teot L, Meaume S. The healing properties of Promogran in venous leg ulcers. J Wound Care. 2002; 11:335-41.
PubMed
 
Mostow EN, Haraway GD, Dalsing M, Hodde JP, King D, OASIS Venus Ulcer Study Group. Effectiveness of an extracellular matrix graft (OASIS Wound Matrix) in the treatment of chronic leg ulcers: a randomized clinical trial. J Vasc Surg. 2005; 41:837-43.
PubMed
CrossRef
 
Falanga V, Margolis D, Alvarez O, Auletta M, Maggiacomo F, Altman M, et al. Rapid healing of venous ulcers and lack of clinical rejection with an allogeneic cultured human skin equivalent. Human Skin Equivalent Investigators Group. Arch Dermatol. 1998; 134:293-300.
PubMed
CrossRef
 
Falanga V, Sabolinski M. A bilayered living skin construct (APLIGRAF) accelerates complete closure of hard-to-heal venous ulcers. Wound Repair Regen. 1999; 7:201-7.
PubMed
 
Krishnamoorthy L, Harding K, Griffiths D, Moore K, Leaper D, Poskitt K, et al. The clinical and histological effects of Dermagraft in the healing of chronic venous leg ulcers. Phlebology. 2003; 18:12-22.
CrossRef
 
Omar AA, Mavor AI, Jones AM, Homer-Vanniasinkam S. Treatment of venous leg ulcers with Dermagraft. Eur J Vasc Endovasc Surg. 2004; 27:666-72.
PubMed
CrossRef
 
Lindgren C, Marcusson JA, Toftgård R. Treatment of venous leg ulcers with cryopreserved cultured allogeneic keratinocytes: a prospective open controlled study. Br J Dermatol. 1998; 139:271-5.
PubMed
CrossRef
 
Navrátilová Z, Slonková V, Semrádová V, Adler J. Cryopreserved and lyophilized cultured epidermal allografts in the treatment of leg ulcers: a pilot study. J Eur Acad Dermatol Venereol. 2004; 18:173-9.
PubMed
CrossRef
 
Harding KG, Krieg T, Eming SA, Flour ML, Jawien A, Cencora A, et al. Efficacy and safety of the freeze-dried cultured human keratinocyte lysate, LyphoDerm 0.9%, in the treatment of hard-to-heal venous leg ulcers. Wound Repair Regen. 2005; 13:138-47.
PubMed
CrossRef
 
Vanscheidt W, Ukat A, Horak V, Brüning H, Hunyadi J, Pavlicek R, et al. Treatment of recalcitrant venous leg ulcers with autologous keratinocytes in fibrin sealant: a multinational randomized controlled clinical trial. Wound Repair Regen. 2007; 15:308-15.
PubMed
CrossRef
 
Stacey MC, Mata SD, Trengove NJ, Mather CA. Randomised double-blind placebo controlled trial of topical autologous platelet lysate in venous ulcer healing. Eur J Vasc Endovasc Surg. 2000; 20:296-301.
PubMed
CrossRef
 
Bishop JB, Phillips LG, Mustoe TA, VanderZee AJ, Wiersema L, Roach DE, et al. A prospective randomized evaluator-blinded trial of two potential wound healing agents for the treatment of venous stasis ulcers. J Vasc Surg. 1992; 16:251-7.
PubMed
 
Blair SD, Backhouse CM, Wright DDI, Riddle E, McCollum CN. Do dressings influence the healing of chronic venous ulcers? Phlebology. 1988; 3:129-34.
 
Dimakakos E, Katsenis K, Kalemikerakis J, Arkadopoulos N, Mylonas S, Arapoglou V, et al. Infected venous leg ulcers: management with silver-releasing foam dressing. Wounds. 2009; 21:4-8.
 
Harding K, Gottrup F, Jawien A, Mikosinski J, Twardowska-Saucha K, Kaczmarek S, et al. A prospective, multi-centre, randomised, open label, parallel, comparative study to evaluate effects of AQUACEL® Ag and Urgotul® Silver dressing on healing of chronic venous leg ulcers. Int Wound J. 2012; 9:285-94.
PubMed
 
Michaels JA, Campbell B, King B, Palfreyman SJ, Shackley P, Stevenson M. Randomized controlled trial and cost-effectiveness analysis of silver-donating antimicrobial dressings for venous leg ulcers (VULCAN trial). Br J Surg. 2009; 96:1147-56.
PubMed
 
Michaels JA, Campbell WB, King BM, Macintyre J, Palfreyman SJ, Shackley P, et al. A prospective randomised controlled trial and economic modelling of antimicrobial silver dressings versus non-adherent control dressings for venous leg ulcers: the VULCAN trial. Health Technol Assess. 2009; 13:1-114, iii.
PubMed
 
Schuler JJ, Maibenco T, Megerman J, Ware M, Montalvo J. Treatment of chronic venous ulcers using sequential gradient intermittent pneumatic compression. Phlebology. 1996; 11:111-6.
 
Ieran M, Zaffuto S, Bagnacani M, Annovi M, Moratti A, Cadossi R. Effect of low frequency pulsing electromagnetic fields on skin ulcers of venous origin in humans: a double-blind study. J Orthop Res. 1990; 8:276-82.
PubMed
CrossRef
 
Kenkre JE, Hobbs FD, Carter YH, Holder RL, Holmes EP. A randomized controlled trial of electromagnetic therapy in the primary care management of venous leg ulceration. Fam Pract. 1996; 13:236-41.
PubMed
CrossRef
 
Hammarlund C, Sundberg T. Hyperbaric oxygen reduced size of chronic leg ulcers: a randomized double-blind study. Plast Reconstr Surg. 1994; 93:829-33.
PubMed
 
Chang DW, Sanchez LA, Veith FJ, Wain RA, Okhi T, Suggs WD. Can a tissue-engineered skin graft improve healing of lower extremity foot wounds after revascularization? Ann Vasc Surg. 2000; 14:44-9.
PubMed
CrossRef
 
Carter MJ, Fife CE, Walker D, Thomson B. Estimating the applicability of wound care randomized controlled trials to general wound-care populations by estimating the percentage of individuals excluded from a typical wound-care population in such trials. Adv Skin Wound Care. 2009; 22:316-24.
PubMed
 
Wu SC, Marston W, Armstrong DG. Wound care: the role of advanced wound-healing technologies. J Am Podiatr Med Assoc. 2010; 100:385-94.
PubMed
 
Sullivan N, Snyder DL, Tipton K, Uhl S, Schoelles KM.  Negative Pressure Wound Therapy Devices. Technology Assessment Report. (Prepared by the ECRI Institute under contract 290-2007-10063.) Rockville, MD: Agency for Healthcare Research and Quality; 2009. Accessed at www.ahrq.gov/research/findings/ta/negative-pressure-wound-therapy/index.html on 25 April 2013.
 

Figures

Grahic Jump Location
Appendix Figure 1.

Summary of evidence search and selection.

* One article provided outcomes for both diabetic and venous ulcers.

Grahic Jump Location
Grahic Jump Location
Figure 1.

Healed diabetic ulcers.

Each dot represents 1 trial. Shaded rows indicate therapies for which meta-analyses were possible (see Figure 2 and Appendix Figure 2). BSE = biological skin equivalent; HBOT = hyperbaric oxygen therapy; NPWT = negative pressure wound therapy; PDGF = platelet-derived growth factor; PRP = platelet-rich plasma.

* Shire Regenerative Medicine, San Diego, California.

† Organogenesis, Canton, Massachusetts.

‡ Compared biological dressing with BSE (Dermagraft) and found no significant difference (15).

§ Compared biological dressing with PDGF and found no significant difference (14).

∥ A second study of silver cream did not report the proportion of healed ulcers (36).

¶ Found extracorporeal shock wave therapy to be more effective than HBOT (40).

Grahic Jump Location
Grahic Jump Location
Appendix Figure 2.

Meta-analyses of the proportion of diabetic ulcers healed.

BSE = biological skin equivalent; M–H = Mantel–Haenszel; PDGF = platelet-derived growth factor.

* Shire Regenerative Medicine, San Diego, California. † Organogenesis, Canton, Massachusetts.

Grahic Jump Location
Grahic Jump Location
Figure 2.

Healed venous ulcers.

Each dot represents 1 trial. Shaded rows indicate therapies for which meta-analyses were possible (see Appendix Figure 3). BSE = biological skin equivalent; EMT = electromagnetic therapy; HBOT = hyperbaric oxygen therapy; IPC = intermittent pneumatic compression; PRP = platelet-rich plasma.

* Shire Regenerative Medicine, San Diego, California.

† Organogenesis, Canton, Massachusetts.

‡ Found silver cream to be more effective than tripeptide copper cream (57).

Grahic Jump Location
Grahic Jump Location
Appendix Figure 3.

Meta-analyses of the proportion of venous ulcers healed.

M–H = Mantel–Haenszel.

Grahic Jump Location

Tables

Table Jump PlaceholderAppendix Table 1. Search Strategy 
Table Jump PlaceholderAppendix Table 2. Baseline Characteristics: Diabetic Ulcer Studies 
Table Jump PlaceholderTable 1. ARDs and RRs for Percentages of Healed Ulcers: Diabetic Ulcer Studies 
Table Jump PlaceholderAppendix Table 3. Strength of Evidence for Advanced Wound Care Therapies: Diabetic Ulcers 
Table Jump PlaceholderAppendix Table 4. Baseline Characteristics: Venous Ulcer Studies 
Table Jump PlaceholderTable 2. ARDs and RRs for Percentages of Healed Ulcers: Venous Ulcer Studies 
Table Jump PlaceholderAppendix Table 5. Strength of Evidence for Advanced Wound Care Therapies: Venous Ulcers 

References

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Veves A, Sheehan P, Pham HT. A randomized, controlled trial of Promogran (a collagen/oxidized regenerated cellulose dressing) vs standard treatment in the management of diabetic foot ulcers. Arch Surg. 2002; 137:822-7.
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Donaghue VM, Chrzan JS, Rosenblum BI, Giurini JM, Habershaw GM, Veves A. Evaluation of a collagen-alginate wound dressing in the management of diabetic foot ulcers. Adv Wound Care. 1998; 11:114-9.
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Reyzelman A, Crews RT, Moore JC, Moore L, Mukker JS, Offutt S, et al. Clinical effectiveness of an acellular dermal regenerative tissue matrix compared to standard wound management in healing diabetic foot ulcers: a prospective, randomised, multicentre study. Int Wound J. 2009; 6:196-208.
PubMed
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Niezgoda JA, Van Gils CC, Frykberg RG, Hodde JP. Randomized clinical trial comparing OASIS Wound Matrix to Regranex Gel for diabetic ulcers. Adv Skin Wound Care. 2005; 18:258-66.
PubMed
CrossRef
 
Landsman A, Roukis TS, DeFronzo DJ, Agnew P, Petranto RD, Surprenant M. Living cells or collagen matrix: which is more beneficial in the treatment of diabetic foot ulcers? Wounds. 2008; 20:111-6.
 
Gentzkow GD, Iwasaki SD, Hershon KS, Mengel M, Prendergast JJ, Ricotta JJ, et al. Use of Dermagraft, a cultured human dermis, to treat diabetic foot ulcers. Diabetes Care. 1996; 19:350-4.
PubMed
CrossRef
 
Naughton G, Mansbridge J, Gentzkow G. A metabolically active human dermal replacement for the treatment of diabetic foot ulcers. Artif Organs. 1997; 21:1203-10.
PubMed
 
Marston WA, Hanft J, Norwood P, Pollak R, Dermagraft Diabetic Foot Ulcer Study Group. The efficacy and safety of Dermagraft in improving the healing of chronic diabetic foot ulcers: results of a prospective randomized trial. Diabetes Care. 2003; 26:1701-5.
PubMed
CrossRef
 
Veves A, Falanga V, Armstrong DG, Sabolinski ML, Apligraf Diabetic Foot Ulcer Study. Graftskin, a human skin equivalent, is effective in the management of noninfected neuropathic diabetic foot ulcers: a prospective randomized multicenter clinical trial. Diabetes Care. 2001; 24:290-5.
PubMed
CrossRef
 
Edmonds M, European and Australian Apligraf Diabetic Foot Ulcer Study Group. Apligraf in the treatment of neuropathic diabetic foot ulcers. Int J Low Extrem Wounds. 2009; 8:11-8.
PubMed
 
DiDomenico L, Emch KJ, Landsman AR, Landsman A. A prospective comparison of diabetic foot ulcers treated with either a cryopreserved skin allograft or a bioengineered skin substitute. Wounds. 2011; 23:184-9.
 
Aminian B, Shams M, Soveyd M, Omrani GR. Topical autologous platelet-derived growth factors in the treatment of chronic diabetic ulcers. Arch Iran Med. 2000; 3:55-9.
 
Agrawal RP, Jhajharia A, Mohta N, Dogra R, Chaudhari V, Nayak KC. Use of a platelet-derived growth factor gel in chronic diabetic foot ulcers. Diabetic Foot Journal. 2009; 12:80-8.
 
Hardikar JV, Reddy YC, Bung DD, Varma N, Shilotri PP, Prasad ED, et al. Efficacy of recombinant human platelet-derived growth factor (rhPDGF) based gel in diabetic foot ulcers: a randomized, multicenter, double-blind, placebo-controlled study in India. Wounds. 2005; 17:141-52.
 
Bhansali A, Venkatesh S, Dutta P, Dhillon MS, Das S, Agrawal A. Which is the better option: recombinant human PDGF-BB 0.01% gel or standard wound care, in diabetic neuropathic large plantar ulcers off-loaded by a customized contact cast? Diabetes Res Clin Pract. 2009; 83:13-6.
PubMed
CrossRef
 
Wieman TJ, Smiell JM, Su Y. Efficacy and safety of a topical gel formulation of recombinant human platelet-derived growth factor-BB (becaplermin) in patients with chronic neuropathic diabetic ulcers. A phase III randomized placebo-controlled double-blind study. Diabetes Care. 1998; 21:822-7.
PubMed
CrossRef
 
Jaiswal SS, Gambhir RP, Agrawal A, Harish S. Efficacy of topical recombinant human platelet derived growth factor on wound healing in patients with chronic diabetic lower limb ulcers. Indian J Surg. 2010; 72:27-31.
PubMed
CrossRef
 
Steed DL. Clinical evaluation of recombinant human platelet-derived growth factor for the treatment of lower extremity diabetic ulcers. Diabetic Ulcer Study Group. J Vasc Surg. 1995; 21:71-8.
PubMed
CrossRef
 
Steed DL. Clinical evaluation of recombinant human platelet-derived growth factor for the treatment of lower extremity ulcers. Plast Reconstr Surg. 2006; 117:143S-149S.
PubMed
CrossRef
 
d'Hemecourt PA, Smiell JM, Karim MR. Sodium carboxymethylcellulose aqueous-based gel vs becaplermin gel in patients with nonhealing lower extremity diabetic ulcers. Wounds. 1998; 10:69-75.
 
Saad Setta H, Elshahat A, Elsherbiny K, Massoud K, Safe I. Platelet-rich plasma versus platelet-poor plasma in the management of chronic diabetic foot ulcers: a comparative study. Int Wound J. 2011; 8:307-12.
PubMed
CrossRef
 
Driver VR, Hanft J, Fylling CP, Beriou JM, Autologel Diabetic Foot Ulcer Study Group. A prospective, randomized, controlled trial of autologous platelet-rich plasma gel for the treatment of diabetic foot ulcers. Ostomy Wound Manage. 2006; 52:68-70, 72, 74 passim.
PubMed
 
Belcaro G, Cesarone MR, Errichi BM, Ricci A, Dugall M, Pellegrini L, et al. Venous and diabetic ulcerations: management with topical multivalent silver oxide ointment. Panminerva Med. 2010; 52:37-42.
PubMed
 
Jacobs AM, Tomczak R. Evaluation of Bensal HP for the treatment of diabetic foot ulcers. Adv Skin Wound Care. 2008; 21:461-5.
PubMed
CrossRef
 
Jude EB, Apelqvist J, Spraul M, Martini J, Silver Dressing Study Group. Prospective randomized controlled study of Hydrofiber dressing containing ionic silver or calcium alginate dressings in non-ischaemic diabetic foot ulcers. Diabet Med. 2007; 24:280-8.
PubMed
CrossRef
 
Viswanathan V, Kesavan R, Kavitha KV, Kumpatla S. A pilot study on the effects of a polyherbal formulation cream on diabetic foot ulcers. Indian J Med Res. 2011; 134:168-73.
PubMed
 
Blume PA, Walters J, Payne W, Ayala J, Lantis J. Comparison of negative pressure wound therapy using vacuum-assisted closure with advanced moist wound therapy in the treatment of diabetic foot ulcers: a multicenter randomized controlled trial. Diabetes Care. 2008; 31:631-6.
PubMed
CrossRef
 
Karatepe O, Eken I, Acet E, Unal O, Mert M, Koc B, et al. Vacuum assisted closure improves the quality of life in patients with diabetic foot. Acta Chir Belg. 2011; 111:298-302.
PubMed
 
McCallon SK, Knight CA, Valiulus JP, Cunningham MW, McCulloch JM, Farinas LP. Vacuum-assisted closure versus saline-moistened gauze in the healing of postoperative diabetic foot wounds. Ostomy Wound Manage. 2000; 46:28-32, 34.
PubMed
 
Wang CJ, Wu RW, Yang YJ. Treatment of diabetic foot ulcers: a comparative study of extracorporeal shockwave therapy and hyperbaric oxygen therapy. Diabetes Res Clin Pract. 2011; 92:187-93.
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