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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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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)

5 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)

10 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)

15 (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]

20 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)

25 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)

30 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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Yes

Considering collagen dressings as a stand-alone category presents challenges as they are 

frequently used as deliver vehicles for silver, growth factors, protease inhibitors, etc. This 

should be acknowledged as a limitation. As such there may be other studies to be considered 

for inclusion under collagen [1-5]; apligraf [6]; and silver.[2] 

1. Blume, P., et al., Formulated collagen gel accelerates healing rate immediately after 

application in patients with diabetic neuropathic foot ulcers. Wound Repair & Regeneration, 

2011. 19(3): p. 302-8.

2. Gottrup, F., et al., Collagen/ORC/silver treatment of diabetic foot ulcers; A randomised 

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

3. Letendre, S., et al., Pilot trial of biovance collagen-based wound covering for diabetic 

ulcers. Advances in Skin & Wound Care, 2009. 22(4): p. 161-6.

4. Motzkau, M., et al., Expression of matrix-metalloproteases in the fluid of chronic 

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

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

inert collagen matrix product.

We have reviewed the suggested references:

1. This trial has been added.

2. An abstract – not eligible for inclusion (we were unable to find the data in a peerreviewed publication)

3. A case series – not eligible for inclusion

4. This study has been mentioned in the collagen section but due to a difference 

in the goal of the study and incomplete reporting is not given as much attention as 

other trials

5. A “cohort” study – not eligible for inclusion

6. This report presents data from one site of a multisite trial that is included in the 

report (Veves 2001)

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 

products. Care needs to be made in recommendations. Also you did assess that HBO was 

inferior to shockwave and therapy that was later shown in the US to not be superior to 

standard off-loading of diabetic feet.

We identified and discussed one HBO trial conducted in Taiwan that directly 

compared HBO to shockwave therapy. We did not identify any trials meeting our 

inclusion criteria that directly compared shockwave therapy to standard off-loading 

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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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.

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.
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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?

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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The report and tables are comprehensive but limitations to the methodology are not 

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

Additionally, whether or not compliance with standard wound healing practices,(debridement, 

off-loading) is equally allocated between treatment and control groups is not highlighted.

We reported recurrence and amputation if reported by the study authors. 

We have added comments about compliance. Most studies indicated that off 

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 

support the products used every day. The recommendations for criteria for future research 

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

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. Thank you

2. We have added more specific information to the limitations and future research 

sections.

1. None of the citations described on page 77 have accompanying references. 

2. In paragraph 3 of the discussion on page 77, greater emphasis should be placed the 

importance of offloading and adherence for DFU healing. The largest effect sizes for DFU 

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

methodology for DFU trials.[4] This limitation should also be described on page 26 in the 

quality assessment section. Greater emphasis should also be placed on the importance of 

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. 

1. The reference list is now complete.

2. We have added information about off-loading for DFU healing and compression 

for VLU (including the suggested references). Thank you for the reference 

suggestions.

3. We have added to these sections. Thank you for the reference suggestions.

4. We have added absolute risk reduction data to the executive summary.
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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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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 

report. He has a list of whom are most expert in the field within the VA.

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, ...

We thank the reviewer for these comments. Dr. Robbins is involved with this 

project.

1) This is a long report and while the tables and appendices are important they should 

probably come at the end and be referenced in the body of the document.

2) We could release the executive summary widely and reference the full document. I am 

concerned that the field clinicians will not read a 178 page document.

3) In addition I am interested in helping in the production of some publications based on 

these findings to share with the scientific community.

1 and 2) We recognize the length of the report. We believe the information 

included is needed to provide the “interested reader” the full body of evidence we 

considered. We agree clinicians and policy makers are unlikely to read the whole 

document. We have tried to highlight the main findings in the executive summary 

and are willing to conduct other dissemination activities including Cyberseminars, 

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

United Kingdom

Funding Source: NR

Therapy Type: 

Hyperbaric oxygen 

(HBOT)

Inclusion: diabetes; ischemic lower extremity 

ulcers (>1 cm and <10 cm in maximum 

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

N=16 (of 18 randomized)

Age (years): 71

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

Wound type: ischemic diabetic

Wound size, mm2

 (median): HBOT 106; 

control 78

Wound grade (Wagner*, %): Grade I 6; 

II 94

Wound duration, months: HBOT 6; 

control 9

Comorbid conditions (%):

History of CAD/CVD: (previous bypass 

31, angioplasty 6)

History of DM: 100

History of amputation: minor 19

Intervention (n=9): HBOT; 2.4 ATA 

for 90 minutes on 30 occasions 

over 6 weeks; multi-place chamber

Control (n=9): sham (hyperbaric 

air)

ALL: specialized multidisciplinary 

wound management program 

(off-loading, debridement, moist 

dressing)

Antibiotic Use: As needed

Treatment Duration: 6 weeks

Follow-up Duration: 1 year

Study Withdrawal (%): 20 (n=2)

Treatment Compliance: “The 

protocol was strictly followed 

throughout the study” 

Allocation concealment: 

Adequate

Blinding: Patients, 

investigators, outcome 

assessors

Intention to treat analysis 

(ITT): No, two withdrawals 

not included in analysis

Withdrawals/dropouts 

adequately described: Yes
113

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

Agrawal 200928

India

Funding Source: NR

Therapy Type: 

Platelet-derived 

Growth Factor

Inclusion: ≥30 years of age; Wagner stage I, II, 

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

N=28

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 

Intervention (n=14): rhPDGF 0.01% 

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 

Allocation concealment: 

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

Iran

Funding Source: 

Government 

Therapy Type: 

Platelet-Derived 

Growth Factor

Inclusion: chronic non-healing diabetic ulcers 

of at least eight weeks duration; controlled 

blood sugar; normal peripheral blood platelet 

count (>150,000/cu mm); negative history of 

malignancy 

Exclusion: determined to have non-diabetic 

ulcers 

N=12 ulcers (7 patients) of 14 ulcers (9 

patients) randomized

Age (years): 60

Gender (% male): 100

Race/ethnicity: NR

BMI: NR

Pre-albumin: NR

HbA1

c (%): NR

Smoking: NR

# Work days missed: NR

ABI: NR

Wound location: foot

Wound type: diabetic ulcer

Wound size: 5.9 cm2

Wound grade: NR

Wound duration: 12.9 wks

Infection: NR

Comorbid conditions (%): 

Diabetes: 100 

Intervention (n=7 ulcers): 

autologous platelet extract (APE) 

+ silver sulfadiazine dressing 12 

hours on and 12 hours off 

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)

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

Allocation concealment: 

Inadequate

Blinding: Unclear

Intention to treat analysis 

(ITT): No

Withdrawals/dropouts 

adequately described: Yes 

– 2 patients with 2 ulcers 

excluded after entering 

study (non-compliance, 

non-diabetic ulcer)
114

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

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)
115

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

Bhansali 200930

India

Funding Source: 

Industry (provided 

gel)

Therapy Type: 

Platelet-derived 

Growth Factor

Inclusion: >20 years old with type 1 or 2 

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

N=20 (24 ulcers)

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

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%

Intervention (n=13): 0.01% rhPDGF-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)

Antibiotic Use: As needed 

Treatment Duration: 20 weeks

Follow-up Duration: NR

Study Withdrawal (%): 0

Treatment Compliance: NR

Allocation concealment: 

Unclear

Blinding: No (open label)

Intention to treat analysis 

(ITT): Yes

Withdrawals/dropouts 

adequately described: Yes 

(none)

Bishop 199263

United States (2 

sites)

Funding Source: 

Industry

Therapy Type: Silver 

Products

Inclusion: age 21 to 90 years; venous stasis 

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)

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

N=86 (of 93 randomized)

Age (years): 56

Gender (% male): 50

Race/ethnicity: white: 62; black: 33; 

other: 6

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%

Intervention (n=29): 0.4% tripeptide 

copper complex cream

Comparator (n=28): 1% silver 

sulphadiazine cream

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

Allocation concealment: 

Unclear

Blinding: Yes (evaluator)

Intention to treat analysis 

(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

United States (22 

sites)

Funding Source: 

Industry

Therapy Type: 

Collagen

Inclusion: type 1 or 2 diabetes; over age 18 yrs; 

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

N=52

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

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

Intervention (n=33): formulated 

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

Antibiotic Use: NR

Treatment Duration: 12 weeks

Follow-up Duration: None

Study Withdrawal (%): 6/5 (8/124)

Treatment Compliance: see WD

Allocation concealment: 

Unclear

Blinding: Investigators 

were blinded; other study 

personnel were not

Intention to treat analysis 

(ITT): Yes for safety 

analysis; per-protocol for 

other outcomes

Withdrawals/dropouts 

adequately described: Yes 

(including 2 in FCG group 

for non-compliance)

Brigido 200674

United States

Funding Source: NR

Therapy Type: 

Collagen

Inclusion: full thickness (Wagner grade II) 

chronic wound ≥6 weeks without epidermal 

coverage; non-infected; palpable/ audible pulse 

to the lower extremity

Exclusion: none reported

N=28

Age (years): 64

Gender (% male): NR

Race/ethnicity: NR

BMI: NR

Pre-albumin: NR

HbA1

c (%): 8.0

Smoking: NR

# Work days missed: NR

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 

Intervention (n=14): Graftjacket 

(single application); mineral oil 

soaked fluff compression dressing 

changed on days 5, 10, and 15 

then weekly assessment

Comparator (n=14): Curasol 

wound gel; gauze dressing; weekly 

debridement

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

Allocation concealment: 

Unclear

Blinding: No

Intention to treat analysis 

(ITT): Yes

Withdrawals/dropouts 

adequately described: Yes 

– 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

United States

Funding Source: NR

Therapy Type: 

Biological Skin 

Equivalent

Inclusion: non-healing foot ulcer or required 

partial open foot amputation; ABI <0.5 prior to 

revascularization surgery; underwent bypass or 

angioplasty within 60 days of inclusion 

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

N=31

Age (years): 70

Gender (% male): 77

Race/ethnicity (%): NR

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

Wound duration: NR

Infection: excluded

Comorbid conditions (%):

History of DM: 58%

History of amputation: 45% History of 

PVD: 100%

History of renal failure: 39%

Intervention (n=21): meshed 

(N=10) or unmeshed (N=11) tissue 

graft (Apligraf); non-adherent 

dressing, Unna boot & ace wrap; 

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

Antibiotic Use: NR

Treatment Duration: wound closure 

or ≥ 6 months after randomization

Follow-up Duration: same

Study Withdrawal (%): NR

Treatment Compliance: NR

Allocation concealment: 

Unclear

Blinding: No

Intention to treat analysis 

(ITT): Unclear 

Withdrawals/dropouts 

adequately described: 

Unclear if any dropouts

d’Hemecourt 199835

United States (10 

sites)

Funding Source: 

Industry

Therapy Type: 

Platelet-derived 

Growth Factors

Inclusion: ≥19 years old; type 1 or 2 diabetes; at 

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 

N=172

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

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 

Intervention (n=30): becaplermin 

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

Antibiotic Use: systemic control of 

infection if present

Treatment Duration: 20 weeks

Follow-up Duration: NR

Study Withdrawal (%): 24

Treatment Compliance: NR

Allocation concealment: 

Unclear

Blinding: Yes – patients, 

evaluators

Intention to treat analysis 

(ITT): Yes

Withdrawals/dropouts 

adequately described: Yes
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

United States

Funding Source: 

Industry

Therapy Type: 

Biological Skin 

Equivalent

Inclusion: type 1 or 2 diabetes; Wagner grade 1 

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

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

N=28 patients (29 wounds)

Age (years): NR

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: diabetic ulcer

Wound size: 1.9 cm2

Wound grade: see inclusion

Wound duration: see inclusion

Comorbid conditions (%): NR 

Intervention (n=17 wounds): 

Apligraf; up to 5 applications 

Comparator (n=12 wounds): 

Theraskin; up to 5 applications

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

Allocation concealment: 

Unclear

Blinding: Unclear

Intention to treat analysis 

(ITT): Unclear

Withdrawals/dropouts 

adequately described: Yes

Dimakakos 200965

Greece

Funding Source: NR

Therapy Type: Silver 

Dressing

Inclusion: leg ulcer classified as exclusively 

infected and venous in origin

Exclusion: pregnancy; psychiatric disorders; 

diabetes; collagen disease; steroid use; history 

of allergies; ABPI<1

N=42

Age (years): 60

Gender (% male): 38

Race/ethnicity: NR

BMI: NR

Pre-albumin: NR

HbA1

c (%): NR

Smoking: NR

# Work days missed: NR

ABI: NR

Wound location: leg

Wound type: venous

Wound size: NR

Wound grade: NR

Wound duration: 62% >1 mo

Infection: excluded

Comorbid conditions: 0% DM

Intervention (n=21): non-adhesive 

silver-releasing foam 

Comparator (n=21): non-adhesive 

foam

ALL: cleansing with sterile water 

and 10% povidone iodine solution; 

compression bandage 

Antibiotic Use: as needed

Treatment Duration: 9 weeks

Follow-up Duration: NR 

Study Withdrawal (%): NR

Treatment Compliance: NR

Allocation concealment: 

Unclear

Blinding: Unclear

Intention to treat analysis 

(ITT): No withdrawals/

dropouts reported

Withdrawals/dropouts 

adequately described: 

None reported
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

United States

Funding Source: 

Industry

Therapy Type: 

Collagen 

Inclusion: >21 years of age; serum albumin 

>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

N=75

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

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 

Intervention (n=50): collagenalginate

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

Antibiotic Use: NR

Treatment Duration: 8 weeks

Follow-up Duration: NR 

Study Withdrawal (%): 19

Treatment Compliance: NR

Allocation concealment: 

Unclear

Blinding: No

Intention to treat analysis 

(ITT): Yes

Withdrawals/dropouts 

adequately described: Yes

Driver 200637

United States (14 

sites including VA 

wound care clinics)

Funding Source: 

Industry

Therapy Type: 

Platelet Rich Plasma 

Inclusion: type 1 or 2 diabetes; age 18-95; ulcer 

>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; 

≥4 cm from any other wound; adequate 

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)

N=40 (of 72 randomized)

Age (years): 57

Gender (% male): 80

Race/ethnicity: Caucasian: 60; Hispanic: 

30; black: 7.5; other: 2.5

BMI: NR

Pre-albumin: NR

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 

Intervention (n=40): platelet rich 

plasma (AutoloGel); applied twice 

weekly

Comparator (n=32): saline gel 

(Normlgel); applied twice weekly

Antibiotic Use: NR

Treatment Duration: 12 weeks

Follow-up Duration: 3 months

Study Withdrawal (%): 44

Treatment Compliance: NR

Allocation concealment: 

Adequate

Blinding: Yes (patients, 

investigators, outcome 

assessors)

Intention to treat analysis 

(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

Turkey

Funding Source: NR

Therapy Type: 

Hyperbaric Oxygen 

(HBOT)

Inclusion: diabetic; ≥18 years; foot wound 

present for ≥4 weeks despite appropriate 

local and systemic wound care; wounds were 

categorized according to a modification of 

the Wagner classification; contraindication 

to hyperbaric oxygen therapy (untreated 

pneumothorax, COPD, history of otic surgery, 

upper respiratory tract infection, febrile state, 

history of idiopathic convulsion, hypoglycemia, 

current corticosteroid, amphetamine, 

catecholamine, or thyroid hormone use)

Exclusion: none reported

N=100

Age (years): 61

Gender (% male): HBOT 74%; 

Std Care 54%; p<0.05

Race/ethnicity: NR

BMI (>30, %): 63 (HBOT 80% 

Std Care 46%; p<0.05)

Pre-albumin: NR

HbA1

c (%): 8.4

Smoking: 56%

# Work days missed: NR

ABI: NR

Wound location (%): foot 

Wound type: diabetic

Wound size, cm2

: NR

Wound grade (Wagner) (%):

Grade II 18%; III 37%; IV 45%

Wound duration, months: NR

Comorbid conditions (%):

History of DM: 100%

History of HTN: 60%

History of hyperlipidemia: 58%

Intervention (n=50): HBOT

administered at maximum working 

pressure of 20 ATA; unichamber 

pressure room; volume of 10m3

at 2 to 3 ATA for 90 minutes + 

standard therapy; treatment was 2 

sessions/day, then 1 session on the 

following day

Comparator (n=50): standard 

therapy 

ALL: daily wound care (dressing 

changes, debridement); amputation 

when indicated

Antibiotic Use: as needed

Treatment Duration: 20 to 30 days

Follow-up Duration: 92 weeks

Study Withdrawal (%): None 

reported

Treatment Compliance: NR

Allocation concealment: 

Inadequate “according 

to a predetermined 

sequence wherein 

consecutively enrolled 

patients corresponding to 

an even random number 

received ST, and those 

corresponding to an odd 

random number received 

ST+HBOT”

Blinding: None reported

Intention to treat analysis 

(ITT): Yes

Withdrawals/dropouts 

adequately described: 

None reported

Edmonds 200925

Europe, Australia 

(multi-site)

Funding Source: NR

Therapy Type: 

Biological Skin 

Equivalent

Inclusion: diabetes type 1 or 2; 18-80 years 

old; primarily neuropathic origin, not infected; 

present at least 2 weeks; surface area 1-16 

cm2

; adequate vascular supply; able to follow 

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)

N=72 (of 82 randomized)

Age (years): 59

Gender (% male): 86

Race/ethnicity (%): NR

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

Intervention (n=33): Apligraf (at 

week 0 and weeks 4 and 8, if 

needed) + Mepitel contact layer 

dressing

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

Allocation concealment: 

Adequate

Blinding: No

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

United States (15 

sites)

Funding Source: 

Industry 

Therapy Type: 

Biological Skin 

Equivalent

Inclusion:18-85 years of age; ulcer due to 

venous insufficiency (clinical signs/symptoms); 

no significant arterial insufficiency (ABI>0.65); 

evidence of venous insufficiency (air 

plethysmography or photo-plethysmography

(refilling time <20 seconds)

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 

month

N=275 (of 309 randomized) 

Age (years): 60

Gender (% male): 52

Race/ethnicity(%): white 76; black 18; 

Asian 1; Hispanic 4

BMI: NR

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 

months: 21%; 1-2 years: 14%; >2 years: 

35%

Comorbid conditions (%): NR

Intervention (n=146): human skin 

equivalent (Apligraf) + elastic 

wrap; applied up to 5 times in first 

3 wks (days 0, 3-5, 7, 14, and/or 

21) until estimated area of graft 

“take” >50%; compression alone 

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; 

analysis of 275/309 (89%)

Treatment Compliance: NR

Allocation concealment: 

Adequate

Blinding: No

Intention to treat analysis 

(ITT): No

Withdrawals/dropouts 

adequately described: 

Partial – number of 

dropouts (n=72) is 

different than number not 

included in data analysis 

(n=34)

Falanga 199955

See Falanga199854

United States (15 

sites)

Funding Source: 

Industry

Therapy Type: 

Biological Skin 

Equivalent

Inclusion: same as above with ulcer duration of 

>1 year

Exclusion: same as above

N=120 for efficacy analysis 

(demographics from n=122; 2 

extra in treatment group by “double 

randomization”)

Age (years): 58

Gender (% male): 61

Race/ethnicity (%): white 71; black 22; 

Asian 0; Hispanic 6

Wound size: 1.74 cm2

Wound duration >1 year: 100%

Comorbid conditions (%): NR

Intervention (n=74): same as above

Comparator (n=48): same as above

Antibiotic Use: NR

Treatment Duration: 8 weeks 

Follow-up Duration: 6 months

Study Withdrawal (%): NR for 

subset of patients

Treatment Compliance: NR

Allocation concealment: 

Not applicable to subset

Blinding: No

Intention to treat analysis 

(ITT): No

Withdrawals/dropouts 

adequately described: No 

– number of dropouts in 

subset not reported

Fumal 200279

Belgium

Funding Source: NR

Therapy Type: Silver 

Products

Inclusion: at least 2 similar looking chronic leg 

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 

microcirculation or blood coagulation

N=17 patients (34 ulcers)

Age (years): 55

NOTE: no other patient characteristics 

reported

Intervention (n=17 ulcers): 1% 

silver sulfadiazine cream applied 

3x/week

Comparator (n=17 ulcers): 

standard care

ALL: saline rinse, hydrocolloid 

dressing, compression bandage

Antibiotic Use: NR

Treatment Duration: 6 weeks

Follow-up Duration: none

Study Withdrawal (%): NR

Treatment Compliance: NR

Allocation concealment: 

NR

Blinding: No

Intention to treat analysis 

(ITT): Yes (no withdrawals 

reported)

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

Pilot study for 

Naughton

United States (5 

sites)

Funding Source: 

Industry

Therapy Type: 

Biological Skin 

Equivalent 

Inclusion: type 1 or 2 diabetes under reasonable 

control; ulcers on plantar surface or heel; 

full-thickness defect >1 cm2

; wound bed free 

of necrotic debris/infection and suitable for 

skin graft (no exposed tendon, bone, or joint; 

no tunnels or sinus tracts that could not be 

debrided); adequate circulation (clinical signs 

and ankle-arm index (AAI) >0.75); ability to 

complete 12-week trial

Exclusion: >1 hospitalization during previous 6 

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

N=50

Age (years): 61

Gender (% male): 70

Race/ethnicity (%): NR

BMI: NR

HbA1

c (%): 8.4

Smoking: NR

# Work days missed: NR

ABI: ankle-arm index 1.0

Wound location: plantar surface or heel

Wound type: diabetic ulcer

Wound size: 2.4 cm2

Wound grade: NR

Wound duration: 55.6 weeks

Comorbid conditions (%): NR

Intervention: Dermagraft

Group A (n=12): weekly (8 pieces & 

8 applications) 

Group B (n=14): every 2 wks (8 

eight pieces & 4 applications) 

Group C (n=11): every 2 wks (4 

pieces & 4 applications) 

Control Group D (n=13): standard 

wound therapy 

ALL: sharp debridement; salinemoist gauze; off-loading 

Antibiotic Use: NR

Treatment Duration: 12 weeks

Follow-up Duration: mean 14 mos

Study Withdrawal (%): NR

Treatment Compliance: NR

Allocation concealment: 

Adequate

Blinding: No

Intention to treat analysis 

(ITT): Yes

Withdrawals/dropouts 

adequately described: No 

Hammarlund 199472

Sweden

Funding Source: NR

Therapy Type: 

Hyperbaric Oxygen 

(HBOT)

Inclusion: non-diabetic chronic (> 1 year 

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)

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

N=16

Age (years, median): HBOT 71; control 

63

Gender (% male): 50

Race/ethnicity: NR

BMI: NR

Pre-albumin: NR

HbA1

c (%): NR

Smoking: 0% (excluded)

# Work days missed: NR

ABI: NR

Wound location: leg

Wound type: venous

Wound size: 992 mm2

Wound grade: NR

Wound duration: NR but >1 yr

Comorbid conditions (%):

History of DM: 0%

Intervention (n=8): HBOT at 2.5 

ATA for 90 minutes 5 days/week; 

multi-place hyperbaric chamber; 

pressurized for total of 30 sessions 

over 6 weeks 

Comparator (n=8): placebo 

(hyperbaric air) 

ALL: continued pre-study treatment

Antibiotic Use: NR

Treatment Duration: 6 weeks

Follow-up Duration: 18 weeks (12 

from week 6)

Study Withdrawal: 0 

Treatment Compliance: 100%

Allocation concealment: 

Adequate

Blinding: Patients, 

investigators

Intention to treat analysis 

(ITT): Yes (none)

Withdrawals/dropouts 

adequately described: Yes 

(none)
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

Europe (43 sites)

Funding Source: 

Industry (reported 

that sponsor 

designed study and 

approved final article; 

authors had full 

control over contents 

of article)

Therapy Type: Silver 

Products

Inclusion: ≥18 years; male or female; ABI ≥0.8; 

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 

high levels of exudate

Exclusion: current antibiotics (week before 

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

N=281

Age (years): 70

Gender (% male): 35

Race/ethnicity: NR

BMI: 30

Pre-albumin: NR

HbA1

c (%): NR

Smoking: NR

# 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

Wound duration: 0.76 yr

Comorbid conditions (%): NR

Intervention (n=145): AQUACEL Ag 

(4 wks); AQUACEL (4 wks)

Comparator (n=136): Urgotul Silver 

(4 wks); Urgotul (4 wks)

ALL: compression; dressing 

changes per clinical condition & 

exudate; cleansing; mechanical 

debridement if needed

Antibiotic Use: NR

Treatment Duration: 8 weeks

Follow-up Duration: none

Study Withdrawal (%): 8% 

AQUACEL; 12% Urgotul

Treatment Compliance: NR 

Allocation concealment: 

Adequate

Blinding: Unclear

Intention to treat analysis 

(ITT): Modified (had at 

least one exposure to 

treatment)

Withdrawals/dropouts 

adequately described: Yes

Ieran 199070

Italy

Funding Source: NR 

Therapy Type: 

Electromagnetic 

(EMT)

Inclusion: skin lesions (ulcers due to idiopathic 

chronic venous insufficiency or post-phlebitic 

venous insufficiency) present at least for 3 

months

Exclusion: patients treated with steroids or 

affected by systemic diseases; concomitant 

arterial occlusive disease

N=37 (of 44 randomized)

Age (years): 66 

Gender (% male): 38

Race/ethnicity: NR

BMI: NR, Obese 51%

Pre-albumin: NR

HbA1

c (%): NR

Smoking: NR

# Work days missed: NR

ABI: NR

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

Intervention (n=22): EMT stimulator 

(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 

hours daily)

Comparator (n=22): sham EMT 

ALL: no elastic compression 

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 

Allocation concealment: 

Adequate

Blinding: Patients, 

investigators

Intention to treat analysis 

(ITT): No

Withdrawals/dropouts 

adequately described: Yes
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

United States

Funding Source: NR

Therapy Type: Silver 

Sulfadiazine Cream 

(SSC) 

Inclusion: Wagner grade 1 or 2 ulcerations 

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)

N=40

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

Intervention (n=20): Bensal HP 

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

Allocation concealment: 

Unclear

Blinding: Yes

Intention to treat analysis 

(ITT): Yes

Withdrawals/dropouts 

adequately described: Yes 

(none)

Jaiswal 201032

India

Funding Source: NR

Therapy Type: 

Platelet-derived 

Growth Factors 

Inclusion: type I or type II diabetes and chronic 

ulcers of at least 4 weeks duration; IAET stage 

III and IV

Exclusion: ankle brachial pressure index (ABI) 

<0.9 

N=50

Age (years): 53

Gender (% male): 84

Race/ethnicity: NR

BMI: 22.4

Pre-albumin: NR

HbA1

c (%): NR

Smoking (%): 18

# Work days missed: NR

ABI: NR

Wound location: lower limb

Wound type: diabetic

Wound size: 28.2 cm2

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%

Intervention (n=25): topical rhPDGF 

gel (PLERMIN) applied once daily

Comparator (n=25): topical KY Jelly 

applied once daily

ALL: off-loading in patients with 

plantar ulcers

Antibiotic Use: NR

Treatment Duration: 10 weeks

Follow-up Duration: NR

Study Withdrawal (%): NR

Treatment Compliance: NR

Allocation concealment: 

Adequate

Blinding: Unclear

Intention to treat analysis 

(ITT): Yes

Withdrawals/dropouts 

adequately described: Yes 
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

Europe and North 

America (7 countries, 

15 sites)

Funding Source: 

Industry

Therapy Type: Silver 

Products

Inclusion: chronic venous or mixed venous/

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), 

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

N=129

Age (years): 74 (median)

Gender (% male): 36

Race/ethnicity: NR

BMI: NR

Pre-albumin: NR

HbA1

c (%): NR

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

Intervention (n=65): sustained 

release silver foam dressing 

(Contreet Foam)

Comparator (n=64): foam dressing 

without added silver (Allevyn 

Hydrocellular)

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

Allocation concealment: 

Adequate

Blinding: No (open study)

Intention to treat 

analysis (ITT): For safety 

outcomes; per-protocol 

analysis for performance 

outcomes 

Withdrawals/dropouts 

adequately described: Yes

Jude 200740

United Kingdom, 

France, Germany, 

Sweden (18 sites) 

Funding Source: 

Industry

Therapy Type: Silver 

Products (dressing)

Inclusion: type 1 or 2 diabetes with HbA1

c 

≤12%; serum creatinine ≤200 μmol/l; Grade 1 or 

2 (Wagner) diabetic foot ulcer of non-ischemic 

etiology

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 

(sitting))

N=134

Age (years): 60

Gender (% male): 74

Race/ethnicity: NR

BMI: NR

Pre-albumin: NR

HbA1

c (%): 8.0

Smoking: NR

# Work days missed: NR

ABI: 1.8

Wound location: 68% plantar; 32% nonplantar

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%

Intervention (n=67): sterile, nonwoven sodium carboxymethylcellulose primary ionic silver 

(AQAg, 1.2%) dressing; in place up 

to 7 days or as indicated

Comparator (n=67): sterile, nonwoven calcium alginate (CA) 

dressing (moistened for use on dry 

wounds, changed daily on infected 

wounds)

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

Allocation concealment: 

Adequate

Blinding: No

Intention to treat analysis 

(ITT): No (final wound 

evaluation for 65 of 67 in 

each group)

Withdrawals/dropouts 

adequately described: Yes
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

Turkey

Funding Source: NR

Therapy Type: 

Negative Pressure 

Wound Therapy

Inclusion: diabetic foot ulcer

Exclusion: none reported

N=67

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

Wound type: diabetic ulcer

Wound size: 32.4 cm2

Wound grade: NR

Wound duration: 9.9 weeks

Comorbid conditions (%):

History of DM: 100

Intervention (n=30): Negative 

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

Treatment Compliance: NR

Allocation concealment: 

Unclear

Blinding: No

Intention to treat 

analysis (ITT): Yes – no 

withdrawals

Withdrawals/dropouts 

adequately described: Yes 

– no withdrawals

Kenkre 199671

United Kingdom

Funding Source: 

Industry

Therapy Type: 

Electromagnetic 

(EMT)

Inclusion: venous ulcer with unsatisfactory 

healing for at least the previous 4 weeks

Exclusion: none reported

N=19

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

# 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

Comorbid conditions (%): NR

Intervention 1 (n=5): EMT 

(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) 

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

Allocation concealment: 

Unclear

Blinding: Patients, 

investigators (reported as 

double-blind)

Intention to treat analysis 

(ITT): Yes (no dropouts) 

Withdrawals/dropouts 

adequately described: Yes 

(no dropouts)
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

France

Funding Source: 

Foundation

Therapy Type: 

Hyperbaric Oxygen 

(HBOT)

Inclusion: type 1 and type 2 diabetes; chronic 

foot ulcers (Wagner grades I, II, and III)

Exclusion: gangrenous ulcers, severe 

arteriopathy (TcPo2<30 mmHg), emphysema, 

proliferating retinopathy, claustrophobia

N=27 (of 28 randomized)

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

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

Intervention (n=15): HBOT; 2.5 

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, 

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

Allocation concealment: 

Unclear

Blinding: Outcome 

assessors (surface area 

of the ulcer)

Intention to treat analysis 

(ITT): No, one withdrawal 

not included in analysis

Withdrawals/dropouts 

adequately described: Yes

Krishnamoorthy 

200356

Multinational (6 sites)

Funding Source: 

Industry

Therapy Type: 

Biological Skin 

Equivalent

Inclusion: full thickness venous leg ulcer without 

exposure of muscle, tendon or bone; venous 

reflux in veins of superficial or deep systems; 

ulcer duration ≥2 months but ≤ 60 months; size 

of 3-25 cm3

; ABPI ≥ 0.7; < 50% healing from 

screening visit to day of first intervention (with 

use of multi-layer compression bandage during 

14 day screening period)

Exclusion: other causes of ulceration 

(rheumatoid vasculitis, diabetic foot ulcer); 

severe leg edema (could not be controlled with 

compression bandages); soft-tissue infections 

that would interfere with wound healing; 

impaired mobility; any underlying medical 

condition (e.g., PVD, renal disease)

N=53

Age (years): 69

Gender (% male): 42

Race/ethnicity (%): Caucasian: 94; 

black: 4; Asian: 2

BMI: 30.4

HbA1c (%): NR

Smoking: NR

# Work days missed: NR

ABI: 1.1

Wound location: leg

Wound type: venous 

Wound size (median): 7.0 cm2

 Wound 

grade: NR

Wound duration (median): 47.7 days 

Infection: NR

Comorbid conditions (%): NR

Intervention: compression and 

Group 1 (n=13): 1 piece of 

Dermagraft applied weekly during 

the first 11 weeks (12 applications)

Group 2 (n=13): 1 piece of 

Dermagraft applied at day 0, weeks 

1, 4 and 8 (4 applications)

Group 3 (n=14): 1 piece of 

Dermagraft applied at day 0

Comparator (n=13): compression 

therapy alone (Profore)

Antibiotic Use: as needed

Treatment Duration: 11 weeks

Follow-up Duration: NR

Study Withdrawal (%): 11.3

Treatment Compliance: NR

Allocation concealment: 

Adequate

Blinding: No

Intention to treat analysis 

(ITT): Yes

Withdrawals/dropouts 

adequately described: No
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

United States (4 

sites)

Funding Source: NR

Therapy Type: 

Collagen Compared 

with Biological Skin 

Equivalent

Inclusion: ≥18 years, insulin or non-insulin 

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 

N=26

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

Intervention (n=13): extracellular 

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

Allocation concealment: 

Adequate

Blinding: No

Intention to treat analysis 

(ITT): Yes

Withdrawals/dropouts 

adequately described: No

Lindgren 199858

Sweden

Funding Source: 

Industry

Therapy Type: 

Biological Skin 

Equivalent, 

Cryopreserved 

Inclusion: out-patients; venous ulcers over 

medial part of the distal third of the legs as 

determined by clinical impression and ABI 

(cutoff not given)

Exclusion: none reported

N=27

Age (years): 76 (median)

Gender (% male): 33.3

Race/ethnicity: NR

BMI: NR

HbA1c (%): NR

Smoking: NR

# Work days missed: NR

ABI: 1.0

Wound type: venous 

Wound size: 6.3 cm2

Wound duration:

<2 years: 44.4%

>2 years: 55.6%

Comorbid conditions (%): NR

Intervention (n=15): keratinocyte 

allograft + dressing (Mepitel)

Comparator (n=12): dressing only

ALL: CO2 laser debridement; if 

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

Antibiotic Use: as needed

Treatment Duration: 8 weeks

Follow-up Duration: 8 weeks

Study Withdrawal (%): 0%

Treatment Compliance: NR

Allocation concealment: 

Unclear

Blinding: No

Intention to treat analysis 

(ITT): Unclear

Withdrawals/dropouts 

adequately described: No
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

Sweden

Funding Source: 

Foundation

Therapy Type: 

Hyperbaric Oxygen 

(HBOT)

Inclusion: diabetes; ≥1 full-thickness wound; 

below ankle; >3 months; previously treated 

at diabetes foot clinic for at least 2 months; 

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; 

suspected poor compliance

N=94

Age (years): 69

Gender (% male): 81

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 

12; dorsal 1

Wound type: diabetic

Wound size: 3.0 cm2

Wound grade (Wagner) (%): Grade II 

26; III 56; IV 18

Wound duration, months: 9.5

Comorbid conditions (%):

History of CAD/CVD: MI 29%; stroke 

16%

History of DM: 100%

History of amputation: 11% major; 39% 

minor

History of HTN: 75%

History of hyperlipidemia: 88%

Intervention (n=49): HBOT; ATA 

of 2.5; multi-place hyperbaric 

chamber; compression of air for 

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 

(debride, off-load, treatment 

of infection, revascularization, 

metabolic control)

Antibiotic Use: Allowed

Treatment Duration: 8 weeks

Follow-up Duration: 1 year

Study Withdrawal (%): 20 (n=19)

Treatment Compliance: 57% 

attended 40 sessions; 80% 

attended >35 sessions; compliance 

with standard tx NR

Allocation concealment: 

Unclear (“sealed 

envelopes”)

Blinding: Patients, 

investigators, outcome 

assessments

Intention to treat analysis 

(ITT): Yes

Withdrawals/dropouts 

adequately described: Yes
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

United States (35 

sites)

Funding Source: 

Industry

Therapy Type: 

Biological Skin 

Equivalent

Inclusion: ≥18 years; type 1 or 2 diabetes; 

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 

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 

N=245 (ulcer duration >6wks)

Age (years): 56

Gender (% male): 74

Race/ethnicity (%): Caucasian 72; NonCaucasian 28

BMI: NR

HbA1c (%): 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 

Intervention (n=130): Dermagraft; 

applied weekly up to 8 times over 

12 week study

Comparator (n=115): standard 

wound care

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

Allocation concealment: 

Unclear

Blinding: Yes

Intention to treat analysis 

(ITT): Yes

Withdrawals/dropouts 

adequately described: No

McCallon 200044

United States

Funding Source: NR

Therapy Type: 

Negative Pressure 

Wound Therapy

Inclusion: diabetes; age 18-75 years; nonhealing foot ulceration present >1 month

Exclusion: venous disease; active infection not 

resolved by initial debridement; coagulopathy

N=10 (pilot study)

Age (years): 52.8

Gender (% male): NR

Race/ethnicity: NR

BMI: NR

Pre-albumin: NR

HbA1

c (%): NR

Smoking: NR

# Work days missed: NR

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

Intervention (n=5): continuous 

pressure (125 mmHg) for 48 hrs; 

dressing change then intermittent 

pressure (125 mmHg); dressing 

change/assessment every 48 hrs

Comparator (n=5): saline 

moistened gauze; changed every 

12 hrs; assessed 3 times/wk

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

Allocation concealment: 

Inadequate

Blinding: No

Intention to treat 

analysis (ITT): Yes – no 

withdrawals

Withdrawals/dropouts 

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

England (2 locations)

Funding Source: 

Government

Therapy Type: Silver 

Products

Inclusion: active ulceration of lower leg, present 

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 

oral or parenteral antibiotic treatment

N=213

Age (years): 71

Gender (% male): 46

Race/ethnicity: NR

BMI: NR

Pre-albumin: NR

HbA1

c (%): NR 

Smoking: 18.3%

# Work days missed: NR

ABI: NR

Wound location: leg

Wound type: venous

Wound size: 72% <3 cm diam

Wound grade: NR

Wound duration: 38.5% present for >12 

weeks

Comorbid conditions (%):

History of CAD/CVD: 14% history of MI 

or cardiac failure, 8% history of stroke 

or TIA

Intervention (n=107): silverdonating 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); 

dressings changed weekly unless 

needed; other interventions used if 

clinically appropriate

Antibiotic Use: NR

Treatment Duration: 12 weeks

Follow-up Duration: to 1 year after 

entry

Study Withdrawal (%): 2.3%

Treatment Compliance: NR

Allocation concealment: 

Adequate

Blinding: No

Intention to treat analysis 

(ITT): No

Withdrawals/dropouts 

adequately described: Yes

Miller 201078

Australia (2 sites)

Funding Source 

Foundation, 

Government

Therapy Type: Silver 

Products

Inclusion: lower leg ulcer; ABI ≥0.6; diameter 

≤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 

to ulcer; not receiving palliative care; no known 

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

N=266 (of 281 randomized)

Age (years): 80

Gender (% male): 41

Race/ethnicity: NR 

BMI: NR

Pre-albumin: NR

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

Intervention (n=140): Acticoat 

(silver); clinician chose dressing 

Comparator (n=141): Iodosorb 

(iodine); clinician chose dressing

ALL: treated until signs of critical 

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

Allocation concealment: 

Adequate

Blinding: No – open label

Intention to treat analysis 

(ITT): No

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

United States, United 

Kingdom, Canada 

(12 Sites)

Funding Source: 

Industry

Therapy Type: 

Biological Dressings

Inclusion: chronic venous insufficiency (clinical 

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 

tissue

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

N=120

Age (years): 64

Gender (% male): 42

Race/ethnicity (%): white 81; black 16; 

Asian 1; other 3

BMI: 31.9

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

Intervention (n=62): OASIS; each 

week to non-epithelialized portion

Comparator (n=58): standard 

wound care

ALL: weekly debride, dressing 

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

Allocation concealment: 

Adequate 

Blinding: No

Intention to treat analysis 

(ITT): Yes

Withdrawals/dropouts 

adequately described: Yes

Naughton 199722

United States (20 

sites)

Funding Source: 

Industry

Therapy Type: 

Biological Skin 

Equivalent – 

Dermagraft 

Inclusion: diabetes; neuropathic full-thickness 

plantar surface foot ulcers of the forefoot or 

heel; ulcer size >1.0 cm2

Exclusion: initial rapid healing in response to 

standard care during a screening period

N=235 (of 281 randomized)

Age (years): NR

Gender (% male): NR

Race/ethnicity (%): NR

BMI: NR

HbA1

c (%): NR

Smoking: NR

# Work days missed: NR

ABI: NR

Wound location: plantar forefoot or heel

Wound type: Diabetic ulcer

Wound size: NR

Wound duration: NR

Comorbid conditions (%):

History of DM: 100

Intervention (n=109): Dermagraft; 

day 0 and weeks 1-7 (8 total)

Comparator (n=126): standard 

wound care

ALL: debridement, infection control, 

saline-moistened gauze dressings, 

and off-weighting

Antibiotic Use: NR

Treatment Duration: 12 weeks (8 

week intervention)

Follow-up Duration: to 32 weeks

Study Withdrawal (%): 16.4

Treatment Compliance: NR

Allocation concealment: 

Unclear

Blinding: “Single-blinded”

Intention to treat analysis 

(ITT): No

Withdrawals/dropouts 

adequately described: No
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

Czech Republic

Funding Source: 

Government

Therapy Type: 

Biological Skin 

Equivalent, 

cryopreserved 

versus lyophilized 

allografts

Inclusion: venous ulcer diagnosed by 

history, physical examination, and Doppler 

ultrasonography

Exclusion: arterial ulcer; ulcer size <2 cm2

; 

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

N=50

Age (years): 63

Gender (% male): 36

Race/ethnicity: NR

BMI: 30.1

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 

12.4 cm2, lyophilized 9.0 cm2)

Wound duration: 23.7 months 

(cryopreserved 21 months, lyophilized 

17 months)

Comorbid conditions (%): NR

Intervention (n=25): single 

application of cryopreserved 

cultured epidermal keratinocytes; 

nonadherent silicone dressing 

and gauze bandages; dressings 

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 

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

Allocation concealment: 

No

Blinding: No

Intention to treat analysis 

(ITT): Yes

Withdrawals/dropouts 

adequately described: 

None reported
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

United States (11 

sites)

Funding 

Source: Industry 

(compensation to 

study personnel and 

consultants involved 

in data interpretation 

and writing; therapy 

provided at no 

charge)

Therapy Type: 

Collagen

Inclusion: ≥18 years; type 1 or 2 diabetes; 

diabetic foot ulcer; 1-25 cm2

; absence of 

infection; adequate circulation to affected 

extremity (TcPO2 >30 mmHg, ABI 0.70–1.2, or 

biphasic Doppler waveforms in arteries of lower 

extremity)

Exclusion: poor glycemic control (HbA1

c >12%); 

serum Cr >3.0 mg/dl; sensitivity to antibiotics 

used in preparation of cellular matrix; non 

revascularable surgical sites; ulcers probing to 

bone; wound recently treated with biomedical 

or topical growth factors

N=85 (of 86 randomized)

Age (years): 57

Gender (% male): NR

Race/ethnicity (%): NR

BMI: 33.8 (based on n=83)

HbA1

c (%): 7.9

Smoking: NR

# Work days missed: NR

ABI: NR

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 (%):

History of DM: 100; Type 1 – 8.2; Type 

2 – 91.8

Intervention (n=47): single 

application - 4x4 cm 

human acellular dermal 

regenerative tissue matrix graft 

(GRAFTJACKET); sutured or 

stapled in place; silver-based 

non-adherent dressing (Silverlon) 

applied; secondary dressings as 

determined by investigator 

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

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

Allocation concealment: 

Unclear

Blinding: No

Intention to treat analysis 

(ITT): Yes (included all 

but one intervention 

group patient who 

was removed from 

participation due to noncompliance)

Withdrawals/dropouts 

adequately described: 

Yes

Romanelli 200775

Italy

Funding Source: 

Industry

Therapy Type: 

Biological Dressing

Inclusion: >18 years; mixed A/V leg ulcer by 

clinical and instrumental assessment; venous 

reflux by Doppler flow studies; ABPI >0.6 and 

<0.8; ulcer duration >6 weeks; 2.5-10 cm2

; 

>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

N=54

Age (years): 63

Gender (% male): 48

Race/ethnicity (%): NR

BMI: NR

HbA1c (%): 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

Wound duration: 7.8 weeks

Comorbid conditions (%):

History of DM: 0

History of PVD: 100

Intervention (n=27): OASIS

Comparator (n=27): Hyaloskin

ALL: saline + secondary dressing; 

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

Study Withdrawal (%): 7.4 (4/54)

Treatment Compliance: NR

Allocation concealment: 

Inadequate (every other 

patient that was selected 

by clinician for study)

Blinding: No

Intention to treat analysis 

(ITT): No

Withdrawals/dropouts 

adequately described: 

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

Italy

Funding Source: 

Industry

Therapy Type: 

Biological dressing

Inclusion: venous or mixed A/V leg ulcer; ABI 

0.6-0.8; duration >6 months; size >2.5 cm2

; 

50% granulation tissue on wound bed

Exclusion: clinical signs of infection; ABI <0.6; 

necrotic tissue on wound bed; known allergy to 

treatment products; unable to follow protocol

N=50

Age (years): NR

Gender (% male): 48

Race/ethnicity (%): NR

BMI: NR

HbA1

c (%): NR

Smoking: NR

# Work days missed: NR

ABI: NR but for inclusion 0.6-0.8

Wound location: leg

Wound type: venous or mixed A/V ulcer

Wound size: 24.4 cm2

Wound duration: 7.1 weeks

Comorbid conditions (%): NR

Intervention (n=25): OASIS 

Comparator (n=25): petroleumimpregnated gauze

ALL: moistened with saline + 

secondary nonadherent dressing; 

assessed weekly for up to 8 wks; 

patients changed secondary 

dressing at home

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

Allocation concealment: 

Unclear

Blinding: Unclear

Intention to treat analysis 

(ITT): No

Withdrawals/dropouts 

adequately described: 

Yes

Saad Setta 201136

Egypt

Funding Sources: 

NR

Therapy Type: 

Platelet Rich Plasma

Inclusion: age 40-60 yrs; type 1 or 2 diabetes; 

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

N=24

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 

Wound size: 9.4 cm2

Wound grade: NR

Wound duration: ≥12 weeks

Infection: NR

Comorbid conditions (%):

History of HTN: 70

Intervention (n=12): platelet rich 

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

Treatment Compliance: NR

Allocation concealment: 

Unclear

Blinding: No

Intention to treat analysis 

(ITT): Unclear

Withdrawals/dropouts 

adequately described: No 

(not reported)
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

United States

Funding Source: 

Industry

Therapy Type: 

Intermittent 

Pneumatic 

Compression

Inclusion: age >18 years old; ulcers <50 cm2

; 

ulcers <2 years old

Exclusion: ABI <0.9; cancer; massive leg 

edema due to congestive heart failure; cellulitis; 

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

N=54

Age (years): 57

Gender (% male): 46

Race/ethnicity: NR

BMI: 33

Pre-albumin: NR

HbA1

c (%): NR

Smoking (%): 31

# Work days missed: NR

ABI: 1.1

Wound location: NR

Wound type: venous ulcer

Wound size: 9.9 cm2

Wound grade: NR

Wound duration: 306 days

Comorbid conditions (%): NR 

Intervention (n=28): below-knee 

gradient compression elastic 

stocking + external pneumatic 

compression; applied daily (1 hour 

in morning + 2 hours in evening)

Comparator (n=26): Unna’s boot

ALL: leg elevation 2X/day

Antibiotic Use: NR

Treatment Duration: 6 months

Follow-up Duration: NR

Study Withdrawal (%): 13

Treatment Compliance: 93% (4 

total dropped for non-compliance)

Allocation concealment: 

Unclear

Blinding: No

Intention to treat analysis 

(ITT): No

Withdrawals/dropouts 

adequately described: 

Yes

Stacey 200062

Australia

Funding Source: 

Government, 

Industry

Therapy Type: 

Platelet Rich Plasma 

Inclusion: venous ulceration based on ABI >0.9, 

venous refilling time < 25 seconds, blood tests 

negative for other causes of ulceration

Exclusion: none reported

N=86

Age (years): 71

Gender (% male): 42

Race/ethnicity: NR

BMI: NR

Pre-albumin: NR

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 

Intervention (n=42): bandage 

soaked in platelet lysate in 

phosphate buffered saline (PBS) 

Comparator (n=44): placebo (PBS) 

soaked bandage

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

Allocation concealment: 

Adequate

Blinding: Unclear

Intention to treat analysis 

(ITT): Unclear

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

Europe (Hungary, 

Czech Republic, 

Germany) 

Funding Source: NR

Therapy Type: 

Keratinocytes 

(autologous 

keratinocytes 

combined with fibrin 

sealant: BioSeed-S)

Inclusion: age 18-90; chronic venous leg ulcers 

(>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 

seconds, duplex sonography, or phlebography); 

ulcer located below knee joint excluding ulcers 

of distal metatarsal area

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 

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

N=225

Age (years): 67

Gender (% male): 37

Race/ethnicity: NR

BMI: 28.6

Pre-albumin: NR

HbA1

c (%): NR

Smoking: 19.1%

# Work days missed: NR

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:

3-12 months: 59.1%(133/225) 

>12 months: 40.9% (92/225)

Comorbid conditions (%): NR

Intervention (n=116): 2 wks before 

Day 0 – skin biopsy to collect and 

cultivate autologous keratinocytes

Day 0 – debride, disinfect & rinse; 

applied autologous keratinocytes 

within fibrin sealant; pressure 

dressing; compression therapy; 

repeated up to 3X in first 3 mos; 

further applications allowed if >2 

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

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

Allocation concealment: 

Unclear

Blinding: No

Intention to treat analysis 

(ITT): Yes

Withdrawals/dropouts 

adequately described: No
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

United States (24 

sites)

Funding Source: 

Industry

Therapy Type: 

Biological Skin 

Equivalent

Inclusion: type 1 or 2 diabetes; age 18-80 

years; HbA1

c 6-12%; full thickness neuropathic 

ulcers ≥2 weeks in duration (excluded dorsum 

of foot and calcaneous); ulcer size 1-16 cm2

; 

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

N=208 (of 277 randomized)

Age (years): 57

Gender (% male): 78

Race/ethnicity: white: 69; African 

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 

Intervention (n=112): Graftskin 

(Apligraft); at baseline then weekly, 

if needed, for maximum of 4 weeks 

(max of 5 application)

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%

Allocation concealment: 

AdequateBlinding: No

Intention to treat analysis 

(ITT): Modified (excluded 

69 patients during 1 week 

run-in)

Withdrawals/dropouts 

adequately described: 

Yes

Veves 200216

United States

(11 sites)

Funding Source: 

Industry

Therapy Type: 

Collagen

Inclusion: ≥18 years of age; diabetic foot ulcer; 

≥30 days duration; Wagner grade 1 or 2; area 

≥1 cm3

; adequate circulation 

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; 

inability to be fitted with off-loading device; 

multiple ulcers on same foot

N=276

Age (years): 58.5

Gender (% male): 74

Race/ethnicity (%): white 63, African 

American 10; Hispanic 16; Native 

American 12

BMI: NR

Pre-albumin: NR

HbA1

c (%): 8.6

Smoking: NR

# 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 

Intervention (n=138): collagen & 

oxidized regenerated cellulose 

dressing (Promogran); application 

frequency at clinicians’ discretion 

Comparator (n=138): isotonic 

sodium chloride solutionmoistened gauze

ALL: surgical debridement at all 

study visits; dressing changes 

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)

Allocation concealment: 

Unclear

Blinding: No

Intention to treat analysis 

(ITT): Yes

Withdrawals/dropouts 

adequately described: 

Yes
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

France (14 sites)

Funding Source: 

Industry

Therapy Type: 

Collagen

Inclusion: venous leg ulcers; free of infection; 

≥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

N=73

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

Intervention (n=37): Promogran 

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

Allocation concealment: 

Unclear

Blinding: Partial 

(investigator assessment 

validated by 2 clinicians)

Intention to treat analysis 

(ITT): Yes

Withdrawals/dropouts 

adequately described: 

Yes

Viswanathan 201141

India

Funding Source: 

Industry 

Therapy Type: Silver 

Products

Inclusion: type 2 diabetes; Wagner Grade I, II, 

or III ulcer 

Exclusion: clinical signs of severe infection; 

exposed bone; unwilling to participate in study

N=38 (of 40 randomized)

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 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

Intervention (n=20): diabetic 

wound cream (polyherbal 

formulation)

Comparator (n=20): silver 

sulphadiazine cream

ALL: daily dressing changes 

(saline wash, cream applied)

Antibiotic Use: If ulcers showed 

clinical signs of infection

Treatment Duration: unclear

Follow-up Duration: 5 months

Study Withdrawal (%): 5

Treatment Compliance: NR

Allocation concealment: 

Unclear

Blinding: Unclear

Intention to treat analysis: 

No

Withdrawals/dropouts 

adequately described: 

Yes
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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

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
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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

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
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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

Wang 201145

Taiwan

Funding Source: 

Research Fund 

through a University

Therapy Type: 

Hyperbaric Oxygen 

(HBOT)

Inclusion: chronic non-healing foot ulcers of 

more than 3 months duration

Exclusion: cardiac arrhythmia or pacemaker; 

pregnancy; skeletal immaturity; malignancy 

N=77 (of 86 randomized)

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 (HBOT0.91, control 1.07; 

p=0.06 between groups)

Wound location (%): plantar foot 71; 

dorsal foot 29

Wound type: diabetic

Wound size, cm2 (median): HBOT7; 

control 4 (p=0.06)

Wound grade (Wagner) (%): NR

Wound duration, months (median): 

HBOT6; control 6 

Comorbid conditions (%):

History of DM: 100%

Intervention: HBOT (n=45, 2 with 

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)

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

Allocation concealment: 

Inadequate (odd-even)

Blinding: No

Intention to treat analysis 

(ITT): No

Withdrawals/dropouts 

adequately described: 

Yes

Wieman 199831

United States (23 

sites)

Funding Source: 

Industry

Therapy Type: 

Platelet-derived 

Growth Factors

Inclusion: type I or II diabetes; ≥1 full thickness 

(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

N=382

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

Intervention: becaplermin gel#

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%

Allocation concealment: 

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
147

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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)
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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

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
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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

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)
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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
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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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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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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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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
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*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
156

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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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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

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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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)
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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

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)
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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

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)
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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

Dimakakos 

200965

(Silver Dressing)

100% painfree at 8 wks62% 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
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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

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
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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

Jørgensen 

200577

(Silverreleasing 

Dressing)

Both groups 

reported 

de-creased 

pain during 

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 

200581

(NPWT)

17 (13/77)

(p=0.04)

6 (5/85) 3 (2/77)

(p=0.06)

11 (9/85) 

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
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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
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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

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
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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)
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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)
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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)
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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)

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
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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)

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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Advanced Wound Care Therapies for Non-Healing Diabetic, 

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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 

200356

(Dermagraft)

Group 1:

0/13

Group 2:

1/13

Group 3:

Unclear†

(all p=ns)

Group 4:

0/13

Group 1: 

18 AE’s, 1 

serious

Group 2:

15 AE’s, 1 

serious

Group 3:

15 AE’s, 4 

serious

Group 4:

17 AE’s, 0 

serious

No deaths 

Keratinocytes

Harding 200560

(Lyophilized, 

allogeneic)

NOTE: Control 

group is 

combined 

standard care 

and standard 

care + vehicle 

group

Local AE: 

Tx phase

22 (21/95)

Follow-up

8 (7/89)

General AE:

Tx phase

25 (24/95)

Follow-up

16 (14/89)

(all p=ns)

23 (23/99)

5.5 (5/91)

23 (23/99)

14 (13/91)

1 (1/95)

(p=ns)

0/99 Reported no 

differences between 

treatment groups in 

“sensations such as 

burning, stinging, pain, 

or itching”

Vanscheidt 

200761

(Autologous, in 

fibrin sealant)

33 (38/116)

(63 events)

(p=ns for 

patients)

Serious AEs:

10 (12/116) 

(12 events)

25 

(27/109) 

(51 

events)

10 

(11/109) 

(14 

events)

0.9 (1/116)

(p=ns)^

0.9

(1/109)

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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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

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)
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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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Advanced Wound Care Therapies for Non-Healing Diabetic, 

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

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, 

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

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.