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Greer N, Foman N, Dorrian J, et al. Advanced Wound Care Therapies for Non-Healing Diabetic, Venous, and Arterial Ulcers: A Systematic Review [Internet]. Washington (DC): Department of Veterans Affairs (US); 2012 Nov.

Cover of Advanced Wound Care Therapies for Non-Healing Diabetic, Venous, and Arterial Ulcers: A Systematic Review

Advanced Wound Care Therapies for Non-Healing Diabetic, Venous, and Arterial Ulcers: A Systematic Review [Internet].

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Chronic ulcers (i.e., ulcers that are unresponsive to initial therapy or that persist despite appropriate care) are estimated to affect over 6 million people in the United States.1 The incidence is expected to increase as the population ages and as the number of individuals with diabetes increases.1 Chronic ulcers negatively affect the quality of life and productivity of the patient and represent a financial burden to the health care system.1,2,3 Within the Veterans Health Administration, during fiscal year 2011, there were over 227,000 ulcer encounters (inpatient and outpatient) involving over 54,000 patients and nearly 77,000 new ulcers.(Source: PAVE ProClarity Cubes (Prevention of Amputations in Veterans Every ProClarity Cubes)).

We focus on chronic ulcers of the lower extremity, in particular, ulcers attributed to either diabetes, venous disease, or arterial disease. Because advanced wound care therapies are typically used for ulcer healing following amputation, we also included post-amputation wounds. Identifying the ulcer etiology is important because the correct diagnosis is one factor in determining appropriate wound care interventions.4 Treatment modalities and wound care therapies are also selected based on patient factors, past treatment, and provider choice. A brief description of each ulcer type is provided below. We recognize that a non-healing ulcer is likely a result of multiple factors and comorbid conditions. We categorize included studies as diabetic, venous, or arterial according to the study author's description of the ulcer type.


Diabetic Ulcers

Approximately 15% to 25% of individuals with diabetes develop a foot ulcer at some point in their lifetime and an estimated 12% of those patients require lower extremity amputation.1 Diabetic foot ulcers account for nearly 2/3 of all nontraumatic amputations.4 Ulcer healing is complicated by diabetic neuropathy, decreased cellular synthesis, and susceptability to infection.5 Neuropathy can be categorized as sensory (loss of protective sensation), motor (the anatomic structure of foot is deformed creating areas where pressure from an ill-fitting shoe can create ulcers), or autonomic (resulting in denervation of sweat glands so the skin becomes dry and cracked predisposing the foot to infection, calluses etc.).3,4 Diabetic ulcers are typically located on the plantar aspect of the foot, over the metatarsal heads, or under the heel.6 The ulcers are characterized by even wound margins, a deep wound bed, cellulitis or underlying osteomyelitis, granular tissue (unless peripheral vascular disease is also present), and low to moderate drainage.6 Patients should be assessed for adequacy of circulation (claudication or extremity pain at rest, diminished or absent pulses, cool temperature, pallor on elevation, ABI), although due to issues with non-compressible vessels, toe pressures, ultrasonography, or other noninvasive vascular studies may be needed.7 Diabetic ulcers are typically graded using the Wagner8 classification:

  • Grade 0 – no open lesions in a high-risk foot
  • Grade 1 – superficial ulcer involving full skin thickness but not underlying tissue
  • Grade 2 – deeper ulcer; penetrating to tendon, bone, or joint capsule
  • Grade 3 – deeper ulcer with cellulitis or abscess formation, often with osteomyelitis or tendinitis
  • Grade 4 – localized gangrene
  • Grade 5 – extensive gangrene involving the whole foot

The University of Texas Diabetic Wound Classification System is also used.9 This system incorporates ischemia and infection in ulcer assessment. Standard treatment for Grade 1 and 2 diabetic ulcers includes debridement of necrotic tissue, infection control, local ulcer care (keeping the ulcer clean and moist but free of excess fluids), mechanical off-loading, management of blood glucose levels, and education on foot care.4,7 Osteomyelitis is a serious complication and a delay in diagnosis is associated with significant morbidity (e.g., non-healing, ulcer sepsis, limb loss).5

Venous Leg Ulcers

The most common cause of lower extremity ulcers is venous insufficiency. This accounts for 70-90% of leg ulcers.1,5 The ulcers develop within the setting of venous hypertension; elevated pressures are most commonly caused by valvular incompetence and result in an inefficient return of venous blood upon muscle contraction. Although a number of initiating factors may lead to the valvular incompetence of deep or perforating veins (e.g., deep vein thrombosis, phlebitis, trauma, surgery, or obesity), the resulting clinical picture of chronic venous insufficiency is the same. The congested vessels and pooling of blood result in increased vascular permeability. Water, proteins, and red blood cells leak out into the interstitial space, and pericapillary fibrin deposition occurs. This results in the symptoms of leg edema, hyperpigmentation (from extravasation of red blood cells and hemosiderin buildup), and lipodermosclerosis. Ulcers are thought to develop in this setting of venous stasis for a number of reasons: pericapillary fibrin deposits limit diffusion of oxygen and nutrients to skin tissue; leaked extravascular proteins may trap growth factors and matrix materials necessary for preventing and repairing the breakdown of tissue; and the accumulation or “trapping” of white blood cells may cause the release of proteolytic enzymes and inflammatory mediators.10 Venous ulcers occur most commonly in the leg (compared with the foot predominance of arterial and diabetic ulcers) and are characteristically found over the medial malleolus. These ulcers are often shallow and can be very large relative to other types of ulcers.11 Standard treatment is centered on the use of mechanical compression and limb elevation to reverse tissue edema and improve venous blood flow by increasing the hydrostatic pressure.12

Arterial Leg Ulcers

Ulcers associated with peripheral artery disease, also commonly known as ischemic ulcers, account for approximately 10% of lower extremity ulcers.3 This ulcer type develops due to arterial occlusion, which limits the blood supply and results in ischemia and necrosis of tissue in the supplied area. This occlusion is most commonly from atherosclerotic disease, so major risk factors for ischemic ulcers are the same as those in peripheral arterial disease (PAD); cigarette smoking, diabetes, hyperlipidemia, and hypertension.3 Similarly, patients with ischemic ulcers will complain of PAD-related symptoms such as intermittent claudication or pain that continues despite leg elevation. Other signs of decreased limb perfusion may also be present, such as a shiny, atrophic appearance of the skin, diminished leg hair, cold feet, and dystrophic nails.4,6

Evidence of diminished arterial blood flow may be established by finding diminished or absent pedal pulses or, most importantly, by measuring an ankle-brachial index (ABI).4,5 Because ischemic ulcers are related to poor perfusion, they typically occur at the most distal sites (e.g., the tips of toes) or in areas of increased pressure (e.g., over bony prominences). These painful ulcers often present as well-demarcated, deep lesions, giving the lesions a classically described “punched-out” appearance.5 Care for ischemic ulcers is centered on reestablishing blood flow and minimizing further losses of perfusion. With severe ischemia, the primary methods for achieving this are vascular surgery and lifestyle modifications. It is important to avoid treatment with mechanical compression if arterial occlusion is a contributing source for the development of an ulcer, as this leads to a worsening of tissue ischemia and necrosis.4


If ulcers do not adequately heal with standard treatment, additional modalities may be required. We define advanced wound care therapies as interventions used when standard wound care has failed. A large and growing array of advanced wound care therapies of different composition and indications have been developed though their efficacy, comparative effectiveness and harm is not well established. Therapies included in this review are: collagen products (COL), biological dressings (BD), biological skin equivalents (BSE), keratinocytes, platelet-derived growth factor (PDGF), platelet-rich plasma (PRP), silver products, intermittent pneumatic compression therapy (IPC), negative pressure wound therapy (NPWT), electromagnetic therapy (EMT), hyperbaric oxygen (HBOT), topical oxygen, and ozone oxygen. Because collagen may be a vehicle to deliver other bioactive ingredients, we have included in the collagen section only studies of collagen as a matrix material.

A complete description of these therapies, including reference citations, is presented in Appendix A; a brief description follows.

Collagen: Naturally occurring proteins known as collagens have diverse roles in ulcer healing including 1) acting as a substrate for hemostasis, 2) chemotactic properties that attract granulocytes, macrophages, and fibroblasts to aid healing, 3) providing a scaffold for more rapid transition to mature collagen production and alignment, or 4) providing a template for cellular attachment, migration, and proliferation.

Biological Dressings: These dressings consist of biomaterials made from various components of the extracellular matrix and are theorized to stimulate ulcer healing by providing a structural scaffold and the growth signals important to complex cellular interactions within ulcers, both of which are dysfunctional and contribute to the persistence of chronic ulcers.

Biological Skin Equivalents: These products are laboratory-derived tissue constructs, designed to resemble various layers of real human skin. They are thought to increase healing by stimulating fibrovascular ingrowth and epithelialization of host tissues.

Keratinocytes: Keratinocyte-based therapies for wound healing exist in a variety of forms and are proposed to work by stimulating proliferation and migration of host epithelium from wound edges through the production of growth factors and other cytokines.

Platelet-Derived Growth Factors: These products are designed to help repair and replace dead skin and other tissues by attracting cells that repair wounds and helping to close and heal the ulcers.

Platelet-Rich Plasma: Plasma with a high platelet concentration aids wound healing by attracting undifferentiated cells and activating cell division.

Silver Products: Multiple silver-based products have been developed to aid wound healing due to their broad bactericidal action. Cytotoxicity to host cells, including keratinocytes and fibroblasts, may delay wound closure.

Intermittent Pneumatic Compression: Delivered through inflatable garments containing one or more air chambers, compression propels deep venous blood towards the heart. This treatment benefits the non-ambulatory patient by increasing blood flow velocity in the deep veins and reducing stasis, decreasing venous hypertension, flushing valve pockets, and decreasing interstitial edema.

Negative Pressure Wound Therapy: This therapy involves creating a tightly sealed dressing around a wound and using a suction pump to apply negative pressure evenly across the surface in a continuous or intermittent manner. This process is proposed to enhance wound healing by increasing granulation tissue and local perfusion, reducing tissue edema, decreasing bacterial load, and stimulating cellular proliferation via induction of mechanical stress.

Electromagnetic Therapy: This process uses the electrical field that develops from exposure to an oscillating magnetic field. The treatment is thought to work by mimicking or enhancing natural wound-induced electrical fields produced in normal human skin.

Hyperbaric Oxygen Therapy: This therapy requires specialized compression chambers capable of delivering increased concentrations of oxygen (usually 100% oxygen) under elevated atmospheric pressures. Many key aspects of ulcer healing are oxygen dependent and raising arterial oxygen tension and the blood-oxygen level delivered to a chronic ulcer is thought to supply a missing nutrient, promote the oxygen dependent steps in ulcer healing, up regulate local growth factors, and down regulate inhibitory cytokines.

Topical Oxygen Therapy: These products aim to promote ulcer healing by correcting the low oxygen levels found within chronic ulcer.

Ozone Oxygen Therapy: Ozone is an oxidizing agent theorized to promote tissue healing by assisting in the destruction of defective cells, bacteria, and viruses.


A large and growing array of advanced wound care therapies of different composition and for different indications has been developed though the effectiveness, comparative effectiveness, and potential harm is not well established. The purpose of this review is to synthesize the evidence on advanced wound care therapies for treatment of non-healing diabetic, venous, and arterial lower extremity ulcers. We focus on FDA-approved therapies used in adult patients. Our outcomes of interest are complete healing and time to complete healing. Secondary outcomes and adverse events are also reported.


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