Skin ulceration of the lower extremity affects millions of people in the United States alone and may be secondary to a myriad of etiologies including pressure, metabolic, trauma, venous, arterial and diabetic neuropathy.1 The medical, psychosocial and financial impacts imposed by lower extremity ulcerations are tremendous. The attributable cost for the treatment of chronic lower extremity ulcerations has been estimated to be as high as $3.6 billion dollars per year.2 Medicare expenditures for lower extremity ulcer patients were, on average, three times higher than those for Medicare patients in general.3
In addition, a lack of immediate attention to these wounds can often serve as a prelude to serious health problems due to associated infections that may lead to amputations or induce life-threatening situations.1,4
Wound repair is an orchestra of highly integrated cellular and biochemical responses to injury.5 Certain pathophysiologic and metabolic conditions can alter this normal course of events and lead to impaired or delayed healing, resulting in chronic, non-healing wounds.5 Integrating biotechnological advances with our growing understanding of the complex cellular and biochemical mechanisms of the wound healing process has led to the development of various advanced wound healing modalities.
Many have advocated the use of negative pressure wound therapy (Vacuum Assisted Closure or VAC therapy, Kinetic Concepts Inc.,) in the management of lower extremity ulcerations. Negative pressure wound therapy (NPWT) is the controlled application of subatmospheric pressure to a wound using an electrical pump and specialized wound dressing.6-11 Studies have shown that applying subatmospheric pressure optimizes blood flow, decreases local tissue edema, removes excessive fluid and pro-inflammatory exudates from the wound bed.11 These physiologic changes promote a moist wound healing environment and facilitate the removal of bacteria from the wound.11 Applying sub-atmospheric pressure may also help increase the rate of cell division and subsequent formation of granulation tissue.11
Recently, a number of clinicians have advocated the concomitant use of advanced wound healing modalities with NPWT as a synergistic approach in the armamentarium of wound healing. Accordingly, let us take a closer look at some of the more commonly used modalities that one may combine with NPWT to help treat lower extremity ulcerations.
Hyperbaric oxygen therapy (HBOT) is an intermittent inhalation therapy in which the patient breathes oxygen at greater than 1 atmosphere of pressure. This modality requires the patient to be in an entirely enclosed pressure chamber for treatments. HBOT relies on the systemic circulation to deliver highly oxygenated blood to target tissues and raise tissue oxygen tensions to levels where one can expect wound healing. HBOT may also potentiate the action of leukocytes and researchers have noted improved healing in living tissues, especially those poor in oxygen.13,14 Numerous studies suggest that HBOT can be an effective adjunct in the management of complicated and compromised wounds.13-17
In a comparative analysis looking at either compromised post-surgical wounds or wounds secondary to arterial insufficiency, Neizgoda et. al., found that the combination of NPWT with HBOT produced results that exceeded those produced when either modality was used alone.18 In addition, the combined use of both therapies helped decrease the average number of HBOT treatments required.18
Conversely, Fabian, et. al., evaluated the efficacy of subatmospheric pressure and hyperbaric oxygen in the treatment of hypoxic full- thickness wounds in a rabbit model.19 They found that using NPWT increased the rate of healing while the application of HBOT did not significantly affect the rate of healing. Further trials are required to validate the combination use of NPWT and HBOT.
Collagen and oxidized regenerated cellulose (Promogran, Johnson & Johnson) is a sterile, freeze-dried matrix sheet that is approximately 3 mm thick. Oxidized regenerated cellulose (ORC) absorbs wound exudate and forms a soft, biodegradable gel that binds and inactivates matrix metalloproteases (MMP), which researchers have shown to have a detrimental effect on wound healing when present in excessive quantities.20,21
ORC also binds growth factors within the wound, protects them from degradation and releases them back into the wound in an active form as the matrix is slowly broken down. Researchers have demonstrated the effectiveness of ORC in several studies.22,23 ORC seems like an ideal wound healing modality to combine with NPWT as it requires the maintenance of a moist wound healing environment and may be left undisturbed for two to three days if the wound exudate is controlled. Clinical trials are required to help assess the possible clinical benefits of the combination.
Becaplermin (Regranex, Johnson & Johnson) is a hydrogel that contains 0.01% platelet derived growth factor-BB (rhPDGF-BB) and is currently the only commercially available topical growth factor for use in cutaneous wound healing.
Researchers have shown that PDGF-BB promotes wound healing by increasing proliferation and migration of dermal fibroblasts and extracellular matrix deposition. PDGF also promotes chemotaxis of neutrophils, monocytes and smooth muscle cells in wounds.24 Several studies have demonstrated the efficacy and safety of becaplermin.25,26
Some clinicians advocate combining becaplermin with NPWT with the belief that NPWT may remove excess fluid to create an environment that helps facilitate the actions of the PDGF-BB. It has been suggested that the imbalance between levels of matrix metalloproteases and their inhibitors in the fluids of ulcers causes elevated levels of proteases.26 The proteases in turn destroy essential growth factors, extracellular matrix proteins and receptors, including the ones specific for PDGF-BB, to ultimately prevent wounds from healing.20 Others argue that NPWT may indiscriminately remove the PDGF-BB while removing the excess fluid. There is currently no published data pertaining to the combination of becaplermin gel with NPWT. Further research and analysis are necessary to understand, validate and refine this approach to facilitate wound healing.
Researchers have noted that a human fibroblast-derived dermal substitute (Dermagraft, Smith and Nephew) and an allogeneic bilayered cultured skin equivalent (Apligraf, Organogenesis) facilitate angiogenesis and promote the healing of chronic ulcerations. Numerous studies have shown the efficacy of these modalities in the healing of full thickness chronic wounds.27-32
Seroma formation is one of the most common reasons leading to the “failure” of bioengineered skin replacements. The application of NPWT at a lower setting may serve as a mechanical, highly effective bolster dressing to mitigate shear forces and hematoma/seroma formation, and facilitate “uptake.” This would be similar to the technique one would employ to potentiate the uptake of autogenous skin grafts.33-35
Although there are currently no clinical trials that validate the combined use of NPWT with bioengineered skin replacements, there have been anecdotal reports of combining NPWT with other bioengineered tissue equivalents such as regenerative tissue matrix (Graftjacket, Wright Medical Technology), bilayered cellular matrix (Orcel, Ortec), and bilayer matrix wound dressing (Integra, Integra LifeSciences).
Jeschke et. al., examined the healing of deep, complex wounds with the combinational use of bilayer matrix wound dressing and NPWT.36 This combination expedited wound healing and resulted in wounds that were ready for split thickness skin grafts in a mean of 7.25 days. They found that NPWT improved both the take rate and time to vascularization of a bilayer matrix wound dressing when compared to previously published results using the bilayer matrix wound dressing alone.
Over the past decade, there have been numerous advances in wound care. Despite these advances, it is important to realize that the causes of ulceration are often multifactorial and there is no one product that will heal all wounds. Caring for a patient with chronic ulceration is complex and necessitates multidisciplinary collaboration to achieve the goal of providing comprehensive wound care. The combined use of NPWT with other advanced wound healing modalities may be a useful synergy in the armamentarium of wound healing. We are hopeful that future works in the literature will guide the clinician toward what may ultimately be a common sense conclusion.
Dr. Wu is an Assistant Professor in the Department of Surgery at the William A. Scholl College of Podiatric Medicine at the Rosalind Franklin University School of Medicine in Chicago. She is a Fellow at the Center for Lower Extremity Ambulatory Research (CLEAR) in Chicago.
Yoon is a second-year student at the William A. Scholl College of Podiatric Medicine at the Rosalind Franklin University School of Medicine in Chicago.
Dr. Armstrong is a Professor of Surgery, Chair of Research and Assistant Dean at the William M. Scholl College of Podiatric Medicine at the Rosalind Franklin University of Medicine in Chicago. He is also a member of the National Board of Directors of the American Diabetes Association.
Dr. Steinberg (pictured) is an Assistant Professor in the Department of Surgery at the Georgetown University School of Medicine in Washington, D.C. He is a Fellow of the American College of Foot and Ankle Surgeons.
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