Effect of negative pressure wound therapy on wound healing

Current Problems in Surgery 51 (2014) 301–331

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Current Problems in Surgery journal homepage: www.elsevier.com/locate/cpsurg

Effect of negative pressure wound therapy on wound healing Introduction Vacuum-assisted closure (VAC), sometimes referred to as microdeformational wound therapy (MDWT) or negative pressure wound therapy (NPWT), has revolutionized wound care over the last 15 years (Fig 1). This monograph describes our current understanding of these technologies, the questions that remain, and what the future may hold for technologies based on mechanotransduction principles. Dressings to treat complex wounds have traditionally been made of cotton gauze which could be soaked with a variety of chemicals including normal saline and sodium hypochlorite solutions. In the 1960s, the importance of keeping the wound moist was discovered and a wide array of hydrogels, alginates, and other polymeric and biologically based dressings were developed. More recently, these dressing materials have been combined with antimicrobial compounds such as silver. Collectively, there are approximately 1500 dressing types available to be used by clinicians in the United States. Most of these products are used based on clinicians experience often coupled with in vitro and in vivo experimental work and limited noncontrolled clinical trials. For the average clinicians, finding the best dressing for a specific wound can be a daunting task. In contrast, advanced wound care products such as growth factors, bioengineered skin, and dermal scaffolds are few in number and have more robust clinical data demonstrating their effectiveness, but they are expensive and can be logistically challenging to use. Generally, these products are used only after traditional moist-dressing products have failed or for large wounds. When NPWT was introduced in the United States, there were a series of devices (V.A.C., KCI, San Antonio, TX) manufactured and marketed by 1 company. Common to these devices was an open-pore foam to fill the wound cavity, a semiocclusive wound dressing, a suction tubing, and a suction device. Because there was significant wound surface deformation at the foam-wound interface, we believe that the generic term MDWT helps distinguish this technology from other NPWT devices that use different interface materials or suction settings. Owing to the early introduction, most of the mechanistic work and large clinical studies were done using the V.A.C. devices, and these results do not necessarily apply to all NPWT devices (Figs 1 and 2). It is important when reviewing the literature to be aware of the specific device used for either basic science or clinical application, as the results from a particular device studied may not translate to all NPWT results.

http://dx.doi.org/10.1067/j.cpsurg.2014.04.001 0011-3840/& 2014 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

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Fig. 1. A visual representation of the definitions used in this monograph. Negative pressure wound therapy (NPWT) is a term that refers to any device that applies differential suction (ie, reduced local pressure) to wounds. Microdeformational wound therapy (MDWT) refers specifically to NPWT systems that create microdeformations (appearing as microdomelike structures) at the wound surface. A number of commercially available devices exist within these definitions; the vacuum-assisted closure (VAC) therapy systems are some of the most commonly used. (Color version of figure is available online.)

When using NPWT devices in mobile areas such as the abdomen, significant shrinkage of the wound can be observed as the wound edges come together by a combination of foam shrinkage and drawing the edges of the wound together by foam contact. At the wound interface, the foam creates microdeformations that stretch cells and activate molecular pathways for angiogenesis and cell division. For wounds with edema, these devices have the capacity to remove a large amount of fluid. For example, in large open abdominal or fasciotomy wounds, significant quantities of edematous fluid can be removed, resulting in decreased tissue swelling. In addition, because of the materials used to cover the wound, the dressing acts as an insulator to keep the wounds warm and moist. In our practice, we use these devices after the wounds are debrided and are clean of visible necrotic material (Fig 3). They can be used until the wound is closed or used in preparation for surgical closure such as a skin graft or flap. These devices also have the advantage in that they often only need to be changed every 2-3 days, reducing the number of dressing changes for patients. The early clinical results of case reports and small series were

Fig. 2. The mechanisms of MDWT. (Color version of figure is available online.)


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Fig. 3. The 4 primary mechanisms of action of MDWT. (Color version of figure is available online.)

impressive, prompting surgeons to apply this technology to a wide range of clinical problems. These devices have been commonly used to treat pressure sores, open abdomens, sternal wounds, traumatic wounds, diabetic foot infections, second-degree burns, and skin graft recipient sites. They are contraindicated in untreated fistulas, untreated osteomyelitis, or in a wound with malignant tumor present. Caution should be used when the porous foam is used around vascular structures such as the heart or large blood vessels because erosion may occur, resulting in massive blood loss. Caution must also be taken when placing the porous foam in contact with visceral organs because erosion can occur, leading to fistula. The porous interface material is highly efficient at removing blood; therefore, appropriate alarms need to be present on the suction device to avoid exsanguination. Many suction pumps have design features that allow continuous or intermittent application. The optimal waveform for intermittent application has not been determined. Although there are basic science studies showing a greater response using intermittent therapy, this therapy often causes discomfort to patients or can be bothersome during sleep. Currently, there is much innovation in the NPWT space. Variations of these therapies have been used to treat closed incisional wounds, decrease edema, and facilitate healing. Instillation devices have been designed that allow delivery of a variety of irrigation solutions, including antibiotics. Finally, changes in the interface material may allow surgeons to customize the biological response of specific wounds. For example, pore size appears to be a large determinant on the rate of granulation tissue formation. NPWT devices can be combined with other surgical advances such as dermal scaffolds or processed allogeneic or xenogenic materials. We hope that future research in this area will lead to better wound therapy options for our patients.

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Pressure is defined as force divided by the area to which it is applied. On earth, we live in a pressurized atmosphere that allows us to survive. The relationship of pressure and volume can be approximated using the ideal gas equation: PV ¼ nRT. In this equation, P ¼ pressure, V ¼ volume, n ¼ number of moles of gas, R ¼ the universal gas constant, and T ¼ temperature in degrees Kelvin. As such, pressure must always be a positive quantity and “negative pressure” is a misnomer. Gauge pressure, where a pressure is compared with a standard, can be reported as a negative quantity. At sea level, the air that surrounds us presses on our skin in every direction at 1.0 atm, 760 mm Hg or 101 kilopascals. As we travel to higher altitudes, this pressure decreases. For example in Denver, Colorado, at approximately 5000 ft above sea level, the barometric pressure decreases by 125 mm Hg (approximately 635 mm Hg). Similar pressures are maintained in commercial aircraft at cruising altitudes. In contrast, if we travel to levels below sea level, the pressure increases. Because water is denser than air, divers and submarines can be exposed to very high pressures when descending in water. For example, at a depth of just 5.6 ft, the pressure would increase by 125 mm Hg (or 885 mm Hg). Within our bodies, structural elements maintain pressure differentials that are responsible for fluid flows. On a macroscopic scale, the rib cage and diaphragm allow subatmospheric pressure to develop within the thoracic cavity facilitating air transport into the lung via the tracheobronchial tree. In the cardiovascular system, blood vessels constrain high pressures from being transmitted into surrounding tissues. On a microscopic scale, arterioles, capillaries, venules, lymphatic vessels cells, and the extracellular matrix (ECM) exist in close proximity, yet differential pressures are maintained through structural elements in the connective tissues. Arterial blood pressures, of the order of 100 mm Hg, provide the necessary driving force for blood to perfuse capillary networks and arrive in venous systems of 5-10 mm Hg. Lymphatic fluid transudes through the walls of capillaries and is regulated by osmotic and pressure differentials. Much of this is related to structural elements in the ECM such as collagen, glycosaminoglycans, and elastin. Accumulation of fluid within the extracellular space results in edema. Excessive pressure within arterial systems can result in proliferation of cells within the arterial wall or excessive dilatation of arteries (aneurysms). Suction devices applied to wound surfaces are commonly applied at values around 125 mm Hg (Fig 4). The same structural elements in tissues that maintain pressure differentials in the vascular system also modulate the transfer of suction throughout tissues. The applied differential suction, as it interacts with the wound surface through the interface material is critical to activating biological pathways.

Part I—History of negative pressure therapy The role of the local microenvironment as it responds to mechanical influences has gained increasing attention from both clinicians and researchers interested in wound healing. There is a large class of wound care systems being used today or in the process of being developed that have been broadly referred to as NPWT devices.1 In particular, systems that apply an interface material to evenly distribute vacuum to wounds, while causing microdeformations, have been referred to as MDWT.2 A specific commercial device that has had a large market penetration and has been used in most clinical studies to date is referred to as V.A.C., based on the pioneering work of Argenta and Morykwas3 (Fig 3). These novel therapies have been shown to facilitate the healing of various types of wounds derived from trauma, infection, congenital deformities, and tumors. The surging number of clinical trials and fundamental studies in this field has provided us with a more detailed understanding of the observed clinical effects as well as the mechanism of action at the tissue, cellular, and molecular levels. Suction has been used in medicine for many years. Bier described the use of suction cups for a variety of ailments that have been largely abandoned.4 Suction is frequently used for many indications including evacuation of purulence, closed suction drainage of surgical wounds, removal of gastric fluids, and collapse of the pleural space. Excessive suction can damage tissues,


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Fig. 4. Temporal and spatial relationship of wound interstitial pressure. Paradoxically, there is an increase in interstitial pressure close to the wound. The pressure differentials attenuate over time. Artist representations of the increase in tissue pressure occurring with MDWT, approximated by the results observed by Kairinos and colleagues, assuming an application of 125 mm Hg suction pressure (common clinical value). The size of the increase decreases with distance from the wound surface, dissipating exponentially beyond 1 cm. However, no definitive data exist to the authors' knowledge regarding pressure changes within the first centimeter of depth below the wound surface. Based on FEA and the formation of microdeformations at the surface, it would not be surprising for the most superficial tissue to experience subatmospheric pressures. The magnitude of pressure increases also decrease gradually over the course of treatment, although tissue pressure may remain elevated even after 48 hours of treatment, compared with the preMDWT baseline. Owing to a dearth of data in sample size and consistency between wound types, this chart merely depicts the general trends observed. Of the 10 treated wounds studied by Kairinos and colleagues, only 3 were found to eventually decrease in pressure to below baseline levels during prolonged therapy. (Color version of figure is available online.)

and manufacturers have built devices to limit high levels of suction to fragile organs such as the lung. Typically, these devices have been designed to apply low levels of suction ( o40 mm Hg). Liposuction uses high levels of suction that facilitate tissue removal. Mechanical forces have been used outside of medicine for centuries to create tissue. Women in Ethiopia use ceramic plates of increasing diameter to expand the lower lip while some in Thailand use metal rings to stretch out the neck. The importance of mechanics in repair was popularized by Julius Wolff (1836-1902), a German surgeon, who recognized that bone morphology adapts to applied mechanical loads. The pioneering Russian surgeon, Gavriil Ilizarov, put this principle into practice treating patients in need of bone lengthening. Although he further developed the science behind this during the 1950s, his work did not become well known in the United States until the 1980s. His observations led to the field of distraction

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osteogenesis. In soft tissue, surgeons recognized the skin's ability to expand during weight gain or pregnancy, inspiring the development of tissue expanders. In 1957, Neumann5 described the use of a rubber balloon to expand the skin for the purpose of covering exposed cartilage. Radovan and Austad both developed tissue expanders in 1975, which led to a new class of devices that could generate tissue de novo. As the largest organ in the human body, skin and the underlying subcutaneous tissues are constantly subjected to both extrinsic and intrinsic mechanical forces. For example, gravity, body movement, and trauma are extrinsic forces, while blood flow or growth of the skeleton generates intrinsic forces. Endothelial cells, keratinocytes, and fibroblasts (among others) respond to these mechanical forces. Given the existence of this cellular mechanosensitivity, the spatial and temporal responses of skin to mechanical stimulation are current areas of growing interest in wound management. The increased clinical demand combined with a better understanding of the skin's mechanotransductive properties has spawned significant innovation in wound healing therapies using mechanical forces. The interaction of wound healing and mechanical forces is analogous to where forces have been applied in other areas of the human body. The understanding and application of tensile forces (eg, stretching) are also related to the pathogenesis and treatment of excessive wound healing such as hypertrophic scarring or keloid formation. Microdeformation, caused by suction devices with an interface material, has only been recently recognized as having the capacity of applying tensile forces to the wound surface. Its application in both acute and chronic wound management is a nonpharmacologic strategy. Its modulation of the healing process relies on a class of devices based or engineered on the concept of wound suction. In 1997, Argenta and Morykwas3 first described applying controlled suction through open-cell foam to create an environment conducive to healing and granulation tissue formation.6 This device was one of several developed by their group that uses suction to treat wounds, which they defined as NPWT. The forces that resulted from the application of suction differed from the traditional dressings, such as elastic compression wraps, that often applied a compressive force to the wound. Although a number of device systems have been described, currently, the most popular clinical systems use open-pore foam dressings, which result in the formation of tiny, domelike structures at the wound surface that cause microdeformations to the wound surface. Therefore, we use the term MDWT for devices that deform wounds on the micron-to-millimeter scale, incurring morphologic and functional changes in cells that further improve wound healing.7 As an aside, the application of MDWT actually generates a seemingly paradoxical increase in pressure below the wound surface, reinforcing MDWT as the clearest definition for such therapies.8

The VAC system The VAC system is a relatively new technology in wound management. The general system is made up of 4 major components: (1) a filler material or sponge placed into the wound; (2) a semipermeable dressing to isolate the wound environment and allow the vacuum system to transmit subatmospheric pressures to the wound surface; (3) a connecting tube; (4) and a vacuum system (Fig 3). A fluid collection canister is also incorporated with the device. As a precautionary measure, an alarm sounds if the canister is full, alerting clinicians to potential bleeding problems.9 The structure of the material packed into the wound may be important in the efficacy of NPWT. Although different materials may be used with various NPWT devices, reticulated, open-pore foam is the most common. This foam is made of many cells or bubbles that are highly interconnected. This structure, as the name suggests, resembles a 3-dimensional net, which is in the form of a lattice of open-faced polyhedra. Importantly, this attribute permits the vacuum to be distributed evenly throughout the foam and improves fluid drainage.


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As part of the commercial VAC system, 3 general types of foam are available: black polyurethane ether (V.A.C. GranuFoam, KCI), black polyurethane ester (V.A.C. VeraFlow, KCI), and white polyvinyl alcohol (V.A.C. WhiteFoam, KCI). Other types of foams are available in other commercial devices and other types of interface materials continue to be developed. The traditional polyurethane ether foam is hydrophobic, whereas the polyvinyl alcohol and polyurethane ester foams are more hydrophilic. The polyurethane ester devices are designed for use with instillation therapy. Clinicians have often used the traditional polyurethane ether foams for wounds with large fluid drainage and for stimulating granulation tissue formation. In contrast, the polyvinyl alcohol sponges have been used in cases where the wound tunnels or when delicate underlying structures, such as tendons or blood vessels, need to be protected. Finally, the increased density and smaller pores of the WhiteFoam help to restrict ingrowth of granulation tissue, thereby diminishing pain associated with dressing changes and reducing risk when hypergranulation is a concern.10,11 NPWT therapy is most commonly applied to an open wound, accelerating the healing process and bringing the wound margins closer together. Other uses, methods of application, and different patient conditions have been discussed at greater length in the section Clinical applications of NPWT, following an explanation of the mechanisms of action. Overall, the healing of both acute and chronic wounds is improved through the combination of components that include the wound-foam interface, semiocclusive microenvironment, and the mechanical forces incorporated into NPWT.

Part II—Mechanisms of action The events underlying the improvement in wound healing observed with MDWT can be broadly classified as primary mechanisms and their associated secondary effects. Overall, 4 primary mechanisms of action have been proposed: (1) wound shrinkage or macrodeformation; (2) microdeformation at the foam-wound surface interface; (3) fluid removal; and (4) stabilization of the wound environment (Figs 2 and 3).12 There are also several secondary effects likely involved in mechanotransduction pathways that alter the biology of wound healing including angiogenesis, neurogenesis, granulation tissue formation, cellular proliferation, differentiation, and migration. Primary mechanisms Macrodeformation Macrodeformation refers to induced wound shrinkage caused by collapse of the pores and centripetal forces exerted onto the wound surface by the foam. Polyurethane ether foams exposed to 125 mm Hg suction can decrease the foam volume by approximately 80%13 and result in a substantial decrease in wound surface area in a porcine model.14 The extent of contraction is largely dependent on the deformability of the wound. The baseline tension in skin causes wound margins to naturally pull apart. Because of the inherent tension of the dermis and variable attachment to underlying structures, different wounds contract to different degrees. For example, the low elasticity of scalp skin over the rigid calvarium is likely to contract less than a large abdominal wound in an obese patient. Interestingly, in both in vivo and in vitro studies, a seemingly paradoxical increase in extracellular pressure is observed in the tissue underlying the wound bed, presumably due to tissue compression induced by macrodeformation.8,15 Such a phenomenon may seem more obvious with circumferential NPWT dressings, for example, in treating large degloving injuries encompassing a limb. As suction is applied, air is evacuated from the foam and its reduction in volume results in the compression of underlying tissue. Increased tissue pressure is also observed when NPWT is applied to more cavitary wounds, where the top of the foam is virtually at level with the surrounding skin. Logically, one might assume that negative gauge pressures would translate to lower pressure in adjacent tissues. However, pressure in the underlying tissue

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increases with elevated suction. These extracellular pressure changes also vary with distance from the foam-wound interface and the time of treatment (Fig 4).8 Taking these findings into consideration can reduce the risks of NPWT in patients with compromised perfusion, potentially contraindicating this treatment, especially if circumferential dressings or higher suction pressures are to be used. Overall, the effects of macrodeformation depend on the type of tissue treated,12 the level of suction,14 the volume of the foam,16 the pore volume fraction of the filler material (proportion of sponge occupied by air),17 and the deformability of the surrounding tissues.12 Microdeformation Microdeformation refers to the undulated wound surface induced by the porous interface material when exposed to suction. These physical changes occur on the micron-to-millimeter scale, given common pore diameters are in the range of 400-600 μm, and set in motion a host of other effects that aid in the healing process. To better understand the micromechanical changes involved, models have been designed to mimic tissue stretched by a combination of suction and a counteracting downward force by the sponge struts. In computer simulations of this interface with finite element analysis (FEA), our model indicates that at 110 mm Hg, MDWT application using typical foam pore sizes causes an average tissue strain of 5%-20% over most of the wound surface. Quantitatively, tissue strain corresponds to the percentage increase or decrease in length of a given material subjected to external forces.18 These mechanical forces appear to be transmitted to individual cells via the ECM. In MDWT, cells are subjected to a variety of mechanical forces, including shear and hydrostatic pressure from extracellular fluid, stretch and compression from their surrounding matrix, and the ubiquitous pull of gravity.12 These mechanical forces, particularly microstrain, are also highly variable across the wound surface (albeit in a repeating pattern between sponge pores). FEA has demonstrated that tissue immediately below the foam struts experiences compression, whereas tension is found along the wound surface centrally in the pore.18 Overall, the regular yet highly variable microenvironment created during this therapy is what causes microdeformation. Microdeformation, in essence, is the morphologic result of these integrated mechanics. Cell shape has been demonstrated to be a determinant of cellular function.19 In addition, cells are known to adapt to physical stresses.20 Therefore, changes in cellular functions can be initiated by these dynamic physical inputs. This concept has been discussed in greater detail in the secondary effects of NPWT action. Fluid removal Fluids in the body have been classically divided among 3 compartments: (1) intravascular, (2) intracellular, and (3) extracellular. Fluid transport between these compartments is primarily governed by the Starling equation, which takes into account the hydrostatic and osmotic pressure differentials across semipermeable membranes. The most variable of these compartments is the extracellular space. Excess fluid in this compartment is commonly seen as edema, whereas a lack of fluid in this compartment is a sign of dehydration. The extracellular fluid compartment is drained by lymphatics, the disruption of which can lead to lymphedema. Depending on the underlying pathology, chronic wounds and edema are often concomitant, as is the case with lower extremity diabetic ulcers. Excess fluid buildup is commonly accepted as a contravening factor in healing, partly owing to the compressive effect it can exert on local cells and tissues. Individual cells generate intrinsic tension via their cytoskeleton and interactions with the ECM, inducing a proliferative response.12 Elevated fluid pressures in the interstitium diminish this response by dampening intrinsic tension buildup. Fluids from the extracellular space appear to communicate with the wound surface. Applying vacuum to this surface results in fluid removal from many wounds, including the extracellular space. In our experience, particularly in fasciotomy wounds or in open abdominal wounds, large amounts of fluid can be removed.21 Fluid removal likely reduces compression of the microvasculature, optimizing tissue perfusion by reducing difference and potentially allowing increased blood flow to the area (Fig 5).3,22 The polyurethane drape is semipermeable, allowing a small amount of air to enter the


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Fig. 5. MDWT helps to remove excess extracellular fluid, reducing hydrostatic compression at the capillaries and reducing the required diffusion distance. The net result is optimized tissue perfusion, aiding in the healing process. (Color version of figure is available online.)

system, thereby preventing a fluid lock and allowing continuous evacuation of fluid. NPWT also likely reduces the amount of fluids that must be cleared through the lymphatic system. Toxins from the wound, bacteria, and exudate can also be removed with the fluids.7 MDWT also influences fluid removal more indirectly. The associated microdeformation enhances fluid drainage, ultimately reducing tissue edema, by generating an increased pressure gradient between the interstitial space and the interface material.7 This compression might also be a mechanism for increased lymphatic drainage from the wound. In addition, MDWT induces a gradual increase in lymphatic density at wound edges, thereby improving drainage (Fig 6).23 Alteration of the wound environment Fluid removal is an important element in achieving a wound environment conducive to healing. Complete evacuation of fluid with its accompanying electrolytes and proteins does, in theory, also stabilize osmotic and oncotic gradients at the wound surface.12 The foam material and semiocclusive drape act as thermal insulators to maintain wound warmth.24 The

Fig. 6. Lymphatic density increases gradually at wound edges during the course of treatment. (Color version of figure is available online.)

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semiocclusive polyurethane drape is fundamental in maintaining subatmospheric pressures at the wound bed and prevents evaporative water losses. The dressing is impermeable to proteins and microorganisms, significantly reducing the risk of wound contamination. In addition, the drape exhibits limited permeability to water vapor and other gases, helping to maintain a stable, moist wound environment.24-26 Different types of NPWT can also optimize the wound environment to address specific aspects of the healing process. Instillation of bioactive factors27 and using foam bound with antimicrobial silver28 are 2 common examples of how the wound interface may be altered. These methods for enhancing the wound environment and possibly improving patient outcomes, have been discussed in greater detail in a later section devoted specifically to clinical applications. In general, NPWT devices assist in wound healing partly because of control of wound fluids while maintaining a warm and moist microenvironment. In comparison with conventional therapies, the reduced number of required dressing changes in NPWT also can add to patient comfort. Secondary effects Wound healing is most often described in terms of 4 overlapping phases: hemostasis, inflammation, proliferation, and remodeling. An alternative model divides the process into early and cellular phases, offering clearer delineation between processes involved in wound healing.29 The early phase is immediately initiated by tissue injury and largely involves the hemostatic response and ensuing biochemical changes that set the inflammatory processes in motion. The cellular phase encompasses the ensuing inflammatory response, rapid proliferation, differentiation and granulation tissue formation, and finally, re-epithelialization and scar formation. These classifications of wound repair mechanisms offer a suitable context to discuss current knowledge of the secondary effects of NPWT. Hemostasis The efficient open-pore foams require that hemostasis is nearly complete before application of suction, using caution in patients with coagulopatihies. Suction devices should have overflow alarms to alert clinicians when there is excessive blood loss. Modulation of inflammation During the inflammation phase, MDWT removes infiltrating leukocytes while simultaneously inducing inflammation. These findings are supported by the evidence of increased wound exudate cellularity (particularly leukocytes and erythrocytes) and increased gene expression of leukocyte chemoattractants, such as IL-8 and CXCL5, in wounds treated with NPWT.30 Cellular responses—division, migration, and differentiation MDWT generates a complex mechanical environment at the wound surface. The resultant cell deformations lead to altered function in cellular proliferation, migration, and differentiation. Cell shape has been well established to govern its behavior31; the alteration of the cytoskeleton generates organizational guidance cues for cells (Fig 7).32 For example, cell sensitivity to soluble mitogens is enhanced with increasing distortion.33,34 Thus, the cellular deformation and associated cell stretch caused by MDWT induce cell proliferation, thereby promoting wound healing. This is supported by evidence that short (6 hours) intermittent applications of MDWT to a diabetic mouse model caused an extended proliferative cell response with increased expression of Ki-67, a marker for cell proliferation.35 It is also worth noting that the tissue strain induced by MDWT (5%-20% increase in length) is the same level of strain needed to promote cellular proliferation in vitro.18 Huang and Ingber36 demonstrated the need for cells to experience isometric tension in order to provide the mechanical context necessary for cellular proliferation. Growth factors and cell attachment to ECM proteins were discovered to be essential yet insufficient stimulation in the absence cellular isometric tension. Chronic wound beds may lack the stable, structural


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Fig. 7. Representation of wound bed fibroblast requirement for a trifecta of growth factors, extracellular matrix protein binding, and isometric tension to undergo proliferation and differentiation. In wound beds, ECM destabilization precludes buildup of isometric tension, eventually resulting in cell death. This can be compensated by the mechanical microenvironment generated during microdeformational wound therapy (MDWT). The particular cellular response is also correlated with the amount of tension the cell experiences: proliferation requires greater stretch than differentiation. (Color version of figure is available online.)

scaffolding required for cell extension and adherence, thereby preventing the development of isometric tension within the cell. This leads to spherization and eventually apoptosis. However, the suction forces generated by MDWT can elicit an array of mechanical forces within the tissues, thus allowing cells to proliferate in response to other mechanical and chemical activators.18 In addition to promoting cellular proliferation, tissue treated with MDWT exhibits a host of other characteristics: increased epithelial cell migration, as evidenced by gene ontology enrichment analysis30; increased endothelial migration, analyzed in histologic penetration depth37 or endothelial ingress38; and increased dermal fibroblast migration, indicated by migration assay.39 Resident skin mesenchymal cells and circulating progenitor cells have also been observed migrating into granulation tissue because of MDWT application.40 Although epithelial cell proliferation and migration increase, their differentiation during MDWT has been shown to decrease.30 MDWT inhibits keratinocyte differentiation, as supported by evidence of downregulated keratin genes (eg, KRT1, 2, 10, 13, and 15) and major cornified envelope genes (eg, annexin A9, filaggrin, and loricrin).30 Changes elicited in the wound tissue matrix by MDWT may influence differentiation, given that mesenchymal stem cell lineages are highly specific to the mechanical characteristics of the ECM. In these cells, soft, stiffer, and rigid matrices guide differentiation down the paths of neurogenesis, myogenesis, and osteogenesis, respectively.41 The overall interpretation of various studies is that MDWT can promote healing by modulating inflammation and cell migration, while inhibiting epidermal development and maturation.30 Angiogenesis Wound-site angiogenesis is mechanically initiated through microdeformation, which establishes hypoxia and a subsequent vascular endothelial growth factor (VEGF) gradient that drives the directionalized blood vessel growth (Figs 8 and 9).42 It has been suggested that the temporary reduction of blood flow at the wound edge15,43 stimulates angiogenesis through the

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Fig. 8. MDWT stimulates wound-site angiogenesis through a number of mechanisms: mechanical stimulation (microdeformation), removal of factors inhibiting angiogenesis, and upregulating proangiogenic factors. Blood vessel dilation is also observed. (Color version of figure is available online.)

hypoxia-inducible factor-1α–VEGF pathway; tissue hypoxia instigates the upregulation of hypoxia-inducible factor-1α, which in turn stimulates VEGF expression.42 It is not surprising that MDWT demonstrates increased microvessel density during chronic wound treatment.44 In vitro studies using intermittent MDWT achieved similar results of angiogenic response stimulation.38

Granulation tissue formation The result of endothelial cell and fibroblast ingrowth at the wound surface, that is, granulation tissue, which also includes the ancillary ECM and migratory macrophages, represents a specialized stroma designated for repair (Fig 7). In the proliferation phase, effects of MDWT include robust tissue granulation, cell proliferation, and blood vessel sprouting. Early and continuous activation by mast cells is a necessary component of these processes, which are absent in mast cell–deficient mice.45 Similarly, collagen maturation exhibits strict mast cell dependence in the proliferation and remodeling phases. However, collagen production does not share this dependence. Both the production and maturation of collagen are accelerated by MDWT, but in mast cell–deficient mice, only production increased.45 Mechanotransduction, the process by which cells transduce mechanical forces into biological signals (eg, altered intracellular environment or gene expression), is integral to the mechanisms underlying MDWT in that it allows cells to respond directly to applied pressure differentials.46,47 Mechanotransduction signaling in connective tissue has been thoroughly studied in fibroproliferative disorders; research has focused primarily on the regulation of cell-ECM interactions through a variety of signals such as transforming growth factor-β (TGF-β)-Smad, mitogenactivated protein kinase (MAPK), RhoA-ROCK, Wnt-β-catenin, and tumor necrosis factor-α/ nuclear factor kappa-light-chain enhancer of activated B cell (TNF-α/NF-κB).48 On the contrary, mechanotransduction research in MDWT is a relatively new area of study. Currently, hypoxia pathway molecules such as nitric oxide are thought to be involved.9


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Fig. 9. Summary of events that contribute to directionalized angiogenesis. (1) MDWT results in increased pressure in tissue below the wound surface, leading to the compression of small blood vessels. (2) Localized decreases in perfusion generate a hypoxia gradient in the wound tissue. (3) Upregulation of hypoxia-inducible growth factor-1α (HIF-1α), which in turn increases vascular endothelial growth factor (VEGF) production. The resulting growth factor concentration gradient (4) stimulates directionalized vessel sprouting. (Color version of figure is available online.)

Given the complexity of the mechanical environment generated at the wound bed during MDWT, much of our current data result from in vitro studies (Fig 10). Tissue engineering bioreactors are commonly used to simulate the in vivo micromechanical environment as well as the foam-wound interface. Wilkes and colleagues developed a novel 3-dimensional bioreactor to best mimic the wound bed environment as well as the applied commercially available dressings. With this device, they subjected tissue analogues to topical NPWT. Following a 48-hour incubation period, fibroblast cell bodies were observed to have thickened from their initial elongate bipolar morphology. Dense actin cortical structures were also observed following treatment.49 Using a 3-dimensional fibrin matrix, McNulty and colleagues39 discovered that MDWT influences fibroblast energetics: energy charge, adenosine triphosphate–adenosine diphosphate ratio, and cytochrome c oxidase levels were shown to increase. Importantly, they also discerned that the observed increase in energy status was geared toward biosynthetic processes associated with healing; levels of the growth factors TGF-β and platelet-derived growth factors α and β were also shown to increase with the combined application of subatmospheric pressure and a reticulated open-cell foam. Both are important in granulation tissue formation as they upregulate collagen production, but platelet-derived growth factors α and β also upregulate glycosaminoglycans and fibronectin synthesis in fibroblasts.39 In our own study, it was found that 48 hours after exposure to a suction or foam or perfusion bioreactor, cells exhibited an upregulation of fibroblast growth factor, TGF-β1, Type I collagen α1, and smooth muscle actin α2 messenger RNA expression.40 Peripheral nerve response Younan and colleagues demonstrated that MDWT also activates the neurocutaneous system, thereby stimulating neural growth and neuropeptide expression. Upregulated peptides include substance P, calcitonin gene–related peptide, and neurotrophin nerve growth factor (Fig 11). The

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Fig. 10. Morphologic and biochemical changes of fibroblasts subjected to NPWT. Fusiform cell bodies have been observed to increase in thickness along with the density of actin cortical structures. Microdeformational wound therapy (MDWT) also affects cellular energy status, fueling cellular processes associated with wound healing. ATP, adenosine triphosphate. (Color version of figure is available online.)

Fig. 11. MDWT promotes neural growth and neuropeptide expression (substance P, calcitonin gene–related peptide, and neurotrophin nerve growth factor). Transient elevations of plasma epinephrine and norepinephrine have also been observed. (Color version of figure is available online.)


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extent to which this occurs is correlated with the amount of microdeformation, and intermittent MDWT was shown to have a more pronounced effect than continuous suction.50 In addition, MDWT has been shown to elicit transient elevations of plasma epinephrine and norepinephrine, followed by a slow but long-lasting increase in substance P and neuropeptide Y.51 Currently, neuropeptides are recognized as key homeostatic factors in the skin and their secretion may play a role in the secondary mechanism of MDWT.7,52 Alterations in bioburden The influence of NPWT on bacterial load remains controversial. The findings are conflicted regarding the effect of NPWT on bacterial burden. Some studies have shown a decrease in bacterial load in response to NPWT.6,53 Others have indicated comparable levels between treatment and control groups, comparing foam dressings in the presence and absence of suction, respectively. However, this result was in the context of an in vitro analysis using nonviable tissue, focusing predominantly on the relationship between bacteria and suction force.54 This suggests that any observation of decreased bacterial load results from more than just pure physical suction. In contrast, another study observed a decrease in the number of nonfermentative gram-negative bacilli, whereas the level of Staphylococcus aureus increased.55 The effect of NPWT on bacterial load remains an area to further explore, particularly in terms of the variety of responses that may be elicited by different strains. High bacterial counts have been measured in sonicated foams.56 A very high polymicrobial bacterial load was found in all foams studied. Porous polyurethane ether foam on high suction (125 mm Hg) had fewer bacteria than polyvinyl alcohol foams on lower suction.

Part III—Clinical applications of NPWT NPWT has been applied to a wide variety of wounds varying in location, complexity, and underlying pathology. It alters the traditional phases of wound healing (Fig 12) and is used in a variety of anatomical sites throughout the body (Fig 13). The original application of suction to wounds seems to be a very simple concept. However, the determination of the optimal mode of NPWT for a specific wound eludes us. The following sections review the several wound types that have been studied. Open wounds Basic applications of NPWT Classically, NPWT has been used in the context of open wound management; the interface foam is applied directly to the wound bed, which is visible at the body surface. Given the effect that pressure differentials can exert at the wound bed, poorly healing ulcers are common targets for treatment. Ulcers derived from pressure necrosis, diabetes, and venous or arterial pathologies can often benefit from NPWT. In the treatment of pressure ulcers, serial randomized controlled trials (RCTs) demonstrated a reduction in wound surface area,55 volume and depth,57 improved granulation, and a reduced frequency of hospitalization in patients undergoing NPWT.58 This therapy can be an option for managing nonhealing deep-pressure ulcers covered by soft necrotic tissue; wounds treated with NPWT often show a rapid formation of granulation tissue.59 In a retrospective cohort study evaluating chronic diabetic, arterial, and venous ulcers in high-risk patients, treatment with NPWT was shown to increase the incidence of closure (by a factor of 3.3, 2.3, and 6.3, respectively). Earlier application of NPWT to these wounds also results in faster healing times.60 In the treatment of diabetic foot ulcers, NPWT promotes wound area reduction, wound bed granulation, and microbial clearance,61 thereby enabling a higher rate of limb salvage, especially in Wagner grade 3 and grade 4 ulcers.62 NPWT prevents digit amputation in the nonoperative management of scleroderma ulcers.63

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Fig. 12. Influence of NPWT and MDWT on the 4 stages of healing. (1) Although contraindicated in cases of bleeding, MDWT does generate pressure in the tissue underlying the wound bed, which can compress small blood vessels. (2) NPWT modulates inflammation at the wound bed, while the vacuum pulls out infiltrating leukocytes along with wound exudates. (3) MDWT stimulates cellular proliferation, angiogenesis, and the formation of granulation tissue during the proliferative phase of healing. These processes are stimulated by mast cells, as is the maturation (not production) of collagen during the remodeling phase. (4) MDWT increases both collagen production and maturation. (Color version of figure is available online.)

The effects of NPWT are both location and disease specific. NPWT should be applied in conjunction with treatment of other comorbid diseases such as diabetes, hypertension peripheral vascular disease, and venous stasis disease. Zutt and colleagues64 showed the importance of concurrent medical treatment of vasculitis and pyoderma gangrenosum along with adequate debridement and application of NPWT. Surgical wounds are usually treated with NPWT, often as a bridge to closure with a skin graft or flap, or secondary closure with NPWT (Fig 14). For example, following melanoma excision, the application of NPWT provides functional and cosmetic outcomes that include improved vascularity and reduced scar height.65 Similarly, postoperative NPWT for lymphangioma in children has demonstrated its effectiveness in decreasing the risk of recurrence and infection.66


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Fig. 13. Potential targets for NPWT. SSG, split-thickness skin graft. (Color version of figure is available online.)

Skin graft and dermal scaffold recipient site preparation NPWT is commonly used for recipient site preparation for both skin grafts and dermal scaffolds. Autologous skin grafting is commonly a rapid method to surgically close large wounds that have granulation tissue that spans the wound. In wounds with small areas of exposed bone or tendon, dermal scaffolds can often be an effective strategy to produce a complete vascularized wound bed before skin grafting.67,68 The combination of NPWT with dermal scaffolds provides excellent immobilization and contact between the scaffold and wound surface. A multicenter RCT demonstrated related long-term effects when combining dermal scaffolds (Matriderm, Dr Suwelack Skin & Health Care AG, Billerbeck, Germany) with NPWT; scars were observed to have greater elasticity and more natural skin pigmentation 12 months postoperatively, while the rate of postoperative wound contamination decreased.69 Combination therapy—incorporating bioactive factors in NPWT There have been several novel approaches to NPWT, which have been recently developed. Antimicrobial silver in NPWT Traditional NPWT uses polyurethane ether foam; however, its effect on bacteria in the wound has been inconsistent. To attempt to reduce the amount of bacteria in the wound, silver has been added to the coating of the foam. Silver has been added to many wound dressings and has been

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Fig. 14. A 69-year-old woman with a history of endometrial carcinoma with metastases to the right hip, after hemipelvectomy complicated by complete wound dehiscence: (A) open wound 28 cm 17 cm; (B and C) buttock was pulled up and held together and foam was placed into the remaining open area; (D) 1 month postoperatively; (E) 2 months postoperatively; and (F) 3 months postoperatively. (Color version of figure is available online.)

popular as a treatment for burns.70 Stinner and colleagues investigated this potential therapy by simulating proximal leg wound infections in a goat model; silver dressings were placed beneath negative pressure dressings in complex orthopedic wounds inoculated with bacteria. The authors observed a decline in bacterial load (particularly S. aureus) with this treatment compared with standard MDWT.71 A step further in addressing issues of infection is to modify the foam itself by impregnating the MDWT foam with silver, additional antimicrobial benefits can be conferred. This technique has been used successfully in wound bed preparation for substantial split-thickness skin grafts (STSGs) in the treatment of recalcitrant venous stasis ulcers.28 Instillation MDWT Instillation therapy provides a methodology to intermittently add fluid to the wound through either the same or a different port on the NWPT connecting tubing (Fig 15). It is possible to instill normal saline or other agents to help wound healing such as antimicrobial agents. This has been demonstrated in the sterilization of massive venous stasis wounds before STSG. The authors administered dilute Dakin solution (sodium hypochlorate) for a short period after intermittent cycles of growth-stimulating MDWT. This single-delivery-instill system engineered a unique wound environment that appeared to maximize wound bed preparation.72 Continuousinstillation MDWT is another variation with a second port being connected to a continuousdrip system. Insulin in continuous-instillation MDWT successfully achieves a decrease in time to wound healing.73 Other bioactive factors suggested by Scimeca and colleagues,73 which may be introduced through the continuous-instillation system include doxycycline, dilute Betadine,


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Fig. 15. Instillation VAC. (Color version of figure is available online.)

lactoferrin, and phenytoin. Carefully controlled clinical trials will be needed to better demonstrate the efficacy of this concept.27 Other potential adjuvants Several other possible NPWT methods have been proposed including the use of platelet gel. In the case of a nonhealing ileocutaneous fistula, platelet gel was added to the wound bed after initial NPWT-induced granulation tissue formation. NPWT was then continued, eventually leading to definitive surgical repair.74 Adjunctive administration of activated protein C, an anticoagulant, has also generated positive results where even long-term standard NPWT has failed. In their pilot study, Wijewardena and colleagues administered activated protein C injections into the beds of recalcitrant orthopedic wounds. The authors subsequently observed a successful reduction in wound area and depth, accompanied by significant granulation tissue formation, within only the first week of treatment. Patient tolerance of this treatment regimen was also satisfactory.75 Arginine-rich dietary supplements have also been studied as a nutritional complement to NPWT. This is a subject of interest owing to its potential for improving local circulation at the wound bed. Results indicated that infection-induced wound dehiscence had resolved with complete healing within the first month of treatment, with no evidence of recurrence at 6-month follow-up.76 Other adjuncts, such as Manuka and Leptospermum honeys, have been used in the treatment of an abdominal phlegmonous lesion and a nonhealing postsurgical wound, respectively.77,78 NPWT in the treatment of deep infected wounds Many clinicians have applied NPWT to deep wounds, a situation that has also been studied in a porcine model. Soft tissue blast injuries were simulated in pigs to more thoroughly observe changes in bacterial load following NPWT. Compared with traditional gauze dressings, this study showed that NPWT decreased the bacterial load, blocked infection-induced tissue necrosis, and resulted in earlier initiation of granulation tissue formation.79

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In humans, NPWT has generally been shown to be effective in the control of wound infections. This is particularly true of thoracic and abdominal injuries, and deep wounds, where infection management is paramount in treatment. Although often useful, dressings infused with silver are not always indicated80 or even necessary with NPWT. NPWT systems are able to isolate wounds from the external environment with a drainage system that may be superior to standard surgical drains. NPWT in cases of exposed bone or joints or both Recently, open fractures, particularly of the lower extremity, are frequently being treated with NPWT systems. These systems keep the wound clean from external contamination and keep it moist and warm. In their retrospective cohort study of open tibial fractures, Blum and colleagues compared the rate of deep infection between NPWT and conventional dressing treatment groups (8.4% and 20.6%, respectively). There was nearly 80% reduction in the risk of deep tissue infection after adjustment for multivariate analysis.81 Similarly, in a patient with left knee-joint exposure, the large soft tissue defect was managed by a 20-day course of NPWT. Despite the original severe wound infection (following open reduction and internal fixation of a patellar fracture), a granulated wound bed fully covering the exposed bones and joint was observed after negative pressure treatment.82 NPWT systems are sometimes used as an alternative treatment for lower-extremity wounds with exposed bones or joints or both when free-flap transfer is contraindicated.82,83 NPWT can help to reduce both the need for flap transfer and the size of the flap, as demonstrated in type IIIB open tibial fracture treatment. However, it is worth noting that the authors discouraged the application of negative pressure for a period lasting longer than 7 days owing to the significantly higher rate of infection and the associated risk of amputation.84 Deep sternal wound infection Deep sternal wound infection (DSWI), also known as mediastinitis, is a devastating complication of open heart surgery posing severe risks to patients postoperatively. Without prompt treatment, the mortality rate from this condition can exceed 50%. Traditional packing of sternal wounds often resulted in massive bleeding or chronic draining sinus tracts. In a study cohort of patients with DSWIs, NPWT reduced the risk of early reinfections when used as the first line of therapy. The data were also suggestive of a decrease in the incidence of late chronic sternal infections and mortality.85 Furthermore, meta-analysis assessing the effect of NPWT on sternal infections found the length of hospital stay to decrease by 1 week.86 In the case of methicillin-resistant postcardiotomy DSWIs, MDWT shortened healing time and hospital stay and lowered the recurrence of infection relative to closed mediastinal irrigation with antibiotics.87 Similar to DSWI, poststernotomy osteomyelitis remains a huge concern for patient morbidity, prolonging recovery time, and necessitating surgical reinterventions.88 NPWT does not substitute for adequate debridement and antibiotic therapy when osteomyelitis is present.89,90 NPWT as an augmented surgical drain Deep wound infections can often be associated with the buildup of fluid, either in natural anatomical cavities or in pathologic abscesses. NPWT offers an improved modality for draining these infections, partly by providing a greater suction distribution over a larger surface area than conventional drainage methods. This was shown to help prevent the accumulation of purulent material in the case of a deep neck abscess involving the mediastinum, thereby avoiding the need for open thoracotomy.91 Similarly, for postoperative or recurrent pleural empyema, NPWT used in conjunction with open window thoracostomy can help control sepsis, rapidly eradicating the local infection in most cases. In addition, NPWT therapy has also been used in complex chest wall wounds that facilitated improved lung expansion and eliminated empyema recurrence.92 Deep cavitary defects, particularly those derived from high-velocity projectiles or blast injuries, have also appeared to have benefitted from NPWT. These wounds are unique in that the


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visible superficial tissue defect is often relatively small compared with the underlying injury. NPWT has been combined with conventional draining methods to achieve an optimized therapy for such injuries. In their practice, Rispoli and colleagues connected surgical drains to the base of superficial foam dressings (Fig 16), modifying standard NPWT to convert deep cavitary defects into superficial ones. This generated suction deep in the wound cavity, reducing dead space and edema, thereby reducing the risk of infection. Compared with conventional methods, this allowed the surgeons to minimize further tissue damage to facilitate draining and reduced the risk of deeper cavities closing off, which can occur with traditional VAC therapy.93 Intra-abdominal NPWT The nature of deep intra-abdominal wound infections has made them another potential target for NPWT. A number of such techniques have been documented in medical literature. As a basic principle, NPWT can be used in the abdominal cavity in a manner similar to its use in treating DSWIs. For example, NPWT has been applied following classical laparotomy and necrosectomy for acute necrotizing pancreatitis; the foam dressing placed in the opening created during lesser sac marsupialization (Fig 17). This combination of therapies provided a number of advantages; importantly, improving patient outcome by accelerating abdominal closure (open abdomen associated with increased morbidity and mortality). Other benefits included prevention of abdominal compartment syndrome, improved examination of wound secretions, and simplification of care.94 Other novel approaches to NPWT have been described including the endoscopic placement of a NPWT device to treat anterior rectal wall anastomotic disruptions.95 NPWT and congenital deformities NPWT also may provide an alternative to the management of congenital deformities such as complex gastroschisis96 and giant omphalocele.97 The Food and Drug Administration (FDA)

Fig. 16. NPWT use in deep wound drainage. The fenestrated end of a surgical drain is inserted into a superficial foam dressing, reducing the risk of deep cavity foam adherence without necessitating an increase in superficial wound size. (Color version of figure is available online.)

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Fig. 17. Intra-abdominal MDWT following lesser sac marsupialization. (Modified and reprinted with permission by Wiley from Sermoneta et al.94) Please note that the lumbostomy drains have been omitted in this illustration. (Color version of figure is available online.)

states that: “The safety and effectiveness of NPWT systems in newborns, infants and children has not been established at this time and currently, there are no NPWT systems cleared for use in these populations.”98 Variations of the traditional NPWT systems Closed surgical incisions Recent in vivo and in vitro studies provide some evidence for the use of NPWT in high-risk surgical incisions that are closed primarily, to reduce complications of wound dehiscence, infection, hematoma, and seromas. Preclinical studies have supported this hypothesis, with an in vivo porcine model demonstrating reduced hematoma and seroma levels in clean, closed surgical incisions.99 In a prospective randomized multicenter clinical trial, NPWT applied to closed incisions reduced the relative risk of developing an infection, demonstrating the prophylactic role of topical NPWT.100 Another RCT demonstrated a decreased development of postoperative seromas following incisional NPWT after total hip arthroplasty.101 NPWT has also been shown to decrease the rate of incisional wound dehiscence following abdominal wall reconstruction (9% compared with 39% in the original dressing group).102 FEAs further support the role of NPWT in preventing wound dehiscence. FEA simulations demonstrated a reduction in peri-incisional lateral stress of approximately 50% following NPWT. Additionally, the directions of these stress vectors were seen to mimic the distribution found in intact tissue.103 Such studies have led to the development of commercial systems such as Prevena, designed specifically for incisional wound management. In contrast, Masden and colleagues104 randomized high-risk patients with lower extremity and abdominal wound incisions to VAC therapy or a dressing consisting of a nonadherent layer (Mepitel, Mö lnlycke Health Care AB, Gö teborg, Sweden) and a


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silver dressing (Acticoat, Smith & Nephew, Hull, United Kingdom) and found no statistically significant difference in the rates of infection and dehiscence between the 2 groups. Skin graft immobilization The take of STSGs is governed by many factors including the vascularity of the wound surface, immobilization of the skin graft, and avoidance of infection seroma or hematoma.105 Historically, tie-over bolsters immobilize the graft by applying gentle pressure and are left in place for several days. NPWT has been used by several groups instead of a bolster.106,107 The suction applied to the interface materials stabilizes the graft and eliminates excess fluids.106,107 NPWT improves the contact zone for graft integration, aiding in the processes of plasmatic imbibition and vascularization.105 Several prospective randomized clinical trials have shown the effectiveness of using NPWT systems for skin graft immobilization.105-108 For congested lower extremity pedicle flaps and free flaps without anastomotic thrombosis, NPWT can improve and resolve tissue edema and venous insufficiency, prevent further flap necrosis, and promote granulation, thereby avoiding the risk of further surgical reexplorations.109 In random local flaps prone to ischemia and distal necrosis for complex ankle wounds, NPWT contributes to their viability by decreasing venous congestion.110 In a retrospective study, NPWT was thought to reduce healing complications of large back donor sites used for free flaps for head and neck reconstruction.111 Degloving injuries involve the shearing of skin and subcutaneous tissue from the underlying fascia and muscle, including the avulsion of musculocutaneous and fasciocutaneous perforators.112 If left alone, the degloved skin will predictably die. After excising the degloved skin and removing the fat from the dermis, the skin can then be reapplied to the wound as a fullthickness skin graft. A NPWT device can then be placed on the graft for immobilization.112,113 Combining NPWT with a dermal regeneration template is an additional option and has shown both excellent functional and esthetic results in treating a subtotal degloving injury of the right lower limb. In a case study, Dini and colleagues applied NPWT directly to the wound bed for the first 10 days, providing temporary wound closure and early granulation tissue development. A dermal regeneration template was then applied directly to the wound bed and covered with a NPWT device. Following an additional 21 days of NPWT with Integra, the cryopreserved degloved flap was successfully grafted to the wound site with a NPWT device used to immobilize the graft.114

Part IV—Clinical considerations A wide array of wound types has been reportedly treated with NPWT. The FDA has approved NPWT for managing poorly healing wounds. Manufacturer guidelines for the widely used KCI V.A.C. therapy systems list chronic, acute, traumatic, subacute, and dehisced wounds, partialthickness burns, ulcers (such as diabetic, pressure, or venous insufficiency), flaps and grafts as indications for use.115 Contraindications Because inappropriate use of NPWT devices has the potential for patient harm, the clinician should carefully weigh the risks, benefits, and alternatives of using NPWT. According to the FDA and KCI guidelines, NPWT is contraindicated in conditions involving (1) necrotic tissue with eschar present, (2) untreated osteomyelitis, (3) nonenteric and unexplored fistulas, (4) malignancy in the wound, (5) exposed vasculature, (6) exposed nerves, (7) exposed anastomotic site, and (8) exposed organs.98 In some cases, clinicians have used NPWT despite the established contraindications. For example, some studies have successfully implemented VAC therapy in cases of exposed organs,94 exposed anastomotic sites (Fig 18),116 and osteomyelitis.89 The use of polyurethane foam under vacuum forces can have detrimental effects when in direct contact

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Fig. 18. Treating intra-abdominal abscesses based on the procedure performed by Weidenhagen and colleagues to treat a perianastomotic abscess following anterior rectal resection. MDWT foam is first lead through a guide tube into the abscess, which is then drained by vacuum suction. (Reprinted with permission by Springer from Weidenhagen et al.116) (Color version of figure is available online.)

with exposed neurovasculature, tendons, and organs. Thus, when applying NPWT in close proximity to these structures, a nonadherent barrier layer (petroleum gauze, nonadherent dressings, and oil emulsion dressing) placed over the structure is recommended.11 Sermoneta and colleagues94 described intra-abdominal dressings consisting of the VAC foam placed inside sterile bags (3M Steri-Drape Isolation Bag) with holes cut over their entire surface, allowing fluid absorption while protecting the surrounding tissue.

Patient risk factors and complications Given the broad scope and relative ease of NPWT implementation, potential risk factors must be considered. The FDA has identified a series of patient risk factors and other characteristics that warrant consideration before NPWT. These include the following: (1) high risk of bleeding and hemorrhage; (2) ongoing treatment with anticoagulants or platelet aggregation inhibitors; (3) friable or infected blood vessels, vascular anastomosis, infected wounds, osteomyelitis, exposed organs, vessels, nerves, tendon, or ligaments, sharp edges at the wound, spinal cord injury, and enteric fistulas; (4) patient requires magnetic resonance imaging or hyperbaric chamber or defibrillation; (5) patient weight and size; (6) proximity of foam to vagus nerve; (7) circumferential dressing application; and (8) mode of therapy (continuous or intermittent suction).98,117 Although NPWT has been used in a large number of patients, a variety of complications have been reported in clinical trials. Common complications include bleeding, infection, pain, foam retention within the wound (Fig 19), and tissue adherence. Bleeding and infection occur only rarely,98 but they have sometimes been associated with death. These reports have been most common at home or in long-term-care facilities.98 Much care should be exercised in selecting appropriate patients to use NPWT at home. Other rare complications have also been reported. For example, reports indicate that stomal mucocutaneous dehiscence has been observed in patients with open abdomens, likely caused by tension generated during NPWT, on the proximal bowel of the stoma.118 The interval between dressing changes can also adversely factor into patient outcomes. In a case, necrotizing fasciitis developed during NPWT treatment of a stage IV ischial pressure ulcer. The authors cited the 5 days between VAC system dressing changes as a risk factor, masking rapidly spreading infections long enough to allow for significant complications.119 Blast wounds also present health care providers with a host of potential complications. Caution must be emphasized in treating with NPWT, particularly, as its indiscriminate use may correlate with an increased


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Fig. 19. (A) A 39-year-old man with L-1 partial paralysis and left ischial pressure ulcer, treated with MDWT for 2 months. (B) Foam retention discovered. (C) Healed following removal of foreign body and flap surgery. (Color version of figure is available online.)

incidence of sepsis.120 Treatment of deep cavitary defects resulting from blast injuries may require placing the tail of the foam deep within the cavity, posing an increased risk of foam retention.93 Anticipation of complications, vigilance throughout treatment, and prompt reaction to adverse events would best allow health care teams to successfully mitigate many of the potential risks associated with NPWT. Despite the great interest in these new technologies and the exciting results that many have achieved, NPWT is not a cure for all wounds. When carefully performed studies show no difference in outcomes, clinicians will need to use other criteria, such as cost or patient comfort, to help guide them in their decision as to the best wound therapy to offer a particular patient. As with any wound therapy, if the wound is not progressing, changing to another modality is very often appropriate. Considerations for selection of appropriate NPWT protocol A number of factors should be considered when using NPWT including goal of treatment, suction protocol, and the type of dressing. Granulation tissue growth, edema removal, and flap or graft immobilization, each need different NPWT pressure protocols and treatment duration. For example, a chronic ulcer may benefit from continuous suction for the duration of treatment, whereas in an acute wound, it may be most appropriate to begin with 48 hours of continuous suction, followed by cycles of intermittent therapy (eg, 5 minutes on and 2 minutes off).11 Short, intermittent NPWT has demonstrated a more profound tissue response,50 but it may not be suitable in all cases. Intermittent therapy may not be tolerated because of patient discomfort. The optimal NPWT suction applied to various wounds is not currently known. In our practice, we used less pressure on circumferential wounds and when used in conjunction with a free flap. Clinicians are now presented with a variety of interfaces. Reticulated open-pore foams have the most evidence behind them and have been shown to create tissue microdeformation.12 These foams also have the capacity to transmit suction over long distances. More data are required to best inform surgeons of the optimal interface material for a particular clinical situation. Wounds with an increased risk of infection may require an increased frequency in dressing changes.11 Clinical use: device application Correct placement of the interface material is essential for successful NPWT. We like to cut the foam so that it is slightly smaller than the wound and insert the interface material into all undermined areas or tracks. When possible, we use just 1 interface material that is carefully cut to fill any irregularities in the wound. When more than 1 interface is used, it must to be carefully documented to assure that there are no retained foreign bodies. When granulation tissue is desired, the foam should be placed directly on the wound surface.18 A nonadherent contact layer should be used when granulation tissue is not desired or if the interface is over a luminal structure such as the bowel or large blood vessels. Having the suction port come out at a

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distance from the wound can help minimize the risk of additional pressure necrosis if weight is placed on the tube. A bridging technique where the foam continues from the wound to another location is frequently used for wounds located near the perineum or buttock or undermined wounds with a small skin opening (Fig 20). We avoid placing the foam directly on top of intact skin and prefer to place this over a polyurethane drape or hydrocolloid dressing. The duration of treatment is directed by the goals of the therapy. If the device is used to facilitate granulation tissue formation, either for healing by secondary intention or in preparation for skin graft, the therapy can continue until the granulation tissue has reached the level of the skin. Once at skin level, a skin graft can be placed or another type of wound treatment can be initiated to complete the healing process. If the goal is wound contraction for flap surgery, for example, therapy should be stopped once there are no changes in wound measurements after 1-2 weeks. Similarly, if the device is being used to accelerate healing of a surgical wound, it should be discontinued once there is no progress. In our practice, we rarely continue NPWT for more than 3 months. Adverse effects directly attributable to long-term use of the device include skin irritation from the adhesive drape and odor from the dressing or canister or both. They can be mitigated by a brief interruption of therapy for a few days. Skin breakdown can be treated with topical creams or ointments, depending on the etiology of the dermatitis, and wound odor can be treated by packing the wound with saline gauze dressings or dilute bleach solution (Dakin) for 48-72 hours. Once adverse effects have abated, NPWT can be resumed. Not all wounds are amenable to a NPWT device. Some patients do not tolerate the therapy because of pain or sensitivity to the adhesive drape or the foam. Pain may be relieved by decreasing the pressure on the device. If the pain appears to be associated with the surrounding skin, the wound can be framed with a hydrocolloid dressing and the adhesive drape placed over the hydrocolloid. This may decrease the pull and pressure on the skin. If the pain appears to be exacerbated by the foam contacting the skin edges, a nonadherent dressing can be applied just covering the skin edges. The adhesive drape may not stay sealed around wounds near the rectum or over excessive folds in the skin. A hydrocolloid dressing or stoma adhesive can be placed on the skin to fill in irregularities affecting the seal. Tissue integrity should be carefully monitored with each dressing change. If bruising or hematomas are observed, first the pressure is lowered. If they persist, the device should be discontinued. On occasion, the wound bed can become a dusky gray or light pink color. The pressure can be lowered but the device should be removed if the wound bed appears ischemic.

Part V—Future perspectives Interface material Foam pore size has been shown to be directly related to the amount of granulation tissue formation. Larger pores stimulate more granulation tissue formation in a diabetic mouse model.121 Other interface materials such as polyvinyl alcohol sponges with small pores are

Fig. 20. Bridged dressing following dehisced c-section wound. (Color version of figure is available online.)


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nonadherent, with little tissue ingrowth. Several authors have instilled a variety of solutions into these devices, which may be effective, particularly when treating wounds with high bioburden of bacteria.27 Optimal cycling Most biological systems have a more robust response when subjected to variable rather than continuous mechanical forces. In a preclinical model, we found that applying NPWT for 4 hours every 2 days gave a similar granulation tissue response as continuous therapy. Surprisingly, when faster cycle times were used, there was less granulation tissue formed, suggesting that too fast of a cycle time may damage nascent granulation tissue.35,122,123 Adhesives Current devices are often limited to obtaining a good seal at the edges of the device, making it difficult to maintain suction. Advances in adhesive science to allow better adhesion around curved and moist surfaces would make the device more easily applied to difficult wounds.

Summary The efficacy of NPWT in promoting wound healing has been largely accepted by clinicians, yet the number of high-level clinical studies demonstrating its effectiveness is small and much more can be learned about the mechanisms of action. In the future, hopefully we will have the data to assist clinicians in selecting optimal parameters for specific wounds including interface material, waveform of suction application, and the amount of suction to be applied. Further investigation into specific interface coatings and instillation therapy are also needed. We believe that advances in mechanobiology, the science of wound healing, the understanding of biofilms, and advances in cell therapy will lead to better care for our patients. References 1. Schaum KD. A new Medicare part B wound care policy. Adv Skin Wound Care. 2001;14(5):238–240. 2. Orgill DP, Bayer L, Neuwalder J, Felter R. Microdeformational Wound Therapy—A New Era in Wound Healing. Business Briefing: Global Surgery—Future Directions. 2005:1-3. 3. Argenta LC, Morykwas MJ. Vacuum-assisted closure: a new method for wound control and treatment: clinical experience. Ann Plast Surg. 1997;38(6):563–576. [discussion 577]. 4. Meyer W, Schmieden V, Gustav Bier AK. Bier's hyperemic treatment. Surgery, Medicine, and the Specialties: A Manual of its Practical Application.Philadelphia and London: W.B. Saunders Company; 1908. 5. Neumann CG. The expansion of an area of skin by progressive distention of a subcutaneous balloon; use of the method for securing skin for subtotal reconstruction of the ear. Plast Reconstr Surg (1946). 1957;19(2):124–130. 6. Morykwas MJ, Argenta LC, Shelton-Brown EI, McGuirt W. Vacuum-assisted closure: a new method for wound control and treatment: animal studies and basic foundation. Ann Plast Surg. 1997;38(6):553–562. 7. Lancerotto L, Bayer LR, Orgill DP. Mechanisms of action of microdeformational wound therapy. Semin Cell Dev Biol. 2012;23(9):987–992. 8. Kairinos N, Solomons M, Hudson DA. Negative pressure wound therapy I: the paradox of negativ-pressure wound therapy. Plast Reconstr Surg. 2008;123:589–598. 9. Saxena V, Orgill D, Kohane I. A set of genes previously implicated in the hypoxia response might be an important modulator in the rat ear tissue response to mechanical stretch. BMC Genomics. 2007;8:430. 10. Frequently asked questions about V.A.C.s Therapy. 〈http://middleeast.kci-medical.com/ME-ENG/vacfaqs〉; 2013 [accessed 10.02.2014]. 11. Mendez-Eastman S. Guidelines for using negative pressure wound therapy. Adv Skin Wound Care. 2001;14(6): 314–322. [quiz 324-315]. 12. Orgill DP, Manders EK, Sumpio BE, et al. The mechanisms of action of vacuum assisted closure: more to learn. Surgery. 2009;146(1):40–51. 13. Scherer SS, Pietramaggiori G, Mathews JC, Prsa MJ, Huang S, Orgill DP. The mechanism of action of the vacuumassisted closure device. Plast Reconstr Surg. 2008;122(3):786–797. 14. Borgquist O, Ingemansson R, Malmsjo M. The influence of low and high pressure levels during negative-pressure wound therapy on wound contraction and fluid evacuation. Plast Reconstr Surg. 2011;127(2):551–559.

328


15. Kairinos N, Solomons M, Hudson DA. The paradox of negative pressure wound therapy–in vitro studies. J Plast Reconstr Aesthet Surg. 2010;63(1):174–179. 16. Anesater E, Borgquist O, Hedstrom E, Waga J, Ingemansson R, Malmsjo M. The influence of different sizes and types of wound fillers on wound contraction and tissue pressure during negative pressure wound therapy. Int Wound J. 2011;8(4):336–342. 17. Kairinos N, Hudson DA, Solomons M. The influence of different sizes and types of wound fillers on wound contraction and tissue pressure during negative pressure wound therapy. Int Wound J. 2011;8(6):656–657. 18. Saxena V, Hwang CW, Huang S, Eichbaum Q, Ingber D, Orgill DP. Vacuum-assisted closure: microdeformations of wounds and cell proliferation. Plast Reconstr Surg. 2004;114(5):1086–1096. [discussion 1097-1088]. 19. Ingber DE, Levin M. What lies at the interface of regenerative medicine and developmental biology? Development. 2007;134(14):2541–2547. 20. McLeod KJ, Lee RC, Ehrlich HP. Frequency dependence of electric field modulation of fibroblast protein synthesis. Science. 1987;236(4807):1465–1469. 21. Yang CC, Chang DS, Webb LX. Vacuum-assisted closure for fasciotomy wounds following compartment syndrome of the leg. J Surg Orthop Adv. 2006;15(1):19–23. 22. Adamkova M, Tymonova J, Zamecnikova I, Kadlcik M, Klosova H. First experience with the use of vacuum assisted closure in the treatment of skin defects at the burn center. Acta Chir Plast. 2005;47(1):24–27. 23. Labanaris AP, Polykandriotis E, Horch RE. The effect of vacuum-assisted closure on lymph vessels in chronic wounds. J Plast Reconstr Aesthet Surg. 2009;62(8):1068–1075. 24. Winter GD, Scales JT. Effect of air drying and dressings on the surface of a wound. Nature. 1963;197:91–92. 25. Winter GD. Formation of the scab and the rate of epithelization of superficial wounds in the skin of the young domestic pig. Nature. 1962;193:293–294. 26. Hinman CD, Maibach H. Effect of air exposure and occlusion on experimental human skin wounds. Nature. 1963;200:377–378. 27. Kim PJ, Attinger CE, Steinberg JS, et al. Negative-pressure wound therapy with instillation: international consensus guidelines. Plast Reconstr Surg. 2013;132(6):1569–1579. 28. Gerry R, Kwei S, Bayer L, Breuing KH. Silver-impregnated vacuum-assisted closure in the treatment of recalcitrant venous stasis ulcers. Ann Plast Surg. 2007;59(1):58–62. 29. Orgill DP, Blanco C. Biomaterials for Treating Skin Loss. Boca Raton, FL: CRC Press; 2009. 30. Nuutila K, Siltanen A, Peura M, et al. Gene expression profiling of negative-pressure-treated skin graft donor site wounds. Burns. 2013;39(4):687–693. 31. Ingber DE. The mechanochemical basis of cell and tissue regulation. Mech Chem Biosyst. 2004;1(1):53–68. 32. Alford PW, Nesmith AP, Seywerd JN, Grosberg A, Parker KK. Vascular smooth muscle contractility depends on cell shape. Integr Biol. 2011;3(11):1063–1070. 33. Chen CS, Mrksich M, Huang S, Whitesides GM, Ingber DE. Geometric control of cell life and death. Science. 1997;276 (5317):1425–1428. 34. Ingber DE. Mechanical control of tissue growth: function follows form. Proc Natl Acad Sci U S A. 2005;102(33): 11571–11572. 35. Scherer SS, Pietramaggiori G, Mathews JC, Orgill DP. Short periodic applications of the vacuum-assisted closure device cause an extended tissue response in the diabetic mouse model. Plast Reconstr Surg. 2009;124(5): 1458–1465. 36. Huang S, Ingber DE. The structural and mechanical complexity of cell-growth control. Nat Cell Biol. 1999;1(5): E131–E138. 37. Baldwin C, Potter M, Clayton E, Irvine L, Dye J. Topical negative pressure stimulates endothelial migration and proliferation: a suggested mechanism for improved integration of Integra. Ann Plast Surg. 2009;62(1):92–96. 38. Potter MJ, Banwell P, Baldwin C, et al. In vitro optimisation of topical negative pressure regimens for angiogenesis into synthetic dermal replacements. Burns. 2008;34(2):164–174. 39. McNulty AK, Schmidt M, Feeley T, Kieswetter K. Effects of negative pressure wound therapy on fibroblast viability, chemotactic signaling, and proliferation in a provisional wound (fibrin) matrix. Wound Repair Regen. 2007;15(6): 838–846. 40. Lu F, Ogawa R, Nguyen DT, et al. Microdeformation of three-dimensional cultured fibroblasts induces gene expression and morphological changes. Ann Plast Surg. 2011;66(3):296–300. 41. Engler AJ, Sen S, Sweeney HL, Discher DE. Matrix elasticity directs stem cell lineage specification. Cell. 2006;126(4): 677–689. 42. Erba P, Ogawa R, Ackermann M, et al. Angiogenesis in wounds treated by microdeformational wound therapy. Ann Surg. 2011;253(2):402–409. 43. Wackenfors A, Sjogren J, Gustafsson R, Algotsson L, Ingemansson R, Malmsjo M. Effects of vacuum-assisted closure therapy on inguinal wound edge microvascular blood flow. Wound Repair Regen. 2004;12(6):600–606. 44. Greene AK, Puder M, Roy R, et al. Microdeformational wound therapy: effects on angiogenesis and matrix metalloproteinases in chronic wounds of 3 debilitated patients. Ann Plast Surg. 2006;56(4):418–422. 45. Younan GJ, Heit YI, Dastouri P, et al. Mast cells are required in the proliferation and remodeling phases of microdeformational wound therapy. Plast Reconstr Surg. 2011;128(6):649e–658e. 46. Ingber DE. Tensegrity-based mechanosensing from macro to micro. Prog Biophys Mol Biol. 2008;97(2-3):163–179. 47. Ingber DE. Mechanobiology and diseases of mechanotransduction. Ann Med. 2003;35(8):564–577. 48. Huang C, Ogawa R. Fibroproliferative disorders and their mechanobiology. Connect Tissue Res. 2012;53(3):187–196. 49. Wilkes RP, McNulty AK, Feeley TD, Schmidt MA, Kieswetter K. Bioreactor for application of subatmospheric pressure to three-dimensional cell culture. Tissue Eng. 2007;13(12):3003–3010. 50. Younan G, Ogawa R, Ramirez M, Helm D, Dastouri P, Orgill DP. Analysis of nerve and neuropeptide patterns in vacuum-assisted closure-treated diabetic murine wounds. Plast Reconstr Surg. 2010;126(1):87–96.


329

51. Torbrand C, Wackenfors A, Lindstedt S, Ekman R, Ingemansson R, Malmsjo M. Sympathetic and sensory nerve activation during negative pressure therapy of sternotomy wounds. Interact Cardiovasc Thorac Surg. 2008;7(6): 1067–1070. 52. Barker AR, Rosson GD, Dellon AL. Wound healing in denervated tissue. Ann Plast Surg. 2006;57(3):339–342. 53. Morykwas MJ, Simpson J, Punger K, Argenta A, Kremers L, Argenta J. Vacuum-assisted closure: state of basic research and physiologic foundation. Plast Reconstr Surg. 2006;117(suppl 7):121S–126S. 54. Assadian O, Assadian A, Stadler M, Diab-Elschahawi M, Kramer A. Bacterial growth kinetic without the influence of the immune system using vacuum-assisted closure dressing with and without negative pressure in an in vitro wound model. Int Wound J. 2010;7(4):283–289. 55. Moues CM, Vos MC, van den Bemd GJ, Stijnen T, Hovius SE. Bacterial load in relation to vacuum-assisted closure wound therapy: a prospective randomized trial. Wound Repair Regen. 2004;12(1):11–17. 56. Yusuf E, Jordan X, Clauss M, Borens O, Mader M, Trampuz A. High bacterial load in negative pressure wound therapy (NPWT) foams used in the treatment of chronic wounds. Wound Repair Regen. 2013;21(5):677–681. 57. Joseph E, Hamori CA, Bergman S, Roaf E, Swann NF, Anastasi GW. A prospective, randomized trial of vacuumassisted closure versus standard therapy of chronic nonhealing wounds. Wounds. 2000;12:60–67. 58. Schwien T, Gilbert J, Lang C. Pressure ulcer prevalence and the role of negative pressure wound therapy in home health quality outcomes. Ostomy Wound Manage. 2005;51(9):47–60. 59. Nakayama M. Applying negative pressure therapy to deep pressure ulcers covered by soft necrotic tissue. Int Wound J. 2010;7(3):160–166. 60. Yao M, Fabbi M, Hayashi H, et al. A retrospective cohort study evaluating efficacy in high-risk patients with chronic lower extremity ulcers treated with negative pressure wound therapy. Int Wound J. 2012, doi: 10.1111/j.1742-481X. 2012.01113.x. 61. Nather A, Hong NY, Lin WK, Sakharam JA. Effectiveness of bridge V.A.C. dressings in the treatment of diabetic foot ulcers. Diabet Foot Ankle. 2011;2:5893. 62. Ulusal AE, Sahin MS, Ulusal B, Cakmak G, Tuncay C. Negative pressure wound therapy in patients with diabetic foot. Acta Orthop Traumatol Turc. 2011;45(4):254–260. 63. Patel RM, Nagle DJ. Nonoperative management of scleroderma of the hand with tadalafil and subatmospheric pressure wound therapy: case report. J Hand Surg. 2012;37(4):803–806. 64. Zutt M, Haas E, Kruger U, Distler M, Neumann C. Successful use of vacuum-assisted closure therapy for leg ulcers caused by occluding vasculopathy and inflammatory vascular diseases—a case series. Dermatology. 2007;214(4): 319–324. 65. Oh BH, Lee SH, Nam KA, Lee HB, Chung KY. Comparison of negative pressure wound therapy and secondary intention healing after excision of acral lentiginous melanoma on the foot. Br J Dermatol. 2013;168(2):333–338. 66. Katz MS, Finck CM, Schwartz MZ, et al. Vacuum-assisted closure in the treatment of extensive lymphangiomas in children. J Pediatr Surg. 2012;47(2):367–370. 67. Heit YI, Lancerotto L, Cortes R, et al. Early kinetics of integration of collagen-glycosaminoglycan regenerative scaffolds in a diabetic mouse model. Plast Reconstr Surg. 2013;132(5):767e–776e. 68. Kang GC, Por YC, Tan BK. In vivo tissue engineering over wounds with exposed bone and tendon: autologous dermal grafting and vacuum-assisted closure. Ann Plast Surg. 2010;65(1):70–73. 69. Bloemen MC, van der Wal MB, Verhaegen PD, et al. Clinical effectiveness of dermal substitution in burns by topical negative pressure: a multicenter randomized controlled trial. Wound Repair Regen. 2012;20(6):797–805. 70. Khundkar R, Malic C, Burge T. Use of Acticoat dressings in burns: what is the evidence? Burns. 2010;36(6):751–758. 71. Stinner DJ, Waterman SM, Masini BD, Wenke JC. Silver dressings augment the ability of negative pressure wound therapy to reduce bacteria in a contaminated open fracture model. J Trauma. 2011;71(suppl 1):S147–S150. 72. Raad W, Lantis 2nd JC, Tyrie L, Gendics C, Todd G. Vacuum-assisted closure instill as a method of sterilizing massive venous stasis wounds prior to split thickness skin graft placement. Int Wound J. 2010;7(2):81–85. 73. Scimeca CL, Bharara M, Fisher TK, Kimbriel H, Mills JL, Armstrong DG. Novel use of insulin in continuous-instillation negative pressure wound therapy as “wound chemotherapy”. J Diabetes Sci Technol. 2010;4(4):820–824. 74. Scala M, Spagnolo F, Trapasso M, Strada P, Moresco L, Santi P. Association of vacuum-assisted closure and platelet gel for the definitive surgical repair of an enterocutaneous fistula: a case report. In Vivo. 2012;26(1):147–150. 75. Wijewardena A, Vandervord E, Lajevardi SS, Vandervord J, Jackson CJ. Combination of activated protein C and topical negative pressure rapidly regenerates granulation tissue over exposed bone to heal recalcitrant orthopedic wounds. Int J Low Extrem Wounds. 2011;10(3):146–151. 76. Masumoto K, Nagata K, Oka Y, et al. Successful treatment of an infected wound in infants by a combination of negative pressure wound therapy and arginine supplementation. Nutrition. 2011;27(11-12):1141–1145. 77. Rudzka-Nowak A, Luczywek P, Gajos MJ, Piechota M. Application of manuka honey and GENADYNE A4 negative pressure wound therapy system in a 55-year-old woman with extensive phlegmonous and necrotic lesions in the abdominal integuments and lumbar region after traumatic rupture of the colon. Med Sci Monit. 2010;16(11): CS138–CS142. 78. Ganacias-Acuna EF. Active Leptospermum honey and negative pressure wound therapy for nonhealing postsurgical wounds. Ostomy Wound Manage. 2010;56(3):10–12. 79. Li J, Topaz M, Tan H, et al. Treatment of infected soft tissue blast injury in swine by regulated negative pressure wound therapy. Ann Surg. 2013;257(2):335–344. 80. International Concensus. Appropriate use of silver dressings in wounds. An expert working group concensus. London 2012. 81. Blum ML, Esser M, Richardson M, Paul E, Rosenfeldt FL. Negative pressure wound therapy reduces deep infection rate in open tibial fractures. J Orthop Trauma. 2012;26(9):499–505. 82. Lee SY, Niikura T, Miwa M, et al. Negative pressure wound therapy for the treatment of infected wounds with exposed knee joint after patellar fracture. Orthopedics. 2011;34(6):211.

330


83. Barnett TM, Shilt JS. Use of vacuum-assisted closure and a dermal regeneration template as an alternative to flap reconstruction in pediatric grade IIIB open lower-extremity injuries. Am J Orthop. 2009;38(6):301–305. 84. Hou Z, Irgit K, Strohecker KA, et al. Delayed flap reconstruction with vacuum-assisted closure management of the open IIIB tibial fracture. J Trauma. 2011;71(6):1705–1708. 85. Steingrimsson S, Gottfredsson M, Gudmundsdottir I, Sjogren J, Gudbjartsson T. Negative-pressure wound therapy for deep sternal wound infections reduces the rate of surgical interventions for early re-infections. Interact Cardiovasc Thorac Surg. 2012;15(3):406–410. 86. Damiani G, Pinnarelli L, Sommella L, et al. Vacuum-assisted closure therapy for patients with infected sternal wounds: a meta-analysis of current evidence. J Plast Reconstr Aesthet Surg. 2011;64(9):1119–1123. 87. De Feo M, Vicchio M, Nappi G, Cotrufo M. Role of vacuum in methicillin-resistant deep sternal wound infection. Asian Cardiovasc Thorac Ann. 2010;18(4):360–363. 88. Doss M, Martens S, Wood JP, Wolff JD, Baier C, Moritz A. Vacuum-assisted suction drainage versus conventional treatment in the management of poststernotomy osteomyelitis. Eur J Cardiothorac Surg. 2002;22(6):934–938. 89. Tocco MP, Ballardini M, Masala M, Perozzi A. Post-sternotomy chronic osteomyelitis: is sternal resection always necessary? Eur J Cardiothorac Surg. 2013;43(4):715–721. 90. Tocco MP, Costantino A, Ballardini M, et al. Improved results of the vacuum assisted closure and Nitinol clips sternal closure after postoperative deep sternal wound infection. Eur J Cardiothorac Surg. 2009;35(5):833–838. 91. Gallo O, Deganello A, Meccariello G, Spina R, Peris A. Vacuum-assisted closure for managing neck abscesses involving the mediastinum. Laryngoscope. 2012;122(4):785–788. 92. Sziklavari Z, Grosser C, Neu R, et al. Complex pleural empyema can be safely treated with vacuum-assisted closure. J Cardiothorac Surg. 2011;6:130. 93. Rispoli DM, Horne BR, Kryzak TJ, Richardson MW. Description of a technique for vacuum-assisted deep drains in the management of cavitary defects and deep infections in devastating military and civilian trauma. J Trauma. 2010;68(5):1247–1252. 94. Sermoneta D, Di Mugno M, Spada PL, et al. Intra-abdominal vacuum-assisted closure (VAC) after necrosectomy for acute necrotising pancreatitis: preliminary experience. Int Wound J. 2010;7(6):525–530. 95. Bemelman WA. Vacuum assisted closure in coloproctology. Tech Coloproctol. 2009;13(4):261–263. 96. Choi WW, McBride CA, Kimble RM. Negative pressure wound therapy in the management of neonates with complex gastroschisis. Pediatr Surg Int. 2011;27(8):907–911. 97. Kilbride KE, Cooney DR, Custer MD. Vacuum-assisted closure: a new method for treating patients with giant omphalocele. J Pediatr Surg. 2006;41(1):212–215. 98. FDA Safety Communication: UPDATE on Serious Complications Associated with Negative Pressure Wound Therapy Systems [webpage]. 〈http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/ucm244211.htm〉; 2011 [accessed 25.02.2014]. 99. Kilpadi DV, Cunningham MR. Evaluation of closed incision management with negative pressure wound therapy (CIM): hematoma/seroma and involvement of the lymphatic system. Wound Repair Regen. 2011;19(5):588–596. 100. Stannard JP, Volgas DA, McGwin 3rd G, et al. Incisional negative pressure wound therapy after high-risk lower extremity fractures. J Orthop Trauma. 2012;26(1):37–42. 101. Pachowsky M, Gusinde J, Klein A, et al. Negative pressure wound therapy to prevent seromas and treat surgical incisions after total hip arthroplasty. Int Orthop. 2012;36(4):719–722. 102. Conde-Green A, Chung TL, Holton 3rd LH, et al. Incisional negative-pressure wound therapy versus conventional dressings following abdominal wall reconstruction: a comparative study. Ann Plast Surg. 2013;71(4):394–397. 103. Wilkes RP, Kilpad DV, Zhao Y, Kazala R, McNulty A. Closed incision management with negative pressure wound therapy (CIM): biomechanics. Surg Innov. 2012;19(1):67–75. 104. Masden D, Goldstein J, Endara M, Xu K, Steinberg J, Attinger C. Negative pressure wound therapy for at-risk surgical closures in patients with multiple comorbidities: a prospective randomized controlled study. Ann Surg. 2012;255 (6):1043–1047. 105. Llanos S, Danilla S, Barraza C, et al. Effectiveness of negative pressure closure in the integration of split thickness skin grafts: a randomized, double-masked, controlled trial. Ann Surg. 2006;244(5):700–705. 106. Petkar KS, Dhanraj P, Kingsly PM, et al. A prospective randomized controlled trial comparing negative pressure dressing and conventional dressing methods on split-thickness skin grafts in burned patients. Burns. 2011;37(6): 925–929. 107. Azzopardi EA, Boyce DE, Dickson WA, et al. Application of topical negative pressure (vacuum-assisted closure) to split-thickness skin grafts: a structured evidence-based review. Ann Plast Surg. 2013;70(1):23–29. 108. Moisidis E, Heath T, Boorer C, Ho K, Deva AK. A prospective, blinded, randomized, controlled clinical trial of topical negative pressure use in skin grafting. Plast Reconstr Surg. 2004;114(4):917–922. 109. Vaienti L, Gazzola R, Benanti E, et al. Failure by congestion of pedicled and free flaps for reconstruction of lower limbs after trauma: the role of negative-pressure wound therapy. J Orthop Traumatol. 2013;14(3):213–217. 110. Goldstein JA, Iorio ML, Brown B, Attinger CE. The use of negative pressure wound therapy for random local flaps at the ankle region. J Foot Ankle Surg. 2010;49(6):513–516. 111. Schmedes GW, Banks CA, Malin BT, Srinivas PB, Skoner JM. Massive flap donor sites and the role of negative pressure wound therapy. Otolaryngol Head Neck Surg. 2012;147(6):1049–1053. 112. Meara JG, Guo L, Smith JD, Pribaz JJ, Breuing KH, Orgill DP. Vacuum-assisted closure in the treatment of degloving injuries. Ann Plast Surg. 1999;42(6):589–594. 113. Morris M, Schreiber MA, Ham B. Novel management of closed degloving injuries. J Trauma. 2009;67(4):E121–E123. 114. Dini M, Quercioli F, Mori A, Romano GF, Lee AQ, Agostini T. Vacuum-assisted closure, dermal regeneration template and degloved cryopreserved skin as useful tools in subtotal degloving of the lower limb. Injury. 2012;43(6): 957–959. 115. V.A.C.s Therapy Forms and Brochures. 〈http://www.kci1.com/KCI1/vactherapyformsandbrochures〉 [accessed 25.02.2014].


331

116. Weidenhagen R, Gruetzner KU, Wiecken T, Spelsberg F, Jauch KW. Endoscopic vacuum-assisted closure of anastomotic leakage following anterior resection of the rectum: a new method. Surg Endosc. 2008;22(8): 1818–1825. 117. V.A.C. Therapy Indications and Contraindications. 〈http://kci1.com/KCI1/indicationsandcontraindications〉 [accessed 25.02.2014]. 118. Steenvoorde P, den Outer A, Neijenhuis P. Stomal mucocutaneous dehiscence as a complication of topical negative pressure used to treat an open abdomen: a case series. Ostomy Wound Manage. 2009;55(6):44–48. 119. Citak M, Backhaus M, Meindl R, Muhr G, Fehmer T. Rare complication after VAC-therapy in the treatment of deep sore ulcers in a paraplegic patient. Arch Orthop Trauma Surg. 2010;130(12):1511–1514. 120. Marsh DJ, Abu-Sitta G, Patel H. The role of vacuum-assisted wound closure in blast injury. Plast Reconstr Surg. 2007;119(6):1978–1979. 121. Heit YI, Dastouri P, Helm DL, et al. Foam pore size is a critical interface parameter of suction-based wound healing devices. Plast Reconstr Surg. 2012;129(3):589–597. 122. Dastouri P, Helm DL, Scherer SS, Pietramaggiori G, Younan G, Orgill DP. Waveform modulation of negative-pressure wound therapy in the murine model. Plast Reconstr Surg. 2011;127(4):1460–1466. 123. Malmsjo M, Gustafsson L, Lindstedt S, Gesslein B, Ingemansson R. The effects of variable, intermittent, and continuous negative pressure wound therapy, using foam or gauze, on wound contraction, granulation tissue formation, and ingrowth into the wound filler. Eplasty. 2012;12:e5.