Effect of negative pressure wound therapy on wound healing

Effect of negative pressure wound therapy on wound healing

Author's Accepted Manuscript Impact of negative pressure wound therapy on wound healing Chenyu Huang M.D., Ph.D., Tripp Leavitt B.A., B. S., Lauren R...

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Author's Accepted Manuscript

Impact of negative pressure wound therapy on wound healing Chenyu Huang M.D., Ph.D., Tripp Leavitt B.A., B. S., Lauren R. Bayer P.A.-C., Dennis P. Orgill M.D., Ph.D.

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S0011-3840(14)00084-7 http://dx.doi.org/10.1067/j.cpsurg.2014.04.001 YMSG453

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Current Problems in Surgery

Cite this article as: Chenyu Huang M.D., Ph.D., Tripp Leavitt B.A., B.S., Lauren R. Bayer P.A.-C., Dennis P. Orgill M.D., Ph.D., Impact of negative pressure wound therapy on wound healing, Current Problems in Surgery, http://dx.doi.org/10.1067/j. cpsurg.2014.04.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Impact of Negative Pressure Wound Therapy on Wound Healing Chenyu Huang1,2, M.D., Ph.D., Tripp Leavitt1,3, B.A., B.S., Lauren R. Bayer4, P.A.-C., Dennis P. Orgill1,4, M.D., Ph.D.

1 Division of Plastic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA 2 Department of Plastic Surgery, Meitan General Hospital, Hebei United University, Beijing 100028, China 3 Boston University School of Medicine, Boston MA, USA 4 Ambulatory Treatment Room and Wound Care Center, Brigham and Women’s Hospital, Boston, MA, USA

Corresponding author: Dennis P. Orgill, M.D., Ph.D. Professor of Surgery, Harvard Medical School Vice Chairman for Quality Improvement Department of Surgery, Brigham and Women's Hospital 75 Francis St. Boston, MA 02115 Tel: 617-732-5456 Email: [email protected] 1 

Table of Contents IMPACT OF LOCALIZED PRESSURE DIFFERENTIALS ON WOUND HEALING PART I – HISTORY OF NEGATIVE PRESSURE THERAPY The VAC System PART II – MECHANISMS OF ACTION Primary Mechanisms: Macrodeformation: Microdeformation: Fluid Removal Alteration of the Wound Environment Secondary Effects: Hemostasis Modulation of Inflammation Cellular Responses – Division, Migration, and Differentiation Angiogenesis Granulation Tissue Formation Peripheral Nerve Response Alterations in Bioburden PART III – CLINICAL APPLICATIONS OF NPWT Open Wounds Basic Applications of NPWT

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Skin graft and dermal scaffold recipient site preparation Combination Therapy – Incorporating Bioactive Factors in NPWT Antimicrobial Silver in NPWT Instillation MDWT Other Potential Adjuvants NPWT in the Treatment of Deep Infected Wounds NPWT in Cases of Exposed Bone and/or Joints Deep Sternal Wound Infection NPWT as an Augmented Surgical Drain Intra-abdominal MDWT NPWT and Congenital Deformities Variations on the Traditional NPWT System Closed Surgical Incisions Skin Graft Immobilization PART IV – CLINICAL CONSIDERATIONS Contraindications Patient Risk Factors and Complications Considerations for Selection of Appropriate NPWT Protocol Clinical Use: Device Application PART V – FUTURE PERSPECTIVES Interface Material

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Optimal cycling Adhesives FIGURE LEGENDS REFERENCES

Impact of Localized Pressure Differentials on Wound Healing 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 Negative Pressure Wound Care (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 Microdeformational Wound Therapy (MDWT).2 A specific commercial device that has had a large market penetration and has been used in the majority of clinical studies to date is referred to as Vaccum Assisted Closure or VAC® , based on the pioneering work of Argenta and Morykwas (Figure 3).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 tissue, cellular, and molecular levels. 4 

Part I – History of negative pressure therapy Suction has been utilized 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 to collapse the pleural space. Excessive suction can damage tissues 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 (< 40 mmHg). 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 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, Neuman described the use of a rubber balloon to expand the skin for the purpose of covering exposed cartilage.5 Radovan and Austad both developed tissue expanders in 1975, which led 5 

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 utilizing 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 (e.g. 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 non-pharmacologic strategy. Its modulation of the healing process relies on a class of devices based/engineered on the concept of wound suction. In 1997, Argenta and Morykwas, first described applying controlled suction through open-cell 6 

foam to create an environment conducive to healing and granulation tissue formation.3,6 This device was one of several developed by their group that uses suction to treat wounds, which they defined as negative pressure wound therapy (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, dome-like structures at the wound surface that cause microdeformations to the wound surface. Therefore, we use the term microdeformational wound therapy (MDWT) for devices that deform wounds on the micron to millimeter scale, incurring morphological 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 Vacuum Assisted Closure (VAC) system is a relatively new technology in wound management. The general system is made up of 4 major components: (1) a filler material/sponge placed into the wound; (2) a semi-permeable dressing to isolate the wound environment and allow the vacuum system to transmit subatmospheric pressures to the wound surface; (3) a connecting tube; and (4) and a vacuum system (Figure 3). A fluid 7 

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. Though different materials may be used with various NPWT devices, a reticulated, open pore foam is the most common. This foam is made up of many cells/bubbles that are highly interconnected. This structure, as the name suggests, resembles a three-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.

As part of the commercial VAC system, three general types of foam are available, black polyurethane ether (VAC® GranuFoam™, KCI), black polyurethane ester (VAC® VeraFlow™, KCI) and white polyvinyl alcohol (VAC® 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 8 

blood vessels, need to be protected. Finally, the increased density and smaller pores of the white foam help to restrict in-growth of granulation tissue, 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 will be 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, semi-occlusive 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. Four 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 (Figures 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, 9 

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 mmHg suction can decrease the foam volume by around 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 cause 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 10 

is virtually 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 increases with elevated suction. These extracellular pressure changes also vary with distance from the foam-wound interface and the time period of treatment (Figure 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 Pm, and set in motion a host of other effects that aid in the healing process. To better understand the micro-mechanical 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 our model indicates that at 110 mmHg, MDWT application using typical foam pore sizes causes an average tissue strain of 5-20% over the majority of the wound surface. Quantitatively, tissue strain corresponds to the percent 11 

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 extracellular matrix. 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, as well as 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). Finite element analysis has demonstrated that tissue immediately below the foam struts experiences compression while 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 morphological result of these integrated mechanics. Cell shape has been demonstrated to be a determinant of cellular function.19 Additionally, cells are known to adapt to physical stresses.20 Therefore, changes in cellular functions can be initiated by these dynamic physical inputs. This concept will be discussed in greater detail with regard to the secondary effects of NPWT action.

Fluid Removal Fluids in the body have been classically divided between three compartments: 1) intravascular, 2) intracellular and 3) extracellular. Fluid transport between these compartments are primarily governed by the Starling equation which takes into account the 12 

hydrostatic and osmotic pressure differentials across semi-permeable 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 build-up is commonly accepted as a contravening factor in healing, in part due to the compressive effect it can exert on local cells and tissues. Individual cells generate intrinsic tension via their cytoskeleton and interactions with the extracellular matrix, inducing a proliferative response.12 Elevated fluid pressures in the interstitium diminish this response by dampening intrinsic tension build-up. Fluids from the extracellular space appear to communicate with the wound surface. Applying a 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 (Figure 5).3,22 The polyurethane drape is semipermeable, allowing a small amount of air to enter the system preventing a fluid lock and allowing continuous evacuation of fluid. NPWT also likely reduces the amount of fluids that need to be cleared through the lymphatic system. Toxins from the wound, bacteria and 13 

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. Additionally, MDWT induces a gradual increase in lymphatic density at wound edges, improving drainage (Figure 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 semi-occlusive drape act as thermal insulators to maintain wound warmth.24 The semi-occlusive 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. Additionally, the drape exhibits limited permeability to water vapor and other gases, helping to maintain a stable, moist wound environment.24-26

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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 two common examples of how the wound interface may be altered. These methods for enhancing the wound environment, and possibly improving patient outcomes, will be discussed in greater detail within a later section devoted specifically to clinical applications. In general, NPWT devices assist in wound healing in part because of control of wound fluids while maintaining a warm and moist microenvironment. In comparison to 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 four 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 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.

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Hemostasis The efficient open pore foams require that hemostatis is nearly complete prior to 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 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 terms of cellular proliferation, migration and differentiation. Cell shape has been well established to govern its behavior;31 the alteration of the cytoskeleton generates organizational guidance cues for cells (Figure 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 induces cell proliferation thereby promoting wound healing. This is supported by evidence that short (6 hour), 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 16 

proliferation.35 Also worth noting is 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

Ingber et al. demonstrated the need for cells to experience isometric tension in order to provide the mechanical context necessary for cellular proliferation.36 Growth factors and cell attachment to extracellular matrix proteins were discovered to be essential yet insufficient stimulation in the absence cellular isometric tension. Chronic wound beds may lack the stable, structural scaffolding required for cell extension and adherence, 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, 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 analysis;30 increased endothelial migration, analyzed in terms of histological penetration depth37 or endothelial ingress;38 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 as a result of MDWT application.40 Though epithelial cell proliferation and migration increase, their differentiation during MDWT has been shown to decrease.30 MDWT inhibits keratinocyte differentiation, as 17 

supported by evidence of down-regulated keratin genes (e.g. KRT1, 2, 10, 13, 15) and major cornified envelope genes (e.g. 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, myogensis 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 that establishes a hypoxia and subsequent VEGF (vascular endothelial growth factor) gradient that drives the directionalized blood vessel growth (Figures 8 and 9).42 It has been suggested that the temporary reduction of blood flow at the wound edge15,43 stimulates angiogenesis through the HIF-1 (hypoxia-inducible factor)-VEGF pathway; tissue hypoxia instigates the upregulation of HIF-1, which in turn stimulates VEGF expression.42 It is not surprising that MDWT demonstrates increase micro-vessel 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, granulation tissue, 18 

which also includes the ancillary ECM and migratory macrophages, represents a specialized stroma designated for repair (Figure 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. Collagen production however, 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 (e.g. 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 with regard to fibroproliferative disorders; research has focused primarily on the regulation of cell-ECM interactions through a variety of signals such as TGF- (transforming growth factor-)/Smad, MAPK (mitogen-activated protein kinase), RhoA/ROCK, Wnt/-catenin, and TNF-/NF-B (tumor necrosis factor-/nuclear factor kappa-light-chain-enhancer of activated B cell).48 In contrast, 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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Given the complexity of the mechanical environment generated at the wound bed during MDWT, much of our current data is the result of in vitro studies (Figure 10). Tissue engineering bioreactors are commonly used to simulate the in vivo micromechanical environment as well as the foam-wound interface. Wilkes et al. developed a novel 3-dimensional bioreactor in order 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 3D fibrin matrix, McNulty et al. discovered that MDWT influences fibroblast energetics; energy charge, ATP/ADP ratio, and cytochrome c oxidase levels were all shown to increase.39 Importantly, they also discerned that the observed increase in energy status was geared towards biosynthetic processes associated with healing; levels of the growth factors TGF- and PDGF (platelet-derived growth factors,  and ) 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 PDGF also upregulates GAG (glycosaminoglycans) and fibronectin synthesis in fibroblasts.39 In our own study it was found that 48 hrs after exposure to a suction/foam/perfusion bioreactor, cells exhibited an upregulation of bFGF (fibroblast growth factor), TGF-1, Type I collagen 1, and smooth muscle actin 2 mRNA expression.40

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Peripheral Nerve Response Younan et al. demonstrated that MDWT also activates the neuro-cutaneous system, stimulating neural growth and neuropeptide expression. Upregulated peptides include substance P (SP), calcitonin gene-related peptide and neurotrophin nerve growth factor (Figure 11). The 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 Additionally, 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. Findings are conflicted with regard to the impact 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. This result however, was in the context of an in vitro analysis using non-viable 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 non-fermentative 21 

gram-negative bacilli while 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 polymicrocbial bacterial load was found in all foams studied. Porous polyurethane ether foam on high suction (125mmHg) 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 (Figure 12) and is used in a variety of anatomical sites throughout the body (Figure 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 22 

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 non-healing 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 4 ulcers.62 NPWT prevents digit amputation in the non-operative management of scleroderma ulcers.63

The effects of NPWT are both location and disease specific.

NPWT needs to be applied in

conjunction of treatment of other co-morbid diseases such as diabetes, hypertension peripheral vascular disease and venous stasis disease.

Zutt et al. showed the importance of

concurrent medical treatment of vasculitis and pyoderma gangrenosum along with adequate debridement and application of NPWT.64

23 

Surgical wounds are often treated with NPWT, often as a bridge to closure with a skin graft or flap, or secondary closure with NPWT (Figure 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

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 prior to 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

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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 a polyurethane ether foam; however, its effect on bacteria in the wound has been inconsistent. In order 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 popular as a treatment for burns.70 Stinner et al. 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 Staphylococcus aureus) with this treatment compared to 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 successfully been used in wound bed preparation for substantial split thickness skin grafts 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 (Figure 15). It is possible to instill normal saline or other agents to help wound healing such as antimicrobial 25 

agents. This has been demonstrated in the sterilization of massive venous stasis wounds prior to split thickness skin graft. The authors administered dilute Dakin’s 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 Continuous-instillation MDWT is another variation with a second port being connected to a continuous-drip system. Insulin in continuous-instillation MDWT successfully achieves a decrease in time to wound healing.73 Other bioactive factors suggested by Scimeca et al., which may be introduced through the continuous-instillation system include doxycycline, dilute betadine, lactoferrin, and phenytoin.73 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 (PG). In the case of a non-healing ileo-cutaneous fistula, PG 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 (APC), an anticoagulant, has also generated positive results where even long-term standard NPWT has failed. In their pilot study, Wijewardena et al. administered APC 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 26 

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 due to the amino acid’s 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 phelegmonous lesion and a non-healing postsurgical wound, respectively.77,78

NPWT in the Treatment of Deep Infected Wounds Many clinicians have applied NPWT to deep wounds which has also been studied in a porcine model. Soft tissue blast-injuries were simulated in pigs in order to more thoroughly observe changes in bacterial load following NPWT. Compared to 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

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. Though often useful, dressings infused with silver are not always indicated,80 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. 27 

NPWT in Cases of Exposed Bone and/or Joints Recently, open fractures, particularly of the lower extremity are frequently treated with NPWT systems. These systems keep the wound clean from external contamination as well as moist and warm. In their retrospective cohort study of open tibial fractures, Blum et al. compared the rate of deep infection between NPWT and conventional dressing treatment groups (8.4% and 20.6% respectively). There was a nearly 80% reduction in the risk of deep tissue infection after adjustment for multivariate analysis.81 Similarly, in a patient suffering from 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 and/or joints 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. It is worth noting however, that the authors discouraged the application of negative pressure for a period lasting longer than 7 days due 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 28 

complication of open-heart surgery posing severe risks to patients postoperatively. Without prompt treatment, mortality from this condition can be over 50%. Traditional packing of sternal wounds often resulted in massive bleeding or chronic draining sinus tracks. In a cohort study of patients with DSWIs, NPWT reduced the risk of early re-infections when used as the first line of therapy. The data was also suggestive of a decrease in the incidence of late chronic sternal infections and mortality.85 Furthermore, meta-analysis assessing the impact of NPWT on sternal infections found the length of hospital stay to decrease by one week.86 In the case of methicillin-resistant post-cardiotomy 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, post-sternotomy osteomyelitis remains a huge concern in terms of patient morbidity, prolonging recovery time and necessitating surgical re-interventions.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 build-up of fluid, either in natural anatomical cavities or pathological abscesses. NPWT offers an improved modality for draining these infections, in part by providing a greater suction distribution over a larger surface area than conventional drainage methods. This was shown to help prevent the 29 

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 to control sepsis, in most cases rapidly eradicating the local infection. Additionally, NPWT therapy 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, also have appeared to have benefitted from NPWT.

These wounds are unique in

that the visible superficial tissue defect is often relatively small compared to the underlying injury. NPWT has been combined with conventional draining methods to achieve an optimized therapy for such injuries. In their practice, Rispoli et al. connected surgical drains to the base of superficial foam dressings (Figure 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 to 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 30 

for NPWT. A number of such techniques have been documented in medical literature. As a basic principle, NPWT can be utilized in the abdominal cavity in a similar manner to its use in treating deep sternal wound infections. 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 (LSM) (Figure 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 an anterior rectal wall anastamotic disruptions.95

NPWT and Congenital Deformities NPWT also may provide an alternative to the management of congenital deformities such complex gastroschisis,96 giant omphalocele.97

The Food and Drug Administration (FDA)

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

31 

Variations on 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.

Pre-clinical 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 randomized controlled trial (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 to 39% in the original dressing group).102 Finite element analyses (FEA) 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 colleagues randomized high risk patients with lower extremity and abdominal wound incisions to VAC therapy or a dressing consisting of a non-adherent layer (Mepitel, Mölnlycke Health Care AB, Göteborg, Sweden ) and a silver dressing (Acticoat, Smith & Nephew, Hull, United Kingdom) and found no 32 

statistically significant difference in the rates of infection and dehiscence between the two groups.104

Skin graft immobilization The take of split thickness skin grafts (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 re-explorations.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 33 

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 de-gloved skin will predictably die. After excising the de-gloved skin and removing the fat from the dermis, the skin can then be reapplied to the wound as a full thickness skin graft. A NPWT device can then be placed on the graft for immobilization.112,113 Combining NPWT with a dermal regeneration template (DRT) is an additional option and has shown both excellent functional and aesthetic results in treating a subtotal degloving injury of the right lower limb. In a case study, Dini et al. applied NPWT directly to the wound bed for the first 10 days, providing temporary wound closure and early granulation tissue development. A DRT 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 have been reportedly treated with NPWT. The FDA has approved NPWT for managing poorly healing wounds. Manufacturer guidelines for the widely used KCI VAC® therapy systems list chronic, acute, traumatic, subacute and dehisced wounds, partial-thickness burns, ulcers (such as diabetic, pressure or venous insufficiency), flaps and grafts as indications for use.115 34 

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 FDA and KCI guidelines, NPWT is contraindicated in conditions involving: (1) necrotic tissue with eschar present, (2) untreated osteomyelitis, (3) non-enteric 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 (Figure 18),116 and osteomyelitis.89 The use of polyurethane foam under vacuum forces can have detrimental effects when in direct contact with exposed neurovasculature, tendons, and organs. Thus, when applying NPWT in close proximity to these structures, a non-adherent barrier layer (petroleum gauze, non-adherent dressings, oil emulsion dressing) placed over the structure is recommended.11 Sermoneta et al 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.94

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 35 

that warrant consideration prior to NPWT. These include: (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/ligaments, sharp edges at the wound, spinal cord injury, and enteric fistulas; (4) patient requires MRI/hyperbaric chamber/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

Though NPWT has been used in large number of patients, a spectrum of complications have been reported in clinical trials. Common complications include bleeding, infection, pain, foam retention within the wound (Figure 19), and tissue adherence. Bleeding and infection occur only rarely.98 but 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 one 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 36 

rapidly spreading infections long enough to allow for significant complications.119 Blast wounds also present healthcare 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 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 will best allow healthcare 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 on 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 37 

of treatment while in an acute wound, it may be most appropriate to begin with 48 hours of continuous suction, followed by cycles of intermittent therapy (e.g. 5 minutes on / 2 minutes off).11 Short, intermittent NPWT has demonstrated a more profound tissue response,50 but may not be suitable in all cases. Intermittent therapy may not be tolerated due to patient discomfort. The optimal NPWT suction applied to various wounds is not currently known. In our practice we used less pressure on circumfirential wounds and when used in conjunction with a free flap.

Clinicians are now presented with a variety of interface. 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 will be required to best inform surgeons as to 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 one interface material that is carefully cut to fill any irregularities in the wound. When more than one interface is used, it needs to be carefully documented to assure that there are no retained foreign bodies. When granulation 38 

tissue is desired, the foam should be placed directly on the wound surface.18 Use of a non-adherent 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 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 (Figure 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.

39 

Adverse effects directly attributable to long-term use of the device include skin irritation from the adhesive drape and odor from the dressing and/or canister. Both 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’s) 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 due to 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 non-adherent 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 lower the pressure. 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.

40 

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 non-adherant 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 pre-clinical model, we found that applying NPWT for 4 hours every two days gave a similar granulation tissue response as continuous therapy. When faster cycle times were used, surprisingly, 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. 41 

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 are few 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.

Figure Legends Figure 1 A visual representation of the definitions used in this paper. Negative Pressure Wound Therapy (NPWT) is a term that applies to any device that applies differential suction (i.e. reduced local pressure) to wounds. Microdeformational Wound Therapy (MDWT) refers specifically to NPWT systems that create microdeformations (appearing as micro-dome-like 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. 42 

Figure 2 Flowchart depicting the mechanisms of MDWT.

Figure 3 Schematic view of 4 primary mechanisms of action of MDWT.

Figure 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 et al., assuming an application of 125 mmHg 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 exists to the authors’ knowledge regarding pressure changes within the first centimeter of depth below the wound surface. Based on finite element analysis and the formation of microdeformations at the surface, it would not be surprising for the most superficial tissue to experience sub-atmospheric 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 to the pre-MDWT baseline. Due to a dearth of data in terms of sample size and consistency between wound types, this chart 43 

merely depicts the general trends observed. Of the 10 treated wounds studied by Kairinos et al., only 3 were found to eventually decrease in pressure to below baseline levels during prolonged therapy.

Figure 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.

Figure 6 Lymphatic density increases gradually at wound edges during the course of treatment. Figure 7 Representation of wound bed fibroblast requirement for a trifecta of growth factors, extracellular matrix protein binding, and isometric tension in order to undergo proliferation and differentiation. In wound beds, ECM destabilization precludes build-up of isometric tension, eventually resulting in cell death. This can be compensated by the mechanical microenvironment generated during MDWT. The particular cellular response is also correlated with the amount of tension the cell experiences; proliferation requires greater stretch than differentiation.

44 

Figure 8 MDWT stimulates wound-site angiogenesis through a number of mechanisms: mechanical stimulation (microdeformation), removal of factors inhibiting angiogenesis, and upregulating pro-angiogenic factors. Blood vessel dilation is also observed.

Figure 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) upregulating HIF-1, which in turn increases VEGF production. The resulting growth factor concentration gradient (4) stimulates directionalized vessel sprouting. HIF-1, hypoxia inducible growth factor-1 alpha; VEGF, vascular endothelial growth factor Figure 10 Morphological 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. MDWT also affects cellular energy status, fueling cellular processes associated with wound healing.

Figure 11 MDWT promotes neural growth and neuropeptide expression (substance P, calcitonin gene-related peptide, neurotrophin nerve growth factor). Transient elevations of plasma 45 

epinephrine and norepinephrine have also been observed.

Figure 12 Influence of NPWT and MDWT on the four stages of healing: (1) Though 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 exudate; (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.

Figure 13 Potential Targets for NPWT.

Figure 14 Sixty-nine year old female with history of endometrial carcinoma with metastases to right hip, status post hemipelvectomy complicated by complete wound dehiscence. A) Open wound 28 cm x 17 cm. B and C) Buttock was pulled up and held together and foam was placed into the remaining open area. D) One month post-op. E) Two months post-op. F) Three months post-op. 46 

Figure 14 Instillation VAC.

Figure 15 Schematic of 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.

Figure 16 Schematic of intra-abdominal MDWT following lesser sac marsupialization modified and reprinted with permission by Wiley from Sermoneta D et al. Intra-abdominal vacuum-assisted closure (VAC) after necrosectomy for acute necrotising pancreatitis: preliminary experience. Int Wound J. 2010 Dec;7(6):525-30. Please note that the lumbostomy drains have been omitted in this illustration.

Figure 17 Example for treating intra-abdominal abscesses based on the procedure performed by Weidenhagen et al. to treat a peri-anastomotic 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 R, Gruetzner KU, 47 

Wiecken T, Spelsberg F, Jauch KW (2008) Endoscopic vacuum-assisted closure of anastomotic leakage following anterior resection of the rectum: a new method. Surg Endosc 22:1818–1825.

Figure 19 A) Thirty-nine year old male with L-1 partial paralysis and left ischial pressure ulcer, treated with MDWT for two months. B) Foam retention discovered. C) Healed following removal of foreign body and flap surgery.

Figure 20 A-C) Bridged dressing following dehisced c-section wound.

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