Mechanisms of action of microdeformational wound therapy

Seminars in Cell & Developmental Biology 23 (2012) 987–992

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Seminars in Cell & Developmental Biology journal homepage: www.elsevier.com/locate/semcdb

Review

Mechanisms of action of microdeformational wound therapy Luca Lancerotto a,b,d , Lauren R. Bayer c , Dennis P. Orgill c,d,∗ a

Tissue Engineering and Wound Healing Laboratory, Division of Plastic Surgery, Brigham and Women’s Hospital, Boston, USA Institute of Plastic Reconstructive and Aesthetic Surgery, University of Padova, Italy c Division of Plastic Surgery, Brigham and Women’s Hospital, Boston, USA d Harvard Medical School, Boston, USA b

a r t i c l e

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Article history: Available online 2 October 2012 Keywords: Microdeformational wound therapy Negative pressure Wound therapy NPWT Microdeformation Sub-atmospheric Angiogenesis Granulation Foam Dressing Wound closure Wound healing

a b s t r a c t Microdeformational Wound Therapy (MDWT) is a class of medical devices that have revolutionized the treatment of complex wounds over the last 20 years. These devices, are a subset of Negative Pressure Wound Therapy (NPWT), in which there is a highly porous interface material placed between the wound and a semi-occlussive dressing and connected to suction. The porous interface material acts to deform the wound on a micro scale promoting cellular proliferation. These devices appear to significantly improve the speed of healing in many wounds, facilitate granulation tissue formation and reduce the complexity of subsequent reconstructive operations. The mechanisms through which such effects are obtained are beginning to be better understood through basic research and clinical trials. Further work in this field is likely to yield devices that are designed to treat specific wound types. © 2012 Elsevier Ltd. All rights reserved.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mechanism of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Primary mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.1. Macrodeformation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.2. Microdeformation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.3. Optimization of wound environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Secondary effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Microdeformational wound therapy (MDWT) is a class of wound healing devices that apply a highly porous material under suction to the wound surface. Previously, these devices have been referred to as negative pressure wound therapy (NPWT). This is a physical misnomer as pressure cannot be a negative quantity.

∗ Corresponding author at: 75 Francis Street, Brigham and Women’s Hospital, Division of Plastic Surgery, Boston, MA 02115, USA. Tel.: +1 617 732 5456; fax: +1 617 730 2855. E-mail address: [email protected] (D.P. Orgill). 1084-9521/$ – see front matter © 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.semcdb.2012.09.009

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Other authors have more appropriately referred to these therapies as sub-atmospheric wound therapy. Although this is an accurate physical description of these devices, it fails to distinguish between devices that utilize highly porous interface materials. We prefer the mechanistic term, MDWT, for devices that deform wounds on the micron to millimeter scale (Fig. 1). Wound microdeformation induces cellular proliferation. MDWT devices also remove fluids and toxins, keep the wound warm and moist, and bring the wound edges together through macrodeformation. Introduced less than 20 years ago, MDWT has revolutionized the treatment of complex wounds. In most large medical centers, nursing facilities, and in-home care, the devices are preferred treatment for many complex and difficult wounds. The rapid

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2. Mechanism of action 2.1. Primary mechanisms

Fig. 1. MDWT combines occlusive dressing, suction and application of foam material. It keeps the wound moist, provides thermoinsulation, removes excess exudates, pulls centripetally the surrounding tissues increasing interstitial pressure, and mechanically stimulates the wound bed at a micron scale. Modified from: Orgill et al., Surgery, 2009 [63].

international adoption has come as a result of positive results obtained by individual physicians and patients, evidenced by a large number of published, peer-reviewed articles. The vast majority of these are case reports or retrospective series. There are only a few well-designed prospective double blinded clinical trials. The device can be used until a wound is nearly healed, or more commonly in our institution, as a wound bed preparation treatment prior to skin graft or flap closure of a wound. For example, the device is used to reduce the size of a Stage IV pressure ulcer down to a small sinus track so that a relatively small operation with lower morbidity can be performed by excising and closing the wound with a small flap. Modified MDWT devices have been developed for the treatment of infected wounds and of the open abdomen. The various components of MDWT have been used for years in surgery and wound care. Closed suction drainage has been used to drain excess fluids in body cavities and after substantial soft tissue dissection such as a mastectomy [1]. Semi-occlusive dressings are used to maintain a moist environment that accelerates healing as observed by Winter [2]. A variety of foams have been used as dressing materials including those that absorb exudate. The innovation of MDWT as applied to wounds is based on the work of Argenta and Morykwas. Through a series of animal studies in a pig model [3], Argenta and Morykwas demonstrated that the application of controlled suction through an open-cell foam creates an environment conducive to healing and increased granulation tissue formation. They observed that a cyclical stimulation was more effective than continuous, and established an optimal pressure range. Their first published case series showed the dramatic effects of this therapy in a series of chronic and acute wounds [4]. These results, supported by the porcine studies, suggested that edema removal, an increase in vascularity of wounds, and the responses of surrounding tissues to mechanical forces were the interrelated factors which, in combination, promoted healing. Clinical results exceeded the initial expectations, which lead to an exponential diffusion of NPWT in wound care and broadening of its indications.

2.1.1. Macrodeformation Macrodeformation is the centripetal pulling of wound margins as the interface material collapses with suction. Stretching of the tissues directly stimulates the cells and increases interstitial pressure [5]. Combined with suction at the interface, macrodeformation reduces edema by increasing the differential pressure from the interstitial space to the interface material; it also temporary reduces the blood flow at the wound edges, as observed by Wackenfors et al. [6], and confirmed by Kairinos et al. [5,7,8] stimulating cell proliferation and angiogenesis through the HIF1␣/VEGF pathway [9]. The deformation is proportional to the level of suction [10], the total volume of the foam, the pore volume fraction of the filler material and the deformability of the surrounding tissues [11]. When exposed to a pressure of −125 mmHg, open-pore polyurethane foams decrease in volume of about 80% [12]. From a clinical perspective, understanding the tissue type/macrodeformation relationship is key to a successful use of MDWT. For chronic wounds or wounds in areas with limited skin extensibility such as the scalp, MDWT can be expected to stimulate a healthy wound bed, and permit closure with skin grafts. In areas with large amounts of deformable tissues, such as the abdomen, the shrinkage foam placed in the wound can maximize the reduction of wound size, minimizing the need for additional soft tissue transfer. 2.1.2. Microdeformation At the foam–wound interface, wound surface microdeformations occur when suction is applied to the foam. These microdeformations stretch cells, promoting cellular proliferation while creating localized areas of hypoxia stimulating VEGF production. The cell proliferation that results appears as a 3D microdome-like structure to clinicians. Saxena et al. demonstrated on histologic sections an increase of surface length of 22% under typical MDWT conditions compared to areas where suction was applied without the foam interface [13]. Ingber and Huang have shown how cellular deformation – through tension – modulates cell function. Cells that are allowed to become spherical tend to undergo apoptosis, those that are stretched slightly differentiate, while those stretched even more tend to divide and proliferate [14,15]. In vivo, pro-proliferative and pro-angiogenetic responses to tensile forces have been shown [16]. Lu et al. applied suction to a deformable fibrin–fibroblast culture apparatus and observed that matrix deformation induced cell proliferation, changes in cell morphology as well as increased expression of bFGF, TGF-␤, ␣SMA, and collagen 1a1 [17]. In vivo, Scherer et al. looked at the distinct elements of MDWT in a diabetic mouse model (Fig. 2) [12]. Interestingly, foam applied to the wound without suction significantly stimulated granulation tissue formation and angiogenesis. When suction was added to this (MDWT), the microdeformation at the wound surface was maximized, further increasing the thickness of granulation tissue. Heit et al. [18] recently demonstrated the importance of pore size in the biological response to MDWT. Larger pore diameters were associated with higher wound surface deformations and were associated with thicker granulation tissue formation. 2.1.3. Optimization of wound environment MDWT combines multiple mechanisms that potentially improve the wound environment. An open wound is exposed to contaminants and tends to desiccate and form an eschar, which delays the migration of epithelium, stimulates inflammation, and provides a culture media for bacteria. Chronic wounds tend

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as human in vivo studies [33–35] found no benefits of, or even a tendency towards increased bacterial colonization in wounds treated with MDWT. Strategies to reduce bacterial loads within wounds, such as adding silver to the interface material, are now being adopted [36]. 2.2. Secondary effects

Fig. 2. In a diabetic mouse wound model, MDWT maximizes cell proliferation and vessels density at comparison with its distinct elements applied individually (suction, occlusive dressing, foam, foam with compression). *p < 0.05, **p < 0.01. Modified from: Scherer et al., Plastic and Reconstructive Surgery, 2008 [12].

to be inflamed with surrounding edematous tissues. Fluids that accumulate are rich in catabolites and proinflammatory molecules; they also physically expand the third space compressing blood and lymph vessels and increasing the cell-to-vessel distance contribute to local ischemia. The semi-occlusive dressing keeps the wound moist, prevents desiccation, and promotes cellular proliferation. The presence of the semi-occlusive membrane and of the compressed foam permeated by liquid and vapor from the wound also acts as a thermal barrier and is likely to increase the local temperature of the wound bed. Kloth et al. demonstrated that normothermic conditions are conductive to healing in chronic pressure sores [19,20]. Suction facilitates removal of extracellular fluid [5]. Labanaris et al. demonstrated an increase in density of lymph vessels at the edges of the wounds, which may further reduce edema [21]. A reduction of edema was reported in bilateral hand partial thickness burns, in which one hand was treated MDWT and the other was not [22]. Bassetto et al. assessed histologically, a reduction of edema with MDWT in patients with chronic leg ulcers [23], accompanied by decreased inflammation. Simmons et al. reported less edema in a blinded evaluation of biopsies of skin-grafted pig wounds treated with NPWT versus traditional tie-over dressing [24]. MDWT can facilitate removal of catabolites and inflammatory mediators. Stechmiller et al. detected a decrease of TNF-␣ as soon as one day after beginning of MDWT. However, IL-1␤, MMP2, MMP3, or TIMP-1 did not decrease in the fluid collected from stage III/IV pressure ulcers treated with VAC Therapy for seven days [25]. In comparing MDWT to dressing with gauze moistened with various agents, Moues et al. found lower pro-MMP-9 levels and a lower total MMP-9/TIMP-1 ratio in the MDWT group during a tenday follow-up [26]. Labler et al. found higher IL-8 and VEGF in the fluids drained from traumatic wounds treated with MDWT Therapy versus Epigard, which was accompanied by enhanced angiogenesis and accumulation of neutrophils at the first dressing change [27]. The findings of Greene et al. showed decreased MMPs (MMP9/NGAL, MMP9, latent MMP2 and active MMP2) in biopsies of foam-covered areas compared to non-foam covered areas of chronic wounds treated with MDWT Therapy [28], pointing out that the presence of a correct wound filler may be required to optimize this effect. The reduction of local bacterial burden initially reported by Morykwas et al. [29] has not been confirmed by later studies. The results of in vitro studies on the effects of subatmospheric pressure on bacteria are discordant [30,31]. Pre-clinical [32] as well

MDWT interacts with the wound surface and stimulates a proliferative response within the wound bed, but its effects extend in depth, resulting in a “healthier” wound. Abundant granulation tissue formation, even on the surface of otherwise recalcitrant wounds, is one of the main histological features of MDWT [4,37], and is critical to wound bed cleansing, wound closure, and preparation of the wound bed to skin grafting or flaps. It is accompanied by an intense angiogenesis at the surface of the wound [23]. As shown by Scherer et al., the two events are likely interconnected, and explained partially by the foreign body effect to the polyurethane foam used as wound filler [12]. The key role of appropriate modulation of the inflammatory reaction is exemplified by the fact that wounds in mice lacking mast cells are refractory to MDWT [38]: mast cells play a pivotal role in acute inflammation. Angiogenesis is also attributable to the gradient of local ischemia that MDWT induces into the wound bed and edges [8]. However, Erba et al. [9] found reduced expression of HIF-1a in MDWT treated wounds compared to controls, to which corresponded to decreased levels in VEGF. VEGF also presents as a gradient of expression higher close to the interface. Through corrosion casting more physiologically oriented arcades of small vessels in MDWT treated wounds were identified, compared to the tortuous and dilated vessels in controls (Fig. 3). The apparent contradiction between reduced blood flow shown by Kairinos and reduced hypoxia demonstrated by Erba, may indeed be explained by improved vessels structure combined with reduced edema in MDWT treated wounds. This may signify more effective exchange in oxygen and metabolites. Cell proliferation increases with the combination of contact with the foam, microdeformation of the surface, and edema removal [12] that is obtained with MDWT. Granulation tissue formation is maximized by a cyclical application of suction [3,4,39]. The high effectiveness of cyclical regimens reported [6] may be due to a transient hyperfusion of the wound edges that occurs with MDWT is released, paired with the switching between stimulatory phases and phases in which accelerated metabolism is allowed. To further support this hypotheses, the findings of Dastouri et al. [40] suggest that, at least with pressure cycles in the range of minutes, the shape of the pressure waves may be critical to optimize the effects. Scherer et al. showed that repeated brief stimulations (4 h every other day) with MDWT were enough to induce long-lasting effects with wound events equal to those of continuous stimulation in an animal wound [41], while Chen et al. [42] observed initial modifications in the capillaries at wound edges and the shape of endothelial cells at TEM after just 2 min of MDWT, culminating in capillary budding at 24 h, more rapidly than in control wounds. Such reports are in line with the findings of animal experiment on intact skin, by which it was demonstrated that tensional mechanical stretch elicits growth factor transcription, cellular proliferation and angiogenesis, and that cyclical stimulation is more effective than continuous [16,43,44]. MDWT, in particular with cyclical stimulation, has also been shown to affect the local expression of neuropeptides in wounds [45,46]. It can be hypothesized that higher expression of neuropeptides may result in increased pain, which clinically is a limit to a broader adoption of intermittent MDWT [4], on the other neuropeptides are now recognized as key homeostatic factors for the skin [47] and their secretion may be one of the mechanisms through which MDWT positive effects are exerted.

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Fig. 3. Corrosion castings of the vessels of wounds treated for seven days with occlusive dressing (left) or MDWT (right) in a diabetic mouse wound model. MDWT-treated wounds presented a richer network of small vessels with more physiological configuration. Modified from: Erba et al., Annals of Surgery, 2011 [9].

The report of a histological follow-up of chronic venous wounds of the lower limbs treated with MDWT by Bassetto et al. [23] better clarifies the role of such events. Treated wounds developed on surface a constant granulation tissue layer, with rich angiogenetic activity, under which were layers in which cell proliferation, edema and inflammation decreased, while the extracellular matrix underwent remodeling. The granulation tissue layer maintained constant thickness over time, suggesting that the tissue newly formed on surface underwent quick progression through the wound healing phases into an organized scar. The authors suggested that such “stabilization” may be a relevant feature of MDWT, that could explain some of the better outcomes in secondary repair procedure of wounds after MDWT treatment. 3. Clinical use Recent Cochrane Database review of Topical Negative Pressure for chronic wounds [48] cites of the 324 unique publications, only 7 met the evidence criteria to be included in the review. Based on the few studies included, the group concluded there was no benefit to TNP in chronic wounds. Similarly, the 2012 Cochrane review of negative pressure wound therapy for skin grafts and surgical wounds [49] found only five eligible trials and concluded that evidence of complete healing of wounds expected to heal by primary intention remains unclear. Despite a dearth of robust randomized controlled trials, MDWT is widely used for a variety of wound types and patient conditions. There are currently over 12 devices on the market, which use gauze, foam and/or a corrugated composite, are portable, disposable, have instillation capabilities and antimicrobial dressings. MDWT can be used in most chronic wound types including pressure ulcers, diabetic foot ulcers and venous stasis ulcers, large wounds that cannot be closed primarily, including open abdomens and fasciotomies and dehisced or open surgical wounds. The therapy has been successful in improving skin graft take [50–53] and outcomes in lower extremity traumatic wounds [54]. Enhanced granulation tissue formation with tissue substitutes including Integra [55] and Alloderm [56] has been reported. A recent use of MDWT is on surgical incisions. The technique has been reported in orthopedic surgeries [57], hernia repair [58] and for morbidly obese patients undergoing orthopedic surgery [59]. The device is placed over the sutured incision post operatively, to prevent seroma and hematoma formation in the surgical space. Indications include wound complication prevention in patients who are high surgical risk because of obesity, large wound defects or poor nutrition, any of which could lead to wound dehiscence or infection.

Wound infection may also be prevented by using antimicrobial silver foam [60] or the instillation of antimicrobial fluids into the MDWT dressing during use. Indications for instillation of fluids such as antibiotics or polyhexanide solution include infected orthopedic implants [61,62] and improved component retention in previously infected sites. As MDWT use becomes more common, understanding the contraindications and preventing complications is paramount. Regardless of the type of device used, MDWT should not be used if there is malignancy in the wound, untreated osteomyelitis, necrotic tissue or eschar or in a grossly infected wound. MDWT should be used with caution where there are exposed vessels, nerves, organs or anastamoses. Vessels, nerves and organs should be covered with a non-adherent dressing and MDWT should be set at the lowest pressure that will adequately hold a vacuum seal. The skin surrounding the wound should be free of blisters, dermatitis, or any other breaks in the skin. Small skin abnormalities can be covered with a hydrocolloid to prevent worsening of the condition. Dressing application is vital to successful treatment. The foam dressing should be sized slightly smaller than the wound size and packed in any undermined areas or tracks (Fig. 4). The wound should never be over packed. Ideally, only one piece of foam dressing should be used in the wound, especially if there are multiple caregivers doing the dressing changes. If more than one piece of dressing is used, careful documentation of the number of pieces placed and removed is essential. Retained foam can

Fig. 4. Device used in an abdominal wound.

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References

Fig. 5. Granulation tissue after MDWT.

be a devastating complication, causing severe wound infection, osteomyelitis and wound dehiscence. The foam-tissue interface is important for granulation tissue formation (Fig. 5) [13]. Unless there is an exposed organ or vessel, or the dressing is being used over a skin graft, the foam should be placed directly on the wound bed. Use of a non-adherent contact layer should be reserved only for the conditions listed above. Wounds located near the perineum or buttock or wounds with a small skin opening are best treated with the bridging technique. The wound is packed with the foam dressing and an additional long piece of foam is placed over the wound and brought over the skin to a more accessible location. Any time the foam dressing is placed on intact skin, the skin must be protected by either an additional piece of adhesive drape or a hydrocolloid dressing. Most MDWT devices employ a polyurethane foam wound filler. Some devices can be used with gauze and there are other fillers available as well. There are few studies comparing the different fillers. Birke-Sorensen et al. [53] reviewed all the current publications and reported that for rapid granulation formation, deep wounds and split thickness skin grafts, polyurethane foam is optimal. Gauze or polyvinyl alcohol foam may be preferable if the polyurethane foam is painful. Duration of treatment depends on the goal of therapy. For granulation tissue formation in preparation for skin graft, the therapy can be discontinued as soon as the granulation tissue has reached the level of the skin and is adequate to accept a skin graft. For wound contraction for flap surgery or accelerated healing of a surgical wound, therapy should be halted once there are no appreciable changes in wound measurements after 1–2 weeks. MDWT should rarely be used for more than 3 months. Adverse effects 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 “holiday” from the therapy. Skin breakdown can be treated with topical salves based on the dermatitis etiology and wound odor can be treated with saline gauze dressings or dilute bleach solution (Dakin’s) for 48–72 h. Once adverse effects have abated, MDWT can be resumed. Devices employing microdeformational wound therapy have become an integral part of wound care in the 21st century. Bench studies have begun to explain the mechanisms of action of the foam-tissue interface and effects of mechanical forces on the wound bed, but there is much work to be done clinically. Wound care specialists will continue to challenge manufacturers of the devices to take part in robust clinical trials and to improve the technology for increased portability, cost effectiveness, improved outcomes and patient comfort.

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