Clinical Review

The mechanisms of action of vacuumassisted closure: More to learnDennis P. Orgill, MD, PhD,a Emest K. Manders, MD,b Bauer E. Sumpio, MD,CRaphael C. Lee, MD,PhD,d Christopher E. Attinger, MD,e Geoffrey C. Gurtner, MD,r and H. Paul Ehrlich, PhD,g Boston,MA, Pittsburg, PA, New Haven, CT, Chicago,IL, Washington, DC, Stanford, CA, and Hershey,PA

Division of Plastic and &constructive Surgery, Brigham and Women's HosPital, a Boston, MA; Division ofPlastic and &constructive Surgery, University of Pittsburg Schoolof Medicine, bPittsburg, PA; Department ofSurgery, Vale University School of Medicine, c New Haven, CT; Department of Surgery, University of ChicagoHospitals, d Chicago, IL; Limb Center, Georgetown University Medical Center, e Washington, DC; Departmentof Surgery, Stanford University Medical Center/ Stanford, CA; Division of Plastic Surgery, Department ofSurgery, Penn State University Milton S. Hershey Medical Center,gHershey, PA

THERE liAS BEEN RAPID ADOPTION OF VACUUM-ASSISTED

CLOSURE (VAC) TECHNOLOGYto treat many acuteand chronic wounds despite a rudimentary under-standing of the biologic mechanisms of action andfew weIl-controIled, prospective, randomized c1ini-cal trials of its use.

An expert panel carried out a selected review

of published literature regarding the mechanismsof action of the VAC device in the context of

published c1inical studies.The current literature suggests primary mecha-

nisms of action of the VAC device may inc1ude thefoIlowing: (I) drawing the wound edges together;(2) stabilization of the wound environment;(3) decrease in wound edema and rem oval ofwound exudate; and (4) microdeformations of the

wound surface. Secondary effects inc1ude increasedangiogenesis, granulation tissue formation, and, insome cases, a decrease in bacterial bioburden.

Supported by a grant from Kinetic Concepts, Inc. (KCI). Thisdocument reflects the opinion of the authors and was not influ-enced by KCI.

Dr Orgill reports having received consulting fees and a researchcontract from Kinetic Concepts, Inc. (KCI) for studies per-formed at Brigham and Woman's Hospital; he is an expertwitness for KCI and Wake Forest University. Dr Sumpio,Dr Attinger, and Dr Lee disclosed consulting fees from KCI,San Antonio, TX.

Accepted for publication February 2, 2009.

Reprint requests: Dennis P. Orgill, MD, PhD, Division of Plasticand Reconstructive Surgery, Brigham and Women's Hospital, 75Francis Street, Boston, MA 02115. E-mail: dorgill@partners.org.

Surgery 2009;146:40-51.0039-6060/$ - see front matter

@ 2009 Mosby, Inc. AlI rights reserved.

doi: 10.1016/j.surg.2009.02.002

40 SURGERY

INTRODUCTION

The c1inical evidence for the efficacy of the VACdevice is mostly in retrospective case series. A fewrandomized control studies have shown efficacy indiabetic foot infections, pressure ulcerations, andskin grafts. Additional research into the mecha-

nism of action wiIl provide a better understandingof how to best use current devices and help makeimprovements in future device designo

With our aging population and increases inobesity and diabetes, problem wounds are becom-ing an increasing burden to our healthcare system.In addition, c1inicians are faced with an array ofproblem wounds from military and domestictrauma as weIl as from complex surgical procedures.Better, cost-effective methods of c10sing difficultwounds efficiently wiIl reduce the pain and ampu-tation rates associated with wounds. Despite thetheoretical promise of topicaIly applied growthfactors, there is currently only a limited c1inicalrole with only 1 commercial product available forc1inical use in the United States.1 Other methods,

such as bioengineered skin substitutes, have beensuccessful in certain defined areas of wound heal-

ing, but most advanced wound care products inuse today are based on the principIe of moist woundhealing defined by Winter and Scales in the 1960s.2,3

WOUND HEALING PHYSIOLOGY

Acute wounds progress through a complexseries of biochemical and ceIlular events describedas the phases of wound healing: hemostasis, in-flammation, proliferation, and remodeling. Suc-cessful wound healing is contingent on theorchestration of a myriad of biochemical signalpathways from a wide range of ceIl types during the

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SurgeryVolume146, Number 1

Table. Health technology assessment summary

Healthtechnologyassessment Conclusions

Orgillet al 41

Ontario Health Technology AdvisoryCommittee, 200414

Comments

VAC therapy may be useful forhealing various types of woundsbut effectiveness could not be

empirically quantified

AHRQ/BlueCross/BlueShield,200415

- Small sample size and patientpopulations

- Poor study design- Outcome measures could not be

compared- Small number of studies

- Inadequate randomization inmost studies

- Study groups not comparable

Body of evidence insufficient tosupport conclusions abouteffectiveness

Weak evidence of effectiveness

VAC may have advantages over otherforms of wound dressings studiedbut toa few reports to say

Limited evidence for effectivenessand adverse events

Cochrane Review, VI{, 200316Centre for Clinical Excellence,

Australia, 200317

NHS Quality ImprovementScotland,200318

Cochrane Review, VI{, 200119

- 3 articles met inclusion criteria

- No LeveI I or 11were identified

- Saline gauze is not standard treat-ment of wounds in Scotland

- Need for more RCTs

- Small sample sizes- Methodologicallimitations

Weak evidence that TNP is superiorto gauze dressings

VAG,Vacuum-assisted closure; AHRQ, Agency for Healthcare Research and Quality; RGT, randomized clinical lrial; TNP, topical negative pressure.

4 phases. Chronic wounds, in contrast, do notmake an orderly progression through the phasesand are unable to complete the sequence. The lackof wound progression can be due to a number offactors, including increased protease production,infection, nutritional state, vascular disease, andradiation. Common to chronic wounds is a de-

creased proliferative response in the healing cas-cade. There are a variety of pharmacologic,ceIlular, biochemical, and mechanical methodsthat alter the normal wound healing sequence.4-6Correcting defects in the normal healing phasesor devising methods to accelerate wound healingwould be of great benefit. For an active prolifera-tive process to occur in wound healing, the funda-mental drivers of mitogenesis should beconsidered, which include growth factors, extracel-lular matrices, and mechanical forces.

VAC DEVICE

Argen ta and Morykwas7and Morykwas et al8 firstdescribed the beneficial use of the vacuum assisted

closure (VAC) device for wound healing in 1997 (Ki-netic Concepts, Inc., San Antonio, TX). The deviceconsists of a vacuum pump, a canis ter with a con-necting tube, an open-pore foam, and a semiocclu-sive dressing. Although suction devices havecommonly been used to drain surgical sites and in-vestigators such as Fleischmann et al9 have de-scribed a vacuum-sealing technique, the VACdevice has gained increased popularity among users

over the past decade. A number of other deviceshave or wiIl be marketed based on the concept ofwound suction, which is sometimes referred to asnegative pressurewound therapy.Although these de-vices share some of the same design characteristicsof the VAC device, we restricted our review to theVAC device and the most common interface mate-

rial, the open-pore polyurethane ether foam, be-cause of a lack of peer-reviewed articles aboutother devices. The polyvinyl alcohol foam is a white,nonadherent foam that is used by some cliniciansover viscera and to reduce pain with dressingchanges; there are no LeveI I or 11 studies usingthis type offoam.

Since the original reports,7,8 more than 500peer-reviewed papers in the medical literaturehave been published describing the effect of VACin a number of wound types. Most of the reportshave been case series and retrospective reviews,with a few prospective, randomized studies pub-lished in the areas of diabetic foot infection,IO,11pressure sores,12 and skin grafts.13 Several system-atic reviews ofVAC technology have also been pub-lished (Table).14-19 Although a number ofindependent reports suggest compelling evidence,the smaIl number of prospective, randomized stud-ies makes it difficult for public health policymakersto assess clinical efficacy.20 The foIlowing is a se-lected review of the current literature and descrip-tion of current knowledge regarding themechanism of action of the VAC device.

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42 Orgillet ai

Fig 1. Proposed mechanisms of action of the VAC de-vice. The device covers the wound and keeps the woundsurface moist and insulated. For deformable wounds, thedevice can be used to pull the edges together (macrode-formation). It removes extracellular fluid and wound ex-udate and causes microdeformation at the foam-wound

interface. Secondary effects include changes in bloodflow, wound biochemistry, systemic inflammatory re-sponse, and bacterial load.

MECHANISM OF ACTION OF VAC DEVICE

Primary effects. There are 4 primary mecha-nisms of action of the VAC device described in theliterature: (1) contraction of the wound (macro-deformation); (2) stabilization of the wound envi-ronment; (3) removal of extraceIlular fluid; and(4) microdeformation at the foam-wound inter-face (Fig 1).

Contractionof wound (macrorkfvrmation):Skin andsoft tissues have a natural tension in their normal

state. When an incision is made through the skin,it naturaIly pulls apart. For example, in patientswith midline abdominal wounds that are left open,there is shrinkage of the abdominal wall that isreferred to as loss of domain. Maintaining approxi-mation of tissues during wound healing allowsfor earlier closure by delayed primary or secondaryintention. Studies of traumatic abdominal injurieshave shown that use of a modified VAC device can

allow for subsequent wound closure and may cir-cumvent the need for skin grafts over viscera.21The open-pore polyurethane foam that is usedwith the VAC device efficiently transmits pressureand evacuates exudates. When exposed to suctionat 125 mm Hg, the foam volume decreases byabout 80%.22 The shrinkage is in 3 dimensions,and the amount of shrinkage of the wound willmostly be determined by the deformability of thesurrounding tissues.

~.\, ,

; },. t

/ i

Surgeryluiy 2009

The effect of the macroscopic deformation oftissues as a result ofVAC placement will depend onthe type of tissue treated. For example, placementof the VAC device into an incisional wound in anobese abdomen with a large amount of deformableskin and soft tissue wiIl result in near approxima-tion of the wound edges. In contrast, use of thedevice on scalp wounds causes minimal contrac-tion of the wound edges, with the foam shrinkageoccurring mostly perpendicular to the woundsurface.

For deformable wounds, cutting the foam in astrategic fashion will facilitate wound closure byaIlowing the wound edges to come together morequickly. Depending on the structural characteris-tics of the foam, the foam exerts mechanicalforces on the tissue exposed to the VAC device.23For example, in a circumferential extremitywound, there is a theoretical possibility for circum-ferential shrinkage of the foam to cause a com-pressive force on the underlying tissues (Fig 2).Kairinos et al24 recently confirmed this hypothesisin humans treated with VAC therapy for 48 hours.In this same study, they showed that tissue pres-sures were increased when measured about 1 cm

from the wound with the VAC in place. Thesepressures increased as suction levels were in-creased; over time, there was some normalizationof these pressures.24 Quantitative modeling ofthis phenomenon will be important to predictchanges in wound volume as a function of the an-atomic location of the wound and the patient ageand body habitus.

Stabiiization of wound environment The VAC de-vice uses a semiocclusive polyurethane drape thathas limited permeability to gases and water vaporand impermeability to proteins and microorgan-isms. The dressing is typically changed every 2-3days, which eliminates the discomfort of the dailydressing changes typically associated with tradi-tional gauze-based dressings. Gauze dressings canallow evaporation of fluids and concentration ofproteins at the wound surface and eventuallyproduce a scab that delays healing. In contrast,moist wound-healing modalities, such as alginates,promote angiogenesis and the breakdown of ne-crotic tissues while decreasing pain.2,3 The VACdevice appears to evacuate fluid with its accompa-nying electrolytes and proteins, thereby keepingthe osmotic and oncotic gradients at the woundsurface theoretically stable. Objective studies, how-ever, are needed for confirmation. Clinicians usingthe VAC device have noted that part of the woundwill desiccate if a small hole develops in the overly-ing drape.25

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SurgeryVolume146, Number 1

Orgill et al 43

A Macrodeformation

BloocIVessel Deformation

---.

:---!.

J'~'

Without Suction With Suction

B Microdeformation

5trut

NormalWoundTissue

P = 125 mmHg

Stiffer Tissue(Scar)

Fig 2. Wound defonnation. (A) Macrodefonnation: The foam contracts when vacuum is applied and can cause tensionon wound edges to bring the wound edges together, which might potentially cause a compressive force on circumfer-ential wounds. (B) Microdefonnation: The VAC device causes rapid fonnation of granulation tissue that mirrors thefoam surface. Stiffer tissue will deform less with the same foam pore size and suction.

The physical properties of the polyurethaneether foam very like1y contribute to the efficacyof the VAC device by allowing efficient pressuredistribution and removal of exudates. The cur-

rently available polyurethane ether foam (blackfoam) has a mean pore size of 423 J.L,a mean porevolume (when uncompressed) of 97%, a bulkmodulus of e1asticity of 3.06 kPa (23 mm Hg)when 50% compressed, and a Poisson's ratio ofO.O(K. Kieswetter, KCI, San Antonio, TX, personalcommunication, December 2007). Based on clini-cal experience, one suction device is adequate formost large wounds. However, more than 1 suctionpump may be necessary in patients with very largewounds involving a large extremity or trunk area.

More clinical information about the flow and

pressure distribution characteristics of the foamin large and highly exudative wounds would helpclinicians determine the optimal number of suc-tion ports to apply.

The thermal conductivity of the VAC device willbe an aggregate of the conductivity of the overlyingsemiocclusive drape and the polyurethane foam(Fig 3). Because the compressed foam is likely tobe saturated with liquid during application, thethermaI conductivity will be on the order of wateror 0.014 (calorie per second [cal/s] meter degreesCe1sius [m CO]) and will be roughly comparable totissue at a similar thickness. Additional heat trans-fer is minimized because of the reduction of

85

44 Orgillet ai

Wound Environment

SemipermeableMembrane ,~ ThermalInsulation

-.~1

, I

BiomaterlalInteractlon

Fig 3. Wound environment. The VAC device keeps thewound moist and wann compared with dry dressingsthat allow the wound to dry out and fonn a scab. TheVAC device also acts as an insulating layer.

evaporation of water from the wound surface. Arandomized study by Kloth et al26 showed that nor-mothermic wound therapy speeds wound healingin chronic, full-thickness pressure sores. Morework with actual temperature measurements andwater content of the wound and foam would be

helpful in better understanding this mechanismof action.

The uniform apposition of a skin graft orartificial dermal matrix to the underlying woundis critical for optimal take. Randomized studies ofskin graft take comparing VAC devices to conven-tional bolster dressings have shown better, morereliable take in the skin grafts and dermal matriceswhen they are bolstered with a VAC device.27Jeschke et al27 compared 11 patients treated witha combination of artificial dermis (Integra; IntegraLifeSciences, Plainsboro, NJ), fibrin glue, and VACtherapy with 6 patients that received Integra cov-ered with a compression dressing. The researchersfound a significant increase in the Integra take anda decreased time to apply the autograft in the studygroup.27 Moisidis et al13 designed a prospective,randomized study in which skin-grafted woundswere divided into 2 areas-I treated with VACand the other treated with a standard bois ter dress-

ing. They were able to show improved graft take inthe areas treated with the VAC device. Two weeks

after grafting, the VAC-treated areas appeared tobe of better quality than the bolster group.

Decrease in edema and removai of wound exudate: Anobvious consequence of VAC therapy is the abilityto evacuate wound exudates. Clinicians are well

aware that edema impedes healing and recom-mend eIevation and compression of extremities todecrease edema and facilitate healing. Swelling

Surgeryluiy 2009

Fluid RemovalPore

~I~

Without Suction With Suction

Fig 4. Fluid remova!. The foam distributes the vacuumevenly throughout the wound and allows for transportof extracellular fluid to the wound surface.

from edema may actually cause compression ofcells within the extracellular matrix, thereby de-creasing their intrinsic tension, resulting in adecreased proliferative response (Fig 4). Applica-tion of a distributed suction allows direct evacua-

tion of fluid from the extracellular space andappears to decrease edema (Fig 4). In compart-ment syndrome of the extremities, there is massiveswelling that necessitates release of fascial compart-ments to maintain perfusion and prevent celldeath. By removing extracellular fluid, the VAC de-vice may hasten resolution of compartment syn-drome after fascial release and allow for earlier

closure of the fasciotomy wounds. In addition,there may be an increase in blood flow when theedema fluid concentrated around small blood ves-

seis is evacuated, but more research is needed.

Yang et al28 retrospectiveIy compared lower ex-tremity fasciotomies and demonstrated that thewounds could be closed in an average of 6.7 dayswith the VAC device versus 16.1 days without thedevice. Weiland29 used VAC devices in combina-

tion with hyperbaric oxygen therapy in 3 complexlower extremity crush injuries and suggested thatboth modalities may be synergistic in decreasingedema. DeFranzo et al30 showed decreases in the

extremity circumference and ::5500 ml/24 h re-moval of fluid from lower extremity wounds withexposed bone. The fluid flow past cells in thewound may also exert important shear stressesthat could modulate cell function.

At a basic leveI, tissue is composed of both fluidand solid phases. Within the extracellular matrix,the fluid phase is the interstitial electrolyte solu-tion, whereas the solid phase is the collagenousextracellular matrix. Mechanically deforming thisbiphasic material results in 2 phenomena, (1) astrain field is established in the solid matrix uponwhich the cells are anchored, and (2) a flow of

I

i86

SurgeryVolume146, Number 1

fluid is created within the interstices of the ma-

trix.31 Thus, cells are subjected to mechanicalstretch mediated by their attachments to the ma-trix and shear stress due to fluid flow. It is well es-

tablished that fluid shear stresses can regulatecellular proliferation and biosynthetic responsesin cell cultures.32 In addition, the movement of

ions in solution past matrix glycoproteins estab-lishes electric fields (ie, streaming potentials)that can also stimulate cellular responses.33,34 InVAC therapy, tissue deformation occurs by movinginterstitial fluid and deformation of the solid

phase, which is a process similar to what happenswhen one squeezes a wet sponge. Mechanicalloading directly drives the flow of interstitial fluidand mechanical deformation of structural macro-

molecules such as collagen.Murphey et al35 measured interstitial pressure

adjacent to the VAC device in an animal modeland found a gradient of pressures out to nearly1 mm from the wound surface when suction was

applied. Theoretically, cells embedded in the tis-sue are also deformed or, at the least, subjectedto forces that tend to deform the cell membrane,

Furthermore, deformation of tissue leads to

changes in ionic concentrations of the interstitialfluid as well as generation of interstitial electricalcurrents.31 To date, studies on shear stress have pri-marily concentrated on endothelial, bone, and in-testinal epithelial cells, and the results may not bedirectly translatable to wounds.36-39 In addition,there are notable toxic materiaIs within the wound,

including bacteria, inflammatory cytokines, andmatrix metalloproteinases (MMPs). A preliminarystudy from Stechmiller et al40 showed a significantdecrease in TNF-alpha from VAC wound fluid ex-tracted from pressure sores during the course ofI week.

Argenta and Morykwas 7 and Morykwas et aIS rec-ognized the importance of fluid removal as a sig-nificant benefit of the VAC device. Fluid removalis critical in burns to modulate the 3 zones of

injury originally described by Jackson.41 Jacksondescribed a zone of stasis that is a potentially re-versible area of the burn, which can be made worse

by hypoperfusion and edema. In experimental par-tial-thickness porcine burns, Morykwas et al42 sawsignificant decreases in burn depth when thewounds were treated with the VAC device. Accord-

ing to Jackson's description, the zone of stasis ex-ists for only the first 24 hours after injury; thiszone then becomes incorporated into either thezone of hyperemia (tissue should recover) or coag-ulation (irreversible tissue loss) .41The effect of theVAC device was to decrease the accumulation of

Orgillet ai 45

edema fluid, thereby limiting the depth of cellulardeath. The observed decrease in burn depth hasclinical importance because superficial 2nd-degreeburns have the capacity to heal, whereas deep2nd-degree burns are best treated with the more

invasive method of excision and graftin§.42 In 7patients with bilateral burns, Kamolz et al4 studiedperfusion and the amount of fluid removed. Inthis small study, their impression was that theVAC device increased perfusion to the hand, andthey removed a clinically relevant volume of extra-cellular fluid ($500 ml).

Intraabdominal hypertension can lead to intra-abdominal compartment syndrome. Release of theabdomen can be a lifesaving event but leaves thepatient with a very large, open wound with poten-tial complications of infection, hernia, and fistula.The VAC device provides a method to keep thewound moist, draw the wound together to mini-mize loss of domain, and evacuate excess abdom-inal fluidoThe bowel is covered with a plastic drapeto avoid direct contact of the polyurethane foamwith the bowel. Many centers perform VACchanges on open abdomens every 2-3 days in theoperating room with successive closure of theabdominal wound. Using this approach, skin graft-ing directly over bowel can be avoided in manycases.21

Microdeformation at the foam-wound interface:Woltr4 recognized the fundamental role of me-chanical force in regulating tissue growth, repair,and remodeling more than a century ago. Tissueadaptation to changing physical stresses is a basicrequirement for growth and survival of living sys-tems.32 Application of mechanical loading of tis-sues results in deformation. The magnitude ofthe biomechanical responses described above is de-pendent on the stiffness of the tissue to which theVACis applied and the dynamics ofthe mechanicalloading. If there is a rapid pressure change, thenthe flow of interstitial fluid will be more rapid. Ifthe pressure change is applied slowly,then intersti-tial flows will be more gradual and matrix stress ap-plied to cells will be much less. Thus, it is likely thatthe biologic response to VAC loading will dependon the frequency of vacuum application. There islimited published work done on phasic VAC ther-apy. Morykwas et aIs applied 125-mm Hg suctionto porcine wounds using a 5 minute on/2 minuteoff cycle and noted increased blood flow in thearea and an increase in hyperproliferative tissue.Wackenfors et al45applied 125 mm Hg of pressurewith the VAC device on porcine wounds intermit-tently with increasing periods of time between the"on" vacuum and "off" vacuum. They observed

87

46 Orgill et ai

that peak blood flow in the tissues decreased dur-ing the "on" periods and increased 40-50% abovebaseline when the vacuum was turned off.45 The

optimal waveform for the VAC device has yet tobe determined for specific wound types.

For biphasic materiaIs, mechanical deformationimposed on the surface defuses through the ma-trix at a rate that depends on tissue hydraulicpermeability, matrix stiffness, and deformationkinetics.34 Thus, both shear and deformation

forces acting on cells are dependent on the rateat which the fluid flows through the matrix. Theprecise mechanisms by which the frequency of im-posed stress influences cellular response are notwell described.

Microdeformations induce cellular proliferationand angiogenesis in vivO.22Skin expands as a resultof stretch in growth, morbid obesity, aging, andpregnancy. We commonly take advantage of this ef-fect in tissue expansion that shows a well-definedproliferative and angiogenic response.46 Ilizarov's. .

k b I h . 4748 h dplOneenng wor on one engt enmg , s owethat introducing gradual traction on bone leads toosteogenesis and that skin, muscle, and nervecould lengthen in tandem. A controlled distrac-tion rate of 0.25-0.7 mm per day in experimental

animal models showed increased cellular rrolifera-tion. In soft tissue, Pietramaggiori et al4 showedboth a vascular and proliferative response whenrat ears were placed under tension.

Often, in clinical practice, a number of woundsthat have minimal exudate into the VAC canis ter

have a dramatic proliferative response to VACtherapy. Huang et al50 and Huang and Ingber51 il-lustrated that nonmalignant cells require tensionto divide and prolifera te. Mechanical stresses cause

physiologic changes in cell function through amechanism referred to as mechanotransduction.52

According to the basic cell model proposed byHuang et ai50 and Huang and Ingber,51 much ofthe mechanotransduction cell signaling occursthrough the cytoskeleton. Integrins are also knownto be important in mechanotransduction and cantransmit surface signals to intracellular signalingmechanisms to alter gene transcription. To date,most mechanotransduction experiments havebeen conducted on vascular cells, osteocytes, andenterocytes.37

The currently known responses of vascular cellsto mechanical stimuli include inhibition of apo-ptosis, upregulation of cell signaling molecules(such as extracellular signal-regulated kinase path-way, Jun N-terminal kinase, stress-activated protein

~inase, an~ p38), ~hang.es i~ ~ene expression, andmcreases m prohferatlOn: 3,.4 McNulty et al53

SurgeryJuly 2009

showed greater cell death and less cell migrationand proliferation of fibroblasts with gauze undersuction than with VAC or static controls.Nishimura et al54 observed differences in human

dermal fibroblast response under differentfrequencies of stretch. Jacobs et ai 55 showed in-creased collagen organization and maturationand increased expression of vascular endothelialgrowth factor and fibroblast growth factor-2 in arat wound model using VAC compared to controI.

Saxena et al23 reported a mathematical modelof a wound treated with the VAC device. The

open-pore polyurethane sponge was modeled asa rigid device with a uniform pore structure in a2-dimensional modeI. Linear elastic propertiesfor the underlying tissue were assumed. The modelshowed that the wound would be compressedwhere it was in contact with the foam and, undertension, in the void between the foam struts. The

result was an undulating surface where the woundcontacted the foam. Increasing the vacuum or thepore size resulted in increased wound deforma-tion. Increasing the stiffness of the wound, a com-mon phenomenon during the healing process,decreased the deformation of the wound. When

the model was compared to histologic cross sec-tions ofwounds treated with the VAC device, there

was a remarkable similarity in the deformation pat-tem. The authors hypothesized that lengtheningthe wound surface on a microscale (microdefor-mation) resulted in stretching the cells within thewound.23 The model predicted that the VAC de-vice induced average tissue strains in the range of5-20%, depending on the stiffness of the woundand foam characteristics. These strains are

consistent with the range shown to promote cellu-lar proliferation in vitro.

The optimal physicochemical properties of theinterface materiaIs have not yet been elucidated,but a properly designed interface material may becritical to device performance. The current poly-urethane foam appears to have been discoveredempirically. A previous study by Scherer et al22shows that the foam by itself causes a vascularresponse of the wound. Application of suction tothe foam induces microdeformations of the wound

bed and induces both cellular proliferation androbust angiogenesis. The concept of microdefor-mation will be an important future area ofinvestigation.

Secondary effects. Speedswound healing.Josephet al12 randomized patients with pressure sore(s)to use of a VAC device or normal saline dressings;they found a decrease in wound volume of patientstreated with the VAC device at 6 weeks (78% vs

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SurgeryVolume146, Number 1

30%). Eginton et al56 designed a cross-over, ran-domized trial in diabetic foot wounds and showed

a decrease in wound volume of 59% vs 9%. Largerstudies in different wounds types are needed tobetter understand this effect.

Increasesin bloodflow around wounds: Because ofone or more of the primary mechanisms describedabove, there is an eventual increase in blood flowin the wound due to the VAC treatment. When a

c1inician changes a VAC device a few days afterapplication, increased granulation tissue with nu-merous smaIl blood vessels is observed on histo-logic sections.23 To study potential increasedperfusion to the tissues, most investigators haveused the noninvasive laser Doppler device. Al-though useful, laser Doppler does not determineblood flow directly, and so results from studies us-ing the device need to be interpreted with caution.Laser Doppler measures red ceIl velocity and con-verts it to blood flow by a derived formula. A de-crease in vessel diameter can cause increases influid velocity even though the overaIl flow is de-creased. Timmers et al57showed that laser Dopplerreadings increased when a VAC device was placedon normal human skin. Morykwas et al8 showedsimilar results on open porcine wounds using animplantable Doppler probe. Wackenfors et al45measured blood flow around a porcine groinwound treated with VAC and found an area ofhypoperfusion within about 1.5 cm from thewound edge.

Ichioka et al58designed an experimental modelthat quantitatively visualized the wound bed micro-circulation under subatmospheric application.They determined that a gauge pressure of -125 mmHg significantly increased blood flow in the woundbed immediately after pressure application and for1 minute after pressure release. In contrast, applica-tion of -500 mm Hg caused a decrease in bloodflow, reaching statistical significance after 5 minutes.Recently, Kairinos et al59measured tissue perfusionin healthy human subjects with a radiotracertechnique and showed a decrease in perfusion thatcorrelated to increased values of suction. Further

studies using thermal diffusion technology, corro-sion casting, fluorescent particles, or radioactivetracer methods may be more useful in providinga more thorough understanding of the angiogenicresponse to the VAC device and the appropriatetype and application of negative pressure to whichthe wound is exposed.

Changes in bacterialburden: Morykwas et al8 firstdescribed a decrease in bacterial load using theVAC device in experimental pigs. The mechanismbehind the observation is not c1ear, and there

Orgillet al 47

may be several factors that influence the total bac-terial burden of the wound, such as direct removalof bacteria and alterations in blood flow. Clinicalresults from other centers have yielded mixed re-sults. Moues et al60 studied 54 patients in a pro-spective, randomized trial in which one half ofthe patients were assigned to VAC therapy andthe other half was assigned to dressing changeswith normal (0.9%) NaCl. The researchers foundthat patients with wounds culturing nonfermenta-tive, gram-negative bacilli had decreased bacterialloads over time, whereas patients with wounds cul-turing Staphylococcusaureus had increased bacteriallevels over time.60

Alterations of the polyurethane foam may be animportant mechanism to better treat bacterial

colonization. One method involves coatin~ thepolyurethane foam with silver. Gerry et aI 1 re-ported on 2 patients with complex venous stasis ul-cers that were unresponsive to conventional VACtherapy but that responded weIl to the use of asilver-impregnated foam with the VAC device. In-stiIlation of solutions into the foam and wound

via the vacuum pump, a technique popularizedby Moch et al,62 may provide another method tohelp keep bacterial levels low in wounds. The is-sues of biofilms and defensins wiIl be important fu-ture areas of research.

Changes in wound biochemistry and systemic re-sponse: The expression of genes by ceIls in thewound and the regulation of gene expression arelikely to be important factors in explaining themechanisms of action of VAC therapy. Greeneet al63 studied the MMP profiles in 3 debilitatedpatients undergoing VAC therapy. In 1 area ofeach wound, the foam was not placed in contactwith the wound bed. Wound biopsy samples com-paring areas of foam contact with non-foam con-tact showed dramatic differences in angiogenicresponse and decreases in the MMP-9jNGAL(neutrophil gelatinase-associated lipocalin) andMMP-2. Shi et al64 performed a consecutive,1 week study of chronic wounds and showed adecrease in MMP-l and MMP-13 that was deter-mined by real time-polymerase chain reaction ofwound biopsy samples. The researchers64 hypothe-sized that the decreased MMP activity decreasedthe breakdown of the wound connective tissue ma-

trix, thereby blocking the inhibitory effects ofMMPs on wound healing. The biologic responsein the wound likely has some systemic effect.Norbury and Kieswetter65 showed a decrease in cir-culating monocytes and interluekin-6 36 hoursafter injury in porcine wounds treated with theVAC device.

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lmproves wound bed preparation:Surgeons recog-nize that a nicely granulating wound is likely to befavorable for skin grafting. Lack of granulationtissue is commonly seen in radiation or vascularwounds. Morykwas et al8 showed a greater than60% increase in granulation tissue formationwith application of VAC to porcine wounds incomparison to wounds treated with moist gauze.Further porcine studies showed that a 125-mmHg vacuum resulted in faster formation of granula-tion tissue than either 25 mm Hg or 500 mm Hg.66Armstrong and Lavery, in conjunction with theDiabetic Foot Study Consortium,10 performed aprospective, randomized controlled study of 162diabetic foot amputation sites; their study'sprimary endpoint demonstrated a greater rate ofclosure of the VACgroup compared to the controlgroup using standard wound care at 112 days (56%vs 39%).

Blume et al67studied diabetic foot wounds in 2

groups of patients; they noted that granulation tis-sue covered the wound more quickly in the groupof patients treated with the VAC device, resultingin faster wound closure, than the group of patientsreceiving standard treatment. Vuerstaek et al68carried out a prospective, randomized trial oflower extremity ulcerations, mostly venous in na-ture, and compared the effect of VAC therapywith standard compression therapy. When thewounds had filled with granulation tissue, the re-searchers applied 4-mm punch full-thickness skingrafts to the wounds. Wounds healed faster inthe VAC group (29 vs 45 days), and the time towound bed preparation was also shorter (7 vs 17days) .

DISCUSSION

The VACdevice most commonly is used with anopen-pore polyurethane ether foam that appearsto be an important component and contributes toseveral of the device's mechanisms of action byproviding an efficient removal of exudate, evenlydistributing pressure within the wound, and in-ducing angiogenesis. The compressibility of thefoam allows for the VAC device to exert tension

on many types of wounds, drawing the edges to-gether. In skin grafts, the foam provides a uniformdistribution of the vacuum, which results in a morereliable take of skin grafts. Effective fluid removalis important for swollen or edematous wounds,such as burns or the wounds used to relieve a com-

partment syndrome. Furthermore, microdeforma-tions of the wound surface seem to induce amechanotransduction mechanism that alters

Surgeryjuiy 2009

genomic expression to promote increased vasculargrowth and alter wound biochemistry. Additionalresearch in biomaterial properties of the foam, sur-face coatings, optimal pore structure, and mechan-ical properties will be important to identify theoptimal interface material.

Clinical research with wound healing devices ischallenging due to the heterogeneity of thewounds treated by clinicians, the variability ofresponse, the lack of agreement on the best end-point metrics, and the difficulty of blinding thetreatment arms. Most studies of the VACdevice are

case reports or retrospective clinical studies, oftenwithout optimal controls. Carefully designed clin-ical trials based on our recent understanding ofwound healing should add to our understandingof the mechanisms of action. The advances in

molecular biology, including gene chips, proteo-mics, zymography, and advanced methods to studycell biology, provide powerful tools for both basicscientists and clinicians to elucidate mechanismsof action.

The mechanotransduction and alterations in

extracellular fluid may be 2 of the unique mech-anisms of action of the VAC device. The time

course of the biologic response to microdeforma-tion in conjunction with the study of the optimalwaveform should be very important for the designof new therapies. Understanding the response ofcell deformation, cell wall tension, and cell shape,as well as fluid flow past cells may also add newknowledge to the mechanism of action.

Although the VAC device has caused a majorshift in wound care practice, the therapy is notbeneficial for the treatment of alI wounds. In

addition, the use of the VAC device is expensiveand should not be used in wounds that derive no

clinically important benefit. Some patients find thedevice cumbersome to wear as an outpatient andare happy to switch to a less complex modality.

Although most fgatients have reduced pain usingthe VACdevice, 9 some patients have reported sig-nificant pain. Caution should be used with patientsthat are anticoagulated or with bleeding that hasnot completely stopped before application. In-creased levels of bacteria in certain wounds cancause increased odor or delay healing. A better un-derstanding of the mechanisms of bacterial growthwhen the device is used and the effect of biofilms

would be helpful. The introduction of a silver-im-pregnated VACdevice61 and VAC devices irrigatedwith antibiotic solutions 70may provide more effec-tive methods to treat an increased bacterial load,but there are little published data to support theiruse.

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Since being introduced just more than 10 yearsago, the VACdevice has had a major impact on theclinical care of complex wounds throughout theworld. Like with any new technology, clinicians arestilllearning the optimal methods of application. Asmore is discovered about the mechanism of action,clinicians willlearn the most appropriate use ofVACtherapy in specific wound types and better devicesmay be designed in the future for the increasingnumber of complex wounds seen each year.

We would like to thank Lauren Bayer, PA-C, andKimberly Ross for their help with the manuscript, andjason Orgill and Britlyn Orgill for the figures.

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