development of a biodegradable foam for use in negative pressure wound therapy

Development of a biodegradable foam for use in negative pressurewound therapy

Jie Liu, Michael J. Morykwas, Louis C. Argenta, William D. Wagner

Department of Plastic and Reconstructive Surgery, Wound Repair—Nanomedicine Research Program, Wake Forest University

School of Medicine, Winston-Salem, North Carolina 27157

Received 15 June 2010; accepted 24 February 2011

Published online 6 June 2011 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/jbm.b.31854

Abstract: Treatment of wounds using negative pressure

wound therapy (NPWT) uses a nondegradable polyvinyl alco-

hol (PVA) foam in the application of negative pressures typi-

cally for 1–3 days. The purpose of this study was to construct

and test biodegradable poly(e-caprolactone) (PCL) foam as a

substitute for the PVA foam. Such a foam would be left

within the wound until healing was achieved and form a bio-

degradable matrix into which tissue would grow. The use of

such foam would obviate the need for any serial foam

changes and a final foam removal, thus making patient care

much easier and more economical. PCL foams were prepared

by salt leaching and phase separation. Morphological and

mechanical properties of the foams were characterized and

compared to PVA foam. PCL and PVA foams were tested on

the uncut surface of a pig liver maintained in a hydration

chamber continuously replenished with saline under the con-

ditions of negative pressure of 50 mm Hg for 72 h. The

results demonstrated that PCL foam made from phase sepa-

ration had the similar properties and function as the PVA

foam. The results demonstrate that PCL foam is an appropri-

ate substitute for currently used nondegradable PVA foam in

NPWT applications. VC 2011 Wiley Periodicals, Inc. J Biomed Mater

Res Part B: Appl Biomater 98B: 316–322, 2011.

Key Words: negative pressure wound therapy, poly(e-capro-lactone), foam, foam dressing, biodegradable polymer

INTRODUCTION

About 2% of the population in a lifetime will develop achronic wound, with a mortality rate from the wound of �2.5%. Negative pressure wound therapy (NPWT), also knownas vacuum-assisted closure (VACV

R

), is a technique of woundclosure used to promote healing in large or chronic wounds,fight infection, and enhance healing of burns. NPWT was firstdescribed by Argenta and Morykwas.1 It is a noninvasive anddynamic wound closure system that uses topical, controllednegative pressure continuously or intermittently to promotehealing in acute and chronic wounds. A vacuum is used toreduce pressure around the wound, to draw out excess fluidsand cellular wastes, and to promote formation of granulationtissue. This technique can be used to accelerate the rate ofhealing of soft tissue defects without frequent dressingchanges. Positive outcomes include reduced chronic edema,increased local blood flow, and enhanced new tissue forma-tion.2 Originally devised as a treatment for chronic wounds,NPWT has been widely accepted and used for almost everytype of wound. The technique is simple, widely applicable,cost effective, and clinically effective.3,4

In a typical NPWT, sterile, open-cell foam is connectedthrough incorporated tubing to a vacuum source. Thewound, foam, and connecting tubing are sealed with an ad-hesive film, which is semipermeable to water vapor.5 Thesemipermeable-closed system with a controlled subatmo-spheric pressure can be applied to a wound, and thus amoist wound chamber is created with excess fluid being

removed by suction.6 Currently, two major types of foamsare used: a ‘‘black" polyurethane (PU) foam (VAC Gran-uFoamVR , Kinetic Concepts [KCI], San Antonio, TX) or ‘‘white’’polyvinyl alcohol (PVA) foam (VAC VersaFoam (WhiteFoam),Kinetic Concepts [KCI], San Antonio, TX). In comparisonwith the PU foam for use in traumatology, the advantage ofusing PVA foam is defined by the physical characteristics,which include smaller pore size (60–270) mm versus PUfoam (400–600) mm. Therefore, less ingrowth of surround-ing tissue into PVA versus PU foam is observed duringNPWT, despite extensive contact with the surrounding tis-sue. In addition, changing and replacing PVA foam is not aspainful, causes less bleeding, and does not traumatize thewound during dressing changes.7

Even though there are several advantages of PVA whitefoam, as NPWT is used more and more frequently, complica-tions are being reported.8 Wound-healing complicationsinclude the loss of fragments of the foam dressings into thewound. Small fragments are usually inconsequential, butlarger pieces can be detrimental. Detached pieces of foammay become walled off as encapsulating granulation tissuedevelops.9,10 To prevent the complications caused by thefoam, the development of biodegradable foam which can beabsorbed in vivo and does not need further removal wouldrepresent improvement for NPWT. For clinical use, thewound bed would be covered with biodegradable foam cov-ered with an adhesive film and a wound bandage and thenconnected to the VAC system.

Correspondence to: W. D. Wagner; e-mail: [email protected]

316 VC 2011 WILEY PERIODICALS, INC.

In the recent years, biodegradable polymers have beenused in biomedical devices, wound dressing, and tissue scaf-folds in an increasing numbers of applications.11 The safeand predictable degradation of these biomaterials plays animportant role in evaluating their performance. The devel-opment of biodegradable polymers has been extensivelyexplored in the field of wound healing.12 Currently, manykinds of biodegradable polymers are available and are di-vided into two broad classes: naturally derived polymerssuch as collagen, gelatin, chitosan and starch, and syntheticpolymers such as poly(e-caprolactone) (PCL), poly(lactic-co-glycolic acid), and polyethylene glycol.13,14 The search forideal biomaterials is still on-going where properties such asthe structure of the material, mechanical properties, and thecell–material interactions are considered.

In this study, biodegradable foam was developed, whichcould be easily produced and used as a substitute for cur-rently used PVA foam in NPWT. PCL is a versatile syntheticpolymer with a very low glass transition temperature(�61�C) and a low melting point (65�C), which allows easyprocessing.15,16 PCL is a synthetic, biodegradable, and bio-compatible polymer, which has been investigated as a bio-material for surgery and drug-delivery systems.17 Further-more, PCL is the most widely investigated syntheticpolymer and has FDA approval for use in various medicaldevices. PCL is suitable material for the design and fabrica-tion of biocompatible scaffolds based on a low inflammatoryand immunological response. PCL is degraded by hydrolysisof the ester linkages at physiological conditions, and thereare no toxic effects from degradation products. The mechan-ical properties of PCL can be controlled by varying the poly-mer molecular weight and the processing method. In thepresent study, PCL foams were prepared by phase separa-tion and by salt-leaching methods. Physical properties of thefoams from the two different processes were evaluated andcompared to the commercially available PVA foam. The aimof the study was to develop biodegradable foam, with ahighly porous structure, sufficient mechanical strength, and,most importantly, the ability to effectively distribute a nega-tive pressure over a wound bed.

MATERIALS AND METHODS

MaterialsPCL (Mw ¼ 65 kDa), sodium chloride (NaCl) þ80 mesh, and1,4-dioxane were purchased from Sigma Aldrich (St. Louis,MO). Dulbecco’s minimum essential medium (DMEM), phos-phate-buffered saline (PBS), and fetal bovine serum (FBS)were purchased from Gibco (Carlsbad, CA). All otherreagents were of analytical grade. IOBANVR antimicrobialincise drape was purchased from 3M, St Paul, MN.

Foam fabrication and morphological characterizationPCL foams were fabricated by the methods of salt leachingand phase separation. Briefly, for the salt-leaching method,PCL was dissolved in chloroform at a concentration of 10%(w/v). Polymer solution was mixed with sodium chloride(salt) with the weight ratio of polymer:salt (1:10) and castinto glass Petri dish. The mixture was dried in a fume hood

overnight. Porous foam was formed by removing the salt indeionized water overnight.

For phase separation, PCL solution was prepared by dis-solving PCL in 1,4-dioxane at a concentration of 7% (w/v)and mixed for 4 h at room temperature. Six milliliters werethen poured in a 6-cm glass Petri dish and frozen at �70�Covernight. High porosity scaffolds were subsequently pre-pared by immersing the frozen PCL into 80% (v/v) ethanolsolution at 20�C. The pores were achieved through thereplacement of 1,4-dioxane by ethanol. After phase separa-tion, the resulting foam was rinsed using running water.The microstructure of the PCL and PVA foam dressings wascharacterized by scanning electron microscopy (SEM). Poresize was measured. The porosity of samples was calculatedfrom the following equation:

Pore size was measured on five individual foam samplesfor each of the three types of foams studied. For each foamsample, 25 random measurements for pore size werecompleted.

The porosity of samples was calculated from the follow-ing equation:

Porosity ð%Þ ¼ ðVA � VPÞ=Vp

where VA is the apparent volume and VP is the PCL polymervolume, which can be derived from the actual amount ofpolymer, m (g), and density q (g/cm3).

Mechanical testingThe mechanical properties of the PCL and PVA foams weredetermined by tensile testing. The PVA foam was used as acontrol. Foams were soaked in PBS for 12 h before testing.Strips of 2 cm � 2.5 cm � 2.5 mm (w � l � t) were cutfrom each foam and stretched until break at a constantcrosshead speed of 0.5 mm/min using an INSTRON 5500R(INSTRON, Canton, MA). Elastic modulus, elongation atbreak, and tensile strength were obtained from the stress–strain curve instantaneously using the associated software.At least five samples were measured for each kind of foam,and the average values were reported. The PCL foam (pre-pared by salt leaching or phase separation) with the greatermechanical similarity to the PVA foam was selected for thefollowing experiments.

Fluid uptake abilityThe fluid uptake ability was determined by swelling thefoam dressings in PBS (1�). The foam was removed fromPBS after equilibrium swelling was reached, and net weightwas measured after the removal of surface nonabsorbedwater. Each swelling experiment was repeated three times,and the average values were calculated by the followingequation:

EW ¼ ½ðW2 �W1Þ=W1� � 100%

where EW is the percentage of water absorbed by the foamand W1 and W2 are the weights of the samples in the dryand wet conditions, respectively.

ORIGINAL RESEARCH REPORT

JOURNAL OF BIOMEDICAL MATERIALS RESEARCH B: APPLIED BIOMATERIALS | AUG 2011 VOL 98B, ISSUE 2 317

Biodegradation test in vitroThe degree of biodegradation was estimated from the PCLmass loss in PBS solution. First, the dry PCL foams wereweighed and then immersed in 1 mL of PBS (0.01M and pH7.4) at 37�C in an incubator. The PBS was changed every 3days. After a particular period of incubation time, threesamples were taken out of the PBS solution. The residueswere centrifuged, lyophilized until dry, and weighted again.The weight loss was calculated by the flowing equation:

Weight loss ¼ ½ðW0 �WdÞ=Wd� � 100%

where W0 is the initial weight and Wd the weight after deg-radation at different time points.

Biocompatibility evaluation in vitroTwo different groups were tested for cytotoxicity; the con-trol group was human palatal mesenchymal cells (HEPM)(ATCCV

R

, Manassas, VA) grown on plastic culture dishes, andthe sample group was the cells grown in culture in thepresence of the foam. The results are reported as the per-centage of cell numbers in the sample exposed group di-vided by the control group. The PCL foam was cut intopieces of 0.5 g each and sterilized in 70% ethanol followedby ultraviolet irradiation. HEPM cells were cultured in 25-cm2 tissue-culture polystyrene flasks containing growth me-dium and maintained at 37�C in a humidified, 5% CO2

atmosphere. The cell-culture medium was composed ofDMEM, 10% (v/v) FBS, 2 mM L-glutamine, and antibiotics ata final concentration of 100 lg/mL penicillin and 100 lg/mL streptomycin. Cells were seeded in a 24-well culturedish at an initial density of 1 � 104 cells/well, and culturemedium was changed every 3 days. 3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tet-razolium) (MTS) assay was performed on days 1, 3, and 7to determine cell viability in each well. Absorbance wasmeasured at 490 nm. The intensity of blue color is directlyproportional to the metabolic activity of the cell population

and inversely proportional to the toxicity of the material orextract. The results are reported as the percentage of thecontrol (n ¼ 5).

Foam testing under a negative pressure systemThe ability of foam to remove fluid from a tissue was eval-uated by a customized negative pressure system in vitroillustrated in Figure 1. A fresh pig liver was used to mimicthe wound surface. The lower portion of the liver was cutto enable fluid influx through the fresh tissue. The liver wasthen placed in a saline bath. The depth of the saline wasmaintained to ensure fluid immersion of the bottom one-third of the liver. Samples of the PCL and PVA foams wereplaced on the top surface of the liver and covered withIOBAN. A tube for application of vacuum, and evacuation offluid, exited from under the thin film of IOBAN and wasattached to a vacuum source (V.A.C. Classic, KCI, San Anto-nio, TX). The pressure was set as �50 mmHg, and the vol-ume of the fluid removed through the foam was measuredat 24, 48, and 72 h. Data were collected to evaluate continu-ous fluid flow through the biodegradable foam and to verifymaintenance of negative pressure during the testing times.

Statistical analysisThe data were analyzed statistically via ANOVA. All the val-ues were presented as mean 6 standard deviation (SD). Avalue of p < 0.05 was regarded to be statisticallysignificant.

RESULTS

Preparation of foamsThe morphology and the pore structure of PCL foams pre-pared from two different methods were compared to PVAfoam. SEM images showed the porous structure of the PCLfoam prepared by both methods (Figure 2). PCL preparedby phase separation had similar pore size and porosity as

FIGURE 1. A customized negative pressure system to test foams. (a) An illustration of the negative pressure system; (b) foam dressings placed

on a pig liver, all foams were covered with nonporous film IOBANVR (not shown), and terminally fenestrated polyethylene tubing with an inner

diameter of 0.6 mm was used to connect the sponge to the pump through a fluid trap. [Color figure can be viewed in the online issue, which is

available at wileyonlinelibrary.com.]

318 LIU ET AL. BIODEGRADABLE FOAM FOR USE IN NPWT

the PVA foam, whereas PCL prepared by salt leaching hadsignificantly smaller pore sizes and less porosity (Table I).

Mechanical testingFigure 3 shows a typical stress–strain curve obtained fromthe testing a PCL foam. The values of maximum stress, max-imum strain, and elastic modulus were derived from thestress-curve, and all the parameters were comparedbetween the two preparations of PCL foams and the PVAfoam (Table II). For the data before NPWT, there was a sig-

nificant difference for several mechanical parametersbetween the PVA foam and PCL foams prepared by salt-leaching. However, in all cases, the PCL foam prepared bythe phase separation rather than the salt-leaching methodwas more similar to PVA foam. Thus, based on foam mor-phology, pore size, and better tensile properties, functionaltesting was completed only on PCL foams prepared byphase separation to compare to the PVA foam.

Fluid uptake testingFigure 4 demonstrated that the percentage of fluid uptakewas around 200% for both PCL and PVA foams. No signifi-cant difference was found between two foams.

Biodegradation test in vitroDegradation was carried out at pH 7.4 and 37�C and pro-duced erosion and roughness of the PCL foam surface. Theweight of the foam steadily declined with incubation time.The degradation also affected the inner part of the foam.The results in Figure 5 show that more than 80% weightloss was achieved for the porous PCL foam over 33 weeks.

Biocompatibility testing of PCL foam in vitroFor the PCL foam, cytotoxicity was evaluated using MTSassay at 1, 3, and 7 days. The results showed that over 85%cell viability was observed for all the time points demon-strating that over a 7-day period, the foam was biocompati-ble with cells.

Foam testing under a negative pressure systemThe transmission of fluid from the inferior surface of theliver through the two different foams (PVA and PCL) wascompared, and the PCL foam had a similar ability to removethe fluid as PVA foam (Figure 6). This property is criticalfor the application as foam for use in NPWT. In addition, thePCL foam maintained original mechanical properties afterthe negative pressure treatment (Table II).

DISSCUSION

NPWT has significantly changed the way clinicians managea wide range of chronic or acute wounds. In the last 20years, widespread applications of NPWT have been drivenlargely through favorable clinical outcomes.18 One of thefundamental effects of negative pressure delivery at thewound bed is widely believed to be the induction of

FIGURE 2. SEM images of different kinds of foams: (a) PCL (SL); (b)

PCL (PS); (c) PVA (�50). SL, salt leaching method; PS, phase separa-

tion method.

TABLE I. Morphological Characterization of Foams

Foams Pore Size (lm) Porosity (%)

PCL (SL) 145.4 6 22.5* 72.1 6 11.9*PCL (PS) 285.4 6 17.8 81.8 6 7.2PVA 242.5 6 31.3 83.8 6 10.1

All the values are mean 6 SD and five individual foam samples

were used.

For each sample 25 random measurements for pore size were

completed.

SL, salt leaching method; PS, phase separation method.

* (p < 0.05) PCL (SL) < PCL (PS) ¼ PVA for pore size. PCL (SL) <

PCL (PS) ¼ PVA for porosity.



mechanical deformation of the tissue. The interaction of tis-sue and wound foams at the microscopic level is thought toresult in further interrelated biological effects including thepromotion of periwound blood flow, removal of bacteria,and a stimulation of granulation tissue formation, as origi-nally defined and reviewed by Morykwas et al.19,20

Currently, the most commonly used wound bed materialin NPWT is the black PU foam. However, there are a numberof circumstances that require the white PVA foam. Both PUand PVA foams are not biodegradable and, if excessive tis-sue ingrowth occurs, may require surgical removal. Biode-gradable polyesters are widely used in medical device,because they typically have good strength and an adjustabledegradation speed.21 PCL prepared from e-caprolactone hasreceived FDA approval for several clinical applications inhumans where temporary mechanical or therapeutic func-tion is needed.22,23

A biodegradable PCL foam was developed in this studyand tested as a substitute for the PVA foam. Two processingmethods were used to fabricate PCL foams, and the result-ing foams were compared to the commercially available PVAfoam. In the present study, an in vitro porcine liver with alarge surface area was used to mimic an injury site resultingfrom traumatic wounds or decubitus ulcers, which are fre-quently treated with NPWT. The ability to remove the tissuefluid was compared between PVA and PCL foams using acustomized in vitro NPWT system (Figure 1).

To prepare a 3D porous scaffold, a suitable method andsolution are important to achieve the appropriate proper-ties. The pore structure of a material has an importanteffect on cell behavior and tissue growth. The pore structureof the foam can be controlled by selecting specific fabrica-tion parameters, such as solution concentration and proc-essing conditions. The microenvironment can affect the per-formance of the foam. By visual inspection PCL foamsproduced by either salt leaching or phase separation grosslyappeared homogeneous. However, the microscopic features(Figure 2) indicated different morphologic features suggest-ing more homogeneity in PCL foam prepared by phase sepa-ration compared to PCL prepared the salt leaching method.The porosity of the PCL foam prepared by phase separationwas 81.8% and more similar to PVA foams in contrast tolower porosity for PCL foam prepared by phase separation(Table I). The PCL foam (phase separation) should functionbetter in fluid removal and nutrient exchange.

The mechanical integrity of the foams used in NPWTapplications is mainly related to the material selection, themorphology design, and cell–material interaction during cellcultures in vitro and implanted in vivo. PCL foams preparedby phase separation demonstrated high mechanical strengthand elasticity, which permits the maintenance of shape fol-lowing negative pressure application. Desirable mechanicalproperties of the PCL foam make it a suitable candidate tobe used as foam dressing in NPWT. The fluid absorbingcapacity of the foam is one of the important criteria formaintaining a moist environment over the wound bed. The

FIGURE 3. Stress–strain curve of PCL foam. [Color figure can be

viewed in the online issue, which is available at wileyonlinelibrary.

com.]

TABLE II. Mechanical Properties of Foams Before and After NPWT

Foam Max stress (MPa) Max strain (mm/mm) Young’s modulus (MPa)

PCL (PS) Before NPWT 0.52 6 0.11 0.59 6 0.21* 2.42 6 0.36After NPWT 0.46 6 0.09 0.51 6 0.17* 2.58 6 0.74

PCL (SL) Before NPWT 0.29 6 0.16* 0.31 6 0.38 10.5 6 0.83*PVA Before NPWT 0.43 6 0.08 2.95 6 0.59* 0.24 6 0.07

After NPWT 0.41 6 0.05 2.69 6 0.96 0.18 6 0.06

All the data are presented as the value of (mean 6 SD).

Before NPWT.

* p < 0.05. PCL (SL) < PCL(PS) ¼ PVA for max stress.

PCL(SL) ¼ PCL(PS) < PVA for max strain.

PCL(SL) < PCL(PS) < PVA for Young’s modulus.

FIGURE 4. Fluid uptake evaluation.


PCL foam has high-water uptake ability, around (200%),which suggests a high ability to retain water at the woundbed surface.

The mechanism of degradation, bulk or surface erosion,depends on the diffusivity of water inside the matrix, the deg-radation rate of the polymer, and the matrix dimensions. Po-rous PCL foam with interconnected pore network was pro-duced by phase-separation method. The foam had a largepore size and a very high surface area. Once the polymerhydrolyzes, there is a decrease in the molecular weight, fol-lowed by a loss of mechanical properties, and finally a loss ofmass caused by the dissolution of small polymer fragments.24

The success of many medical devices and implants islimited by the interaction of the device materials with thetissues that they contact. Biocompatibility testing in vitroshowed that the PCL foam was safe to cells and was bio-compatible over a 7-day time period during which cell ad-hesion and proliferation are critical. PCL has been reportedto have excellent long-term biocompatibility in vivo.24 Inthis study, using rabbits, PCL implanted for 2 years in a cal-varial defect, a bulk degradation mechanism was suggested,and histologic evaluation illustrated mineralized bone pene-tration into PCL pores and excellent tissue integration.24

In this study, biodegradable PCL foams were success-fully fabricated by phase separation and salt leaching. ThePCL foam produced by phase separation was morphologi-cally and mechanically more similar to the PVA foam com-pared to PCL foam produced by salt leaching. The presentstudy directly compares the properties of PVA foam andbiodegradable PCL foam (phase-separation method ofpreparation). The study shows that the PCL foam and PVAfoam have similar physical properties and ability to deliverfluid through the NPWT system. All testing results indicatethat the biodegradable PCL foam dressing can be used asa substitute for the commercially available PVA foam inNPWT cases requiring at least 3 days of treatment andpotentially longer. Although the mechanical properties ofthe PCL foam were not perfectly comparable to the PVAfoam, the functional data demonstrate that the PCL foamperformed adequately and comparably to the PVA foamand thus could be used in a variety of clinical cases forrepair of superficial as well as deep wounds.

A biodegradable foam would clinically have a significantadvantage over present foams. Present foams must beremoved at 3-day intervals as tissue grows into the foamand thus would encase a nondegradable foreign body. Bio-degradable foam offers the benefit of acting as a regenera-tive matrix into which tissue could grow but without theconsequence of becoming a long-term imbedded foreignbody. A resorbable matrix could be a one-time placementthus negating the need for serial foam changes. A biode-gradable matrix would make patient care more simple, lessuncomfortable, and more cost efficient.

We envision that the PCL foam developed in this studywould be used as a single application where NPWT is con-ducted up to a 3-day period without change of foam. In clin-ical cases where longer NPWT is required, additional stud-ies are warranted before treatment methods of additionfoams to existing foam/wound bed or replacement of exist-ing PCL foam would be recommended.

ACKNOWLEDGMENTS

The authors gratefully acknowledge the excellent technical as-sistance of Eboni Hobley, NC AT&T, Maria Tervel, College ofCharleston, and Rui Wang, Wake Forest University. We thankTabitha Rosenbalm for assistance in reviewing data and RobinShelton for the assistance in manuscript preparation.

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development of a biodegradable foam for use in negative pressure wound therapy

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