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SOCIEDADE BRASILEIRA DE ORTOPEDIA E TRAUMATOLOGIA

w w w . r b o . o r g . b r

Original Article

The effects of ethyl-2-cyanoacrylate and

butyl-2-cyanoacrylate in the process of bone

healing in rats. A controlled experimental study

Evandro Pereira Palacio

a,∗

, Gilberto José Cac¸ão Pereira

a

,

Paulo Roberto de Almeida Silvares

a

, Gabriel Guimarães Di Stasi

b

, Caio de Andrade Staut

b

, Trajano Sardenberg

a

aDepartamentodeCirurgiaeOrtopedia,FaculdadedeMedicinadeBotucatu,UniversidadeEstadualPaulista(UNESP),Botucatu,SP, Brazil

bFaculdadedeMedicinadeMarília,Marília,SP,Brazil

a r t i c l e i n f o

Articlehistory:

Received17October2016 Accepted23December2016 Availableonline6December2017

Keywords:

Cyanoacrylates Tissueadhesives Fractures,bones Fracturehealing

a bs t r a c t

Objective:Syntheticadhesivesareusedbyvariousmedicalspecialties,especiallyinsurgery;

however,studiesreportingtheiruseinorthopedicpracticearescarce.Theaimofthisstudy wastocomparetheresultsinusingethyl-2-cyanoacrylateorbutyl-2-cyanoacrylateinthe treatmentoffracturesinrats.

Methods:Thiswasanexperimentalprospectivecontrolledstudyin90rats,withhumerus, femur,andtibiafractures,treatedwithethyl-2-cyanoacrylate(SBgroup;n=45)orbutyl- 2-cyanoacrylate(HAgroup;n=45).Biomechanicalandhistomorphometricanalyseswere performedatthreedifferentmoments(60,120,and180days);besidesaclinicalstudyper- formedweeklybymeasurementoftheanimalsbodymass.

Results:Nodifferenceswereobservedregardingbodymass(p=0.07).Inbothgroups,there were no significant differences regarding maximum load(p=0.6), yieldpoint strength (p=0.6),andstiffnesscoefficient(p=0.4)ofthefemurs.Thesamewasobservedintibias formaximumload(p=0.4),yieldpointstrength(p=0.7),andstiffnesscoefficient(p=0.6).

Thehumerusfrombothgroupshadsimilarbonecallusarea(p=0.66).Inbothgroups,there werenostatisticaldifferencesrelatedtoinflammatorycells(p=0.4),osteoblasts(p=0.2),and osteoclasts(p=0.2).

Conclusion: Ethyl-2-cyanoacrylate was more effective than butyl-2-cyanoacrylate in the treatmentoffracturesinrats.

©2017SociedadeBrasileiradeOrtopediaeTraumatologia.PublishedbyElsevierEditora Ltda.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(http://

creativecommons.org/licenses/by-nc-nd/4.0/).

夽StudyconductedattheDepartamentodeCirurgiaeOrtopedia,FaculdadedeMedicinadeBotucatu(UNESP),Botucatu,SP,Brazil.

Correspondingauthor.

E-mail:palacio@fmb.unesp.br(E.P.Palacio).

https://doi.org/10.1016/j.rboe.2017.11.010

2255-4971/©2017SociedadeBrasileiradeOrtopediaeTraumatologia.PublishedbyElsevierEditoraLtda.Thisisanopenaccessarticle undertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).

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morfométricasemtrêsmomentos(60,120e180dias),alémdoestudoclínicopelaaferic¸ão semanaldamassacorporaldosanimais.

Resultados: Nãoforamobservadasdiferenc¸asrelacionadasàmassacorporaldosanimais (p=0,07).Osfêmuresdeambososgruposnãoapresentaramdiferenc¸acomrelac¸ãoàcarga máxima(p=0,6),limitedeelasticidade(p=0,6)ecoeficientederigidez(p=0,4).Analisando- seastíbias,omesmofoiobservadocomrelac¸ãoàcarga máxima(p=0,4),aolimite de elasticidade(p=0,7)eaocoeficientederigidez(p=0,6).Osúmerosdeambososgruposapre- sentaramamesmaáreadecaloósseoformado(p=0,66).Emambososgrupos,nãohouve diferenc¸aestatísticarelacionadaaonúmerodeosteoblastos(p=0,2),osteoclastos(p=0,2)e célulasinflamatórias(p=0,4).

Conclusão:Oetil-2-cianoacrilatofoimaiseficazdoqueobutil-2-cianoacrilatonotratamento defraturasemratos.

©2017SociedadeBrasileiradeOrtopediaeTraumatologia.PublicadoporElsevier EditoraLtda.Este ´eumartigoOpenAccesssobumalicenc¸aCCBY-NC-ND(http://

creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Theuseofsyntheticadhesivesinmedicalpracticehasdrawn the attentionofresearchersworldwide.Theidealadhesive shouldhavethefollowingessentialcharacteristics:fastadhe- siontothetissue,lowheatrelease,goodadhesioneveninan internalhumanenvironment,theabilitytobesterilizedand, especially,itshouldnothavecarcinogenicpotential.1

Inmedicine,cyanoacrylatesarewellknownfortheirbacte- ricidalcharacteristics.2DeAlmeidaManzanoetal.3reported the effective antimicrobial action of ethyl-2-cyanoacrylate against Staphylococcus, Streptococcus, Escherichia coli, and Escherichia faecalis strains. Shamiyeh et al.4 and Coulthard etal.5 didnotobserve anyincrease ininfection ratesafter the use of cyanoacrylates. Regarding histotoxicity, several authors6–13haveanalyzedtheinflammatoryandcarcinogenic effectsoftheseadhesives,findingfewornodeleteriouseffects tothehumanbody.

Themedicalliteratureleavesnodoubtastothesafetyand efficacyoftheuseoftheseadhesives.However,therearefew reports14–17ontheiruseinthetreatmentofbonelesions.

Inthecaseofintra-articularfractures,itisagreedthatfix- ationmustbeanatomical.Withtheexceptionoflargebones (femur,humerus,tibia,etc.),whichmustbereconstructedwith theaidofmetalimplants,thereisagreatdebateonthebest treatmentoptionforsmallandtubularbones.

Thus,consideringthelackofpublicationsonthesubjectin thevariousdatabasesavailable,thepossibilityofopeningnew linesofresearchand,primarily,thegoalofreducingfinancial costs,sequelae,andhospitalizationtime,thisstudyisaimed

atcomparingtheresultsoftheuseofethyl-2-cyanoacrylate to butyl-2-cyanoacrylate in the treatment of fractures in rats.

Material and methods

All procedures were approved bythe Ethics Committeeon AnimalUseofthisinstitutionunderNo.1495/2014.

Thesamplesizewasdeterminedpriortothestartofthe study,consideringthe␣-risk(0.5%)and␤-risk(80%),andthe range ofthe variables, reachinga total often animals per group.

Ninety male Wistar rats (Rattus novergicus albinus) were used.Atthebeginningofthestudy,theratswere60-days-old and,afterbeingclinicallyevaluatedandweighed,werehoused inpolypropylenecages,inanenvironmentwithacontrolled temperatureof22Candalight–darkcycleof12h.Rodentfeed andwaterwereofferedadlibitum.

The animals were randomly selected by the process of opaqueandsealedenvelopes18,19 intotwogroups:GroupSB (n=45)andGroupHA(n=45).

Osteotomies were performedafter intraperitoneal anes- thesia (30mg/kg ofsodium pentobarbital 3%) and bilateral trichotomy along the humerus, femur, and tibia. Subse- quently, theanimalsunderwent regionalasepsiswithsoap and water, followed by antisepsis with 0.2% chlorhexidine aqueoussolution,and thenwereplacedonasurgicaltable inthelateraldecubitusposition.

Afterfenestratedsteriledrapeswereplaced,longitudinal incisions weremadeinthe skinbetweenthe shoulderand

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Fig.1–Dissectionandexposureofthefemurpriorto osteotomy.

Fig.2–Femoralosteotomy.

elbowjoints(foraccesstothehumerus),betweenthehipand knee(foraccesstothefemur),andbetweenthekneeandankle (foraccesstothetibia).

Theboneswereexposed,passingthroughthemusclelay- ers,allowingaccesstothem(Fig.1).Boneosteotomywasthen performedin diaphyseal regions (Fig. 2), undercontinuous manualirrigationwith0.9%salinesolution.

The osteotomies on the right side were treated with two drops of colorless ethyl-2-cyanoacrylate or butyl-2- cyanoacrylate, placed directly between the osteotomized ends.Theosteotomiesontheleftsideweretreatedwithout any exogenous substance, serving as controls. Muscle and skinweresuturedwithMononylon*3-0(Ethicon®).Afterthe surgicalprocedures,theanimalswerekeptinconfinement, receiving0.1mLofsodiumdipyroneevery6h,for36h.

Throughoutthestudy period,theanimalswereweighed weekly.

Theanimalswereeuthanizedinthreemoments:60,120, and180postoperativedays,when15animalsfromeachgroup wereeuthanizedwithalethalintraperitonealdoseof80mg/kg ofsodiumpentobarbital3%.Therightandlefthumeri,femurs

Fig.3–TibiafromtheHAgroupwithabscessregion (arrow).

Fig.4–TibiafromtheSBgroupwithadhesiveextrusion (arrow).

andtibiaeweredisarticulatedandcleansedofallsofttissue (Figs.3and4).

Theanatomicalpieceswerewrappedingauzesoakedin 0.9% saline, then wrapped in aluminum foil, labeled, and immediatelysentforbiomechanicalandhistomorphometric assays.

Bodymassanalysis

Measurementsweremadeweekly,preferablyonthesameday oftheweek,usingaportableelectronicscale,withacapacity of600g×0.01g.

Biomechanicalanalysis

ThebiomechanicaltestswereperformedusinganEMIC©uni- versal testing machine, model DL 10,000,with accuracyof

±(0.018+F/3700) kN,conformingtothespecificationsofthe following standards: ABNT NBRNM ISO 7500-1: 2004 (Cor- rectedVersion:2004)andABNTNBRISO376:2012(Corrected Version:2013).

Axial compressiontests wereperformed onthe femurs:

thefemoraldistalendswerefixatedverticallyin35mLplastic containerswith30mLofself-polymerizingacrylicresin(Jet®).

Thecleaverofthetestingmachine,itsendbeingconcave,was positionedattheheadofthefemur,fittingitperfectly.

Oncethetestwasinitiated,thecleaverwassetataspeed of30mm/mintothebreakingpointofthetestpiece,atwhich pointtheMtest®programautomaticallystoppedthetestand providedthe final resultsthrougha “loadvs. deformation”

diagram(Fig.5).

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Deformation (mm)

Fig.5–Diagramofloadvs.deformation.

Thesameprocedureswereadoptedforthetibiae,butthree- pointflexiontestswereconducted:thetibiaewerepositioned horizontally, supported at their extremities. The distance betweenthesupportpointswasstandardizedastwo-thirds ofthelengthofthetestpiece.Thecleaverdeliveredaload perpendiculartothebonediaphysis.

Thefollowingvariableswerestudiedbothinthefemurs andtibiae:yieldpointstrength(N),maximumsupportedload (N),andstiffnesscoefficient(N/mm).

Histomorphometricanalysis

Thehumerusslideswerepreparedwithhematoxylin–eosin (HE)staining,soastoprovidelongitudinalcutsoftheareaof interest(bonecallus).20

Inthehistologicalanalysis,the followingvariables were studied: number of osteoclasts per mm2 (n−1), number of osteoblastspermm2 (n1),and numberofanomalouscells (tumororinflammatory)permm2(n1).

For the morphometric analysis, the slides were placed underamicroscope(Laica®)coupledtoavideomonitorwitha resolutionof1024×768pixels,whichsentthedigitalimagesto acomputer.Thearea(␮m2)ofneoformedbonewascalculated withtheImageProPlusimagingprogram(MediaCybernetics, SilverSpring,MD,UnitedStates).

Statisticalanalysis

Thestatistical analysis wasperformed byanalysis ofvari- ance, in a completely randomized model, complemented

Throughout the experiment, the animals were examined daily;noclinicalorbehavioralchangeswereobserved.

Regardingthebodymassoftheanimals,nostatisticaldif- ferencerelatedtotheadhesiveusedwasobservedthroughout theexperiment(p=0.07;Table1).

Regarding the maximum load,the analysisofvariances demonstratedthatthefemursoftheSBgroupsupportedan axialloadequaltothatofthefemursoftheHAgroup(p=0.6);

thesamewasobservedfortheyieldpointstrength(p=0.6)and thestiffnesscoefficient(p=0.4;Table2).

Inthecaseofthethree-pointflexiontests,thestudyofthe variancesshowedthatthetibiaeoftheSBgroupsupported amaximumloadequaltothatofthetibiaeintheHAgroup (p=0.4);thesamewasobservedfortheyieldpointstrength (p=0.7)andthestiffnesscoefficient(p=0.6;Table3).

Regardingtheareaofbonecallusformation,thestatistical analysisdemonstratedthatthehumerifromtheSBgrouphad thesameneoformedboneareaasthosefromtheHAgroup (p=0.66;Table4).

The results of the statistical analysis of the cellularity, shown in Table 5, demonstrated that the concentrationof osteoblastsfoundinthebonesoftheSBgroupwasthesame asintheHAgroup(p=0.2);thesamewasobservedforosteo- clastconcentration(p=0.2)andforinflammatorycells(p=0.4), althoughtheresultsfoundinthelattervariableweremarkedly higherintheHAgroup.

Notumorcellswereidentifiedinanyofthegroups.

Allspecimensassessedpresentedadhesiveresidue;how- ever,inthebutyl-2-cyanoacrylategroup,theseresidueswere largerindiameter.Infact,therapidpolymerizationofthat adhesivemayoriginatesolidnodulesthatactastrue“foreign bodies.”Theseremainattachedtobonetissueandadjacent musculature, perpetuatingawhitecell lineathighlevels17 (Table5).

Discussion

Since 1940, the use of synthetic adhesives for the recon- structionofhumantissueshasbeenintensivelyresearched.

Table1–Meanandstandarddeviationofbodymass(g),accordingtotheadhesiveusedandthemomentofeuthanasia.

Adhesiveused Momentofeuthanasia

60days 120days 180days

Ethyl-2-cyanoacrylate 204±15.3 289.1±23.6 330.8±6.4

Butyl-2-cyanoacrylate 195.4±7.2 273.5±14.8 312.2±21.2

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Table2–Resultsoffemoraltests:meanandstandarddeviationofthemaximumload(N),yieldpointstrength(N),and stiffnesscoefficient(N/mm),accordingtotheadhesiveusedandthemomentofeuthanasia.

Studiedvariable Adhesiveused Momentofeuthanasia

60days 120days 180days

Maximumload(N) Ethyl-2-cyanoacrylate 138.7±12.4 141.4±13.1 153.7±10.6

Butyl-2-cyanoacrylate 112.6±8.9 124.2±12.2 129.8±14.8

Yieldpointstrength(N) Ethyl-2-cyanoacrylate 119.8±14.1 124.6±16.8 129.7±13

Butyl-2-cyanoacrylate 105.8±8.9 112.6±9.2 113±11.4

Stiffnesscoefficient(N/mm) Ethyl-2-cyanoacrylate 171.7±15.1 214.3±28.2 236.2±32.7

Butyl-2-cyanoacrylate 130.1±19.3 158.2±11 176.4±6.7

Table3–Resultsofthetibialtests:meanandstandarddeviationofthemaximumload(N),yieldpointstrength(N),and stiffnesscoefficient(N/mm),accordingtotheadhesiveusedandthemomentofeuthanasia.

Studiedvariable Adhesiveused Momentofeuthanasia

60days 120days 180days

Maximumload(N) Ethyl-2-cyanoacrylate 124.7±10.5 133.8±11.3 137.5±9.8

Butyl-2-cyanoacrylate 111.4±12.6 121.3±16.6 125.1±8.3

Yieldpointstrength(N) Ethyl-2-cyanoacrylate 121.5±6.3 129.6±10.2 132.9±11.1

Butyl-2-cyanoacrylate 108.4±4.7 118.3±9.8 119.8±7.5

Stiffnesscoefficient(N/mm) Ethyl-2-cyanoacrylate 178.1±10.7 222.5±17.1 229.8±17.9

Butyl-2-cyanoacrylate 144.3±11.2 163.7±12.9 170.4±15.2

Table4–Meanandstandarddeviationofthebonecallusarea(m2),accordingtotheadhesiveusedandthemomentof euthanasia.

Adhesiveused Momentofeuthanasia

60days 120days 180days

Ethyl-2-cyanoacrylate 304,468±72,101 334,785.2±111,205 356,903.8±98,003

Butyl-2-cyanoacrylate 102,448.1±86,247 175,978.5±144,632 195,925.4±106,022

Table5–Meanandstandarddeviationofthecellularityobserved(osteoblasts,osteoclasts,inflammatorycells;n−1), accordingtotheadhesiveusedandthemomentofeuthanasia.

Adhesiveused Cellularity Momentofeuthanasia

60days 120days 180days

Ethyl-2-cyanoacrylate Osteoblasts 251±4 306±23 280±26

Osteoclasts 21±7 37±19 28±11

Inflammatorycells 115±11 299±24 187±25

Butyl-2-cyanoacrylate Osteoblasts 221±16 274±31 255±30

Osteoclasts 19±8 25±11 23±12

Inflammatorycells 227±12 512±28 461±39

Initially,the useofadhesivesofbiologicaloriginwas more common.However,from 1960onwards,syntheticpolymers havebecomeatherapeuticoptioninallmannerofmedical specialties.

Amongall the available adhesives, cyanoacrylates have drawn specialattention from medicalprofessionals due to theirlowcostand,primarily,theireasyhandling.

Inthepresentstudy,theadhesiveeffectbetweenthefrac- turedextremitiespresentedbetterresultsintheSBgroup,a factthatcouldbeverifiedbythesimpleobservationofthe animals,who wereabletofullweight-bearingon theoper- atedlimbsimmediatelyaftertheanestheticrecovery,afact notobservedintheanimalsfromtheHAgroups.

In the HA group, it was observed that, once the butyl-2-cyanoacrylate was added, it polymerized almost instantaneouslyuponminimalcontactwiththebone,elim- inating any possibility of repositioning the fragments or redoingafracturereduction.

Another fact toconsider isthe inflammatory/infectious processesthatareoftenassociatedwithnewproductsand/or surgicaltechniques.Inthepresentstudy,amarkedincrease ininflammatorycellularityinthegrouptreatedwithbutyl-2- cyanoacrylatewasobserved.

Inpublicationsonsyntheticadhesives,itisnotcommon tosearchfortumororcarcinogeniccells.Infact,inthevari- ousdatabasessearched,theauthorswereunabletoretrieve

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observedinthose groups,allowtheassumptionthatethyl- 2-cyanoacrylate provided conditions for the bone healing processtooccurwithoutanomalies,i.e.,ethyl-2-cyanoacrylate didnotinterferewithlocalosteoblasticactivity.

Itisimportanttohighlightthevaluesobservedintheanal- ysisofthestiffnesscoefficient.Thehighervalueobservedin thebonesoftheSBgroupmaypredictagreater fragilityof thebonecallousformed,i.e.,althoughthebonestreatedwith ethyl-2-cyanoacrylatewere ableto withstandahigherload (Tables2and 3), surprisingly,they were onlyableto with- standa little deformation, which madethem more brittle.

Infact,previousstudies21–23 havedemonstratedthebrittle- nessofboneswithhighstiffnesscoefficients,whichiswhy the authorsdonot recommendthe useofsynthetic adhe- sivesinbonesthataresubmittedtomoderate/highintensity deformingforces.

Amidthewiderangeoftherapeuticoptionsrelatedtotrau- matology,thefactthatsyntheticadhesivesareeasytoobtain, havelowcost,and presentgood resultsandeasy handling makesthemafeasibleoptioninthetreatmentofsmallvol- umebonefracturesand,especially,inthere-establishmentof jointanatomy.

Conclusion

Under the conditions of the present study, ethyl-2- cyanoacrylatewasmoreeffectivethanbutyl-2-cyanoacrylate inthetreatmentoffracturesinrats.

Conflicts of interest

Theauthorsdeclarenoconflictsofinterest.

Acknowledgments

Tothe FoundationforResearchSupportoftheStateofSão Paulo(Fundac¸ãodeAmparoàPesquisadoEstadodeSãoPaulo [Fapesp])for the supportgiven tothe development ofthis research(processes:8514-6/2014and8605-1/2014).

SincerethankstoProf.Dr.LuizCláudioDiStasi,Adjunct ProfessoroftheDepartmentofPharmacologyoftheInstitute ofBiosciences (Unesp/Botucatu), without whom this study wouldnothavebeenpossible.

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11.SouzaM,FagundesDJ,GomesPO,Ascenc¸ãoAM,Guimarães CA,Mendonc¸aITMJr,etal.Fiosdesutura:umarevisão histórica.PublUEPGCiBiolSaúde.2001;2(1):98–100.

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PonpermayerLG.Empregodeadesivobutil-2-cianoacrilatona fixac¸ãodeesquírolasemfraturasdefêmurdecães.Aspectos radiológicos.ArqBrasMedVetZootec.1992;44(1):29–41.

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17.XavierMSV,LeiteVM.Efeitodoadesivobutil-2-cianoacrilato emosteotomiaseenxertoósseoemcoelhos:aspecto macroscópicoeradiográfico.RevBrasOrtop.

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