Workplace bullying in the nursing profession : A cross-cultural scoping review

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ContentslistsavailableatScienceDirect

Japanese

Dental

Science

Review

j o u r n a l ho me p a g e : w w w . e l s e v i e r . c o m / l o c a t e / j d s r

Review

Article

Effects

of

the

local

administration

of

antibiotics

on

bone

formation

on

implant

surface

in

animal

models:

A

systematic

review

and

meta-analysis

Ali

Alenezi

a,∗

_,

_Bruno

_Chrcanovic

b

a_Department_of_{Prosthodontics,}_College_of_Dentistry,_Qassim_University,_Saudi_Arabia b_Department_of_{Prosthodontics,}_Faculty_of_Odontology,_Malm¨_o_University,_Malm¨_o,_Sweden

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received11June2020

Receivedinrevisedform25July2020 Accepted19September2020 Keywords: Dentalimplants Boneformation Animalmodels Drugdelivery Antibiotics Systematicreview

a

b

s

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r

a

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Purpose:Thisreviewaimedtoevaluatetheeffectsofthelocaldeliveryofantibioticsincorporatedin

implantsurfacesonsomequantitativeparametersofboneformation.

Materialsandmethods:Anelectronicsearchwasundertakeninthreedatabases(PubMed,Scopus,Embase)

inadditiontohandsearching.Thesearchwaslimitedtoanimalexperimentsusingendosseousimplants

combinedwithlocalizedantibioticsrelease.Meta-analyseswereperformedforthepercentagesofbone

volume(BV)andbone-to-implantcontact(BIC).

Results:Ninestudiesmettheinclusioncriteria.Severalmethodswereidentiﬁedforlocaldeliveryof

antibioticsatthebone-implantinterface,butthemostcommonlyusedmethodwasbycoating

(incor-poratingtheimplantsurfacewiththeantibioticagents).Differentantibioticagentswereused,namely

bacitracin,doxycycline,enoxacin,gentamicin,minocycline,tobramycin,andvancomycin.Therewasno

statisticallysigniﬁcantdifferenceinthepercentageofBICbetweenimplantswithorwithoutlocalized

antibioticrelease(P=0.59).Themeta-analysisrevealedhigherBVaroundimplantscoatedwithantibiotics

comparedtocontrolgroups(withoutantibiotics)(P<0.01).

Conclusion:Itissuggestedthatthelocaladministrationofantibioticsaroundimplantsdidnotadversely

affectthepercentageofdirectbonecontactaroundimplants,withatendencyforaslightlybetterbone

formationaroundimplantswhencombinedwithlocaladministrationofantibiotics.Itisamatterof

debatewhethertheseinvivoresultswillhavethesameeffectintheclinicalsetting.However,therisk

ofbiasofthesestudiesmay,tosomeextent,questionthevalidityoftheseresults.

Science.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/

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

1. Introduction

Implantrestorationstoreplacemissingteethbecametodayone ofthemaintreatmentmodalitiesindentalpracticewithmillions ofimplantsplacedeveryyeararoundtheworld[1,2].Manyofthe long-termstudiesonimplantrestorationsreportedsurvivalrates exceeding90%after10yearsoffollow-up[3,4].

However,implantassociatedinfectionsremainagreatthreat thatmayleadtoseveralcomplicationssuchasmarginalboneloss, complexrevisionprocedures,andeventuallyimplantfailure. Bio-materialassociatedinfectionsareseenasabigchallengesincethey aredifﬁculttotreat[5,6].Asaresultoftheseofinfections,aseries

∗ Correspondingauthorat:DepartmentofProsthodontics,CollegeofDentistry, QassimUniversity,P.O.Box6700,Burydah,51452,SaudiArabia.

E-mailaddresses:dr.ali.alenezi@qudent.org,4110@qu.edu.sa(A.Alenezi).

ofinﬂammatoryresponsesaregenerated,whichcouldcomplicate theintegrationofimplantsandbonehealing[7].

Thebacterialinvasiontotheimplantsite isbelievedto hap-penfollowingthetraumatothehardandsofttissueafterimplant surgery [8]. Following that, different bacterial strains, mainly Staphylococcusepidermidis,attachtoimplantsurfacetostimulate thesynthesisofextracellularmatrix[9,10].Thepresenceofthis matrixwillfacilitatethebioﬁlmformationand,ifnoactionsare taken,couldleadtoinfection[11,12].Suchcasesrequireearly treat-menttoavoidtheneedofadvancedprocedurestokeeptheimplant. In dentistry, antibiotics are occasionally prescribed prior to implantsurgerytodecreasetheriskofinfections [13].The sys-temicadministrationofantibioticsisstilltheconventionalmethod used,althoughconventionalantibioticadministrationcouldhave limitationsrelatedtotheantibioticconcentration[14].Improper antibioticconcentrationinthebloodcouldbringsomeunwanted

https://doi.org/10.1016/j.jdsr.2020.09.003

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sideeffects,beingtoxicataveryhighlevel,andineffectiveatavery lowlevel[15].

Besidesthesystemicwayofadministration,thereisalsothe release of antibiotics using local drug delivery systems, which isrecognizedasapromisingmethodtosuppresslocalinfection, alsominimizingthesideeffectsassociatedwiththeconventional administrationofantibiotics.AstudybyMoojenetal.showed bet-terformationofbonearoundimplantscoatedwithantibioticsin comparisontocontrolimplants[16].Theauthorssuggestedthat thiseffectwasaconsequenceofthereducedinfectionratesinthe antibioticgroup,andclaimedthatinfection-freebonemayallow betterboneformationcomparedtoinfectedbone[16].

Mostoftheusedmethodswerebasedonincorporatingor coat-ing theimplantsurface withtheantibioticagents,and someof thesetechniquessucceededtoprovidesustainedantibioticrelease [17,18].Thereleaseofantibioticsdirectlyattheimplantsitecould providelowbuteffectivetherapeuticdosesofdrugcomparedtothe conventionalmethods.Apossiblenegativeeffectofthismethod would be therisk of interferingwith thebone healing process around theimplant. It hasbeenreported in someexperiments that antibiotics could have negative inﬂuenceon thefunctions of osteoblasts and osteoclasts [19,20]. Moreover, immobilizing antibacterialagentsontothesurfacesofimplantscouldresultina rapidburstreleaseofantibioticsandlowantibacterialeffects[21]. Theaimofthepresentstudywastoreviewandevaluatethe effectsofthelocaldeliveryofantibioticsincorporatedinimplant surfacesonsomequantitativeparametersofboneformation.

2. Materialsandmethods

2.1. Searchstrategies

Anelectronicsearchwithouttimerestrictionswasundertaken in December2019inPubMed,Scopus,andEmbase.The follow-ingterms,relatedtothreemaincomponents(bone,implant,and antibiotics),wereusedinthesearchstrategiesineachdatabase:

(“boneremodeling”OR“boneformation”OR“bone regenera-tion” OR“bonedevelopment”OR“bonegrowth”OR “osseointe-gration”)AND(“biocompatiblecoatedmaterials”OR“endosseous dental implantation” OR “dental implants” OR “implants” OR “bone-implantinterface”)AND(“antibiotics”OR“antibacterial”OR “antimicrobial”OR“infection”OR“drugdelivery”OR“drugdelivery device”OR“drugdeliverysystem”OR“drugrelease”OR“localdrug delivery”)AND(“animalexperimentation”OR“animalmodels”OR “animals”OR“invivo”).

In addition,thereferencelistofthestudiesandtherelevant reviewsonthesubjectwerealsochecked,besideshandsearching ofimplant-relatedjournals.

2.2. Inclusionandexclusioncriteria

Eligibilitycriteriaincludedpublicationsevaluatingtheuseof localizedantibioticsdeliverywithendosseousimplantsinanimal studies.Theimplantinsertionneededtobecombinedwitha antibi-otics agentthat wasadministratedlocallyor releasedfromthe implant surface. Theantibioticagent shouldhave beenapplied locallybeforeoratimplantinsertion.Onlypublicationswrittenin Englishwereconsidered.

2.3. Studyselection

ThestudywasdesignedbasedonthePRISMAguidelinesto per-formsystematicreviewsandmeta-analysis[22].Potentialstudies identiﬁedintheinitialsearchwererequiredtomeettheinclusion criteria.Theabstractsofthestudiesidentiﬁedwereread indepen-dentlybythetwoauthorsofthisstudy.Fulltextswerereadfor

thestudiesappearingtomeettheinclusioncriteria,orforwhich therewereinsufﬁcientdatainthetitleandabstracttomakeaclear decision.Disagreementswereresolvedbydiscussionbetweenthe authors.

2.4. Dataextraction

Thefollowing datawerethenextracted onastandard form, whenavailable:typeofantibioticagent,deliverysystem/method, typeofanimal,numberofanimals,numberofimplants,timeperiod betweentheimplantationsurgeryandtheeuthanasiaofthe ani-mals,meanvalues andstandarddeviationofthepercentagesof bonevolume(BV)andbone-to-implantcontact(BIC)aroundthe implants.

2.5. Riskofbiasinindividualstudies

Theanalysisof theriskof biasfor theincludedstudieswas performedaccordingtotheSystematicReviewCentrefor Labora-toryAnimalExperimentation’s(SYRCLE)riskofbiastoolforanimal studies[23].

2.6. Dataanalysis

PercentagesofBVandBICwerethecontinuousoutcomes eval-uated.Weightedmeandifferenceswereusedtoconstructforest plots.Thestatisticalunitwasthenumberofimplantsusedinthe experimentsineachgroup.

Wheneveroutcomesofinterestwerenotclearlystated,thedata werenotusedforanalysis.TheI2_statistic_was_used_to_express_the

percentageofthetotalvariationacrossstudiesdueto heterogene-ity.Theinversevariancemethodwasusedforrandom-effectswhen therewasstatisticallysignificant(P<0.05) heterogeneity,and a fixed-effectsmodelwasusedwhenheterogeneitywasnot statisti-callysignificant.Theestimatesofaninterventionwereexpressedin meandifference(MD)inpercentage,witha95%confidenceinterval (95%CI).ThesoftwareReviewManager(version5.3.3,TheNordic CochraneCentre,TheCochraneCollaboration)wasusedtoperform themeta-analysis.

3. Results

ThesummaryofthestudyselectionprocessisshowninFig.1. Thesearchprocessusingthe3selecteddatabasesandthehand searchingresultedin1407papersthatwereinitiallyscreened.The secondscreeningphaseforpapersthatappearedtomeetthe inclu-sioncriteriaresultedin38articlesthatweresubjectedtofulltext reading,forwhichtwowerecitedinmorethanonedatabase (dupli-cates),and27wereexcludedfornotmeetingtheinclusioncriteria (TableS1–Supplementalmaterial).Thus,atotalof9publications wereincludedinthereview.Detailsoftheincludedstudiesare showninTable1.

The main method for delivering the antibiotic agents was byloadingantibioticsintocoatedlayersontheimplantsurface. Theselayerscanbeformedashydroxyapatite(HA)ormadefrom polymeric materials. The animal group mainly used to exam-ine local antibiotics release from implant surface wasrodents, eitherratsorrabbits.Differentantibioticsagentswereinvestigated, namelybacitracin,doxycycline,enoxacin,gentamicin,minocycline, tobramycin,andvancomycin(Table1).

Theincludedstudiesshowedaconsiderableriskofbias,dueto lackofinformationregardingmanyoftheresearchsteps(TableS2 –Supplementalmaterial).

FiveoutofthenineincludedstudiesreportedBICmeanvalues. Ingeneral,resultsofthepercentageofBICrevealedsimilarvalues betweenimplantswithorwithoutantibioticscoating(Fig.2).The

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Fig.1.Studyscreeningprocess.

Table1

Detailsoftheincludedstudies.

Study Antibiotic Animalmodel Implantsite No.ofanimals

used

MethodsforBIC andbonevolume measurements

Drugdeliverysystem

Adamsetal.[24] Vancomycin Rat Femur 11 ␮CTanalysis Vancomycin-containingsol-gelﬁlmon

titaniumalloyrods Moojenetal.[16] Tobramycin Rabbit Tibia 72 Histological

evaluation

Tobramycin-loadedperiapatite-coated titaniumfoamimplants

Altetal.[25] Gentamicin Rabbit Tibia 45 Histological

evaluation

Gentamicin–hydroxyapatite(gentamicin– hydroxyapatite)andgentamicin–RGD (arginine–glycineaspartate)–hydroxyapatite coatings

Fassbenderetal.[26] Gentamicin Rat Tibia 72 ␮CTanalysis Gentamicinlocallyappliedfromapolymeric coatingofintramedullarynails

Walteretal.[27] Doxycycline Rabbit Tibia 10 ␮CTanalysis Bindingofdoxycyclineontoatitanium zirconiumalloysurface

Neutetal.[28] Gentamicin Beagle Femur 12 Histological

evaluation

Poly(lactic-co-glycolicacid)

gentamicin-loadedhydroxyapatite-coated surface

Nieetal.[29] Bacitracin Rat Femur 15 Histological

evaluationand␮CT analysis

Bacitracinimmobilizationonthetitanium surface

Lietal.[30] Enoxacin Rat Femur 12 ␮CTanalysis Enoxacinloadedintotitanium-nanotubesand immobilizedtypeIcollagen/hyaluronic multilayercoatingonthesurfaceoftheTi-NT Shapiroetal.[31] Minocycline Rat Femur 22 ␮CTanalysis Minocyclinefemoralintramedullaryinjection followedbyimplantationoftitaniumalloyrods

BICmeasurementsweredividedintotwosubgroupsaccordingthe reportedhealingtime,4weeksand12weeks.Nosigniﬁcant differ-enceswereobservedbetweenthegroups(P=0.59),withamean differenceofonly1.84%.SixstudiesreportedthepercentageofBV aroundtheimplants(Fig.3).Theresultssuggestedahigher per-centageofBVaroundimplantscoatedwithantibioticscomparedto thecontrolgroup(withoutantibiotics)(P=0.0002),althoughwith smallmeandifference(4.14%).

4. Discussion

Implantsuccessfultreatmentisbelievedtobeamatterofgood integrationwithbone.Thisintegrationisachievedafteraseries ofhealingphasesfollowingimplantsurgery,anddifferentfactors areknowntoaffecttheprocess[32,33].Itisimportanttoensure properboneformationlevelstoobtaingoodimplantintegration withbone.Withthatinmind,theamountofBVaroundimplants

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Fig.2.Forestplotforthecomparisonofthepercentagesofbone-to-implantcontactbetweenimplantscoatedornotwithantibioticsagents,accordingtohealingtime.

Fig.3. Forestplotforthecomparisonofthepercentagesofbonevolumeformationbetweenimplantscoatedornotwithantibioticsagents.

waschosenasthemainoutcomeforthisreview,inordertohelp evaluatewhetherantibioticscoatingwouldinterferewithimplant osseointegration.ThevaluesofBVandBICwereusedconsistently intheliteratureasadescriptionofosseointegration.

Forlocalantibioticdeliveryapplications,thesubjectofstudyin thepresentreview,itisnecessaryfortheselectedcarriermaterialto exhibitgreatbiocompatibilitywithlittleantigenicproperties[34]. Inaddition,thesematerialsshouldensurereleaseofthe therapeu-ticagentatthetargetsiteinacontrolledrateandduration[35].In theirexperiment,Altetal.coatedthegentamicin–hydroxyapatite (gentamicin–HA)andgentamicin–RGDonsteelk-wires[25].The drug release analysisshowedan initialburstrelease of around 65% ofthegentamicinduringtheﬁrsthour followedbyslower releasekineticsinthelater24h.Moreimportantly,theinfection ratedecreaseddramaticallyforgentamicin-coatedk-wires com-paredtothek-wireswithoutantibiotics.

According to the present results, it is suggested that the release of antibiotics locally around implants has no signifi-cant influence on the percentage of BIC. One of the possible explanationsforthisfindingistherelativelylowamountof antibi-otics that can be released by these drug delivery techniques. The results from the literature do not show a consensus on this matter.Altetal.investigated theeffectsof gentamicin–HA andgentamicin–(arginine–glycine–aspartate)–HAcoatingsonnew bone formation [25]. In their experiment, 250␮g/cm of gen-tamicin was coated on steel k-wires inserted in rabbits’ tibia for the observation periods of 4 and 12 weeks. The

quantita-tive and qualitative histological evaluation revealed better BV andbetterdirectimplantcontactinthecontrolgroupcompared withgentamicin coatinggroup but withnostatistically signiﬁ-cantdifferences.Meanwhile,otherreportswithvariousantibiotics concentrationswereassociatedwithdifferentBVlevelswhen com-paredwithcontrolimplants.Forinstance,Neutetal.showedthat theboneingrowtharoundpoly (lactide-co-glycolide)-gentamicin-HA-coatedpinsinfemoralcondylesofdogswasnotimpairedby thepresenceofthegentamicin-loadedcoating[28].Althoughin theiranimal experimentthebone growwasslightlyless inthe pinscoated with10␮g/mlgentamicin compared tothecontrol group.

Ontheother hand,theresultsoftheanalysisof BVsuggest thatthelocalreleaseofantibioticshasaslightlypositiveinﬂuence onthepercentageofBVintheregionaroundtheimplants.Some experimentsshowedthatdifferentconcentrationsof antibiotics canbeassociatedwithdifferenteffectsonbonecell.Forinstance, Adamsetal.[24]. investigatedthetotal bonevolumeformation aroundimplantrodsimplantedintoinfectedfemurofrats,andthe implantscoatedwithsol–gelﬁlmscontainingvancomycinshowed slightly highertotal bone volume in comparisonto thecontrol group.Walteretal. foundthat 141_␮g/cm2 _dose_of _doxycycline

revealedanosteoinductiveeffects byenhancingthe differentia-tionofosteoprecursorcells atanearlystage[27]. Ontheother hand,Edinetal.[36].reportedthathighconcentrationsof van-comycin(morethan10,000␮gml−1)couldcausecelldeath,while concentrationslowerthan1000␮gml−1hadnegligibleeffectson

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thereplicationofosteoblasts.Miclauetal.reportedthatosteoblasts deathcanoccuratconcentrationhigherthan400␮gml−1[20].

Thereweretwomainkindsofanimalsforthistypeof experi-ments,dogsandrodents.Theseﬁndingsaresimilartowhatwas reported ina previousreview [37].Small animalslikeratsand rabbitsarecommonlyusedinimplantresearchevenwiththe bio-logical dissimilaritiesthattheirboneshavecomparedtohuman bones[38,39]. Thiscanbeunderstoodsincetheseanimalshave shorterhealingtime,whichenableevaluationofboneformation aroundimplantsatdifferenthealingphases[39,40].

Antibioticsagentswithvariousspectrawereexaminedamong theincludedstudies,andgentamicinwasthemostcommonused agent.Gentamicinbelongstoaminoglycosidegroupofantibiotics andiscommonlyprescribedtopreventimplantassociated infec-tionsandotherperiodontalinfections[41,42].Gentamicinhasa relativebroadantibacterialspectrumbutmainlyforGram-negative bacteria.Theantibacterialmechanismofgentamicinisbasedon interruptingproteinsynthesisbybindingthe30Ssubunitofthe bacterialribosome[43].

Varioustechniqueswereexaminedtoobserveandevaluatethe directboneformationaroundimplants.Itisimportantforanyused techniquetoallowaccuratereadingoftheexperimentaldata.All theincludedstudiesinthisreviewevaluatedtheboneformation usingeitherhistologicalsectionsormicro-CT(␮CT),orboth. Pre-viously, manyresearchers usedthin histologicalsectionsofthe implantwiththesurroundingbonetoobservedirectbone forma-tionunderlightmicroscopy[44].Thesesectionsneedtobeground downtobefewmicrometersinthicknesstoallowexaminingsingle cellslayer[45].Themaindrawbacksofthistechniquearethatitis atwo-dimensionalevaluationandneedtobepreparedwith sev-eralsawingandgrindingprocedures.Recently,␮CTisusedmore toobservethetotalamountofbonearoundtheimplantinthree dimensions.The␮CTimagespermitobservingtheBVformation andtheentiresurroundingregioninthreedimensions.Forthat, ␮CTimagesarebelievedtobemoredescriptivethanthe histolog-icalsectionswhenassessingboneformationaroundimplants.

Thestudiesincludedinthisreviewusedmethodswerebasedon implantscoatingwhileothersusedcarriermaterialssuchasgelsor polymersforthelocalreleaseofantibiotics.SomestudiesusedHA coatings[16,25].OneofthelimitationsoftheHAcoatingisthatit needshighprocessingtemperaturetobeformed,whichmakeit dif-ﬁcultforanantibioticagenttobeincorporatedinthecoatinglayer [18].Acommonlyusedtechniqueforloadingthetherapeuticagents intoHAcoatinglayerissimplybyimmersionthecoatedimplant indrugsolution.However,severalstudiesreporteduncontrolled release kineticsassociatedwiththis techniquecharacterizedby earlyburstreleaseintheﬁrsthourformostoftheloadeddrugs [17,28].

Recently, numerous studies examined the use of some biodegradable polymersasimplantcoatingforlocaldrug deliv-ery[46,47].Thesepolymerscandemonstratesustainedandslower releaseratecomparedtotheHAcoating[46].Anothergreat advan-tageofthesepolymercoatingsisthattheyallowtheuseofhigher volumeandseveraltypesofantibacterialagents[47].Forinstance, gentamicinwasloadedintopoly(d,l-lactide)(PDLLA)coatingto treat implantassociated infectioninananimal model[48]. The gentamicin demonstrated sustain release kineticsfrom(PDLLA) coatingthatlastedmorethantwo days.InthestudyofLietal. enoxacinwasloadedintoimmobilizedcollagen/hyaluroniccoated implant[30].Thismethodinvolvedtheuseofacarriermaterialin theformoffoamorpolymericcoating.Inotherwork,Alenezietal. developedathinsurfacecoatingimplantsconsistsofathinpoly (N-isopropylacrylamide)-co-acrylamide(PNIPAAm-AAm)polymer forvancomycinreleaseinvitro[49].Thevancomycindemonstrated sustainreleasefromthesurfaceandwasabletoeradicate Staphy-lococcusepidermidisbacteriainculture.Furthermore,Neutetal.

developedagentamicin-HA-coatingwithaprotectivePLGA[poly (lactic-co-glycolicacid)]-overlayertobeexaminedastreatment option for infectionin cementless total jointreplacement [28]. Thisgentamicincoatedlayershowedresistanceofinfectionand evengoodantibacterialefﬁcacytowardsomegentamicin-resistant staphylococcalstrains.PLGAisanotherpolymermaterialthatis commonlyusedfor encapsulationand release ofwide range of drugsandchemicalagents.Thispolymermaterialisknownforits highbiocompatibilityandfavorablebiodegradablebehaviorthat werefoundtobesuitablefordrugdeliveryapplications[46,50].

Implantsurfacescanalsobemodiﬁedtoshowspecialnano fea-tures,suchastubesorpores,forantibioticreleasedirectlyfrom implantsurface[51,52].Acommonmethodusedfortheformation ofhighlyporousstructuresonimplantsurfaceisbyanodization [53].Forlocaldrugdeliveryapplications,theseporousstructures canbemodiﬁedtoexhibithighloadingcapabilities.Somereports revealedthattitaniananotubesloadedwithantibioticscanenhance cellattachment,proliferation,andosteogenicdifferentiation[54]. However,somereleasebehaviortestsshowedthatdrugrelease fromtitaniananotubescanbeassociatedearlyburstrelease,which canleadtotoxicity[55–57].Therefore,acontrolledrelease behav-iorofantibacterialagentsiscrucial.MesoporousTiO2coatingonTi

implantswasexaminedinseveralexperimentsasatoolforlocal drugdeliveryattheboneimplantinterface[58,59].These meso-porouscoatingscanbeformedasuniformedandthinﬁlmswith highlyporoussurfacethatallowloadingandreleasingofseveral drugsagents.Forinstance,Gallietal.investigatedimplantscoated withmesoporousTiO2ﬁlmsincorporatedwithmagnesium[60].In

theirexperiment,thereleaseofmagnesiumfromthecoatedlayer revealedbetterboneformationinrabbitboneafterthreeweeks ofhealingtimeincomparisontonon-loadedmesoporouscoated implants.

Thelimitationsofthepresentreviewincludethesmallnumber ofincludedstudiesandthevariationsamongeachstudy regard-ingtheanimalspecies,theobservationperiodforboneformation levels,theusedantibioticagentwithdifferentconcentrations,and thetechniquesusedtocalculatethepercentageofbonearoundthe implants.Allthesevariationsandconfoundingfactorsmaylimit thecapacitytodrawﬁrmconclusions.Theincludedstudieshavea considerableriskofselection,performance,anddetectionbias. Fur-thermore,theﬁndingsobtainedfromanimalexperimentscannot bedirectlyappliedtohuman.

5. Conclusion

Theresultsofthepresentreviewsuggestthatthelocal adminis-trationofantibioticsaroundimplantsdoesnotadverselyaffectthe directbonecontactwithimplants.Therewasbetterbone forma-tionaroundimplantswhencombinedwithlocalantibioticsrelease incomparisontoimplantswithoutantibiotics,butthemean differ-encewassmall.Itisamatterofdebatewhethertheseinvivoresults willhavethesameeffectinthehumanclinicalsettinginthelong term.However,theriskofbiasofthesestudiesmay,tosomeextent, questionthevalidityoftheseresults.

Funding/grantsupport

Thisstudyreceivednospeciﬁcgrantfromanyfundingagency inthepublic,commercial,ornot-for-proﬁtsectors.

Conﬂictofinterest

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AppendixA. Supplementarydata

Supplementary materialrelated tothis article canbefound, intheonlineversion,atdoi:https://doi.org/10.1016/j.jdsr.2020.09. 003.

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