Guided Bone Regeneration in the Edentulous Atrophic Maxilla Using Deproteinized Bovine Bone Mineral (DBBM) Combined with Platelet-Rich Fibrin (PRF)-A Prospective Study

Abstract

Background:
Bone regeneration procedures represent a major challenge in oral surgery. This study aimed to evaluate a composite PRF/particulate xenograft in guided bone regeneration.

Methods:
Edentulous patients with horizontal ridge deficiencies in the anterior maxilla and candidates to an immediate-loading full-arch rehabilitation were included. Horizontal linear measurements indicating bone gain were assessed from computer beam computer tomography (CBCT) scans obtained at pre-surgery, post-surgery, and the 12-month follow-up. Mean bone values were presented as mean ± 95% CI. Non-parametric tests were used as appropriate, and the effect size was calculated with Cohen's d repeated measures.

Results:
Eighteen patients were rehabilitated with 72 implants. The mean horizontal bone width was 4.47 [4.13-4.80] mm pre-surgically, 9.25 [8.76-9.75] mm post-surgically, and 7.71 [7.28-8.14] mm 12 months after.

Conclusions:
PRF associated with a xenograft seems to promote an effective horizontal bone gain. Randomized clinical trials are needed to confirm the benefits of this surgical approach.

Full text

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J.Clin.Med.2022,11,894.https://doi.org/10.3390/jcm11030894www.mdpi.com/journal/jcm
Article
GuidedBoneRegenerationintheEdentulousAtrophicMaxilla
UsingDeproteinizedBovineBoneMineral(DBBM)Combined
withPlatelet‐RichFibrin(PRF)—AProspectiveStudy
JoãoManuelMendezCaramês
1,2,3,
*,FilipeAraújoVieira
1
,GonçaloBártoloCaramês
1
,AnaCatarinaPinto
1
,
HelenaCristinaOliveiraFrancisco
1,2
andDuarteNunodaSilvaMarques
1,2,3

1
InstitutodeImplantologia,AvenidaColumbanoBordaloPinheiro,nº50,1070‐064Lisbon,Portugal;
fmaraujo.vieira@gmail.com(F.A.V.);caramesgoncalo@gmail.com(G.B.C.);
anacatarina.pinto@institutoimplantologia.com(A.C.P.);helenafrancisco@campus.ul.pt(H.C.O.F.);
duarte.marques@campus.ul.pt(D.N.d.S.M.)
2
FaculdadedeMedicinaDentária,UniversidadedeLisboa,1600‐277Lisbon,Portugal
3
LIBPhys‐FCTUID/FIS/04559/2013,FacultyofDentalMedicine,UniversityofLisbon,
1600‐277Lisbon,Portugal
*Correspondence:carames@campus.ul.pt;Tel.:+351‐91972‐7353;Fax:+351‐21721‐0989
Abstract:Background:Boneregenerationproceduresrepresentamajorchallengeinoralsurgery.
ThisstudyaimedtoevaluateacompositePRF/particulatexenograftinguidedboneregeneration.
Methods:Edentulouspatientswithhorizontalridgedeficienciesintheanteriormaxillaand
candidatestoanimmediate‐loadingfull‐archrehabilitationwereincluded.Horizontallinear
measurementsindicatingbonegainwereassessedfromcomputerbeamcomputertomography
(CBCT)scansobtainedatpre‐surgery,post‐surgery,andthe12‐monthfollow‐up.Meanbonevalues
werepresentedasmean±95%CI.Non‐parametrictestswereusedasappropriate,andtheeffect
sizewascalculatedwithCohen’sdrepeatedmeasures.Results:Eighteenpatientswererehabilitated
with72implants.Themeanhorizontalbonewidthwas4.47[4.13–4.80]mmpre‐surgically,9.25
[8.76–9.75]mmpost‐surgically,and7.71[7.28–8.14]mm12monthsafter.Conclusions:PRF
associatedwithaxenograftseemstopromoteaneffectivehorizontalbonegain.Randomized
clinicaltrialsareneededtoconfirmthebenefitsofthissurgicalapproach.
Keywords:platelet‐richfibrin;deproteinizedbovinebonemineral;guidedboneregeneration;
horizontalaugmentation;atrophicmaxilla;naturalscaffold

1.Introduction
Theatrophicmaxillarepresentsasurgicalandprosthodonticchallengeforan
implant‐supportedreconstruction[1,2].Withinthefirst6monthsfollowingananterior
toothextraction,themaxillaexhibitsaprimaryvolumetricchangerangingfrom29to63%
horizontallyand11to22%vertically[3].Thepresenceofperiodontaldisease,trauma,
otherhard‐tissueinfections,orcongenitalmalformationsworsensthisboneloss,which
continuouslyprogressesovertheyearsfollowingacentripetalpattern[4,5].Cawoodand
Howell’sclassificationdescribesdifferentstagesofmaxillaatrophyassociatedwiththe
collapseofthecircumoralmusculature,triggeringmouthnarrowing,lossoflipsupport,
andinversionofthelips[6].Thislatteraspectismoresignificantintheanteriormaxilla
[7–9].
Despitethecurrentperspectivetowardaminimallyinvasivegraftlessapproach,itis
recognizedthatmostedentulousmaxillaedemandsometypeofboneaugmentation
procedure[10,11].Implantsinthegraftlessedentulousmaxillashowhighsurvivalrates
butarenotexemptfromsideeffectsorprosthodonticcomplications[12].Moreover,the
Citation:Caramês,J.M.M.;
Vieira,F.A.;Caramês,G.B.;
Pinto,A.C.;Francisco,H.C.O.;
Marques,D.N.d.S.GuidedBone
RegenerationintheEdentulous
AtrophicMaxillaUsing
DeproteinizedBovineBoneMineral
(DBBM)CombinedwithPlatelet‐
RichFibrin(PRF)—AProspective
Study.J.Clin.Med.2022,11,894.
https://doi.org/10.3390/jcm11030894
AcademicEditors:
MarkA.Reynolds
Received:13January2022
Accepted:7February2022
Published:8February2022
Publisher’sNote:MDPIstays
neutralwithregardtojurisdictional
claimsinpublishedmapsand
institutionalaffiliations.

Copyright:©2022bytheauthors.
LicenseeMDPI,Basel,Switzerland.
Thisarticleisanopenaccessarticle
distributedunderthetermsand
conditionsoftheCreativeCommons
Attribution(CCBY)license
(https://creativecommons.org/license
s/by/4.0/).

J.Clin.Med.2022,11,8942of14
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levelofboneatrophyhasbeenreportedtoimpactrestorativeandregenerativetreatment
schemesinafixedfull‐archrehabilitation[13].Itisclearthatboneregenerationprioror
simultaneouslytoimplantplacementinafixedfull‐archrehabilitationinthemaxillais
essentialnotonlyforaprosthodonticallydrivenconceptbutalsotopromotelocalbone
defectandfacialaestheticcorrections[6].Manytechniques,suchasridgesplitting,bone
blockgrafting,orguidedboneregeneration(GBR)combinedwithseveralbonegrafts
(autografts,allografts,xenografts,andalloplasts)ordifferenttypesofmembranesor
mesheshavebeendescribedtohorizontallyreconstructanalveolarridgeintheanterior
region[14–17].Despitetheplethoraofprocedures,themostadequateoptiontoobtaina
stablehorizontalbonedimensionincreaseandalong‐termimplantandprosthesis
survivalrateisyetundetermined[15,18,19].
Basedonhigh‐evidencelevelpublications,GBRseemsmorepredictable,
reproducible,andtoresultinfewercomplicationsthanothertechniques[12,15,20].GBR
entailsusingamechanicalhindrance—usuallyaresorbableoranon‐resorbable
membrane—toseparatethebonydefectfromepithelialandconnective‐tissueingrowth,
allowingcreatingaspaceforosteogeniccellstoproliferate[21].Theneedforoptimizing
horizontalbonegainandacceleratingbonetissueformationhashighlightedthe
importanceofaddinggrowthfactorstoGBRprocedures[22].
Abettercomprehensionofthecellulareventsthatregulatebonetissueformation
unveiledtherationalebehindnaturalbiologicalmediators.Accordingly,inorderto
enhanceangiogenesis,stemcellmigration,andosteogenicdifferentiationinherenttothe
regenerativeprocedure,severalauthorshavesuggestedthepotentialofgrowthfactorsto
bonegraftsandtissuehealing,mainlyusingautologousplateletconcentrates(APCs)
[22,23].Sincethat,theefficacyofplateletconcentratesinpromotingwoundhealingand
tissueregenerationhasbeenthecenterofanenrichedandparticipatedacademicdebate.
In2005,Dohanetal.namedasecondgenerationofAPCsasPRF,richinplatelets,
leukocytes,andmonocytes[24].PRFisobtainedaccordingtoastandardizedprotocolby
venipunctureand2700‐rpmcentrifugationfor12min,withoutusinganticoagulants
[25,26].Itconsistsofanetworkofnanoscalefibersofferinganaturalscaffoldforcell
proliferation,migration,anddifferentiation[27].Additionally,itslowlyreleasescrucial
growthfactorsduring10to14days,suchasPDGF,TGF‐β1,IGF,andVEGF[27].These
factorsplayanimportantroleintissuehealing[23].Accordingtoarecentrandomized
clinicaltrial,PRFhasproventopromotewoundhealingafterdentalextraction[28].
AliquidpresentationofPRF,fibrinogen,canalsobeobtainedbymodifying
centrifugationforces[27].ThisflowablePRFmayberegardedasanautologousbinder,
aggregatinggraftbiomaterial,andchoppedPRFmembranesinacomposite
PRF/particulatexenograftasusedinthisprospectivestudy.Clinicalresearchhasshown
promisingresultsfromtheassociationofPRFandparticulatebonegraftsinregenerative
procedures[29].However,accordingtoarecentsystematicreview,limitedstudies
investigateitsapplicationinintraoralbonegrafting,especiallyinhorizontalandvertical
boneaugmentation[30].
Basedonthedescribedbackground,thisstudyaimstoprospectivelytest
deproteinizedbovinebonemineral(DBBM)combinedwithPRFinGBRsimultaneously
toimplantplacementinedentulouspatientswithanteriormaxillaryatrophywhoare
candidatesforimmediate‐loadingfull‐archrehabilitation.
2.MaterialsandMethods
2.1.PatientSelection
Thisstudywasasingle‐armprospectiveclinicalstudywithapre‐postdesign,carried
outbetweenDecember2015andJanuary2018.Thestudyprotocolwasapprovedbythe
LocalEthicalCommitteewiththeID:II2015‐06andregisteredatClinicalTrials.gov(U.S.
NationalLibraryofMedicine,Bethesda,MD,USA)withtheregistrationNCT03391258.

J.Clin.Med.2022,11,8943of14
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AlltreatmentphaseswereconductedpertheHelsinkiDeclarationof1975,asrevisedin
2008.
Eighteenpatientswereincludedinthisstudyandsignedthewrittenconsentforms
beforesurgery.Patientswereconsecutivelyrecruitedaccordingtothefollowinginclusion
criteria:(1)beingover18yearsofage;(2)beingASAIorASAIIwithmildsystemic
disease;(3)beingedentulousorpartiallyedentulouswithfailingteethindicatedfora
fixedfull‐archreconstruction;(4)havingahorizontalbonedefectintheanteriormaxilla;
(5)havingananteriorridgewidthallowingforlateralboneaugmentationsimultaneously
toimplantplacement;(6)beingcomplianttoparticipateinaclinicalstudy.Theexclusion
criteriaconsideredwere:(1)ASAIIIorASAIV;(2)oncologichistoryand/orchemo‐and
radiotherapytreatmentsintheprevioustwoyears;(3)havingahorizontalbonedefect
causedbytumorresection;(4)pregnantwomen;(5)uncontrolleddiabetes;(6)taking
immunosuppressantmedicationormedicationrelatedtoosteonecrosisofthejaw
(MRONJ);(7)heavysmokinghabits(overtencigarettes);(8)hematologicdiseases;(9)any
typeofpsychiatricdisorders;(10)participatinginanotherclinicalstudy.
Theprimaryoutcomemeasurewasdefinedasthelinearhorizontalbonegain(mm)
immediatelyaftersurgeryand12monthslater,measuredbyCBCTpost‐surgicallyandat
the12‐monthfollow‐up.Thesecondaryoutcomemeasuresweretherateofaugmented
bonestabilityatthe12‐monthfollow‐up,theincidenceofpost‐operatorycomplications
(softtissuedehiscence,sensorydisorder,woundinfection,orgraftexposure)recordedat
10daysand1monthaftersurgery,andimplantsurvival.
2.2.OutcomesAssessment
Foreachpatient,CBCT(CBCTPlanmecaProMaxDimax3DigitalPlan/Ceph)scans
wereobtainedpre‐surgery,immediatelyafterthesurgery(post‐surgery),andatthe12‐
monthfollow‐up.Theywereperformedwitha0.20voxelsize,80kV,and15mA,within
anexposuretimeof12saccordingtothemanufacturer’sinstructions.Cross‐sectional
imageswerereconstructedtoa0.6‐mmthickslicewiththeartifactremovaloption
applied.Twoindependent,calibratedoperators(D.M.;A.P.)assessedeachCBCTscan,
andwhenindisagreement,meanvaluesbetweentheirmeasurementswerecalculated.
Forthepurposeofthisstudy,onlythepre‐maxillaregion,delimitedbytheanterior
bordersofthemaxillarysinus,wasanalyzed,regardlessofimplantplacementinthe
posteriormaxillaryareas.Fourimplantswereanalyzedperpatientinthelocationsofthe
formerlateralincisorsandfirstpremolars.Inthesagittalcuts,eachimplant’slengthwas
measuredfromthenecktothetop.Site1forlinearbonemeasurementwastheneckofthe
implant,perpendiculartothelongaxisoftheimplant.Site2forlinearbonemeasurements
wasthemiddlepointofthetotallengthoftheimplant.Bothsitesweremeasuredfromthe
mostpalatalpointtothemostbuccalpoint(Figure1A–C).Thefollowingvariableswere
determinedinsites1and2,andmeanvalueswerecalculatedtoassesstheoutcomesof
thisstudy.

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Figure1.Exampleofmeasurementsinthreeimplantsitesfromdifferentpatients(A–C)evaluated
throughCBCTscansusingthePlanmecaRomexisVersion2.5.1.R.Imagescorrespondto
measurementsinthedifferentperiods:beforetreatment,aftertreatment,andatthe12‐month
follow‐up.
Implantpositioninthepre‐surgicalCBCTscanwasobtainedfromthepost‐surgical
CBCTscanaccordingtoapreviouslydescribedmethodology[31].Ontheaxialviewof
thepost‐surgicalCBCT,inthemidlineofthemaxilla,theneareranatomicreproducible
landmark(nasalspine,incisiveforamen,maxillarysinusanteriorwall)wasidentified,and
astraightlinewasdrawntotheneckoftheimplant.Thedistancewasobtainedusingthe
PlanmecaRomexissoftware’srulerandreplicatedinthepre‐surgicalCBCTscan.The
pre‐surgicalwidth(mm)wasmeasuredfromthecorticalbone’spalatalpointtothenative
bone’sbuccalpoint,perpendiculartothelongaxisoftheimplantposition.Thepost‐
surgicalwidth(mm)wasmeasuredfromthecorticalbone’spalatalpointtothe
regeneratedbone’sbuccalpoint,perpendiculartothelongaxisoftheimplant.The
augmentedhorizontalbonewidth(mm)wascalculatedbythedifferencebetweenpre‐
andpost‐surgicalCBCTlinearmeasurements.Thesamemethodwasusedtocalculatethe
horizontalregeneratedbonegainoneyearaftersurgery,usingasreferencethepost‐
surgicalandthe12‐monthlinearmeasurements.
2.3.ClinicalProcedures
Invisit1,inclusionandexclusioncriteriawerescreenedforeachparticipant.After
anamnesisandclinicalexamination,participantsunderwentpreoperativeprosthetic
preparation(analysisofaestheticfeatures,suchasfacialprofile,lipsupport,smileline,
andresidualridgeexposure).Subsequently,afterthepatientsignedtheinformedconsent,
apre‐surgicalCBCTscan(PlanmecaRomexis,Planmeca,Helsinki,Finland)was
performedtoevaluatemaxillaryresorption,whichallowedplanningforimplantposition
andboneaugmentationprocedures.
Invisit2,onthedayofsurgery,PRFmembranes,acompositeformedbyparticulate
xenograft(Bio‐Osssmallparticles,GeistlichAG,Wolhusen,Switzerland),andan
averageofeightPRFmembranesandliquidfibrinogenwereobtainedaccordingtoa
(A)

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describedprotocol(Figure2A–C)[26].Allsurgicalprocedureswereperformedunder
strictsterileconditions,andeachpatientsubmittedtolocalanesthesia(articaine4%with
epinephrine1:200,000,Inibsa,Sintra,Portugal),bothbuccallyandpalatally.Amidcrestal
incisionwasperformed,followedbyamucoperiostealflaprelease(totalthickness)to
exposethefullextensionofthebuccalbonedefect(Figure3A,B).Inpartiallyedentulous
patients,theremainingteethwereextractedintheleasttraumaticwaytoavoidtissue
damage,andanosteotomywasperformedtoleveltheboneheightandimprovethe
prosthodonticdesignandfeatures.Regardlessofimplantneedsintheposteriorregionof
themaxilla,fourimplantswereplacedintheformerpositionsofthelateralincisorsand
firstpremolars(Straumann
®
BoneLevelTaperedImplants,Basel,Switzerland)witha
minimumconfirmedprimarystabilityvalueof45Ncmineachimplant(Figure3C).The
compositePRF/particulateDBBMpreparedwasappliedinthebuccalplateofthepre‐
maxillaandshapedtorestorebonevolume.Thegraftedareawasthencoveredwithat
leastfourlayersofPRFmembranestoprotectitfromexposureandoptimizewound
healing(Figure3D,E).Atensionlessprimaryclosurewasobtainedthroughhorizontal
periostealreleasing,flapadvancement,andsimplesuturesusinganon‐resorbablesuture
(6‐0polypropylenePermaSharp
®
Sutures,Hu‐Friedy,Chicago,IL,USA).

Figure2.ClinicalphotographsoftheprotocolsequencetoobtainthecompositePRF/particulate
xenograft:(A)ExtractionofthePRFmembranesfromthered‐toppedtubes.Themembraneswere
posteriorlypressedinapropermetalbox;(B)Irrigationofautologousboneandxenograftwith
liquidfibrinogenobtainedfromthewhite‐toppedtubes;(C)ObtainingacompositePRF/particulate
xenograft.Notethestiffnessofthiscomposite,whichacquiredarectangularform.

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Figure3.Clinicalphotographsofsequentialsurgicalstages:(A)Atrophicmaxillaofapartially
edentulouspatientwhoworearemovableprosthesisformorethan15years;(B)Incisionandfull‐
thicknessflapreleasing.Notethethinbuccalplate;(C)Implantplacement.Notethebuccal
fenestrationoftheimplantsinthepre‐maxilla;(D)Guidedboneregenerationwithacomposite
PRF/particulatexenografttoreconstructthebuccalaspectofthemaxilla;(E)Overlayofthe
compositePRF/particulatexenograftwithatleastfourPRFmembranes,providingprotectionofthe
graftedarea;(F)Full‐archimplant‐supportedprovisionalrestorationplacedaftersurgery.
Immediatemetal‐reinforcedfixedcompletedenturesweremade,inserted,and
adjustedonthesamedayofsurgerytoserveasimmediateprovisionalrestorationsduring
healingandosseointegration(Figure4F).Manufactureandinsertionandadjustment
proceduresfollowedtheprinciplesdescribedbyCaramesetal[32].Patientswere
medicatedwithamoxicillin+clavulanicacid875/125mg(startingthedaybeforesurgery
withonetabletevery12h,for8days),600mgofibuprofen(every12hfor3days),and1
gofparacetamol(every8h,forthefirstthreedays)Theywerealsoinstructedtorinse
twiceadaywithchlorhexidine(PerioAid0.12%;Dentaid,Spain)mouthrinseandnot
brushthesurgicalareauntilsutureremovalatday10.


Figure4.Clinicalphotographsreportingtherelevanceoftheissuepresentedinthisstudy.
Evaluationoftheaestheticfeaturesrelatedtolipsupportandprosthesis,aswellassofttissue
healingandemergenceprofileatthe12‐monthfollow‐upappointment.(A)Lipsupportatrest

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beforetreatment;(B)Lipsupportatrestatthe12‐monthfollow‐upappointment;(C)Lipsupportat
smilingpositionbeforetreatment;(D)Lipsupportatsmilingpositionatthe12‐monthfollow‐up
appointment;(E)Emergencyprofileofthesiximplantsplacedinthemaxilla.(F)Superiorand
inferiorfull‐archprosthesisinmonolithiczirconia.Notethatthemaxillaryprosthesisincludeda
veryreducedbuccalflangeduetothehardandsoftregenerationobtainedaftersurgery.
Patientsweresubmittedtomandatorypost‐surgicalcontrolappointmentsat10days,
1month,and6monthsaftersurgery,andothersifneeded.Atthe10‐dayand1‐month
follow‐upappointments,post‐operatorycomplications,suchassensorydisorder,
infection,graftexposure,anddehiscencewereassessed,andthenumberofeventswas
determined.Atthe1‐yearfollow‐upappointment,participantswerealsosubmittedtoa
clinicalobservationtomonitoraestheticfeaturesrelatedtolipsupportascomparedto
baseline(Figure4A–D),prostheses,softtissuehealing,andtheemergenceprofile(Figure
4E,F).
2.4.StatisticalAnalysis
AllthecollecteddatawereprocessedinSPSSsoftware(version24;IBMSPSS
Statistics,Chicago,IL,USA)forstatisticalanalysis.Resultswereexpressedasamean±
95%confidenceinterval(CI)inmillimetersforlinearbonemeasurementsorasa
percentageforaugmentedbone.NormalityofdistributionwastestedbyShapiro–Wilk’s
normalitytest,andLevene’stestwasusedtoassesstheequalityofvariance.Accordingto
thevariablestobeassessed,thenon‐parametricFriedman’s,Mann–WhitneyU,or
Kruskal–Wallistestswereusedtocompareoverallordifferentsitesforregeneratedbone
linearchanges(α =0.05)usingthepatientasthestatisticalunit.Theeffectsizewas
calculatedwithCohen’sdrepeatedmeasuresbetweenpre‐ andpost‐surgical
measurementsandbetweenpost‐surgicaland12‐monthfollow‐upmeasurements,and
consideredassmall(<0.3),moderate(0.3–0.8),orlarge(≥0.8)effect.Asamplesize
determinationwasperformedtodetectalargeeffect(≥0.8)inbonegainatthe12‐month
follow‐upappointment,usingG*Power3.1software(Heinrich‐Heine‐Universität,
Düsseldorf,Germany).Consideringasignificancelevelof5%andapowerof80%,a
minimumof12participantswasrequired.Tooffsetapossibleattritionbias,50%was
addedtothetotalsample,resultingin18patients.Anindependentstatisticianperformed
thestatisticalanalysis.
3.Results
The18participantsincludedfivemenand13women,withagesrangingfrom36to
76years(mean:58years).Sevenweresmokers(lessthantencigarettesperday).No
dropoutswereregistered.Thisstudyassessedatotalof72implants,ofwhichonewas
lostduringthefollow‐upperiod,equatingtoasurvivalrateof98.61%.
Table1presentshorizontalbonechangespersiteatdesignatedtimepoints:pre‐
surgery(beforetreatment),post‐surgery(aftertreatment),anda12‐monthfollow‐up.For
bothsites,thepost‐surgicaland12‐monthfollow‐uphorizontalwidthwasstatistically
higher(Friedman’stest,p<0.05)thanthepre‐surgicalvalues,withadrepeatedmeasuresof2.38
[2.07;2.67]and1.66[1.39;1.94],respectively.Site2alsoshowedstatisticallyhighervalues
thansite1atthepost‐surgicaland12‐monthfollow‐upCBCTs(Figure5).Themean
horizontalwidthatthe12‐monthfollow‐upwasstatisticallydifferentfromthepre‐and
post‐surgeryvalues(Friedman’stest,p<0.05),withadrepeatedmeasuresof−1.12[−1.38;−0.86]
betweenthepost‐surgicalandthe12‐monthfollow‐uphorizontalwidths.Theobtained
effectsizeswereabovetheminimumdetectableeffectsizeof0.098,withanalfaof0.05
andabetaof0.2.Theoverallmeanaugmentedbonegainatpost‐opwas4.54mm[4.09;
4.98]withstatisticallysignificantdifferencesbetween3.96[3.51;4.41]mmforsite1and
4.96[4.32;5.60]mmforsite2(Mann–WhitneyUtest,p<0.05).Nosignificantdifferences
weredetectedwhencomparingaugmentedbonestabilitybetweensites(Mann–Whitney
Utest,p>0.05)orimplantlocationsintheaestheticarea(Kruskal–Wallis,p>0.05).

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Table1.Linearbonechanges(inmm)foreachlocationandoverallatdifferentevaluationtimes.
Pre‐SurgeryPost‐Surgery12‐MonthFollow‐UpBoneGain(12Months—Pre‐Surgery)
Site1
Mean3.527.796.533.01
95%CI3.19–3.857.30–8.286.09–6.962.51–3.50
Range6.167.536.68.17
Site2
Mean5.510.848.993.5
95%CI5.04–5.9510.19–11.488.42–9.572.87–4.13
Range8.599.768.478.46
Total
Mean4.479.257.713.24
95%CI4.13–4.808.76–9.757.28–8.142.85–3.64
Range8.8911.5610.928.5
Noneoftheincludedpatientspresentedcomplicationsduringthefollow‐upvisits
(10daysand12‐monthpost‐operation).

Figure5.Linearbonechanges(mm)(mean±95%CI)fordifferenttimepointsin144locations[n=
18patients].p<0.05betweenlocationsandtimepoints.
4.Discussion
Theevaluationoffacialchanges,suchaslossoflipsupport,hasincreasinglybeen
consideredwhenplanningimplant‐supportedrehabilitationofedentulouspatients
[33,34].Aspreviouslyreported,horizontalboneaugmentationinimmediatefull‐arch
reconstructionsisafrequentprocedurethatshouldalsoconsiderthepatient’spreferences,
expectations,andmorbidity[13].Althoughautogenousboneisregardedasthegold
standardgraftmaterialduetoitsosteogenic,osteoinductive,andosteoconductive
properties,itisalsoassociatedwithincreasedmorbidity,alimitedamountofvolume,and
variableresorptionrates[5].Thus,fromapatient‐centeredperspective,cliniciansshould
avoidasecondinvasiveharvestingsurgerytocollectautogenousbone.Toovercomethese
limitations,researchontissueengineeringandhard‐tissueregenerationhasescalatedin
thelasttwodecades[35].Oneofthestrategiesfocusedongrowthfactors,aimingto
modulatecellulareventsinvolvedintissuehealingandrepair[35].Platelet‐richfibrinisa
secondgenerationofAPCsusedinthemanagementofseveremedicalconditions[23].In
dentistry,PRFwasrecognizedasreducingpost‐operativepain,post‐surgicalbleedingin

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patientstakingantiplateletdrugs,andpromotingsofttissueepithelization[28,29].Few
studieshavebeenidentifiedregardingitsuseinhorizontalorverticalboneregeneration
[29,36–38].Totheauthors’bestknowledge,thisisthelargestprospectiveclinicalstudy
conductinganimmediate‐loadingprotocolinthemaxillasimultaneouslywithaGBR
procedureusingamixtureofparticulatexenograftandPRFmembranesembeddedin
liquidfibrinogentoformacompositegraft.
Theresultsofthisprospectiveclinicalstudybasedonasamplesizeof18patients
suggestthatcombiningPRFmembraneswithparticulatedeproteinizedbovinebone
mineralcanbeeffectiveandsafeintreatinghorizontalbonedefectsintheanteriormaxilla
togetherwithimplantplacement.Themeanhorizontalbonegainof3.24[2.85;3.64]mm
observedagreeswiththemainfindingsofsystematicreviewsofrandomizedclinicaltrials
analyzingaGBRtechniqueforlateralridgeaugmentation[15,16,18,19,31,39].Thehigh
heterogeneitybetweenstudiesincludedintheseSRsmayexplainslightlydifferent
outcomesbetweenthem[15,18,39].Namely,Milinkovicetal.describeda3.31mm
horizontalbonegainwhenusingGBR,whereasElnayefetal.reported2.59±0.23mmfor
thesameapproach[15,18].MostoftheincludedGBRstudiesuseddifferenttypesofbone
grafts—eitherautologous,xenogenous,allogenous,oramixtureofboth,withdifferent
typesofmembranesandindifferentedentulousregions.Moreover,severalotherfactors
mayinfluencethemeanhorizontalbonegainoutcome:regenerationtechnique,incision
design,flapmanagement,recipientsitepreparation,graftstability,tension‐freeprimary
closing,anddefectmorphology[5].Ridgeaugmentationproceduresaretechnique‐
sensitiveandrelyontheoperator’sskillfulnessandproficiency[5].Inthisstudy,the
previouslyreferredaspectswereconsistentlymanagedbyasingleexperiencedsurgeon
(J.M.M.C.),exceptdefectmorphology,intrinsictothepatient.
Regardlessofthetechniqueorbiomaterialsused,differentlevelsofgraftresorption
areexpectedtooccur[5,29].Untilnow,fewstudieshaveprovidedinformationaboutbone
graftstabilityatlong‐termfollow‐ups(12months).However,itisrelevantforlong‐term
implantsuccessandfacialaestheticcorrections[18].Thisstudyevaluatedgraftstability
bycomparinghorizontalwidthatthe12‐monthfollow‐upwithpost‐surgicalwidth,and
foundastatisticallydifferentvalue(Friedman’stest,p<0.05)withadrepeatedmeasuresof−1.12
[−1.38;−0.86].mm.Arecentproof‐of‐conceptstudyproposingthecombinationofPRFand
DBBMinhorizontalboneaugmentationreportedanaveragebonegraftstabilityof84.4%
inashorterfollow‐upperiodof5to8months[38].Elanayefetal.alsofoundaslight
horizontalresorptionof1.130.25mmatthe6‐monthfollow‐upforGBRprocedures.
Estimatingthisvalueisextremelyusefulforpredictingthesurgicalapproachand
properlyovercorrectingthebonedefect[40].Intheauthor’sopinion,thisslowresorption
rateisprobablyattributedtothepresenceofxenograft.Thebiocompatibilityand
osteoconductivityofDBBMarewelldocumentedinpre‐clinicalandclinicalstudies.
However,areducedosteoclasticactivitytowardthisbonesubstituteishypothesized[40].
Inaclinicaltrial,ahistomorphometricanalysisshowedthatDBBMparticlesremained
unchangedandintegratedwithinthebonefor11years[41].
GBRinmaxillaboneaugmentationproceduresisusuallyassociatedwithanimplant
survivalrate(ISR)rangingfrom96.1%to100%[12].HigherISRvaluesareobtainedwhen
GBRisperformedsimultaneously,andimplantsareplacedinnativebone[17,39].Itwas
thecaseinthepresentstudy,wherea98.61%ISRwasobtained.Horizontalridge
augmentationwithxenogenousbonegraftisassociatedwithacomplicationrateof7.85%
[19].Membraneexposureisthemostfrequentcomplicationinthistypeofintervention
[19,40].Inthisstudy,nocomplicationswereregisteredduringthefollow‐upvisits.
However,noindicationsorconclusionscanbewithdrawnbasedonthisfindingina
single‐armclinicalstudy.Accordingtoasystematicreview,PRFmembranesare
associatedwithimprovedwoundhealing,softtissueregeneration,andepithelization[42].
Thus,wemightspeculatethatthisadvantagefavoredsofttissuehealingafterahorizontal
boneaugmentationprocedureandsubsequentlyavoidedmembraneandgraftexposure.
ThestandardizationoftheprotocoltoobtainPRFmembranesandliquidfibrinogenwas

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accomplishedaccordingtoapublishedstudyandisanadvantageofthisresearchwork
[26].
Thepresentstudymayentailsomelimitations.Theprimaryoutcomewasassessed
throughlinearmeasurementsofCBCTscans.Severalstudiesappliedasimilar
methodologybymeasuringthehorizontalbonegaininspecificpointsofthealveolar
ridge[31,36,43–45].Althoughregardedasareproduciblemethodtoevaluatebonegain
obtainedafterGBR,dentalimplantsmaycauseartifactsinCBCTimages,reducingimage
qualityandanatomicaccuracy[46].Althoughanyblurredscanwassubjectedtoartifact
correctionbythePlanmecaARA™metalartifactremovalalgorithm,aidingoperator’s
measurements,thismethodologyisnotexemptfromlimitations.
Sincehorizontalboneregenerationrepresentsanaddedbonevolume,thelinear
natureoftheacquiredmeasurementsisaweakpointinthisstudy.Althoughthe
measurementlandmarksarerepresentativeofthegraftingarea,avolumetricdescription
variationwouldbepreferable[38].Basedonthisperspectiveandconsideringthe
developmentofhigh‐speedandhigh‐accuracy3Dintraoralscanners,theiruseinfuture
studiesmayrepresentalessinvasiveoptiontoevaluateboneandsofttissuevolumegain.
IntheGBRtechniqueperformed,PRFmembranesweresolelyusedasabarrierto
coverthecompositePRF/particulateDBBMplacedintheanteriormaxilla’sbonedefect.
Contrarytoasimilarstudyaimingatmaxillahorizontalboneaugmentation,no
resorbablecollagenmembraneorfixationpinswereusedformembranestabilization
underPRFmembranes[38].Whenusingparticulatebonesubstitutesinlargedefectslike
thoseregeneratedinthepresentstudy,membranestabilizationforgraftimmobilization
representsachallengeandkeyfactorforGBRsuccess[17,40].Thisobjectivewasmainly
achievedinthisstudybyaddingliquidfibrinogenbindingbonegraftparticlesinthe
compositePRF/particulateDBBMgraft.Inaddition,thePRFmembranecross‐linking
structureprovidedanelasticmechanicalbehaviorsuitableformembranehandlingand
graftcovering[27].Non‐resorbablemembranesfixatedwithpinsystemsshowless
tendencytocollapseandmaintainthehorizontalcontouroftheaugmentedridge[17].
However,thistypeofapproachpresentsmorecomplications,especiallymembrane
exposure,andrequiresadditionalsurgerytoremovethemembraneandthepinswhen
patientssubjectedtoimmediatefull‐archrehabilitationusuallydonotexpectadditional
surgeryprocedures.Immediate‐loadingsimultaneouslytoboneregenerationhasbeen
poorlydescribedintheliterature[47].Althoughimmediateloadinginmaxillafull‐arch
rehabilitationcanbeapredictableprotocolwhenkeyfactorsareachieved,suchas
adequateprimaryimplantstability,afavorabledrillingtechnique,implantdesign,length,
andimplantmicrostructure[48,49].Inaddition,theimportanceofosteotomytechniques
shouldberecognizedwhenaminimuminsertiontorqueof45N.cmisobtainedinamore
medullarybone[50].Aclearinfluenceofabonecompactorpreparationtoimplant
primarystabilitywassuggestedbyAttanasioetal.inthistypeofbone[50].Inthisstudy,
theoperator(J.M.M.C.)followedbrandinstructionsandaccomplishedanunder‐
preparationscheme,promotingamorefrictionalimplantinsertion.Otheraspects,suchas
cross‐archstabilization,prostheticmaterial,andprostheticrehabilitationdesignaidedto
unloadtheregeneratedarea—acrucialaspectoftheboneregenerationprocess.
Becausethisstudyisasingle‐armprospectiveclinicalstudywithoutanycomparison
group,theconclusionsregardingtheuseofPRFinhorizontalboneaugmentationare
limited.AnRCTstudydesignwouldhavethepotentialtobetterclarifythediscussed
biologicalbenefits.AmajoraspectofthebiologicalplausibilityproposedforPRFinbone
regenerationshouldalsobequestioned.Fibrinmatrixdegradationandgrowthfactor
releaseoccurinthefirst10to14days,whereasbonetissueformationoccursin3to4
months[27].Itiseasilyperceivedthatthisnaturalscaffoldlacksaspatial‐temporal
deliveryofgrowthfactorsconcomitanttoboneformationevents.Sinceitderivesfrom
blood,itsspecificity,andminimumconcentrationofgrowthfactorstoaidosteogenesis’s
initialphasesarestillunknown.Therefore,futureresearchshouldaimtoclarifythis
questionandoptimizescaffoldspreparedinordertoassistalleventsofbonetissue

J.Clin.Med.2022,11,89411of14
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
formation,providingacombinedreleaseofgrowthfactorsandextracellularmatrix
components.
5.Conclusions
Withinthelimitationsofthisclinicalstudy,theuseofcompositePRF/particulate
xenograftinGBRforhorizontalboneaugmentationwithsimultaneousimplantplacement
seemssafeandprovidesahorizontalbonegainandgraftstabilitywithinpreviously
describedvaluesforGBRprocedures.Thisresultmightbeparticularlyrelevantsinceno
resorbablecollagenmembraneswereusedtocoveranimmobilizedbonegraftobtained
byaddingliquidfibrinogen.Notypeofcomplicationhasbeenregistered.Furtherstudies
areneededtovalidateorexcludethepotentialbiologicalbenefitsofPRFinGBR
proceduresformaxillahorizontalboneaugmentation.
AuthorContributions:Conceptualization,J.M.M.C.andD.N.d.S.M.;methodology,D.N.d.S.M.;
investigation,J.M.M.C.,G.B.C.,H.C.O.F.,A.C.P.andF.A.V.;supervision,D.N.d.S.M.;surgery
performance,J.M.M.C.;visualization,G.B.C.andH.C.O.F.;writing—originaldraftpreparation,
F.A.V.;writing—reviewandediting,D.N.d.S.M.,F.A.V.andJ.M.M.C.Allauthorshavereadand
agreedtothepublishedversionofthemanuscript.
Funding:Thisstudydidnotreceiveexternalfunding.
InstitutionalReviewBoardStatement:Thestudywasconductedaccordingtotheguidelinesofthe
DeclarationofHelsinkiandapprovedbytheInstitutionalReviewBoardandEthicsCommitteein
Lisbon(II‐04‐2019).
InformedConsentStatement:Informedconsentwasobtainedfromeachpatientconsideredfor
dataanalysis.
DataAvailabilityStatement:Datacannotbesharedduetodataprotectionobligations.
ConflictsofInterest:Theauthorsdeclarenoconflictofinterest.
Abbreviations
PRFPlatelet‐richfibrin
CBCTConebeamcomputedtomography
GBRGuidedboneregeneration
APCsAutologousplateletconcentrates(APCs)
PDGFPlateletderivedgrowthfactor
TGF‐
β
1Transforminggrowthfactor
β
1
IGFInsulin‐likegrowthfactor
VEGFVascularendothelialgrowthfactor
DBBMDeproteinizedbovinebonemineral
ASAAmericanSocietyofAnesthesiology(physicalstatusclassificationscoreI‐VI)
MRONJMedicationrelatedtoosteonecrosisofthejaw
SRsSystematicreviews
ISRImplantsurvivalrate
RCTRandomizedclinicaltrial
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