OriginalContribution
JournalofCosmeticDermatology,13,307--314
Anewdermalfillermadeofcross-linkedandauto-cross-linkedhyaluronicacidinthecorrectionoffacialagingdefects
AdeleSparavigna,MD,1PasqualeFino,MD,2BeatriceTenconi,Sc.D,1NicolaGiordan, PharmD,3VittoriaAmorosi,MD,2Nicolo`Scuderi,MD2
1DermingClinicalResearchandBioengineeringInstitute,Monza,MB,Italy
2DepartmentofPlastic,ReconstructiveandAestheticSurgery,UniversityofRome’Sapienza’,Policlinico’UmbertoI’,Rome,Italy
3ClinicalResearchDepartment,FidiaFarmaceutici,AbanoTerme,Padua,Italy
SummaryBackground AnovelHyaluronicAcid(HA)derivativedermalfillerhasbeendeveloped with characteristics especially suited for nasolabial folds (NLF) and facial defects due tovolumeloss.
AimsAnopen-labelprospectivestudywascarriedouttoevaluatethisHAfiller’sperformanceincorrectingfacialdefectsduetovolumeloss.
MethodsAsingleItaliansitetreatedsubjectsaged30–65forfacialdefectsduetovolumelosswithanewdermalfillerinjectablegel;subjectsreturnedtotheclinicat
7 and 14 days, and 1, 3, 6, 9, and 12 months for follow-up. The primaryeffectivenessendpointwasimprovementinwrinkleseverity(measuredusingthe WrinkleSeverityRatingScale)(WSRS)andfacialvolume(measuredusingtheFacial VolumeLossScale)(FVLS)at6and12monthsfrombaseline.Secondaryendpointswere safety evaluation, performance duration, product handling, subjects’ andinvestigator’streatmentevaluation.Assessmentofaestheticresultsincludedtheskinhydration,imageanalysisofnasolabialfolds(3D),andphotographicdocumentation. ResultsThereductioninnasolabialwrinkleswasstatisticallysignificantat6months afterthefirstimplant.Theaestheticimprovementof1gradeonWSRSwasevident in95%ofsubjectsupto3months,in84%ofsubjectsupto6monthsandin27% upto12months.Aclinically(>1pointimprovement)andstatisticallysignificantimprovementintheFVLSwasobserved ateachstudyvisit;in100%oftreatedcases,upto3monthsandin61%upto9months.Goodresultswereobtained duringthestudyinskinhydration.Therewerenosevereadverseeventsrelatedtotreatment.
Conclusion This injectable gel is well tolerated and has been demonstrated to provide asmoothandnaturalimprovementinfacialdefectsduetovolumelossinnasolabial foldsandthemalarregionthatlastsforupto1year.
Keywords:dermal filler, hyaluronic acid, facial defects, volume loss, patientsatisfaction
Correspondence:PasqualeFino,MD,DepartmentofPlastic, ReconstructiveandAestheticSurgery,UniversityofRome“Sapienza”, PoliclinicoUmbertoI,ViadeiQuinzi,5,Interno21,00175,Roma,Italy.
E-mail:,
AcceptedforpublicationSeptember5,2014
Introduction
Nonsurgicalrejuvenationproceduressuchasbotulinum toxin (BTX) and dermal filler injections are now themostcommonaesthetictreatmentsperformedworld-
wide.1,2 In 2008, theAmericanSocietyof AestheticPlastic Surgeons (ASAPS) published projected nation-widestatisticsofUSdermalfillerpractice,inwhichhyaluronicacid-basedfillerswerethemostcommonlyperformedwithover1.26milliontreatments.3 Thepur- suitoftheidealfillerdatesbackcenturies.Asearlyas1893, autologous fat injection to correct facial defects wasreportedbyNeuberandonlyafewyearslaterpar- affinwasinjectedforcosmetictreatment.4,5Thistech-nique enjoyed much popularity until many patients began to develop severe foreign-body and granuloma- tousreactions.6 Later,inthe1940s,theuseofliquidsil- icon become very popular first in the USandsubsequentlyinGermany,Switzerland,andJapan, until many patients demonstrated numerous complica- tions that prevented approval for cosmetic purposes by theUnitedStatesFoodand Drug Administration(FDA).7,8 Modern soft tissue augmentation began in 1982withtheapprovalofbovinecollagen.Sincethen, softtissueaugmentationandinjectionofmaterialsforcosmeticenhancementhaveincreasedconsiderablyandbecamethesecondmostcommoncosmeticnonsurgicalprocedure in 2009. To date hyaluronic acids account forthemajorityofthesofttissueaugmentationmarket.9Hyaluronicacid(HA)isabiologicalglycosaminoglycandistributed in the extracellular matrix of most tissues, andparticularlyconcentratedwhereverrapidtissuepro-liferation,regeneration,andrepairoccur.10 Itwasfirst isolatedin1934frombovinevitreoushumor.11–13
HAisapolysaccharidecomposedofrepeatingunitsofD-glucuronic acid and N-acetyl-glucosamine. It is found inalltissuesofvertebratesandisveryprevalentinhuman skin. It has been demonstrated to be decreased inintrinsicallyagedskinandtobealteredinphotoaged skin. It is highly hydrophilic, binding much more than itsweightinwater.Inafiller,thecross-linkofthepoly-saccharidechainsservestoslowHAdegradationandtoincreasetissueresidencetime.Hyaluronicacidfillersaremainlyusedinnasolabialfolds,whichwasthesiteoforiginal FDA approval. They are also used in many areasincludingthelipsandmarionettefolds.14–17
Anewdermalfiller,HAderivativeandclassifiedasamedicaldevice,hasrecently been developed. Theproductisbasedonhighlyviscousandabsorbablegelformulation, which thanksto its propertiescan ensure along-lastingvolumizingeffect.Chemically,itisacombinationoftwocomponents:anauto-cross-linkedhyaluronicacid(ACP)andahyaluronicacidcross-linking through BDDE (butanediol-diglycidyl-ether).Thecombinationofthetwoproductsformsagelthatdegradesoveralongperiodoftimeandensuresavolumizingeffect.
Aimofthisopen-label,prospectivestudy,herepre-sented,wastoevaluatethelong-termeffectivenessand safetyofthisnovelHAfillerincorrectingfacialdefects duetovolumeloss.
Methods
Studydesign
Thiswasaprospective,open-labelstudyinwhichahighlycohesiveandviscousHAvolumizingfillerwasevaluatedforitsindicateduseofrestoringfacialvol-ume.ThetrialwascarriedoutincompliancewiththeDeclarationofHelsinkiandtheGuidelinesforGoodClinical Practice. Independent ethics committeeapprovalwasobtainedfromtheIndependentMultidis-ciplinaryEthicalCommittee (Monza,IT)and allsub-jectsprovidedwritteninformedconsent.
Inthisclinicaltrial20adultsubjectswereenrolledfromNovember2011toDecember 2012,atanItalian sitetoevaluatetheefficacyandtolerabilityofanewdermalfillerincorrectingfacialdefectsduetovolumeloss.
Subjects
20 subjects fulfilling the following inclusion criteria wereconsideredeligible:healthysubjectsofbothsexes,
aged30–65,score≥2ontheFacialVolumeLossScale(FVLS),score≥3ontheWrinkleSeverityRatingScale
(WSRS),subjectswillingtocomebacktotheclinicforfollow-upvisits,subjectswillingtoabstainfromothercosmetic procedures (e.g., further augmentation ther- apy, botulinum toxin injections, facelift procedures,laser chemical peeling etc.) during the entire duration of the study, subjects providing signed informed con- sentform.
Subjects were excluded if they were participants in anyongoingclinicaltrialorhadanyconditionscon-traindicatingtheuseofHAfillerssuchasskindisease,(infections,dermatitis,activeeczema,psoriasis,acne,rosacea,herpesetc.),subjectsintherapywithantico-agulant drugs, subjects with facial volume loss caused bytraumasorgeneticdefects,subjectswithhypersen-sitivitytohyaluronicacidand/oritsingredients,aller-gies,autoimmunedisease (LES, sclerodermia etc.),cancer,intherapywithimmunosuppressivedrugs,inpregnancyorlactation.
Subjectswereremovedfromthetrialiftheywith-drew from the study for personal reasons, developed anyoftheconditionsspecifiedintheoriginalexclusion criteriaorcontractedaseriousillnesspreventingcon-
tinuationofthe study. Subjects removed from thestudywerenotreplaced.
Studyprocedures
ParticipantsreceivedIal-SystemDuo® (FidiaFarmaceu- ticiS.p.A.,ViaPontedellaFabbrica3/A,35031,Abano Terme(PD)-Italy),aclassIII,ECmarketmedicaldevice,providedinadisposableprefilledsyringeof1mLvol-ume.Allowabletreatmentsiteswerethenasolabialfolds ormalarregion,withamaximumvolumeof4mL.Intradermal and/or subcutaneous injection was per- formedbyneedle(30G,13mm,linearretrogradetech- nique)atthelevelofnasolabialfoldsorbluntcannula (27G,40mm,fantechnique)forthemalarregion.Theinjectionvolumeselectedforthefirstimplantwasbetween2mLand4mL.
Followingtreatmentwiththishyaluronicacidinject- ablegel,subjectsreturnedtotheclinicforfollow-upvisits at 7days (V2), 2weeks (V3), 1 (V4), 3 (V5), 6(V6), 9(V7),and 12(V8) monthsafterinitial treat- ment. An optional top-up treatment was allowed at 1 week with an injection volume between 0.5 and 1mL.
Datacollectionandstudyendpoints
The primary effectiveness endpoint was improvement inwrinkleseverity(measuredusingtheWrinkleSever- ity Rating Scale) and facial volume (measured using the Facial Volume Loss Scale) at 6 and 12months frombaseline.
Investigatorsrecordedeachsubject’sage,sex,base-
linevolumelossaccordingtotheFVLSandseverityofwrinklesaccordingto theWSRS. Clinicalevaluation byWSRS(scorefrom1to5)andFVLS(from1to5)was usedtoassesstheefficacyoftheproduct.Investigatorandsubjectsatisfactionwasevaluatedbyanumerical
generatea3Dprofileofthemeasuredskinsurface.TheInvestigator’sjudgmentonproducthandling,afterthefirstimplantandthetop-up,wasrecordedasascorefrom1to5.Finally,patient’sglobalassessmentwasevaluatedaskingpatientstocompleteaself-assessmentquestionnaire.
Assessmentofsafetywasperformedbydirectobser-vation of local expected events/reactions induced by theinjection (pain,erythema, edema,bruise), and any otheradverseevent/reaction,alsoofsystemicsource,occurringduringthestudy.
Dataanalyses
The data was summarized with descriptive statistics (e.g., adjusted means, standard deviation, minimum and maximum value). The statistical analysis of clini- caldatawasperformedusingnonparametrictests(Friedmantestfollowed,intheeventofstatisticallysignificant results, by Dunnett test), while parametric testswereusedforinstrumentaldata(ANOVAtestfol-lowed, in the event of statistically significant results, by Dunnett test). The results obtained at each study time point were compared with baseline conditions. Safety and tolerability were evaluated at any follow- upvisit.
Results
Studyparticipants
Twentyfemalewereincludedinthestudy,agerange49–65years (mean=56), with a score ≥2 on the FVLS and a score ≥3 on the WSRS, from whom
informedconsenthadbeenobtained(Table1).
Table1Subjectbaselineanddemographicdata
ratingscalefrom0to10,where0wasnoimprove-
ment and l0 was maximum improvement. Duration time of the volumizing and filler effect was evaluated by image analysis results on nasolabial folds, obtained 14days after the first intradermal implant and com- pared to the ones obtained after 1, 3, 6, 9, and 12months.SkinhydrationwasmeasuredusingtheCorneometerCM825(Caurage–Khazaka,K6ln, Ger-many). Two-dimensional frontal face pictures weretakenwithstandardizedmethods.3Dnasolabialfoldspictures, were taken using the PRIMOS® (GFMesstech-nikGmbH,Teltow,Germany)whichprovidesahigh-resolution profilometry of skin surfaces using
Female(no)20/20
Age(years)
FacialVolumeLossScale
Score2 / 2/20(10%)Score3 / 3/20(15%)
Score4 / 8/20(40%)
Score5 / 7/20(35%)
WrinklesSeverityRatingScale
phase-shiftedlightstripesprojectedbymicromirrorsto
Treatmentandpracticecharacteristics
AllsubjectsreceivedinjectionsofthesamehyaluronicacidfillerinNLFsandthemalarareaonbothsidesof theirfaceatthebaselinevisit.Seventeen subjectsreceivedatop-uptreatmentat1weekinNLFs,whiletop-upwas performedinthemalarregionandnasola- bialchinfoldson3and6subjects,respectively.Themean injection volume was 0.5–1mL. Two subjects, duetothepresenceofbruisesafterthefirstimplant,refusedthetop-uptreatment.Onesubjectdidnotper-
100
90
80
70
60
50
40
30
20
10
0
959595
84
56
27
formV3becauseofpersonalproblems.Noothersignif- icantevent,whichmayhaveinterferedwiththetestresultsoccurredduringthestudyperiod.Five subjectsdroppedoutofthestudyduetopersonalproblemsnot relatedtothetestedproductortheaesthetictreatment;therefore, at V6, the statistical analysis was performed onatotalof19subjects,andatV7andV8thestatis- ticalanalysiswasperformed,respectively,onatotalof 18and15subjectswhocompletedthetrial.
Aestheticoutcomes
Effectiveness
Beforetreatment,nasolabialfoldswereratedbytheinvestigatorsasbeingextremein 30% of subjects,severein50%,andmoderatein20%ofsubjects.ThemeanWSRS at baseline was 4.1, the treatmentresulted in a significant improvement, after 3months the scores decreased by 1.3 points and after 12months from first implant the reduction of WSRS wasstillclinicallyevident.
Treatmentwithhyaluronicacidfillerinducedaclini- callyandstatisticallysignificantimprovementfrombaseline condition, the reduction in WSRS being,
5
*p<0.05vsV1
4.1
V3V4V5V6V7V8
Figure2Proportionofsubjectswith≥1gradeimprovementfrombaselineinWrinklesSeverityRatingScale(WSRS).
FacialVolumeLossScale(FVLS)
4
3
2
1
0
V1V3V4V5V6V7V8
Figure3MeanscoreoftheFacialVolumeLossScale(FVLS)evaluatedatbaseline,after14days,1,3,6,9,12monthsafter injection.
respectively,of32%atV3andV4,of34%atV5,of24%atV6,of15%atV7,and10%atV8,correspond- ingtoavisualscorereductionofatleastonegradein 95%oftreatedcasesuptoV5,in84%atV6,in56%and27%,respectively,atV7andV8(Figs1and2).
4
32,8*2,8*
2
1
2,7*
3,1*
3.5
3.7
At baseline the FVLS score of all subjects ranged from 2to5,themeanscoredeclinedsignificantly(P 0.05 vs. baselinecondition),from4.0atbaselinevisitto2.2 at visits 5 and 6 (3 and 6months after treatment). The reduction in FVLS visual score vs. baseline (V1) was38% atV3, 40%atV4, 45%at V5and V6, 20% atV7,and10%atV8,correspondingtoavisualscorereduction of at least one grade in 100% of treated casesuptoV5andin61%after9months(Fig.3).
V1V3V4V5V6V7V8
Figure1MeanscoreoftheWrinklesSeverityRatingScale(WSRS)evaluatedatbaseline,after14days,1,3,6,9,
12monthsafterinjection.
Thesemeasuresmaybemoreinterestingconsidering
thatatV4andmoreconsistentlyatV5andV6,thepercentageofsubjectswhoshowedareductionintheFVLSvisualscoreof2and3gradeswashigherin
100
90
80
70
60
50
40
30
20
10
0
100100100
95
61
27
theabilityofACP(auto-cross-linkedhyaluronicacid)to bind with the water molecule causing a rapid increase indeepmoistureandaprogressiveimprovementinsuperficial skin hydration, detectable up to 9months afterthetreatment.
Theskinprofilometryofwrinkles(PRIMOS®)atthelevelofnasolabialfoldsshowedfromV3onwardsastatistically and clinically significant reduction (Dun- netttestP0.05V3,V4,V5,andV6vs.baselinecondition)intheroughnessparameter(RA)(Table2).Hyaluronicacidtreatmentachievedareductioninthe
V3V4V5V6V7V8
Figure4Proportionofsubjectswith≥1gradeimprovementfrombaselineinFacialVolumeLossScale(FVLS).
SKINELECTRICALCAPACITANCE(SKINHYDRATION)
65
meandepthoftheRAparameterfrom120.8lmto
55.4lmat2weeks(V3)afterthefirstimplant,indi-cating an excellent filling product activity which was stillmarkedforupto6months;inparticulartheper-centagereductioninRAcorrespondedto51.7%atV3, 46.9%atV4,42.9%atV5,35.2%atV6,16.5%atV7 and6.5%atV8.
Theclinicalandinstrumentalassessments,aswellas
60
55
50.3249.74
50
44.6846.54
52.9854.12
47.9847.22
59.7960.27
53.4855.27
50.27
49.41
thepatientandinvestigatorglobalassessment,con-
firmedthatthefillingandre-densifyingactivityofthestudy product was still marked and clinically signifi- cant 12months after the first implant (Fig.6a–g
45
40
39.04
35
30
25
20
43.3342.98
40.31
47.18
43.59
37.77
photographicdocumentation3Dand2D).
Safety
No adverse events/reactions related to the study prod- uct occurred during the study. Local post-treatment eventssuchaserythemaresolvedinthemajorityof
V1V3V4V5V6V7V8
MEANmean+1/2Std. Dev.mean-1/2Std.Dev.
Figure5Skinhydration(*P0.05Dunnetttestvs.V1).
comparisonwithV3(60%atV4,70%atV5,and69% atV6vs.42%atV3).Theseresultsmaybeexplainedby the stimulating activity of hyaluronic acid on cellu- larfunctionalityandbythelong-lastingperformance(re-densifying activity) and bio-revolumetric effect of thestudyproduct(Fig.4).
Themeanvalueofskinelectricalcapacitance(skinhydration) (Fig.5), measured with the CorneometerCM825 instrument, was 44.7 A.U. at baseline. One (V4),six(V6)andnine(V7)monthsaftertreatment,resultsconfirmedaclinicallyandstatisticallysignificanthydration improvement respectively to 7.4%, 19.7% and23.7%incomparisonwithbaselinecondition(V1)(Dunnett test P0.05). Regarding the other study time points although no statistically significant varia- tionvs.V1wasfound,itisimportanttonoteatrendtowards increase in skin electrical capacitance (+4.2% atV3,+5.7%atV5).Theseresultsmaybeexplainedby
treated subjects within 2–3h, while the resolution
time for edema, was on average of 3–4h. Bruising wasmoremarkedinthemalarregionandtheresolu-tiontime,dependantontheextentandseverityofthelesion, was 10-15 days. Pain, more prominent at the level of the nasolabial folds and less intense in the malar region, was perceived by subjects during injec- tion procedure (resolution time generally 1–2min).Finaltoleranceofstudyproductwasratedbytheinvestigatorasgoodtoverygoodin100%oftreatedpatients. No serious adverse events were occured in the study and no patients withdrew from the study duetosafetyreasons.
Discussion
Minimallyinvasiveor non-invasive procedures cur-rentlyrepresentabout80%ofcosmeticinterventions.AccordingtothestatisticsoftheAmericanSocietyofPlasticSurgeons(ASPS)from2009,thetopfivemini-mallyinvasiveproceduresperformedin2009wereBOTOX injections (4.8million), soft tissue fillers(1.7million),chemicalpeel(1.1million),microderm-
Table2MeanchangeinPRIMOS®measurementsfrombaseline
2 weeks / 1 month / 3 months / 6 months / 9 months / 12 monthsBaseline / V3 / V4 / V5 / V6 / V7 / V8
measurement (SD)120.8 lm (55.2) 55.4 lm (34.2) 68.4 lm (54.0) 72.0 lm (52.7) 77.6 lm (45.0) 97.9 lm (52.6) 105.7 lm (52.0)
Variation % vs. baseline (SD)—51.7 (20.2)—46.9 (20.8)—42.9 (19.3)—35.2 (19.4)—16.5 (14.2)—6.5 (11.1)
(a)
V1(Baselinevisit)
(b)Post-treatmentviewatV314daysaftertreatment
(c)Post-treatmentviewatV41monthaftertreatment
(d)Post-treatmentviewatV53monthsaftertreatment
(e)Post-treatmentviewatV66monthsaftertreatment
(f)Post-treatmentviewatV79monthsaftertreatment
(g)Post-treatmentviewatV812monthsaftertreatment
Figure6(a–g)Preandposttreatmentviewsofa49-years-oldcaucasianwoman:Figures2Dand3DshowthenasolabialfoldfromV1 (baseline)toV8(12monthsaftertreatment).
abrasion, (910000) and laser hair removal (893000).18Manypatientsseesurgicaloperationsashigh-riskprocedures,butdonot perceive any riskrelated to minimally invasive treatments.9,19 Requests forthesetypesoftreatmentareincreasinginpopularity
worldwideandare associatedwithahighlevelof patientsatisfaction.20–23
Amongthenonsurgicalapproachesforfacialrejuve- nation, after treatment with botulinum toxin, dermal filler procedures, and in particular with hyaluronic
acids, are the most frequently performed.3,24 Over 150injectablefillersareavailableontheworldmarket,but only around a dozen have had the approval of the FDA.Fillerscanbedividedintopermanentandtempo- rary and enter into four main categories: autologous fat, collagen, hyaluronic acid and biosynthetic poly- mers.Hyaluronicacidsaccountforthemajoritypartof thesoft tissue increase market.HA fillers are com-monly used for the treatment of wrinkles, filling of folds,andregionalvolumizers.9
Thesuccessofhyaluronicacidsisespeciallyduetotheirproperties,suchasanexcellentrisk-benefitratio,simplicityofuse,long-lastingeffects,versatility,andreversibility.25Various controlled randomized trials(RCTs)havecomparedtheefficacyandsafetyofHAfill- erswithothernon-HAinjectablesubstances.StudiescomparingHAfillerswithbovinecollagenhavefoundthatHAsuppliesamuchlonger-lastingcorrectioninthenasolabialfoldaccordingtothe5-pointWrinkleAssess- mentScalewithsimilarsafetyprofiles.26–28
Conclusions
Thistrialwasdesignedtoevaluatethesafetyandeffi-cacyofanovel,highlycohesive,viscousHAvolumiz-ingfillerinrestoringfacialvolumeinnasolabialfoldsandthe malarregion.Inourclinicalandinstrumental study,usingthisnewdermalfiller,aclinicallyandsta-tisticallysignificantimprovementintheFVLSwasobservedateachstudyvisit.In100%oftreated cases, the reduction of visual score grade was at least onegradeuptoV5(3monthsafterthefirstimplant).Thepercentage of subjects who presented a reduction in FVLSvisualscoreof2and3gradeswashigheratV4, V5, V6 than at V3 (60% at V4, 70% at V5, 69% at V6vs.42%atV3).Thereductioninnasolabialwrin-kles was statisticallysignificant 6months afterthe firstimplantandwasstillclinicallyevidentinmostoftrea- ted cases up to 9months. An aesthetic improvement ofatleast1gradeintheWSRSwasstillevidentin95%ofsubjectsuntilV5,in84%ofsubjectsatV6and 56%atV7.Theclinicallyandstatisticallysignificantincreaseinskinhydration(P 0.05atV4,V6andV7 vs.V1)confirmedthegoodresultsobtainedduringthe study.Investigatorandsubjectsatisfactionwiththeaestheticresultswasveryhigh.
Currently,theFDAhasapprovedseveralHAfilleragentsformid-to-deepdermalimplantation(i.e.,Resty- lane,Juvederm,Hylaform)forthecorrectionoffacialwrinklesand folds,29–32 where HA is subjected tochemicalcross-linkingprocesses,whichimproveitsvis-coelasticpropertiesandincreaseitshalf-life.
The possibility of obtaining cross-linked hyaluronan gels by chemical derivatization has been well knownsince1964;33 inrecentyears,awidevarietyofchemi- cal modifications and subsequent cross-linking have beenproposedtoachievechemicalandmechanicalHArobustness.34
Inhyaluronicacidobjectofthisstudythechemicalnetwork plays a protective role decreasing the rate of HAhydrolysisandimprovinglongterm efficacy.Favouredbyitsprolongedresidencetimeintheappli-cationsite,theproductslowlyreleasesnaturalhyal-uronicacidbytheauto-cross-linkedHA(ACP),whichthankstoitsnaturalhydratingpropertiesandvisco-elasticity, improves the turgidity and the elasticity of theskin.
Thisnewdermalfillerseemstocombinelineefface-ment and volume restoration by BDDE-based cross- linkedHAtoashort-termbio-stimulatingeffectdueto thereleaseofnativehyaluronicacidbytheauto-cross- linkedHA.
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