Pi is 010956411400640 x

d e n t a l m a t e r i a l s 3 1 ( 2 0 1 5 ) 3752

Available online at www.sciencedirect.com

ScienceDirect

jo ur nal home p ag e: www.int l .e lsev ierhea l th .com/ journa ls /dema

Osseointegration: Hierarchical designingencompassing the macrometer, micrometer, andnanometer length scales

Paulo G.a DepartmenNY 10010, Ub Director foc Afliated Fd Departmene Departmen9-75, 17.012

a r t i c

Keywords:

Review

Osseointegr

Design

Macrogeom

Surface

CorresponNY 10010, U

E-mail aestevamab@

1 Tel.: +462 Tel.: +1 93 Tel.: +55

http://dx.do0109-5641/ Coelhoa,b,c,, Ryo Jimbod,1, Nick Tovara,2, Estevam A. Bonfantee,3

t of Biomaterials and Biomimetics, New York University, 345 East 24th Street, Room 804s, New York,nited States

r Research, Department of Periodontology and Implant Dentistry, New York University, United Statesaculty, Division of Engineering, New York University Abu Dhabi, United Arab Emiratest of Prosthodontics, Faculty of Odontology, Malm University, SE 205 06 Malm, Swedent of Prosthodontics, University of So Paulo Bauru College of Dentistry, Al. Otvio Pinheiro Brisola.901 Bauru, SP, Brazil

l e i n f o

ation

etry

a b s t r a c t

Objective. Osseointegration has been a proven concept in implant dentistry and orthope-

dics for decades. Substantial efforts for engineering implants for reduced treatment time

frames have focused on micrometer and most recently on nanometer length scale alter-

ations with negligible attention devoted to the effect of both macrometer design alterations

and surgical instrumentation on osseointegration. This manuscript revisits osseointegration

addressing the individual and combined role of alterations on the macrometer, microme-

ter, and nanometer length scales on the basis of cell culture, preclinical in vivo studies, and

clinical evidence.

Methods. A critical appraisal of the literature was performed regarding the impact of dental

implant designing on osseointegration. Results from studies with different methodological

approaches and the commonly observed inconsistencies are discussed.

Results. It is a consensus that implant surface topographical and chemical alterations can

hasten osseointegration. However, the tailored combination between multiple length scale

design parameters that provides maximal host response is yet to be determined.

Signicance. In spite of the overabundant literature on osseointegration, a proportional incon-

sistency in ndings hitherto encountered warrants a call for appropriate multivariable study

designing to ensure that adequate data collection will enable osseointegration maximiza-

tion and/or optimization, which will possibly lead to the engineering of endosteal implant

designs that can be immediately placed/loaded regardless of patient dependent conditions.

2014 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.

ding author at: Department of Biomaterials and Biomimetics, New York University, 345 East 24th Street, Room 804s, New York,nited States. Tel.: +1 212 998 9214; mobile: +1 646 334 9444.ddresses: [email protected] (P.G. Coelho), [email protected] (R. Jimbo), [email protected] (N. Tovar),gmail.com (E.A. Bonfante).

40 665 8679; mobile: +46 70 203 1025.73 464 9556.

14 3235 8272; mobile: +55 14 98153 0860.

i.org/10.1016/j.dental.2014.10.007 2014 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.

38 d e n t a l m a t e r i a l s 3 1 ( 2 0 1 5 ) 3752

1. Introduction

Bone fusin[1], then byshowed thait would seerable timethen reneby Brnemformation without solevel [3,5]. ple orthopethe way forpatients [6]

The intdentistry hfor advancdecreasingment and fresponse [7the eld otial and hchallenges the interamacrogeominstrument

The impthe achieveoptimal deto be determan academto rehabilit

This revtured form(bulk devicdimensionway and thimplant ha(a primary in light of recent bodand utilizatto implantpotential inchically appdesign.

2. Th(hardwarimplicati

It has beening implantitanium-bdevice willload-bearinsupported

based on a large number of different devices surgically placedin bone through a large variation in surgical instrumenta-

chni of oy to cd inally a plend mutiok is ossere ieal key i

its vioueratisider

Thay

ealined fot sys

teotohroulay btemt exiced pogand issuectly rforce29].

the thatrain er, in

thetion a

bonrquecessal stding essiouene boat haoineed th

and cellh bos heas thg to titanium was described in 1940 by Bothe et al Leventhal more than 6 decades ago [2], who alsot titanium failed to cause tissue reaction and thatrve as an ideal metal for prostheses. After consid-, the term osseointegration was created and it wasd by a series of well-characterized scientic reportsark and colleagues [3,4]. It has been dened as theof a direct interface between an implant and boneft tissue interposition at the optical microscopyThis phenomenon has been the basis for multi-dic and dental rehabilitation procedures, paving

quality of life improvement of a large number of.roduction of titanium and its alloys to implantas marked an era where the main driving forcees in implant engineering has been centered at

or eliminating the hiatus between surgical place-unctional loading due to improved host-to-implant10]. Nonetheless, clinical and basic research on

f implant dentistry resulted in a lack of sequen-ierarchical approach for implant designing thatbiomedical engineers to retrospectively address

ction of the main design parameters such asetry, microgeometry, nanogeometry, and surgicalation in an objective fashion [11].lant design is one of the important parameters forment of osseointegration, however, as of today, thesign for atemporal implant stability in bone is yet

ined [1216]. Atemporal osseointegration becameic and industrial goal since it would allow cliniciansate patients in minimal treatment time frames [17].iew manuscript revisits osseointegration in a struc-at, rst addressing how implant hardware designe design and related surgical instrumentation

s) features potentially inuence bone healing path-e placement of other design parameters within

rdware. Second, the effect of micrometer designinghardware ad-hoc) on osseointegration is discussedthe current literature. Third, and due to its morey of literature, a section on the available evidenceion of nanotechnology (a secondary ad-hoc) applied

surface engineering is presented based on their further improving osseointegration when hierar-lied onto the implant macrometer and micrometer

e effect of implant macrogeometrice design) in bone healing pathway:ons for micrometer scale designing

extensively reported that as time elapses follow-tation of osteoconductive endosteal implants (e.g.ased alloys), intimate contact between bone and

render the system biomechanical stability andg capability [1821]. Such observation has beenby over ten thousand scientic reports that are

tion tecoursenoveltdevoteespeciWhile eter acontribof woraffect literatuendostmajor try andit is obconsidbe con

2.1. pathw

The hobservimplanthe osbone tinterpthe sysplay yeinuenlevel tosions, hard tis diretional [20,25,

Thecept isthat stHowevbeyondformatriggertion tothat exchanicdepencomprsubseqpristinfor whbeen cobtainometryto thethroug

Thiin siteque and sequence. Thus, even though through thever seven decades, osseointegration has gone fromommodity in surgery, substantial attention is still

understanding its principles and characteristicsas a function of endosteal implant modication.thora of studies concerns the effects of microm-ore recently nanometer scale design parametern to osseointegration, a signicantly smaller bodyavailable regarding how hardware design aspectsointegration. For instance, far less explored in thes how osseointegration temporally occurs aroundimplants substantially shift as a function of twomplant design parameters: implant macrogeome-associated surgical instrumentation [2224]. Whiles that two different design parameters are underon, their contribution to the healing mode cannoted separately [22,23].

e interfacial remodeling (tight t) healing

g scenario described in this section is typicallyr tight t screw type implants (i.e. the majority oftems available in the market) as they are placed inmy in intimate contact between the implant andghout the devices threaded bulk. Such intimateetween device and osteotomy dimensions renders

initial or primary stability where no biologic inter-sts [25,26]. This mechanical interlocking is variablyby the implant geometry and surface micrometerraphy, as well as the implant osteotomy site dimen-regulate the distribution of strain applied to the

in proximity with the implant [21,27,28]. Strainelated to bone-implant interfacial stress and fric-, and is clinically expressed as insertion torque

oretical background of the primary stability con- the bone is assumed to be an elastic material andand implant stability will have a linear relation [25].

reality, the stability of the implant would decrease yield strain of the bone due to excessive microcracknd compression necrosis, which both phenomena

e remodeling [25,30,31]. Thus, high degrees of inser- must be questioned since elastic theory predictsive strain not only leads to the decrease of biome-ability, but also incites negative biologic responseson the implant thread design that inuence then [17]. Such cell-mediated bone resorption andt bone apposition most often occurring from thene wall toward the implant surface is responsibles under theoretical [32] and experimental [33] basisd as implant stability dip, where primary stabilityrough the mismatch between implant macroge-

surgical instrumentation dimensions is lost due-mediated interfacial remodeling to be regainedne apposition [32,34].ling mode sequence concerns implant placementat were surgically instrumented to dimensions

d e n t a l m a t e r i a l s 3 1 ( 2 0 1 5 ) 3752 39

Fig. 1 Repimplant pladiameter oimplant peimmediateoccupied thThe yellowsurface (bluremodelingcracking. Tand yellowcreated dueexcessive sthe referenreferred to

that approx[16] (Fig. 1bone-implastability. Astrength ofels are visubetween thtime elapsepresenting [16]. Thus, in multipletal basis [32interlockintime after pextensive barea will beventually (secondarytimes towametallic de

2.2. Intchamber os

The seconsite scenarvoid space

instrumented drilled site walls are formed [42]. These voidspaces left between bone and implant bulk, often referred as

g chalacee howary

ear heandh ape . Suc

towh an

unlg chap pr44]. Ine ark th

the sgu

alingnstrue. Thntialg pat

Thresentative optical micrograph of a screw typeced in a rabbit tibia instrumented to the innerf the implant thread. The blue line depicts therimeter that was in direct contact with bonely after placement (the cortical plate fullye region between the blue and yellow lines).

line depicts the distance from the implante line) which cell mediated interfacial

occurred due to osteocompression and/or bonehe dark stained bone tissue between the blue

lines is bone formed after a void space is to interfacial remodeling to eliminate tissuetrain. Toluidine Blue stain. (For interpretation of

healinafter p. Thessecond

Thetion inBergluand sh[43,44]evolvethrougis thathealincleanu[22, 42,tine bonetwowithining conthe heface, ivolumsubstahealin41,43].

2.3.

ces to color in this gure legend, the reader isthe web version of the article.)

imate the inner diameter of the implant threads). At early time points, an almost continuousnt interface renders the system implant primaryt this stage, microcracks depicting that the yield

bone has been exceeded due to high stress lev-alized along with initial remodeling taking placee implant threads due to compression necrosis. Ass in vivo, an extensive remodeling region is evidentvoid spaces partially lled by newly formed bonethe scenario that has been histologically observed

instances conrms the theoretical and experimen-,33] for the initial stability rendered by mechanicalg between implant and bone that at some point inlacement under stable conditions decreased due toone resorption (Fig. 1). Subsequently, the resorbede altered by newly formed woven bone, whichreestablishes the contact to the implant interface

stability), and will subsequently remodel multiplerd a lamellar conguration that will support thevice throughout its lifetime [3541] (Fig. 1).

ramembranous-like healing pathway (healingseointegration)

d osseointegration pathway concerns the oppo-io of the tight t screw type implant, wheres between the implant bulk and the surgically

interfacial rhealing mo

Recent invimplant destability wsions allowosteotomy [22,47,48]. Tthat threadmary stabidiameter thallowing hbers allowformation the implanimplant thr

While plast ve dehow it dictogy aroundother desigcan furthe[11]. For insbeen desigmacy betwchanging ceHowever, thgic hierarchdesign sinca functionmbers, will be lled with blood clot immediatelyment and will not contribute to primary stabilityever, have been regarded as a key contributor to

stability [23,43].ly healing biology and kinetics of bone forma-ling chambers has been discussed in detail by

et al. [42] while the effect of healing chamber sizeon bone formation has been explored elsewhereh healing chambers, lled with the blood clot, willard osteogenic tissue that subsequently ossies

intramembranous-like pathway [42]. Noteworthyike the interfacial remodeling healing pathway,mber congurations do not encompass the initialocess due to microcracking and ostecompressionn this case, the blood lling the space between pris-nd device will develop toward a connective tissueat provides a seamless pathway for cell migrationpace once lled by the blood clot (Fig. 2). Such heal-ration thus allows new bone formation throughout

chamber from all available surfaces (implant sur-mented bone surface) and within the chamberus, intramembranous-like healing mode presents

deviation from the classic interfacial remodelinghway observed in tight t screw-type implant [21,

e hybrid healing pathway: bringing togetheremodeling and intramembranous-like bonedes

estigations have employed either experimentalsigns with an outer thread design that providedhile the inner thread and osteotomy dimen-ed healing chambers [42,45,46] or alterations indimensions in large thread pitch implant designshe rationale for these alterations lie upon the fact

designing may allow for both high degrees of pri-lity along with a surgical instrumentation outerat is closer to the outer diameter of the implant

ealing chamber formation. Since healing cham- rapid intramembranous-like rapid woven bone[49], such rapid bone growth may compensate fort stability loss due to compression regions whereeads contacts bone for primary stability (Fig. 3).romising developments have been made over thecades regarding implant hardware designing andates bone healing and long-term bone morphol-

endosteal implants, it is widely recognized thatn features do in fact hasten osseointegration andr increase the performance of implant hardwaretance, lower length scale design parameters havened in an attempt to change the degree of inti-een host biouids and implant surface while alsoll phenotype to hasten biological response [5053].eir early effects are directly related to their strate-ical placement as a function of implant hardwaree healing mode and kinetics drastically shift as

of the macrometer scale variables. It is thus


Fig. 2 Stemicrograph(intramemAt 3 weeksevident forosteogenicstained in instrumenwithin thesurface towrevasculariweeks in vthat originimplant suhealing chaby blood vebetter denstructures of the referreferred to

intuitive tdesigned tomaximizinimplant sudesign featmaintenanmigration tacceleratininterfacial initial hardhardware dmore suitemicrometeperformanvenels blue Von Giessons stained opticals of healing chamber implants

branous healing mode) in a beagle dog model. (a) in vivo, the surgical instrumentation line isming the healing chambers that are lled with

tissue presenting initial bone formation (osteoidgreen, bone stained in red) from thetation line toward the center of the chamber,

healing chamber volume, and from the implantard the central region of the chamber. Initialzation is depicted by green arrows. (b) At 6ivo, the healing chambers are lled from boneated form the surgical instrumentation andrfaces along with bone formed within thember. The yellow arrows depict spaces occupiedssels forming the primary osteonic structuresed at (c) 12 weeks, where the primary osteonicare depicted by blue arrows. (For interpretationences to color in this gure legend, the reader is

the web version of the article.)

hat implant hardware should be strategically allow adequate implant primary stability while

g interaction between the host biouids andrface. For instance, the reduced length scaleures intended to improve the establishment andce of continuous pathway for bone forming celloward the implant surface will not be as efcient ing osseointegration in regions where cell-mediatedremodeling initially occurs after placement due toware design interaction with bone. Thus, implantesigns that allow healing chamber formation ared to deliver adequate conditions for improvedr and the nanometer length scale design featuresce in hastening early osseointegration.

Fig. 3 Stemicrographhealing pavivo, the suits estimatchambers initial bonestained in center of thand from tthe chambinitial interthe implanosteotomyremodelingwhere highobserved dsurgical inbone formeinterfacial interface bestablishmregions anhigher degchamber. (this gure of the artic

3. Thdesigningnanomet

One of thesignicant ably the imtopographyous methodvenels blue Von Giessons stained opticals of implants in bone representing the hybrid

thway in a beagle dog model. (a) At 3 weeks inrgical instrumentation line has retracted fromed location (blue line) and is forming the healingthat are lled with osteogenic tissue presenting

formation (osteoid stained in green, bonered) from the instrumentation line toward thee chamber, within the healing chamber volume,

he implant surface toward the central region ofer. Note the extensive micro cracking and thefacial remodeling taking place at regions wheret outer thread diameter was larger than the

diameter (yellow arrows). This interfacial is still evident at (b) 6 weeks (yellow arrows),er degrees of healing chamber lling isue to new bone formation occurring from thestrumentation and implant surfaces along withd within the healing chamber. (c) At 12 weeks,remodeling is nearly complete and an intimateetween bone at the remodeling regions is underent with the implant surface (remodelingd micro cracks depicted by yellow arrows), andrees of lling are observed within the healingFor interpretation of the references to color inlegend, the reader is referred to the web versionle.)

e effect of implant microgeometric in bone healing: a prelude toer scale designing

most researched areas, and one that has hadimpact on treatment strategies, is unquestion-plant surface engineering. Over the years, surface

modication has been attempted through vari-ologies, and dramatic changes in osseointegration


quality and quantity have been witnessed. The primitive sur-face nish of the osseointegrated implants proposed wasthat of turcess. ThesBrnemarkmid-1990s tation [4,54concluded able prognapproach wand 6 monline assumpwith good b

Althougindicationsjects with sdiscomfortvation for fshorten themodalities.surface topin the marking concepthigher inte

One of implant sunique, whiextremely 45 m) as In precliniface topogosseointegrUnfortunatrather nega[5966], resfrom favor

From thdemonstraerated throas sand blation [7577there existThe so-callhave been experimensurfaces w12 m) proable implawith the afing them abone respo

Owing timental sttime needecompetencreduced [8ation in thor immediclinical sucsition in cl

effect of numerous factors and, strictly speaking, cannot beattributed solely to the microroughened surface topography.

althoped ntegrutcoeveed c

suchepor

the r boantle tufromned

turn pos

maties thhichpla

pation thhe sas aded nn of

adeqedge

in she b, proas be, thing b

titaotents of

is a cg/regcatiot of

Thiqu

theeterseal itivelyted i

nan itseee it

drillale (o 10iversned implants manufactured by a machining pro-e turned (machined) implants (better known as-type implants) dominated the market until theand therefore, have the longest clinical documen-]. From such long-term clinical evidences, it can bethat turned implants present a clinically accept-osis, if the traditional healing protocol (2-stageith a healing period of 3 months in the mandible,ths in the maxilla) is followed [55], with a base-tion that the implant sites were fully healed ridgesone quality.h successful from a long-term perspective, the

for turned implants were limited to healthy sub-ufcient bone, and the treatment period created

for the patients. Thus, the central focus and moti-urther surface topography research have been to

time to osseointegrate and to expand the clinical As a result, some implants with extremely roughography were developed and have been circulatedet for some years, based on the simple engineer-

that rougher surfaces would provide mechanicallyrlocking between surface and the bone.the methods commonly used to roughen therface was the titanium plasma spray (TPS) tech-ch yielded a bumpy surface conguration withhigh average (mean) height deviation (Ra of

compared to the turned Brnemark-type implants.cal investigations, such extremely rough sur-raphy of the TPS surface presented improvedation compared to the turned surfaces [5658].ely, the clinical trials seemed to present little ortive outcomes with progressive marginal bone lossulting in TPS-roughened implant surfaces fallingamong implant manufacturers.e mid-1990s to date, it has been experimentallyted that osseointegration is improved and accel-ugh various roughening procedures [67,68], suchsting [6971], acid etching [7274], anodic oxida-], and even laser etching [67,68,7880], and thats an optimal range in the micrometer scale [81].ed moderately microroughened implant surfacesproven to present improved osseointegration intal and in clinical studies [82,83]. Today, implantith moderately textured microtopographies (Savide a basis for the majority of commercially avail-nts. Turned implants as a substrate are treatedorementioned procedures, strategically roughen-t the micrometer length scale to present improvednse.o the improved osseointegration proven in exper-udies, it is now believed that the amount ofd to establish implantbone system biomechanicale for functional load bearing can be signicantly4]. Based on this experimental evidence, alter-e clinical loading protocol (from delayed to earlyate) has been attempted, presenting long-termcess [85]. It must be noted that the dramatic tran-inical loading protocol results from the combined

Thus, develoosseoiis an o

Howimprovationsbeen rparingin poosignicthan threport roughethat ofEven inis drasurfac[89], wened imlife forresecti

In ttion hso-callicatiounlessknowl100 nmulate tfactors

It hbioactivthe livor thesuch pconcepwhichneerinmodiinteres

4. techn

While paramendostis relapresen

Thematteras we scan beeter sc(109 tthe unugh manufacturers commonly claim that a newlyimplant surface can reduce the time needed toate, one must keep in mind that osseointegrationme of the combination of different designs [86].r, microtopography undoubtedly inuenceslinical success, especially in compromised situ-

as poor-quality bone, or irradiated bone. It hasted by Khang et al., in a multicenter study com-success of turned versus dual acid-etched surfacesne quality sites, that the clinical success wasy higher for the moderately roughened implantsrned implants [87]. This is in accordance with the

Pinholt stating that the survival of moderately implants was signicantly higher compared toed implants in grafted maxillary bone sites [88].t-tumor-resected irradiated sites, implant survivalcally higher for moderately roughened implantan for turned surfaces after 5 years in function

indicates that treatment using moderately rough-nts signicantly improved postoperative quality ofents who undergo massive oral and maxillofacialerapy.

pace of a mere decade, implant surface modica-vanced to a new stage with the introduction ofanolevel modication [18,90]. The nanolevel mod-

implant surfaces, normally impossible to detectuate instrumentation is employed, is based on the

that the application of nanostructures (less thanize in at least one dimension) signicantly upreg-iologic responses, since elements such as growthteins, and cells interact at this level [9194].een reported that the nanostructured surface isat is, it has the potential to cause a reaction inody, whereas it is well known that the titanium

nia itself is a bioinert material, and thus has notial [95]. Material bioactivity is one of the core

the biologically inspired biomimetic engineering,ross-link between material science and tissue engi-enerative medicine. The nanometer length scalen has recently received signicant attention in theincreased bioactivity.

e nanometer scale designing: currentes and trends

macrometer and micrometer implant design have been investigated over several decades,mplant designing at the nanometer length scale

new and its recent developments are hereaftern an objective fashion.ometer scale was likely born as early as when

lf came into existence at the Big Bang. The universe is in the macrometer scale (11000 m); however, ited down to the invisible universe, to the microm-103 m) and further down to the nanometer scale6 m, i.e. 11000 nm), where the building blocks ofe, the atom and the sub-atomic particles (protons,


neutrons, and electrons) interact electromagnetically. At thetime of its comprised years later,of organizaganic compcomplex inquintessen

While itfor multiplconfer uninanotechngrain size ointerest in point, nanowhich is ap

The phthe macrothe past, iships, whias condensstatistical mquantum mvalidated bniques for pshown thatheir 3 dimconguratiThis phenoon the numically


between blood clots and the implant surface, immediatelyafter the placement of the implant [22]. While implant hard-ware and minteractionaround thea potentialosseointegries demonosteoblastinanoscale hardware cmay be mestablishedfeatures wiimplant suinteractionthat osteogway towardaltered in design guidture and ch

Reducedpiled in enthis reviewall, of the ing implansince high manufactunanoscale tive and simplant sumade commimplant suavailable uterized to TiUnite (NoStraumannMlndal, Stive manuffeatures, in[84,113,114

Of the cclaimed to face modicomponentadditive mthrough susenting bioNanoTiteTM

Boston, MAWhile theitinctively dinitial subtmethods. Fassisted dein the coatiobtained bthe case of(DCDTM), dtured, acid-

Previous work has demonstrated that the particle componentcovered approximately 50% of the surface [16]. Although both

es pred co

ratio coate thg is

te (P depethe rlciumties reso. Thie ABorpotendf mucal co

remth msseoSs a

micouale sseais fabg mesimuless nanopite

topore wistry ily Cg wie precompetecf OSPubstrpite chiet suse tod oft. A ale s

Cel

AD udieate cond

resueogeicroscale modications will dictate tissue-level and the peri-implant wound-healing cascades

implant [22,23,42,44], nanoscale features present to boost osteoblastic behavior, and thus hastenation. However, although in vitro cell culture stud-strated positive effects of nanoscale features onc cells [110112], any direct translation of suchfeatures to implants, without considering implantharacteristics and microscale design parameters,isleading. Such contradictions resulted in the

rationale for hierarchical placement of nanoscalethin microscale texturing when designing dentalrfaces. This strategy facilitates adequate intimate

between the blood clot and implant surface, soenic cells may travel through a seamless path-

the device surface, and once there, to be furtherphenotype by nanoscale features. Applying thiseline, implant surfaces presenting nanoscale tex-emistry alteration have been manufactured.-scale manufacturing techniques have been com-gineering literature and are beyond the scope of. From a manufacturing perspective, many, if notavailable techniques may be utilized for pattern-t surfaces with nanoscale features [97]. However,throughput is necessary for economically viablere of implant surfaces, industrial methods forsurface modication are restricted to a few addi-ubtractive techniques. To date, 4 representativerfaces presenting nanoscale features have beenercially available. It must be acknowledged that

rfaces other than the ones made commerciallynder the nano label have been also charac-present nanometer scale features. For example,bel Biocare, Zurich, Switzerland), SLActive (Institut, Basel, Switzerland) and OsseoSpeed (Dentsply IH,weden), originally not presented by their respec-acturers as surfaces presenting nanometer scaledeed present nanometer scale surface patterning].ommercially available nanometer scale surfacesbe nano by their manufacturers, 2 contain sur-cations, such as bioactive, calcium-and-phosphates, manufactured through subtractive followed byethods; the other 2 are manufactured mainlybtractive processes. The nanoscale surfaces pre-active ceramic components were both namedby their respective manufacturers (Bicon LLC,

, USA; Biomet 3i, Palm Beach Gardens, FL, USA).r nal physicochemical congurations are dis-ifferent, both surfaces are manufactured by anractive method prior to their divergent additiveor the Bicon surface, a 2050-nm-thick ion beamposition (IBAD) of calcium phosphate (CaP) resultsng of a moderately rough microtextured substratey alumina blasting/acid etching (AB/AE) [115]. In

Biomet 3i surface, Discrete Crystalline Depositioneposition of nanoscale CaP particles onto the tex-etched surface is performed via a solgel process.

surfacintend

Thephousleveragavoidinyapatihighlyshort, tive caproperlution/natureand thfor incwas inhelp ochemi

Theare borst Orequireders aa hydrnanoscond, O(OSS) blastinraphy Regardof the

Desfrom aotextuchemiprimarcoatinsurfacstrate been dcase owith s

Desbeen aimplanresponers angroupsnanosc

4.1.

The IBture stsubstrstudy, mixeding ostesented bioactive components, their purpose, andating kinetics in vivo differed substantially.nale for the IBAD of 2050-nm-thick, mainly amor-ing onto the AB/AE-microtextured surface was toe highly osteoconductive properties of CaP, whilesues presented by thick plasma-sprayed hydrox-SHA) coatings, where long-term performance isndent on implant hardware conguration [116]. Inationale was to expose the healing site to bioac-

phosphate elements with the known osteogenicand simultaneously benet from complete disso-rption of the IBAD coating due to its amorphouss would result in intimate contact between bone/AE-microtextured surface. Biomet 3is techniqueration of nanoscale features on the other hand,ed to increase substrate osteoconductivity with theltiscale (micro- and nano-) texture levels and themposition rendered by the DCD method.aining 2 surfaces presenting nanoscale featuresanufactured by subtractive methods [11]. ThepeedTM (Astra Tech AB, Mlndal, Sweden), (OSP),titanium oxide blasting procedure, which ren-

rometer-level texture to the surface, followed byoric acid etching procedure, which results in atexture within the microscale texture. The sec-nTM (Intra-Lock International, Boca Raton, FL, USA)ricated by robotic microblasting of a resorbabledia (RBM) powder that results in nanoscale topog-ltaneously within a larger-scale microtopography.of the fabrication method, no long-range orderingscale features is obtained [11,117].the substantially different fabrication methods,graphical standpoint, all 4 surfaces present nan-thin microtexture surface features. From a surfacestandpoint, the IBAD-fabricated surface presentsa, P, and O in its surface, since it has a uniformth nanometer-scale thickness, whereas the DCDsents elements from bioactive ceramic and sub-onents [16,118]. Minute quantities of uoride have

ted along with substrate alloy components in the [119], whereas bioactive ceramic is found alongate alloy elements on the OSS surface [120].recent introduction, substantial advances have

ved with nanometer scale materials in the area ofrfaces. Previous studies investigating the biological

nanoscale surfaces were funded by manufactur-en utilized their predecessor surfaces as controlseries of studies have followed, where differenturfaces have been compared.

l culture studies

surface was evaluated in 3 different cell cul-s, where it was compared to its AB/AE uncoatedand as-machined surfaces [121123]. The rstucted with primary human osteoblasts, presentedlts with the IBAD and AB/AE surfaces regard-nesis-related events [121]. The second study was


intended to evaluate the effect of the same 3 surfaces onhuman osteogenic cells, peripheral blood mononuclear cells(PBMC), anexogenouserally obse(always favmachined chad a morerelated to intexture or the same 3 neutrophilsthin CaP coprole of pthese cell csurfaces prtial disagresurfaces, a

The DCalveolar bocare, KloteSwitzerlanand SLA susion. The Dof cell con

The OSPblasted preosteoblast showed noOSP showecontrol at 4BSP, and osing that osaffected bysive real-tiexpressionMC3T3-E1 cells from OSP surfacexpressionmesenchymfavorable othe OSP suwas compaolar bone cfor the OSPOSP altered

Cell cultpared it tostudy, cell activity webone meseconditions.ferentiationcounterpar

In genernanoscale To date, nofor the DCDIBAD surfa

have been related to the dissolution of the amorphous coating.Regarding OSP and OSS, where similar microlevel-textured

es wcalecale fenic

Pre

as m cultorityetric

AD sed, aly imts [1e co

[12 highchanle imt imoatecoatets out to [118,

DCDativehe bos of s of th froto th

thee) [1o rodDCD

the surflaced sig

sur socked am

OSPpreccale[18] C le

(TiOcatiotry an th

or reardiers.dditicrod osteogenic cells cocultured with PBMC without stimuli. Relative differences in results were gen-rved among surfaces for the 3 different culturesoring the IBAD and AB/AE surfaces over the as-ontrol); however, the multi-cell type interactions

pronounced inuence on the in vitro cellular eventsitial stages of bone formation than did the surface

chemistry [123]. Finally, the third study evaluatedsurfaces in a culture of human polymorphonuclear

(PMNs). The results showed that the addition of aating to the AB/AE surface inuenced the secretionroinammatory cytokines [122]. Taken together,ulture studies comparing IBAD, AB/AE, and turnedesented mixed results that demonstrated substan-ement with in vivo preclinical results for the sames subsequently discussed.D surface has been evaluated in primary mousene cells relative to OSP, TiUnite (Nobel Bio-n, Switzerland), and SLA (Straumann, Basel,d) surfaces [124]. Following a 48-h culture, the OSPrfaces displayed the highest degrees of cell adhe-CD surface presented signicantly lower degreesuence relative to the 3 other surfaces [124].

surface has been compared to its titanium oxidedecessor, TiOblast (Astra Tech), in a mouse pre-MC3T3-E1 cell culture model [125]. The results

differences in cell viability and proliferation, butd more branched cell morphology compared to the8 h. At 14 days, increased gene expression of IGF-I,terix were observed for the OSP surface, indicat-teoblast differentiation and mineralization were

the nanoscale surface [125]. A more comprehen-me PCR study that considered bone-specic gene

in the same 2 surfaces plus a turned control in acell culture model as well as in implant-adherenta rabbit tibia model, all demonstrated that thee outperformed the control in osteogenic gene

events [126]. Another study evaluating adherental stem cells on OSP and its predecessor presented

steoinduction and osteogenesis of these cells forrface [127]. As previously mentioned, when OSPred to the DCD surface in a primary mouse alve-ell culture model, superior results were observed

surface [124]. Masaki et al. also demonstrated that cell behavior relative to other surfaces [69].ure studies considering the OSS surface also com-

its microscale-textured predecessor [121]. In thisadhesion, proliferation, and alkaline phosphatasere assessed with human SaOS-2 osteoblasts andnchymal stem cells in nonosteogenic culture

The results demonstrated higher osteoblastic dif- for the nanoscale surface relative to its microscalet [121].al, cell culture studies depicted favorable results forsurfaces relative to their microscale predecessors.

such predecessor comparison has been performed surface, and the mixed results observed for the

ce relative to the uncoated AB/AE substrate may

surfacmicrosnanososteog

4.2.

Wherein cellsuperihistomthe IBobservat earterparthat thresultscantlybiomeavailabnicanto uncPSHA-implanrespectimes

Theels relWith tdegreedegreestrengpared due tosurfactrast teither Whenrough diate pshoweetchedWhendetect

Theratory microset al. and BIcessormodigeomebetweesuperisor regchamb

In aother mere used as controls against nanoscale-within- topography surfaces, it is unequivocal that theeatures substantially altered cell behavior favoring

cellular events.

clinical in vivo models

ixed results were obtained for the IBAD surfaceure assays, a series of studies demonstrated its

to uncoated surfaces for both biomechanical and outcomes [128130]. For cylindrical implants withurface, higher degrees of osteoconductivity werelong with higher degrees of biomechanical xationplantation times, than for their uncoated coun-28130]. Furthermore, it has been demonstratedating thickness played a role in biomechanical

9]. In larger preclinical in vivo models, signi-er levels of bone-to-implant contact (BIC) andical xation were observed when commerciallyplants were utilized [115,118,131133]. While sig-provements were consistently obtained relatived implants, studies that considered IBAD- versusd implants demonstrated that the PSHA-coatedtperformed the IBAD-coated ones, especially with

biomechanical competence at early implantation129,132,134].

surface showed promising results in rodent mod- to its microscale-textured counterpart [135137].ne-healing chamber design in a rat model, higherbone ingrowth were observed [136], and higherbone adhesion were detected, when the pulloutm the bone for the DCD-coated implants was com-e predecessor control (regarded as bone bonding,

presence of nanoscale features on the implant35]. In a beagle canine model, however, in con-ent models, no differences in bone response to

or its predecessor surface were detected [138141].DCD surface was compared to other moderatelyaces in the more challenging scenario of imme-ment within extraction sockets, the DCD surfacenicantly lower BIC levels relative to a dual acid-face, an SLA surface, and an anodized surface.et architecture was considered, no difference wasong the 4 implant groups [142].

surface has also been well documented in labo-linical animal models versus its moderately rough-textured predecessor and other surfaces. Ellingsendemonstrated higher biomechanical competencevels for the OSP relative to its microscale prede-blast, Astra Tech) in a rabbit tibia model. Throughn in the relationship between implant macro-nd surgical instrumentation (healing chambersreads [23,42]), Berglundh et al. [119] demonstratedsults for the OSP surface relative to its predeces-ng the amount of bone formation within healing

ion, the OSP surface has been compared to variousscale surfaces in numerous preclinical laboratory


animal models. In an in vivo rabbit model, the OSP surfacepresented signicantly higher bone response at 2 weeks ascompared ttexturing [ducted in mSLA implanmaintenansurface wit

OSP hastextured suextraction detected inAnother stextraction groups in noted thatevaluation osseointegraround impbeen shown

Comparsurfaces in described b

The OSSparison to in vivo studand AB/AE evaluated isignicant weeks, a rothe OSS surthat bone aical properet al. [150]acid-etchedtexture.

In a proreported boface and bphenomenAB/AE micrbone bondCa and P onbeing prese[151]. Alternto the OSS ture, ratherquestion ofwas responOSS surfacetexture simsilica blasti[152]. Whendifferencesstrongly suthe OSS suthan low lebe conductof nanoscaing of bone

nanomechanical, and gene expression study conducted ina rodent model unequivocally showed higher BIC, bone

nicateogto its

modntegrinal

tion se attting en c

favoce, acaleor b

torqer stumendemn vivnica

OSred se mt mae sa

ue toantl

al tor stu

of O the eekplan

thanSP imigniults pareith n

rent ova

fferencesat th

Cli

es t su

andted ig wit

in t prosons).e hal stutry (o an anodized surface presenting micrometer-level143]. In a crestal bone maintenance study con-inipigs by Heitz-Mayeld et al. [144], both OSP andt surfaces presented higher degrees of crestal bonece as compared to an implant having an anodizedh micrometer-level texturing [144].

also been evaluated against other microscale-rfaces with enhanced surface wettability in freshsockets in beagle dogs [145]. No differences were

host-to-implant response up to 4 and 12 weeks.udy comparing OSP to other surfaces in freshsockets failed to demonstrate differences amongall parameters evaluated [146]. It should be

this particular study primarily comprised of theof soft tissue measurement outcomes and notation measurements. However, bone maintenancelants immediately placed in extraction sockets has

to inuence soft tissue measurements [147,148].isons between the OSP surface and other nanoscalenumerous preclinical laboratory animal models areelow.

surface has also been well documented in com-its AB/AE predecessor in a series of preclinicalies. In the rst, conducted by Marin et al. [149], OSSsurfaces were histometrically and biomechanicallyn a beagle model. Although the group reported nodifferences in BIC between surfaces at both 2 and 4ughly 100% increase in removal torque was seen forface relative to its predecessor, strongly suggestinground the OSS surface presented higher mechan-ties [149]. Similar results were obtained by Marin

where the OSS surface was compared to a dual, moderately rough surface with micrometer-level

tocol similar to that of Mendes et al. [135], whone bonding between DCD nanoscale-modied sur-one, Coelho et al. observed the same bondingon when the OSS surface was compared to itsoscale-textured counterpart. This suggested thating might also be achieved by the lower levels of

the OSS implant surface (crystalline HA particlesnt at much higher numbers for the DCD surface)atively, the authors speculated that bone bonding

surface might have been due to the nanoscale tex- than the lower levels of Ca and P. To address this

whether nanoscale texture or surface chemistrysible for the high osteoconductive properties of the, Coelho et al. tested an implant with a nanoscaleilar to that of the OSS surface but produced throughng, so that Ca and P were not present on its surface

these were compared in vivo in a beagle model, no in bone response (torque and BIC) were detected,ggesting that the nanotopographical component ofrface played a larger role in its osseointegrationvels of Ca and P [152]. Experimental studies shoulded to further address the relative contributionsle texture and surface chemistry to the bond-

to implant surfaces [151]. Another histometric,

mechaand ospared indeedosseoi[153]. Fextracof bonpresen

Whsentedinstanmicrosment, higherAnothassessfaces, point imecha

Theotextua caninimplanwere thtors dsignicremov

Onemancewhereand 3 wOSS imvaluesand Owere sthe resit comtems w3 diffethe remcant didiffereeffect

4.3.

Outcomimplansectionevalualoadinlocateddentalstructisurfacclinicageomel properties (hardness and modulus of elasticity),enic gene expression for the OSS surface as com-

predecessor, indicating that the nanoscale surfaceulates osteoblastic cell response, leading to fasteration and bone mechanical property achievemently, the OSS surface, when evaluated in immediateocket implants, was able to maintain higher levelsachment at the buccal ange relative to implantsa smooth cervical region [154].ompared to various microscale surfaces, OSS pre-rable biomechanical and histometric results. For

study comparing the OSS surface to surfaces-textured by AB/AE or RBM alone, by plasma treat-y RBM plus acid etching, depicted signicantlyue levels for the OSS surface relative to others [70].dy, consisting of histometric and nanomechanical

t of OSS versus OSP, SLA, anodized, and RBM sur-onstrated higher BIC for OSS at the earliest timeo, and slight but not signicant differences in bonel properties between surfaces [120].S surface was also compared to the DCD nan-urface and to 2 microscale-textured surfaces inodel at 10 and 30 days post-implantation [16]. Allcrogeometries and surgical instrumentation usedme, minimizing confounding osseointegration fac-

implant hardware. The OSS surface presentedy higher biomechanical competence (assessed byque) than the other groups at 30 days in vivo [16].dy directly comparing the biomechanical perfor-SS, OSP, and DCD implants has been reported,

implants were placed in the beagle mandible at 1s in vivo prior to euthanasia. When torqued out, thets presented signicantly higher removal torque

the OSP and DCD implants. At 3 weeks, both OSSplants presented comparable results, and both

cantly higher than the DCD surface [155]. However,of this study must be interpreted with caution, asd the performance of the 3 different implant sys-anoscale surfaces and not the performance of the

surfaces on the same implant hardware. Specic tol torque results, it must be noted that the signi-nces between groups may have been inuenced by

in implant hardware that possibly mitigated thee nanometer scale on osseointegration.

nical evidence

of a few published clinical trials regarding somerfaces with nanotopography are described in this

summarized in Table 1. The DCD surface has beenn a prospective 1-year clinical study on immediateh tapered implants placed in 42 patients, with 55%he posterior region (20 single crowns [SC], 30 xedtheses [FDP], and 7 full-arch [FA] maxillary recon-

Survival rate at 1 year was 99.4% [156]. The samed earlier been evaluated in a prospective 1-yeardy with immediate loading using different macro-Prevail). There, 35 patients received 102 implants


Tabl

e

1

Clinical

outcom

es

of

pro

spec

tive

studies

of

implant

surfac

es

pre

senting

nan

otop

ogra

phy.

Auth

or/im

pla

nt

surf

ace

Pros

thes

es

des

ign

Surv

ival

rate

(%)

Obs

erva

tion

per

iod

Imm

edia

te

occl

usa

llo

adin

gCon

trol

grou

p(n

on-n

ano-

enab

led

surf

ace)

st

man

et

al. [

155]

/DCD

20

SC, 3

0

FDP,

7

FA

99.4

%

(1

impla

nt

failure

)

1

year

Yes

No

st

man

et

al. [

156]

/DCD

14

SC, 2

6

FDP,

4

FA

99.2

%

(1

impla

nt

failure

)

1

year

Yes

No

Cec

chin

ato

et

al. [

157]

/OSP

91

SCN

ot

des

crib

ed3

year

sYes

No

Col

laer

t

et

al. [

158]

/OSP

25

FA10

0%

2

year

sYes

No

De

Bru

yn

et

al. [

159]

/OSP

132

SC94

98%

3

year

sN

o

No

Mer

tens

and

Stev

elin

g

[84]

/OSP

31

SC, 4

FDP,

1

FA97

%

5

year

sYes

/ear

ly

load

ing

incl

uded

No

Mer

tens

et

al. [

160]

/OSP

Fixe

d

and

rem

ovab

le

97.8

5%

28

mon

ths

No

No

Noe

lken

et

al. [

161]

/OSP

SC

and

FDP

100%

2

year

s

No

No

Rae

s

et

al. [

162]

/OSP

SC

98%

1

year

Yes

No

Abb

revi

atio

ns: D

CD, d

iscr

ete

crys

tallin

e

dep

ositio

nTM; O

SP, O

sseo

Spee

dTM; S

C, s

ingl

e

crow

n; F

DP,

xe

d

den

tal p

rost

hes

es; F

A, f

ull-a

rch.

(65% in the posterior region), to support 14 SC, 26 FDP, and 4FA reconstructions. The survival rate was 99.2% (one implantfailure) [157

The folloOSP implan

1. Immediuation, [158].

2. Immediarch rehwith a s

3. Immediocclusalrior maxhealed s

4. 17 patiethe man

5. 15 patieral recippreviousafter 3 ma 28-mo97.85% [

6. 37 implaout occlcentral ilars, pre

7. 48 patieafter eitplacemeafter 1 [163].

The stua combinatwithin a sininto grafteddesign, incprosthesesdiameters the mouthparative efsurface, aris that noncomes of ima control (the nano-eimpact of clinical resscale compwhat has bnanoscale sare currenimprovemealso resultifeatures artocols are selected ca].wing list consists of clinical studies evaluating thet surface:

ate loading for soft tissue long-term (3 years) eval-where 93 patients were treated with 93 implants

ate loading of 125 implants placed to support full-abilitations, followed-up prospectively for 2 yearsurvival rate of 100% [159].ate provisionalization (no centric or eccentric

contact) of 132 implants supporting single ante-illary crowns (62 placed in extraction sockets, 70 inites), with survival rates of 94.5% and 98.3% [160].nts receiving 33 implants in the maxilla and 16 indible to support SC, FDP, or FA restoration [85].nts receiving 99 implants at 19 different intrao-ient sites (15 in the maxilla, 4 in the mandible),ly grafted with calvarial split grafts, and loadedonths with xed and removable prostheses, with

nth follow-up showing an implant survival rate of161].nts immediately placed and provisionalized, with-usal contact, with SC and FDP, where 17 replacedncisors, 9 lateral incisors, 6 canines, and 5 premo-senting a 2-year survival rate of 100% [162].nts receiving single implants, immediately loadedher conventional implant placement, immediatent, or site grafting, with a prospective follow-upyear of function indicating a 98% survival rate

dies described above and in the table shows thation of treatment concepts is commonplace, evengle study: immediate and early loading; placement

and nongrafted sites; varied prosthesis type andluding single crowns, FDP, removable, and full-arch, screw- or cement-retained, with various implantand lengths; and placement in different areas in

(anterior or posterior, maxilla or mandible). Com-forts among studies, even for the same implante clearly a heuristic task. Of remarkable intereste of the studies that investigated the clinical out-plants with nanolevel surface alterations included

i.e. same turned implant macro design withoutnabled features) for sound observation of the realnanofeatures in immediate, early, and long-termults. It must be emphasized that the nanometeronent of the present review primarily concernseen made commercially available; a plethora ofurface modications for bone-healing modulation

tly under development and showing remarkablents, such as increasing bone-healing velocity whileng in higher bone mechanical properties [164]. Suche of utmost importance if challenging loading pro-to be common practice and not utilized solely inses.


4.4. Nanotechnology: perspectives and challenges inimplant dentistry

A 2004 repoproducts evalue chareport, revrepresentintronics andof goods inrevenues fapproximacoming froenue rise 201014 besignicant sidering thclinical triastrate that nature of athis does nonly becaupool, standand withoubecause theare commothe promisgeneration[167].

5. Co

It is unequhealing patnanolevel cimmense aeter scale facilitatinghealing thanotype.

Since itlength scalthe osseoinfuture is timplants tnoting thahealth scieematics, wevery knowgroups) hasmatical infthe inconsierature, a sthe adequaoptimizatiosuch germscale desigtandem.

Acknowledgments

thors woratorese

e n

otheultip

940;7evenurg Araneallenf thecand132dell tudydentlbreksteoc001;2arberimancole Bruunctidentmplahigemmedentlinicattp:/headervaurfacmment J Oandeenn

crewelaye013;2oelhardarendsppl Browa, Van

mpland immplattp:/rint]eporerformpladentestoiro Gt al. Trt on the market share of nanotechnology-enabledmphasized that nanotechnology represents ain and not an industry or sector per se. In thatenue projections for 2014 had nanotechnologyg 4% of general manufactured goods, 50% of elec-

IT [information technology] products, and 16% healthcare and life sciences. Ten years ago, theor products incorporating nanotechnology weretely USD 13 billion, with roughly USD 8.5 billionm automotive and aerospace applications. Rev-for 2014 was projected to USD 2.6 trillion, withing a period when nanotechnology would becomein pharmaceuticals and for medical devices, con-at lengthy, well-designed randomized controlledls (RCT) would by then have been able to demon-nano-enabled materials substantially altered the

product and its host response [165]. Obviously,ot seem to be the case in implant dentistry, notse RCTs comprising a substantially large patientardized prosthesis design, and implants both witht nanostructural features are not available, but also

multifaceted success criteria in implant dentistrynly not acknowledged [166]. A large gap betweene of nanotechnology and its integration into a new

of nano-enabled products is remarkably evident

ncluding remarks

ivocal that implant hardware does affect bone-hways and that this may increase the micro- andontribution to osseointegration. There is also anmount of published work supporting that microm-surface modications favor osseointegration by

early host-to-implant response through tissuet facilitates cell migration and also shifts cell phe-

has been experimentally determined that alle implant design levels substantially contribute totegration process, the biggest challenge for the

o optimize the velocity and properties of thesehrough adequately designed studies. It is wortht the word optimization is rarely used in thences as it is in the physical sciences and math-here it usually denotes that the contribution ofn variable related to a phenomenon (alone or in

been experimentally determined and that mathe-erences can be drawn to maximize outcome. Givenstencies hitherto encountered in the implant lit-ubstantial amount of work is warranted to ensurete collection of data that will actually enable then of osseointegration. Upon the completion ofane series of studies, the macro-, micro-, nano-n components will be entirely able to work in

All auauthorcollabowork p

r e f e r

[1] Bm1

[2] LS

[3] BHoS1

[4] Ase

[5] Ao2

[6] Bpo

[7] DfeI

[8] SIecha

[9] VsiI

[10] VWsd2

[11] CCtA

[12] BHiaIhp

[13] DPieR

[14] Ges equally contributed to the manuscript. Theuld like to express their gratitude to all theirrs and students, who are the body and soul of thented in this review.

c e s

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J[33] G

Sai

[34] JYap

[35] MPsyo

[36] IFrye

[37] Iera

[38] CMhmI

[39] CatM

[40] PMbw2

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