Basis of Bone Metabolism Around Dental Implants During

Home , Bone remodeling, Osseointegration

Page 1of38 between this versionandtheVersionrecord. Pleasecitethis articleasdoi:10.1002/jbm.a.36060. through thecopyediting, typesetting, paginationandproofreadingprocess, whichmayleadtodifferences This istheauthormanuscript acceptedforpublicationandhasundergone full peerreviewbuthasnotbeen UniversityMichigan of Periodontal Graduate Student manusc the in listed information or products the in University Medicine, Michigan of Schoolof Dentistr Conflict of interest: of Conflict an draft and design, critical reviewmanuscript. of manuscript of review critic critical the and to contributed draft design, conception, to contributed a draft design, conception, to contributed Insua A. 4 3 2 1

AnnArbor, MI, USA. AnnArbor, MI, USA Author contributions: Author Lauderdale, Florida, Fort USA. Peri of Department fellow, Research USA, MI, Arbor, Angel Insua, DDS, MS, PhD PhD MS, DDS, Insua, Angel ITI scholar, Department of Periodontics and Oral M Oral and Periodontics of Department scholar, ITI D Periodontics, Graduate of Director and Professor Or and Periodontics of Department fellow, Research Or and Periodontics of Department fellow, Research

Accepted Article dur Implants Dental Metabolism around of Bone Basis The authors do not have any financial interests, e interests, financial any have not do authors The Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. 1 , Alberto Monje, DDS, MS MS DDS, Monje, Alberto , Miron, dr. med. dent., DDS, MSc, PhD PhD MSc, DDS, med.dent., dr. Miron, Peri-Implant Bone Loss Loss Bone Peri-Implant

ript. This article was partially supported by the by supported partially was article This ript. d rtcl eiw f aucit A Monje A. manuscript; of review critical nd y,Ann Arbor, MI, USA. 2 Fund. Research

fnig Rcad io cnrbtd to contributed Miron Richard funding; d odontology, Nova Southeastern University, Southeastern Novaodontology, , HomLay Wang, DDS, MS, PhD PhD MS, DDS, Wang, HomLay , edicine, The University of Michigan. Ann Michigan. of University The edicine, al Medicine, The University of Michigan. of University The Medicine, al Michigan. of University The Medicine, al al review of manuscript; HL. Wang, Wang, HL. manuscript; of review al prmn o Prootc ad Oral and Periodontics of epartment ing Osseointegration and and Osseointegration ing 4

ither directly or indirectly, or directly ither 3 , Richard J. J. Richard ,

Running title: title: Running Implant Bone Loss. Bone Implant MeSH Key words: words: Key MeSH figures: and Tables count: 6608 Word address: Email [email protected] 7633383; (734) TEL: FAX:9360374 (734) AnnArbor, 481091078, Michigan USA. NorthUniversity 1011 Avenue UniversityMichigan of Schoolof Dentistry Periodontics Departmentof Oral Medicine and AngelInsuaBrandariz author: Corresponding

Accepted Article Basis of Bone Metabolism around Dental Implants dur Implants Dental around Metabolism Bone of Basis

Bone remodeling, osseointegration, periimplant end periimplant osseointegration, remodeling, Bone 1 table and 3 figures. figures. and 3 table 1 Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. John Wiley& Sons,Inc.

ing Osseointegration and Peri and Osseointegration ing osseus healing, dental implant. dental healing, osseus

Page 2of38 Page 3of38 bone characteristics, as well as meticulous mainten meticulous as well as characteristics, bone byproducts that that byproducts leads hard to soft and tissue break activation should be monitored in future research i research future os in monitored be should impact activation negatively could that Factors Conclusion: These cells are of crucial importance in the presen the in importancecrucial of are cells These dental during regulators key being as discussed is prominen the Moreover, intake. D vitamin low 3) and putative the including healing bone in compromises signal to int subject of areas Three remodeling. bone is and homeostasis metabolism bone Local Results: to articles up September 2016 languagewith no rest Hea Oral Cochrane and Trials Controlled of Register includi databases, several lite in reviewers independent manual and electronic An methods: and Material and immune cells during cells maintenance. bone on focused provided, is remodeling resorptionbone the on update An implants. dental around remodeling the and osseointegration during place taking events provi to is article review this of aim The Purpose: implants and their in implications periimplantmar are limited studiesto date investigating biolo the publicati of number growing the Despite Background: Abstract

future longtermand dental success of stability im

Accepted Article dur Implants Dental Metabolism around of Bone Basis Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. Peri-Implant Bone Loss Loss Bone Peri-Implant John Wiley& Sons,Inc. gymetabolism healing bone of and dental around

down; the so called periimplantitis. plants. ce of biofilm accumulation and their associatedtheir and biofilmaccumulation of ce ginal bone bone ginal loss. de a thorough understanding of the biological the of understanding thorough a de riction. ncluding implant placement/torque protocols, placement/torque implant ncluding ance programs to favor osseointegration and osseointegration favor to programs ance ng MEDLINE, EMBASE, Cochrane Central Cochrane EMBASE, MEDLINE, ng the relevance of the osteocytes, bone lining bone osteocytes, the of relevance the coupling mechanism occurring during bone during occurring mechanism coupling usqet al ad ae hss f bone of phases late and early subsequent mln osonerto ad maintenance. and osseointegration implant effects of 1) cholesterol, 2) hyperlipidemia 2) cholesterol, 1) of effects erest were reviewed due to recent reported recent to due reviewed were erest t influence of osteocytes and immune cells immune and osteocytes of influence t ons in the field of implant dentistry, there dentistry, implant of field the in ons t Gop ras eitr aaae for databases Register Trials Group lth ecatgnss r sel macrophage osteal or teoclastogenesis aue erh a cnutd y three by conducted was search rature fo ssei calciumphosphate systemic from s ing Osseointegration and and Osseointegration ing 3

been demonstrated its causeeffect relationship. causeeffect its demonstrated been be exacerbated by tissue trauma such as overheating as such trauma tissue by exacerbated be 1. Biology of Biology 1. the remodeling bone subsequent and early and boneremodeling late aroun that events biological the of understanding updated the Therefore, periimplantitis. namely infection, e increased the to due prognosis implant the worsen bone periimplant the aggravate might These toque). monocytes/macrophages later discussed in this artic this in discussed later monocytes/macrophages bioact to seems signaling factor3 and complement by modulated hydrophilic towards evolution betweelinktight Nevertheless,a osseointegration. an as well modificati novel of development the in resulted has conseque tissue a remodels knowledgeas how hard on osseointegration breakdownosseointegration even in the of lack irri promine a as loss bone periimplant with associated releas particle titanium / degradation material and implantitis. been have disease periodontal of history or smoking susce a in byproducts its and plaque hesitation, no fi after cells bone by populated is surface implant may osseointegration of process dynamic and complex mes supply to vasculature thus, and canals vascular Introduction

withstanding torsional loading and provides higher provides and loading torsional withstanding structure bony native the into material alloplastic place take events molecular and cellular of series Immediatel implants. endosseous anchored of success arch bone alveolar osseointegration. The successful osteogenesis,where boneformation preceded byis t Nowadays, periimplant disease does not represent a represent not does disease periimplant Nowadays, Into the bargain, early periimplant marginal bone bone marginal periimplant early bargain, the Into rmr o mcaia saiiy n mln dentistr implant in stability mechanical or Primary

Accepted 4 3, Article

oehls, te fcossc a mtra biocom material as such factors other Nonetheless, Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. John Wiley& Sons,Inc. 2 Moreover, certain risk factors/indicators such as such factors/indicators risk certain Moreover, n the osteogenic and osteoclastogenicandthenosteogenicpathways e have been regarded as other potential factors potential other as regarded been have e tants. aim of this narrative review is to provide an provide to is review narrative this of aim itecture of the implant drilling site dictates the dictates site drilling implant the of itecture xation to form to xation ptible host are the primary etiology, as it has it as etiology, primary the are host ptible le. Moreover, the inflammatory response may response inflammatory the Moreover, le. heosteoclastogenesis of the existing tissue. hr hs tsus ilgcly nert the integrate biologically tissues host where enchymal progenitor cells. In this sense, the sense, this In cells. progenitor enchymal or compression necrosis (i.e., high insertion high (i.e., necrosis compression or Wie otcl oe a te ucin of function the has bone cortical While . nt matter of discussion of its implication on implication its of discussion of matter nt d d implants. ae lc drn ipat osseointegration implant during place take initial stability, cancellous bone is richer in richer is bone cancellous stability, initial ons to the implantabutment connections as connections implantabutment the to ons togy ikd ote rvlne f peri of prevalence the to linked strongly nce of biologicalwidth of the nce adaptation. This os vn n n spi evrnet and environment, aseptic an in even loss occur via contact osteogenesis, where the where osteogenesis, contact via occur y and up to several months afterwards, a afterwards, months several to up and y psr o dvlpn a ae anaerobic later a developing of xposure 5 ly frhr oe n selss e by led osteolysis on role further a play

loss was controversial due to limited to due controversial was loss i rgre a a rrqiie for prerequisite a as regarded is y n uncommon condition where, with where, condition uncommon n v ipat ufcs o early for surfaces implant ive de novo de aiiiy ipat placement implant patibility, bone, or via distance via or bone, 1

Page 4of38 Page 5of38 pivotal implications of osteocytes and BLCs during BLCs and osteocytes of implications pivotal be more complex than a simple latent state, latent simple a than complex more be population. prolongations with prolongations surface lining and bone al cells bone structure and mechanosensation. and structure bone surfaces fe rgre a a ao suc o otolss and osteoblasts of source major a as regarded often sebat ad osteocytes. and osteoblasts source of source cytokines playthat role important an in ro their beyond and lineage monocytemacrophage the rud 5 o otolss neg aotss ih ap with osteocytes, apoptosis undergo osteoblasts of 65% around excellent review articlesreview excellent Bone 2 1. remodeling process anan hi poieaie aaiiy n otn d often and capability proliferative their maintain osteoclast and osteoblast activities. activities. osteoblast and osteoclast quiescent stage when there is no bone resorption or resorption bone no is therewhen stage quiescent rsne f Ls bevd itlgcly indicates histologically observed BLCs of presence 1.1 1.1

and rapid rapid and bone formationunderosteogenic signaling in can formation, factors some that shown have studies Various urudd y ieaie bn mti ad rsn w present and matrix bone mineralized by surrounded synthesize new bone matrix.bone new synthesize active function phase by reforming cuboidal appeara cuboidal reforming by phase function active l may inflammation or inhibition sclerostin (FGF2), parathyro irradiation, loading, mechanichal as such sebat ad osteoclasts. and osteoblasts rapid bone formation after mechanical loading witho loading mechanical after formation bone rapid Role of Roleof osteocytes and lining cells bone the rem in Bone lining cells (BLC) are cells involved in bone in involved cells are (BLC) cells lining Bone s oe eoeig s cmlx rcs previously process complex a is remodeling bone As sects r trial dfeetae osteoblast differentiated terminally are Osteocytes Osteocytes are the pivotal cells in the regulation the in cells pivotal the are Osteocytes 8 Fgr 1 ad a b cniee a ltn osteobl latent as considered be may and 1) (Figure

15 12 15

Accepted divide. to unable are osteolasts mature while Article n te eue rmat bcmn BC n chondroi and BLC becoming remnants reduced the and Ti poiet oe n e bn omto ws prev was formation bone new in role prominent This Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. 1

17 10 7 and exceeds the limits of this review, we focuswereview, this of limits theexceeds and hy r caatrzd y fahpd architectu flatshaped a by characterized are They 6 Osteoclasts are terminally differentiated multin differentiated terminally are Osteoclasts sebat ae eie fo msmhml tm cell stem mesemchymal from derived are Osteoblasts John Wiley& Sons,Inc. 8 7 hs selthpe cls r lctd ihn la within located are cells stellateshapped These They act as regulators of bone remodeling by modul by remodeling bone of regulators as act They 16 including catabolic and anabolic bone processes bone anabolic and catabolic including bone homeostasis. so with boneso marrow. remodeling, id hormone (PTH), fibroblast growth factor2 growth fibroblast (PTH), hormone id . ead BLCs to exit the quiescent stage into an into stage quiescent the exit to BLCs ead feetae no te otoei cells. osteogenic other into ifferentiate 16 nce and their secretory capability.secretory their and nce srn sg o otoei potential osteogenic of sign strong a odeling processodeling this process (Figure 2 A). External factors External A). 2 (Figure process this ut previous bone resorption was observed. was resorption bone previous ut

rlfrtn peotolss n h adult the in preosteoblasts proliferating le in bone resorption, these cells are also a also are cells these resorption, bone in le ue hi poieain ro t bone to prior proliferation their duce of bone mass and structure along with with along structure and mass bone of rxmtl 3% ifrnitn into differentiating 30% proximately t cnetos hog cytoplasmic through connections ith wt a rmr fnto t support to function primary a with s formation much like preosteoblasts, like much formation 10 sebat my lo neg a undergo also may Osteoblasts asts. 13 but the function of BLCs mightBLCs of function the but 11 icse i vros other various in discussed 8 osy highlightediously n ua cnelu bone, cancellous human In

8 ie cells. dlike

ucleated cells from cells ucleated specifically on the re along bony bony along re 0 12 10, 2 16 12, 8, 15, 18 15, 8, BLCs when and s 13 cunae ating The and 3 1413, 15 5

eoeig compartmentremodeling le apoptosis osteocyte after BLCs of activation the a surface their to attachment osteoclast facilitate (MMPs) metalloproteinases matrix by mediated fibers signal signal reduction. osteocytes. proport signal, inhibitory this by downregulated is their ability to express key ostoclastogenesis mark ostoclastogenesis key express to ability their t a peiul be son ht lgt odn in loading slight that resorption. shown been previously has it functio mechanoreceptive their during junctions gap syncyt functional a of part are BLCs and Osteocytes collagen fibrillar allowing to osteoblasts attach a to Subsequentially 2B). (Figure osteoclasts by left reaquired and their secretory capacities. o was days three after formation bone of peak Early

factor receptor (receptor factor Ls ae en hw t b i coe otc wt os remodeling. with contact close in be to shown been have BLCs cyclic loading, microdamage (microcracks) or difuse or (microcracks) microdamage loading, cyclic loss bone and BLCs of activation the is consequence examp an is loading mechanical without state disuse gene small a by triggered low, is signal inhibitory iue aae a ipi te nrclua ado e prese the increase and/or may also and BLCs intracellular and osteocytes the impair may damage difuse resorption unless an inhibitory signal from osteocy from signal inhibitory an unless resorption 1. 3 Loadingand3 1. bone resorption niomn. ae, h otorgntr el colon cells osteoclastic cells. osteoprogenitor the Later, environment. stages of bone formation by entering the resorption the entering by formation bone of stages oevr BC eet poiet ucin uig bo during function prominent a exert BLCs Moreover, After the modulation of bone resorption, BLCs play BLCs resorption, bone of modulation the After 0 2120, 23, 2423,

Accepted Article19

hs cls ae en hw t dgs te protrusi the digest to shown been have cells These Thus, an increase in bone remodeling may be observ be may remodeling bone in increase an Thus, uig hs ucin BC ae eoeig activato remodeling are BLCs function, this During

23 M

CSFR Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. 17 ) and and hr otolss eob oe ihu dmgn the damaging without bone resorb osteoclasts where receptor activator of nuclear factor kappaB ligand kappaB factor nuclear of activator receptor John Wiley& Sons,Inc. 12, 16 12,

nd nd depositosteoid. new nd subsequent resorption process. Furthermore, process. resorption subsequent nd this cleaning function, BLCs secrete a layer of layer a secrete BLCs function, cleaning this tes is present. is tes ers including ers lacunae to remove collagen fibers and debris and fibers collagen remove to lacunae ium which regulates communication through communication regulates which ium n. nly possible if BLCs underwent reactivation underwent BLCs if possible nly oa t te ehncl odn sne by sensed loading mechanical the to ional d t te omto o te ocle bone socalled the of formation the to ads bone damage. bone ain inl r rnmsin alr. Bone failure. transmission or signal ration 6 . Transmission failure can be observed in observed be can failure Transmission . nce of cytokines or Ca or cytokines of nce e f o srieeae sga ad the and signal straingenerated low of le Based on finite element analysis/models, element finite on Based n cen h bn srae n re to order in surface bone the clean and z tee eann srae lf by left surfaces remaining these ize ecat ad a as mdlt bone modulate also may and teoclasts taellr lw f inl between signals of flow xtracellular rae bn frain n inhibits and formation bone creases another important role in the early the in role important another 23 e resorption ne macrophage colony stimulating colony macrophage Bone formation by osteoblasts osteoblasts by formation Bone 23 e omnrlzd collagen nonmineralized ve Presence of microcracks or microcracks of Presence ed when the strength of the of strength the when ed 19 rs

22 n pooe bone promote and 19 ++ eosrtd by demonstrated ions resulting in resulting ions ( surrounding RANKL ) . 15 6

Page 6of38 Page 7of38 presence of promotesestrogens osteocytepresence viability by an increase release byrelease RANKLincrease an of bone in leadingto bone formation bone evenin where fibrouscases encapsul are significantly lower when cell apoptosis is pres is apoptosis cell when lower significantly are coupling of bone formation and bone resorption, bei resorption, bone and formation bone of coupling than the total amount of cellular programmedcellular death. of amount total the than to maintain bone remodeling by raising RANKL and lo and RANKL raising by remodeling bone maintain to osteocytes.

eosrtd ht tanidcd inl fo osteo from direction, signals straininduced that demonstrated strain. of levels lower in later and

apoptosis. also increase the levels of RANKL and induce osteoc induce and RANKL of levels the increase also such Inflammatoryinterleukin mediators as –I (IL1 survival. and differentiation path signaling Wnt through function also Osteocytes sensitive than the inner portions of the bonethe of portions inner the than sensitive when osteocyte apoptosis occurs nearest to the bone tonearest occursapoptosisosteocyte when (NO) in in (NO) the osteocytes. i differences the to related is guidance osteoclast 1.4 Regulation of Regulation 1.4 osteocytes ao suc o RNL n bone, in RANKL of source major ees a as be son o rmt otoye apo osteocyte promote to shown been also has levels Some pathologies may also influence RANKL expressioRANKL influencemay also Somepathologies ne fntoa laig odtos te molecular the conditions, loading functional Under oevr ecsv laig n mcoaae ae bee have microdamage and loading excesive Moreover, Osteocytes maintain an important role during bone f bone during role important an maintain Osteocytes 6 24 36 36 24 enhl ulaig ed t rno resorption. random to leads unloading meanwhile

29 Accepted Article

Interestingly, computer simulations stated that the that stated simulations Interestingly,computer Journal ofBiomedicalMaterialsResearch:PartA 6, 30 6, This article isprotected by copyright. All rights reserved.

29, 32 29, Wnt has also been suggested to be involved in the in involved be to suggested been also has Wnt 16 A study utilizing a simulation model by finite ele finite by model simulation a utilizing study A John Wiley& Sons,Inc. 29 eurd o otols dfeetain n functi and differentiation osteoclast for required 25, 26 25, and therefore apoptosis location is more relevantmore is location apoptosis therefore and n canalicular flow and the levels of nitric oxide nitric of levels the and flow canalicular n ent. and reduces cortical bone cortical and bone reduces resorption, but lower ), IL6 and tumor necrosisfactor IL6 alpha (TNF) ), tumor necrosisfactor and surface. 27 ation predominates.ation osteoclastogenesis and bone resorption. ng first increased in higher levels of loading of levels higher in increased first ng In addition, osteocyte apoptosis is followed is apoptosis osteocyte addition, In 25 yte death. yte ways and regulate osteoblast proliferation, osteoblast regulate and ways Indeed, the greatest reduction in signal is signal in reduction greatest the Indeed, tss n rie h lvl o RANKL. of levels the raise and ptosis wering ye gie h otols resorption osteoclast the guide cytes 25 ormation and resorption and are the are and resorption and ormation Bone surface is mechanicallymoresurfaceisBone inl fo otoye las o a to leads osteocytes from signals osteoprotegerin 35 inhibitory signal fromsignal osteocytesinhibitory n of osteocytes. For example, the example, osteocytes.Forof n Finally, PTH basal levels seem levels basal PTH Finally, 21 rltd o ihr osteocyte higher to related n mn ohr atr, this factors, other Among 33

(OPG) release by release (OPG) induction of induction ments 21 28, 2928, on. has

34 31 7

before the monocytes and macrophages infiltrate the infiltrate macrophages and monocytes the before oy s e b RNL wih rmts arpae act macrophage promotes which RANKL, by led is body yrdcs s aiiae ad hs te infiltratio the thus, and facilitated is byproducts recently been shown shown recently be to ~3.5mm. been wid Biologic delivery. restoration after remodeling osseointegration. lamell weeks, 12 to 8 of matter a In later). days 5 leading layer oxide titanium the around deposition and cytokines the release they as homeostasis early eotd hge nme o clne fre ui (C unit former colonies of an in connection cone morse number gingivalis Porphyromonas and higher actinomycetemcomitans a reported sealing better provide connections implant internal presence the in later, and neck implant the around to leads micromovements to associated leakage time, periimplantin cytokines and tissues the stimulate upregul could endotoxins and products bacteria with interface the to due compartment periimplant the to inwards micrometers. implant the of portion endosseous the on connection lead infiltrate cell inflammatory the of regulation twopiec in microgap the that suggested been has It myeloperoxidase( Bone 1.5 remodelingaround dental implants connectio implantabutment the at leakage microbial loss. bone crestal less ne Later, surface. implant the to adhere fibrinogen character and topography surface implant surface on based adsorption implant the by influenced is This osteogenesi eventually and angiogenesis by followed implant marginal bone loss exposes the implant micr implant the exposes loss bone marginal implant fe dna ipat ae nhrd a eune f i of sequence a anchored, are implants dental After s t cus ih h ntrl etto, mlns a implants dentition, natural the with occurs it As 38 40 38

Acceptedputa by gap the of colonization the facilitate and Article 38

pmig fet f h fud otie i te imp the in contained fluid the of effect pumping A 1

MPO 43 Journal ofBiomedicalMaterialsResearch:PartA Nonetheless, it remains to be elucidated the assoc the elucidated be to remains it Nonetheless, This article isprotected by copyright. All rights reserved. ) positivecells are capable of breakingdownthe pe in vitro in 36 John Wiley& Sons,Inc. This physiological boneremodeling This mechanism a to study. 44 Moreover, conical seal systems have been related t related been have systems seal conical Moreover, ar bone initiates the biological stability, namely stability, biological the initiates bone ar of active osteoclasts. the chemotaxis growth factors that stimulate collagen matrix collagen stimulate that factors growth to newlyformed woven bone (usually occurs (usually bone woven newlyformed to of biofilm, to periimplantitis. to biofilm, of n t cetl oe loss. bone crestal to ing tohl pplt te mln rcpet site recipient implant the populate utrophils hn h etra ones. external the than n with the crestal bone loss.bone crestal the with n e implants might be associated with the up the with associated be might implants e area. These events fulfill a key role on the on role key a fulfill events These area. otexture, contamination by bacterial and its and bacterial by contamination otexture, h n uas rud etl mlns has implants dental around humans in th steady inflammatory reaction,inflammatory steady n of large proportions of CD68 and and CD68 of proportions large of n hydrophilicity. Accordingly, thrombin and thrombin Accordingly, hydrophilicity. tk pae o civ osseointegration. achieve to place take s ylcl odn o te implant/abutment the of loading cyclical evs gp n rne f 0 t 50 to 10 of range a in gap a leaves t te xrsin f proinflammatory of expression the ate sis wn t te blt fr protein for ability the to owing istics n ape o tioe oncin vs. connection trilobe of samples in vto it otolss We early When osteoclasts. into ivation e ujce t sf ad ad tissue hard and soft to subjected re tive pathogens. These organic fluidsorganic These pathogens. tive mnnlmaoy responses mmuneinflammatory U o Aggregatibacter of FU) at aiis ih shift might cavities lant iation of the gap size or size gap the of iation riimplantstructures. 42 8 3938,

43 45 emr t al. et Tesmer h abutment The 42 In addition, it addition, In It seems that that seems It 41 38 bone loss bone Over the foreign 37 8 o

Page 8of38 Page 9of38 prevent micromovement that could lead to fibrous e fibrous to lead could that micromovement prevent period and also a higher presence of osteocytes. La osteocytes. of presence higher a also and period competent.biomechanically reported, been have loading of period loss. bone oe erss Fgr 3. t a be son n anim in shown been has It 3). (Figure necrosis bone torque has also been associated with an increase in increase an with associated been also has torque n Vlmn canals. Volkmann and t on occurs resorption bone cortical that evidenced initiatin for stimulator strong a being microdamage histological investigation that clearly identified identified clearly that investigation histological 2.1. Bone biology Bone 2.1. underimplant insertion osteocytes numbers in remodeling.and bone b when year fifth the to up comprises stages second b woven initial of remodeling the bon imply and loading after homeostasis bone maintain to needed cells implants. retrieved human hard and modulus elastic of increase an and loading ligament. from transmitted loading masticatory of impact the This bone. resorbed old the than energy deformation defo viscous and plastic elastic, resist to ability al et GyoonKimdogs, in study shorttermfollowup loadi masticatory the by stimulated as years during establishmen width biological the to due and trauma microgap associated to inflammation. compo original the use to encouraging with together location. supracrestal vs. interfaces position the of influence the controversial remains

2. Excess of Excess of 2. implanttorque healing bone on dqae mln isrin oqe I) aus (254 values (IT) torque insertion implant Adequate s frmnind prmln ipat oe underg bone implant periimplant aforementioned, As 46

45 adsar e a. eosrtd ht oe ny rea only bone that demonstrated al. et Baldassarri

Accepted Article have neutrophils of density greater a though, Even Journal ofBiomedicalMaterialsResearch:PartA 49 This article isprotected by copyright. All rights reserved. hs a i areet ih rdorpi, histomo radiographic, a with agreement in was This 47 Interestingly, a reduction in osteocyte density in density osteocyte in reduction a Interestingly, 48 In this sense, initial healing process takes up t up takes process healing initial sense, this In John Wiley& Sons,Inc. 38, 39 38, 48 Further improvements on the implantabutment seali implantabutment the on improvements Further n a osbe xlnto ws h lmtd number limited the was explanation possible a and 48

rmation but higher viscoelastic capacity to absorb to capacity viscoelastic higher but rmation that implants with a high IT (>50 (>50 IT high a with implants that of the implantabutment connection on crestal on connection implantabutment the of critical pressure triggering microfractures and microfractures triggering pressure critical ng after the postimplantation healing.postimplantation the after ng g targeted bone remodeling. Moreover, it was it Moreover, remodeling. bone targeted g st, the third stage seems to imply a reduction a imply to seems stage third the st, t, but also it keeps in active bone remodeling bone active in keeps it also but t, e ufc o dfeety retd Haversian oriented differently of surface he ness have been observed during that time in time that during observed been have ness one matures after another active remodeling active another after matures one ncapsulation. On the flip side, high insertion high side, flip the On ncapsulation. fact might explain why bone is able to bear to able is bone why explain might fact lower had bone newlyformed that reported . nents might minimize the crestal bone loss bone crestal the minimize might nents one and a high number of osteocytes. The The osteocytes. of number high a and one h ipat n bec o te periodontal the of absence in implant the l oes ht ih T lct a complex a elicits IT high that models al i mtrd wl aind and aligned well matured, is e 5 5 hs auiy fe 5 er of years 5 after maturity ches Ncm e rmdln atr surgery after remodeling oes en eotd n subcrestal in reported been hv be sgetd to suggested been have ) samples after long after samples o the first year of year first the o poercl and rphometrical Ncm 4648 are ) In a a In ng of 9

bone is located in the anterior mandibular region, region, mandibular anterior the in located is bone predictably preserve the periimplant bone level. T level. bone periimplant the preserve predictably asvl placed. passively detected in the posterior maxillary area. Recent fi Recent area. maxillary posterior the in detected highest levels of the antiapoptotic protein Bcl2 protein antiapoptotic the of levels highest apoptosis cell microdamaged promoted byexpre areas 0 mcos wy rm microcracks. from away microns 200 and microcracks from away microns 100200 reported hn oprd o aclos bone. cancellous to compared when density. bone on atrophy 23 cells. apoptotic remove to environment and RANKL of levels higher promote may consequently increas However, observed. be may and levels IT low loss,bone promote disuse bone that and resorption preservationof the the periimplant tissue level. jeopa potentially may stability primary of lack the poros and accumulation microcracks with associated IT. low ea the in loss bone periimplant greater to subject the in loss bone periimplant in mayresult cells, no to minimal implying bone, compact of vascularity Moreover, osteoclasts not only remodel disused bone disused remodel only not osteoclasts Moreover, field of implantology classified the maxillary ridg maxillary the classified implantology of field the crestal in area. achieve high IT, a double layer of dead and dying o dying and dead of layer double a IT, high achieve ihihs h iprac o mnmzn microfractu minimizing of importance the highlights following the direction where the bone was deposite was bone the where direction the following Thes signals. inhibitory osteoclast the emit not do osteoclastsrais attract and signalsto chemotactil In this area two stimuli promote osteoclast activa osteoclast promote stimuli two area this In 51

Finite elements studies have shown that loading inc loading havethat shown studies elements Finite lelr oe est frhr nlecs rmr st primary influences further density bone Alveolar Accepted Article dens lacunar osteocyte that shown was it Moreover,

50 diinly a eet utsae nlss reveale analysis multiscale recent a Additionally, Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. 57 Cortical bone has a higher elastic modulus elastic higher a has bone Cortical John Wiley& Sons,Inc. 53 59 ebrt t l rpre ta val otoye ne osteocytes viable that reported al. et Verborgt oehls, t s ot ntn ta te restraine the that noting worth is it Nonetheless, 29

53 ihr ees f AK hs rvosy been previously has RANKL of levels Higher

e RANKL levels. Secondly, osteocytedeadlevels.Secondly, areasRANKL e event of trauma. In the same way, Kristensen et Kristensen way, same the In trauma. of event was reached 12 mm away from microcracks. from away mm 12 reached was rdize osseointegration, high IT might not favor not might IT high osseointegration, rdize 20 ndings seem to point to the influence of bone of influence the to point to seem ndings rly stages of healing compared to those more those to compared healing of stages rly es in four major types.major four in es hereby, it seems highly coherent to state that state to coherent highly seems it hereby,

d, 21 tion. sgas ih b tasitd preferently transmitted be might signals e , but also damaged bone like microcracks. like bone damaged also but , steocytes was observed when compared to compared when observed was steocytes ssing higher levels of Bax gene and that the of that gene Bax ssingand levels higher so a contradiction between recommendingbetween contradiction a so 21 ed IT may lead to osteocyte apoptosis and apoptosis osteocyte to lead may IT ed hra mr pru taeua bn is bone trabecular porous more whereas lower levels of OPG were observed up to up observed were OPG of levels lower triggering greater periimplant bone loss bone periimplant greater triggering t ices wt age. with increase ity irto o dfeetaig osteogenic differentiating of migration e a a osqec o hg I to IT high of consequence a as res 21 First of all, dying osteocytes release osteocytes dying all, of First reases bone formation and inhibits theinhibitsand bone formation reases EF erto t te surrounding the to secretion VEGF blt. n al pbiain n the in publication early An ability. t i hmn otcl oe is bone cortical human in ity 58 and compressive strength compressive and ta udr rlig to drilling under that d 56 Accordingly, denser Accordingly, 8 5248 hs finding This t to xt 10 54 55 d

Page 10of38 Page 11of38 parameters necessitating parameters adequate control according oe ufc epniua t te odn force, loading the to perpendicular surface bone bone is exposed to the highest strain levelsstrain highest the to exposed is bone blood supply and abscence of bone marrow might limi might marrow bone of abscence and supply blood sebatc el est rqie fr oe repair bone for required density cell osteoblastic impair may supply bone limited The bone. trabecular beshould IT, advocated. tapping Inorder layer. cortical thick a of presence the in Theref (~1.5mm). content cancellous of (<30%) sites (~0.60 minimized significantly was loss bone early agnl oe loss. bone marginal

zone might be occuring. For such reasons, implant p implant reasons, such For occuring. be might zone lncas ae o h ble ht osseointegratio that belief the on based clinicians Implant 2.2. under outcomes high and implant low to surface promotes a more potent resorptive signal th signal resorptive potent more a promotes surface ee. etil, o imdae mln paeet w placement implant immediate for Certainly, level. torque implant high that indicate to seems research load is one and contact in are materials differents bone. in area last the and marrow bone the reach bone that pericytes like osteoprogenitors mesenchymal the from cells of reactivation from come cells osteoblastic the of rec osteblast of routes main three the reported al. Ncm). (>32 necessary is stability edd o bn frain o occur, to formation bone for needed not may area the cases some in and area, remodeling according to histological reports, the highest dens highest the reports, histological to according resorption resorption can place. take n umr, otcl oe rsns ih eea dis several with presents bone cortical summary, In ios t l suid h ascain f h propor the of association the studied al. et Simons hl te eif eid civn hg piay stab primary high achieving behind belief the While Accepted Article

5 2625,

hs ihs sri lvl ae oae o te area the on located are levels strain highest This 62 h atos dniid ht ihr aclos prop cancellous higher that identified authors The Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. 61

65, 66 65, John Wiley& Sons,Inc. Nonetheless, in delayed implant placement, underst placement, implant delayed in Nonetheless, 60 hwn a arse rvra ae wee ny bone only where area reversal arrested an showing 63 and correlates with the most mechanically sensitiv mechanically most the with correlates and to avoid microfractures as a consequence of highof consequence a as microfractures avoid to 6 ruitment during remodeling: aproximately 20% aproximately remodeling: during ruitment hrfr a rae aon o aae n this in damage of amount greater a therefore n would be better warrantied, current clinical current warrantied, better be would n ity of osteocyte canaliculi are observed at the at observed are canaliculi osteocyte of ity ih nt e reached. be not might might be pernicious for the periimplant boneperiimplant the for pernicious be might BLC on quiescent surfaces, 50% are canopy are 50% surfaces, quiescent on BLC to boneto characteristics. their eoeig ra y h canopies. the by area remodeling an found in deeper bone tissues.bone deeper in found an lacement protocols (including IT) are crucial are IT) (including protocols lacement rque .7mm) when compared to implant recipient implant to compared when .7mm) ed. ore, high IT should be omitted, in particular in omitted, be should IT high ore, osteoprogenitors presence and the critical the and presence osteoprogenitors reach the critical osteoblastic cell density cell osteoblastic critical the reach t the amount of osteoblast cells in the bone the in cells osteoblast of amount the t t/ot meit laig sld primary solid loading, immediate ith/out 64 oevr otoye ppoi a the at apoptosis osteocyte Moreover, in f acloscria bn on bone cancellous/cortical of tion lt hs en h ga fr many for goal the been has ility hr ae vascularassociated are third datgs hn oprd to compared when advantages f is cnat hn two when contact first of 60 rin >06%, and (>5060%), ortion eody te crestal the Secondly, 25, 26 25, 60 Limited Thirdly, anding 11 e

Ncm oe ise dd o cue oe aaoim whereas catabolism, bone cause not did tissues bone monkeys, in breakdown elucidated. yet been not has disease periimplant failur late causing agents etiological major the be osseointegration. of process the jeopardize netgtn atraie taeis nldn the including strategies alternative investigating compar loss bone periimplant on have might IT high

recession, notably in the presence of a thin buccal thin a of presence the in notably recession, reported that inadequate oral hygiene and trauma fr trauma and hygiene oral inadequate that reported BIC. impac not did overload that study dog a in reported plaqu if density bone higher a to and plaque dental ov occlusal that reportedal. et Chambrone studies, Traumaocclusion 3. from bone.existing healing certain a that demonstrated was it although a stability secondary adequate shown have IT higher simplified of use the is example One investigated. (≥50 IT high under applied sequenc drilling the dictate might density bone and e the and bone bundle the of process resorption the review systematic a lines, lasers 176 statistically found was association an Strikingly, T hehl (>70 threshold IT inserted at 0 at inserted means of the bone area fraction occupied.fraction area bone the of means impl passive achieve to drilling adequate affected, fate of of fate the periimplant bonelevel. Ncm 82 t months. 4 at 73 t s motn t hglgt lo h sre o an of series the also highlight to important is It

74 Although periimplantitis and overload in conjuncti in overload and periimplantitis Although fo approaches novel reasons, aforementioned the For ). This finding further reflects the role that bone that role the reflects further finding This ).

Accepted or ultrasoundtools Article Ncm 69

Alike, findings from another group also indicated also group another from findings Alike, torque displayed similar outcomes compared to thos to compared outcomes similar displayed torque 70 Ncm n ata areet Cmo e a. on ta alt that found al. et Campos agreement, partial In Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. , t a eiecd ht agnl oe os a sub was loss bone marginal that evidenced was it ), 3 84 83, 85 Ncm eotd ht urclsl otcs n noninfla on contacts supraocclusal that reported 75 vn n h lc o paunue inflammation. plaqueinduced of lack the in even

), it has been shown to be more prone to marginal b marginal to prone more be to shown been has it ), 77

78 John Wiley& Sons,Inc. to enhance osseointegration. enhance to 71 Hence, clinical outcomes echo the uncertain impact uncertain the echo outcomes clinical Hence, 7 68 67, o eape wdr mlns ntle under installed implants wider example, For es, correlated when including all the values (up to (up values the all including when correlated erload may lead to bone loss in the presence ofpresence the in loss bone to maylead erload bone. plcto o osoesfcto protocols, osseodensification of application e and IT. As such, when implant placement isplacement implant when such, As IT. and e delaying was found due to the necrosis of the of necrosis the to due found was delaying antation outperformed over/underdrilling by over/underdrilling outperformed antation e control is performed.is control e 80 t on healthy implants, with no differences in differences no with implants, healthy on t om occlusion resulted in periimplant tissue periimplant in resulted occlusion om stablishment of the bone macroarchitecture bone the of stablishment 79 n sseai rve bsd n animal on based review systematic a In rlig ehd ta hv nt emd to seemed not have that methods drilling ed to low IT. Future research are currently are research Future IT. low to ed the influence of trauma from occlusion on occlusion from trauma of influence the urclsl otcs obnd with combined contacts supraocclusal d ih oetmln cnat (BIC); contact bonetoimplant high nd 67 structure plays and its influence on the on influence its and plays structure ml tde fo Myt e a. who al., et Miyata from studies imal Alike, when compared to even higher even to compared when Alike, on with the host characteristics may characteristics host the with on ipat lcmn ae being are placement implant r that even submerged implants submerged even that e inserted at 30 30 at inserted e og te I ws not was BIC the hough 81 HeitzMayfield et al. et HeitzMayfield tnily higher.stantially e periimplant med 83 Along these these Along one loss and loss one Ncm or 70 or 12 68 72

Page 12of38 Page 13of38 proliferation, maturation and differentiation. and maturation proliferation, biased literature and also due to the fact that mos that fact the to due also and literature biased probably due to the effects of higher levels of TNF of levels higher of effects the to due probably been withbeen an related enhanced hazard periodontalof formation/bone resorption equilibrium by downregul by equilibrium resorption formation/bone n bd ft s ope ad o ttly understood totally not and complex is fat body and Although obesity and high levels of cholesterol pr cholesterol of levels high and obesity Although low. is levels serum and obesity between relation n te wrs fty acids fatty words, other In n h ls tre eae, h cnupin f high of consumption the decades, three last the In increased Cholesterol 4.1 and acids fatty affecting Factors 4. bone metabolism experimental animal studies. butindisrupted the lack of overloading. occlusal (1.8mm), observed was loss bone marginal Interesting excessive examined. implants of majority vast the 4.515.5 osseointegration of loss the trigger might in study radiographic and clinical a Moreover, evidence enough not is there and reported poorly is bone/impl on overloading implant of effect the that significantly inflammation the plaqueindincreased

accumulation of fat cells inside the bone marrow ti marrow bone the inside cells fat of accumulation sebat iblt b idcn aotss n auto and apoptosis inducing by viability osteoblast secrete can adipocytes these and osteoblastogenesis cardiovascular disease and hyperinflamed condition hyperinflamed and disease cardiovascular eecya se cls ifrnito b inhibitin by differentiation cells stem mesenchymal as n BF a be reported. been has BMF and mass RANKL. (e.g., cytokines osteoclastogenic and inflammatory

on done be should conclusions cautious summary, In 95, 96, 98100 96, 95, 87

Acceptedmortality and morbidity the consequence, a as and Article

97 John Wiley& Sons,Inc. n hg lvl o cholesterol of levels high and 9598 ihr dpgnss n M a rsl i lower in result may BM in adipogenesis Higher 97 Animal studies have shown more bone resorption, bone more shown have studies Animal Macaca Fascicularis Macaca 86 92 t of the knowledge in this field is derived from derived is field this in knowledge the of t

months after the overload was commenced in commenced was overload the after months

α and sclerostin.and α uced bone loss. Accordingly, uced bone loss. concluded was it 93 disease man. in ant loss in clinically wellintegrated implants wellintegrated clinically in loss ant phagy. to support a causeandeffect relationship. causeandeffect a support to ssue. o aioeei ad rmtn osteoblast promoting and adipogenesis of g

s have also increased. also have s ating the Wnt signaling pathway. signaling Wnt the ating 94 Nα n I) aioie ad express and adipokines IL6), and TNFα saturated fatty acids which may impair impair may which acids fatty saturated o now. to y i ws ute son ht although that, shown further was it ly, Similarly, the relationship between bone between relationship the Similarly, oduction have been linked for years, the years, for linked been have oduction o mln ws ot hn lqe was plaque when lost was implant no 96 6 97 96, An inverse correlation between bone between correlation inverse An ft n hghlseoit have highcholesteroldiets and fat this topic due to a limited and risk and limited a to due topic this 95 of obesityrelated diseases such as such diseases obesityrelated of dpcts a lo ees pro release also can Adipocytes oe arw a (M) s the is (BMF) fat marrow Bone 103 90, 91 90, confirmed that overloading that confirmed Wnt pathway balances the pathwaybalances Wnt 101

a dsub h bone the disturb may 88, 8988, Obesity has also has Obesity 102 This is This 13 85

by hydroxylation, firstly in the liver and then in in then and liver the in firstly hydroxylation, by osteoblast vitamin D receptors (VDR) and by alterin by and (VDR) receptors D vitamin osteoblast erto ad oe ssei bn resorption bone systemic lower and secretion h rto f 1M mcohgs rmtn a M pro M1 increasingthe numbersof an monocytes/macrophagesin promoting macrophages M1/M2 of ratio the macrophages. eotd n mrvd iaim ce fxto i ova in fixation screw titanium improved an reported rising insufficiency of vitamin D prevalence in var in prevalence D vitamin of insufficiency rising reported in mice after a 12 week highfat diet. highfat week12 a after mice in reported bo the in strength lower and formation bone reduced mineral bone metabolism. bone mineral Vitamin D4.2 date evidence to has been found. im on speculated be might effects negative density, n diin oeiy nue a ytmc inflammati systemic a induces obesity addition, In m of production increased and cytokines circulating remodeling. re bone coupling production, matrix bone osteoblast es oe omto ad oe as n hge levels higher diets. cholesterol and mass bone and formation bone less

osseointegration has not yet been fully elucidated. fully been yet not has osseointegration the but field medical the in described extensively eerh netgtn is fet drn dna im dental during effects its investigating research mln placement. implant mechani and values BIC lower reported and D osseointeg Vitamin the studied (2009) al. et Kelly animals, 3month highfat diet versus normal diet.normal versus diet highfat 3month after differencenoweeksBICwas in 12 there that 123 osteoclastogenesis.

iai D s ftslbe omn ta rglts c regulates that hormone fatsoluble a is D Vitamin The influence of obesity and increased levels of ch of levels increased and obesity of influence The iai Di acmo sbtne n h rvnin a prevention the in substance common a is D Vitamin

Accepted116 Article 109, 110 109,

t nrae clim bopin n h itsie l intestine the in absorption calcium increases It 97

119 101 These cytokines and the accumulation of cholestero ofaccumulation the and cytokinesThese 124 ,5dhdoy iai D cn tmlt bn resor bone stimulate can D3 vitamin 1,25dyhydroxy

105 114

106 It is transformed into the active form (1,25dyhyd form active the into transformed is It

John Wiley& Sons,Inc. 113 As hyperlipidemia might impair bone quantity and and quantity bone impair might hyperlipidemia As 112 On the other hand, Dündar et al. (2016) reported (2016) al. et Dündar hand, other the On implant placement between rabbits followinga placement rabbits between implant 112 ious patient populations.patient ious 1, 1, 118 117, 115, plant osseointegration although no conclusive no although osseointegration plant ln osonerto rmis limited. remains osseointegration plant onocytes, neutrophils onocytes, g the balance between RANKL and OPG. and RANKL between balance the g fet f yelpdma n etl implant dental on hyperlipidemia of effect Significantly more periimplant bone loss, bone periimplant more Significantly h kidney. the circulation. ain rcs i rt wt dfcec in deficiency with rats in process ration sorption to formation and optimize bone bone optimize and formation to sorption eipat nefc hs rvosy been previously has interface neimplant icoie rt atr wes f oral of weeks 8 after rats riectomized f oe unvr akr atr rich after markers turnover bone of a bn srnt atr wes post weeks 2 after strength bone cal olesterol and triglycerides have been been have triglycerides and olesterol nlmaoy niomn thereby environment inflammatory n odto wt hg lvl of levels high with condition on lim hsht hmotss and homeostasis phosphate alcium ih psil ihbto of inhibition possible a with d ramn o otoooi but osteoporosis of treatment nd 109, 111 109, 115 aig o rdcin n PTH in reduction a to eading hs iai cn stimulate can vitamin This

l in macrophagescanin alter l 107, 108107, 124 e confounded by the the by confounded e to b bnig to binding by ption Zhou et al. (2012) al. et Zhou and adipose tissue adipose and roxy vitamin D3) vitamin roxy 118 In 14 120 Page 14of38 Page 15of38 ains u a orlto bten oh atr cou factors both between correlation a but patients bone, the location and mechanical loading.mechanical and location the bone, diabetes 2 Type insulin. of use ineffective body’s healing bone after implant insertion. of adequate evidence. level bu healing implant and health bone improve to seems low serum levels of vitamin Dvitamin of levels serum low supressed osteoblastic function and lower bone form bone lower and function osteoblastic supressed characterized by hyperglycemia, resistance insulin exces of result the largely is worldand the around insulin. diabetes 2 of Type nonin (formerlycalled childhoodonset)is characterized bydeficient insu 2014. in million 422 Hyperglycemia4.3 sugg may results these Therefore, osseointegration. surgery, following an implants around formation bone new significantly ev was dogs in placed implants immediate of surface (10% D vitamin of application topical of effect the implant for approach effective an be may treatment d kidney chronic with mice in reported were periimplant results and higher) times (1.5 contact implant inc significant a showing D, vitamin with treatment implants forunknown reasons. diabetes uncontrolled to related to higher vitamin D levels. D vitamin higher to related assessed, was osteoclasts boneresorbing of number sinus augmentation procedureaugmentation sinus with vitamin cal D and fo bone in differences no reported humans, in trial

Diabetes mellitus has been related to a deficientm a to been related hasmellitus Diabetes inc world the in diabetes with adults of number The

Accepted Article doubl randomized, a in (2016), al. et SchulzeSpate 127 standing out the positive correlation between vita between correlation positive the out standing 129 Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved.

132 ye daee (rvosy nw a insulindepend as known (previously diabetes 1 Type n nndansd ibts ih b a osbe rea possible a be might diabetes nondiagnosed and 133 128

showed a higher incidence of the implant failure r failure implant the of incidence higher a showed 123 John Wiley& Sons,Inc. 118 A retrospective study to correlate early implant f implant early correlate to study retrospective A

131 A higher risk of implant failures have been relate been have failures implant of risk higher A lin and dailyproduction lin requires administration sulindependent or sulindependent or adultonset)fromresults the comprises the majority of people with diabetes with people of majority the comprises andrelative deficiency.insulin rmation nor in graft resorption after maxillary after resorption graft in nor rmation placement in patients with CKD.with patients in placement est that vitamin D has a protective effect on effect protective a has D vitamin that est d o b dtrie. hrfr, iai D vitamin Therefore, determined. be not ld ) bd wih ad hscl nciiy I is It inactivity. physical and weight body s ation potential, independently of the type of type the of independently potential, ation ciumsupplement. rement of periimplant bone density, bone density, bone periimplant of rement 126 aluated. Both topical applications improved applications topical Both aluated. idn a ihr oe eoeig activity remodeling bone higher a finding sae CD, ugsig ht iai D vitamin that suggesting (CKD), isease rdcd rsa bn ls a 1 weeks 12 at loss bone crestal reduced d rbclr microarchitecture. trabecular and melatonin (5%)melatonin and frhr eerh s edd o ban an obtain to needed is research further t etabolism of the skeletal tissue due to ato tissuedue skeletal the of etabolism reased from 108 million in 1980 to 1980 in million 108 from reased ln, lcbotold clinical placebocontrolled eblind, 123 min D and early stages of stages early and D min Only a difference in the differencein Only a 127 solutions on the on solutions 130 n, ueie or juvenile ent,

o o failed of son 125 ate in these in ate 118 Recently, ailure and ailure Similar 15 d

pump inhibitors have been related to an increase in increase an to related been have inhibitors pump hs oe, er atce ae eonzd s foreig as recognized are particles wear model, this tissues. indu that particles release can degration titanium surface.implant from released ions and updated thorough medical recordsare advocated locatio vulnerable particularly a be might mandible dentalaroundimplants. loss bone in changes induce might intake medication like Other 4.4 factors dental implants. upon patients. diabetic than subjects. ones nondiabetic than subjects diabetic for higher osteoblast proliferationreduce and and function in products end glycation advanced of accumulation the and hyperglycemia of episode an following increased (CTX). I collagentype of telopeptide terminal phosphatase alkaline bonespecific and osteocalcin a to related are conditions hyperglycemic Moreover, surface implant the into migration endothelial and 135 format thrombin increased an to due resolution clot promotes diabetes that fact the be could mechanism l cement to and interfibrillar due whereas mineralization affected be might mineralization bone Early osteolysis of and the periimplant bone. macrophages. These facts hinder platelet cytokines and growth f growth and cytokines platelet hinder facts These 144 Not only metabolic issues can influence bone remode bone influence can issues metabolic only Not Ajami et al. reported a delayed bone formation and and formation bone delayed a reported al. et Ajami te ptet mgt rsn sm dge o hyperse of degree some present might patients Other review systematic a in concluded al. et Moraschini 140 Aseptic loosening is the main reason for implant h implant for reason main the is loosening Aseptic Acceptedstatistica a showed patients nondiabetic However, Article

144

Later, M1 cells release inflammatory cytokines tha cytokines inflammatory release cells M1 Later, Journal ofBiomedicalMaterialsResearch:PartA 140 This article isprotected by copyright. All rights reserved. uhe suis r nee t euiae h impact the elucidate to needed are studies Furhter 141 Higher bone turnover seems to expose moreexpose implant seemsto boneturnover Higher 141 John Wiley& Sons,Inc. The corrosion of the implant surface or the dioxid the or surface implant the of corrosion The 144

137 creaseosteoclast resorption. eu lvl o otortgrn OG are (OPG) osteoprotegerin of levels Serum ce inflammatory reactions in the periimplant the in reactions inflammatory ce bone loss and higher implant failure implant higher and loss bone ion, platelet activation and fibrin resistance.fibrin and activation platelet ion, ine mineralization remained normal. remained mineralization ine n. tocomplications.avoid a hypercogulative state and a delay in fibrin in delay a and state hypercogulative a (AGEs) that affect the organic bone matrix,bone organic the affect that (AGEs) nr ewe tp 1 n tp 2 diabetic 2 type and 1 type between nor , 141 it also leads to a lower bone density due to due density bone lower a to leads also it and also bone resorption markers like like markers resorption bone also and euto i bn frain akr like markers formation bone in reduction cells and bone turnover and lead to bone to lead and turnover bone and cells actor release and cause a limited pericytes limited a cause and release actor bd sbtne ad hgctsd by phagocytosed and substances body n oehr ih rdcd angiogenesis. reduced a with together Serotonin reuptake inhibitors and proton and inhibitors reuptake Serotonin cmrmsd nrirla collagen intrafibrillar compromised a that the rate of implant failure is not is failure implant of rate the that lly significant less crestal bone lossbone crestal less significant lly ip longterm failures.longterm ip eoeig n yegyei rats. hyperglycemic in remodeling ling. Some patientspecific factors patientspecific Some ling. svt t ttnu particles titanium to nsivity t promote osteoclastogenesis promote t 137 f hyperglycemia of

138, 139138, surface 145 According

142 134 . so an so . e layer e Other 140 143 and or 16 C 136 133

Page 16of38 Page 17of38 rcdd y arpae cuuain pir o bone to (prior accumulation macrophage by preceded bone, a rapid a accumulation bone, macrophages is of typica ioa t bte caatrz hw mue el and cells immune how characterize better to pivotal oe s o c a imn srelac cls within cells surveillance immune as act to is bone play a pivotal role in the fate of implant osseoint implant of fate the in role pivotal a play oermdln ad oe repair. bone and remodeling bone et al. clearly showed that bone formation on rough on formation bone that showed clearly al. et foreign body biomaterial such as a dental implant i implant dental a as such biomaterial body foreign nerto aon dna implants. dental around integration of Role 5. macrophagesin andperi-implant bone br

arpae, emd sel arpae (r OsteoMac (or macrophages osteal termed macrophages, macrophages), the simple removal of macrophages fro macrophages of removal simple the macrophages), in cls (MNGCs). cells giant macrophages, monocytes, including interactions cell only with surfaces material to behavior fibroblast of 90% over that note to interesting is it finding, 5.1. Macrophage polarization:5.1. phenotypesM1-M2 osseointegration implant andmaintenance. (tissue regeneration) macrophages. They may also fu also may They macrophages. regeneration) (tissue (involv macrophage M1 classical the from completely cell plastic most the of some are they that note to to macrophages of response the concerning available role substantial and vast their to pointed clearly tde fo bsc eerh ae en ioa t b to pivotal been have assoc research found consistently is basic development bone from during Studies keystudie ofbiology. boneseries inA macrophages hosttissues. into how dictate general in cells immune and macrophages decrease in the mineralization potential of bonece of potential mineralization the in decrease Macrophages playinand Macrophages role bo central prominent a

While the objective of this review is not to highli to not is review this of objective the While Accepted Article Journal ofBiomedicalMaterialsResearch:PartA 150 This article isprotected by copyright. All rights reserved. This major discrepancy is difficult to understand understand to difficult is discrepancy major This 151154 John Wiley& Sons,Inc. 146 utemr,i piay sebat utrs (conta cultures osteoblast primary in Furthermore, pcfcly n oe ise, seil ust of subset special a tissues, bone in Specifically

research to date has focused on osteoblast and osteoblast on focused has date to research types found in the human body. They polarize They body. human the in found types a small percentage (10%) dedicated to immune immune to dedicated (10%) percentage small a egration. titanium dental implant surfaces was routinely was surfaces implant titaniumdental lls. s on OsteoMacs has shown that their removaltheir that shown OsteoMacshas on s llyat the implant found surface. n oe ilg, uh es nomto is information less much biology, bone in isre tasmcsly no h alveolar the into transmucosally inserted s otolss ekctsad multinucleated and leukocytes osteoclasts, hi microenvironment. their arpae bhv i rlto t dental to relation in behave macrophages se into osteoclasts and resorb bone or fuse or bone resorb and osteoclasts into se ed in tissue proinflammation) towards M2 towards proinflammation) tissue in ed m these these m 153, 155 153, biomaterials will eventually be integrated be eventually will biomaterials ae wt a euto i bn modeling, bone in reduction a with iated eakdownandregeneration mlne boaeil. t s therefore is It biomaterials. implanted ) hv rcnl be hpteie to hypothesized been recently have s), ght macrophage biology, it is important is it biology, macrophage ght deposition). 146 Therefore, while basic studies have studies basic while Therefore, ne bone/biomaterialand homeostasis The general role of OsteoMacs in OsteoMacs of role general The in vitroin te udrtn te oe of role the understand etter 149 systems leads to a 23fold a to leads systems ept ti prominent this Despite ie te at that fact the given 4, 148147, 149 e we a when Yet Chehroudi ining 17

rdcd n epne o L4 r L1 ad lo secr also and IL13 or IL4 to response in produced biocompatibility interactions not yet fully underst fully yet not interactions biocompatibility yial idcd y F + P o TFα ( TNFα or LPS + IFNγ by induced typically TNFalpha, including cytokines proinflammatory of While this topic has recently been reviewed, been recently has topic this While chemistry topography, material, surface implant of of Impact 5.2 implant surfacetopography and chemis extremely is forthe longterm vital of maintenance nsoitd ih eiipat infections. periimplant with unassociated are implants dental of percentage small A unknown. as monocytes/macrophages of behavior the concerning adlse ai ece (L) srae tns o in to tends surfaces (SLA)] etched acid sandblasted respon proinflammatory a increase to tends general as 3 days and vice versa.vice and days 3 as woundhealingfrom M2 macrophages towards proinM1 al. et Spiller Interestingly, stability. longterm surface implant around polarization their expected, IL1 IL4, VEGF, TGB1, PDGFBB, including cytokines no utncetd in cls MGs wee their where (MNGCs) cells giant multinucleated into

hra a oiiain o hi srae hmsr h chemistry surface surfaces).(modifiedSLA response inflammatory their to modification a whereas aal o ihbtn cl proliferation, cell inhibiting of capable cell proliferation cell and repairthrough polyamineand towards ornithine and polyamines.and ornithine towards citrull and (NO) oxide nitric to M shifted that metabolism is macrophages M2 and M1 between differences of implant stages osseointegration. r prominent the of understanding of advance further During dental implant osseointegration, classical M classical osseointegration, implant dental During

Accepted that research of area one mentioned, previously As Article Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. 162 Therefore, their role, especially as it relates to relates it as especially role, their Therefore, 158 John Wiley& Sons,Inc. M1macrophages produce NO as a main effector molec effector main a as NO produce M1macrophages 159 hl Marpae gnrt ontie increasing ornithine generate M2macrophages while 4, 166146, 146 showed that macrophages can completely polarize completely can macrophages that showed it is important to note that surface roughness in roughness surface that note to important is it n vitro in hs s ot iey asd y mue cell immune by caused likely most is This 164, 165 164, ood and future research in this field is likely to likely is field this in research future and ood dentalimplants. collagen synthesis. s is highly relevant for implant integration and integration implant for relevant highly is s n cmoiin n mue el behavior. cell immune on composition and try on macrophage on try behavior se. It has been shown that roughness [e.g., roughness that shown been has It se. ine, whereas M2 macrophages are shifted shifted are macrophages M2 whereas ine, ole of immune cells during early and late late and early during cells immune of ole rae 1 arpae polarization, macrophage M1 crease oe ean pol defined. poorly remains role Despite this, a great deal of information of deal great a this, Despite ). well as their fusion to MNGCs remains MNGCs to fusion their as well ot vr ya fr e kon reasons known yet for year every lost t a ie ait o proregenerative of variety wide a ete 5, 161 159, L1ea I, l1, M2 MMP9 MMP2, Il12, IL6, IL1Beta, flammatory macrophagesflammatoryas within little s en hw t rdc ti pro this reduce to shown been as has been largely omitted is the effect the is omitted largely been has mcohgs ae hi arginine their have macrophages 1 1macrophages secrete a wide array wide a secrete 1macrophages , C1 (al 1. s a be can As 1). (Table CCL18 0, n otat Marpae are M2macrophages contrast, In 160

periimplant infection,periimplant 5, 157 156, Major 163165 ule 18

Page 18of38 Page 19of38 eidna ptoes r kon o ert lipopoly secrete to known are pathogens periodontal papers provide a platform whereby implant osseointe implant whereby platform a provide papers possesses major possesses clinical implications. ha study of field This implants. cellcell of remodeling bone how determine to relevant highly becomes oaiain Frhroe tee aes tesd he stressed papers these Furthermore, polarization. biomaterial material rejection,material biomaterial s iey drc rsl o a 1M sit n macro in shift M1/M2 a of result direct a likely is arpae/NC ad te cl tps va direct (via types cell other and macrophages/MNGCs likely most (and macrophages Since etc. leukocytes osteoclasts, osteoblasts, including implants dental in found are types cell many Furthermore, implants. date to research little yet macrophage/MGNCs M1/M2 implant prone are cells dental both that likely with is It maintenance. interaction their and MNGCs and integration and integration implant osseointegration. to needed is research further much that evident is examine foreign body reaction, equilibrium between between equilibrium reaction, body foreign examine ufcs ed t boaeil radw ad possibl and breakdown biomaterial to leads surfaces immune cells and biomaterials. bone immunecells 5.3 Macrophages,5.3 Immune Foreignand Cells Bodythe

cuuain n hi boaeil surface. biomaterial their on accumulation M2macro expression of capable are MNGCs that shown M2MNGCs and M1MNGCs towards polarizing of capable derived hypothetically are (which MNGCs that shown NC hv be son o xs i sal hmn bone human stable in exist to implantation shown been have MNGCs molecule influencing proinflammatory M1macrophage proinflammatory influencing molecule cuuain n h ipat ufc. hl MGs ha MNGCs While surface. implant the on accumulation It is therefore a necessity to accurately character accurately to necessity a therefore is It Accepted Article reported Itimplant been that osseointegration has 172174

and have been associated with a rapid increase in in increase rapid a associatedwith been have and Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. 167169 it is interesting to note that accumulating eviden accumulating that note to interesting is it John Wiley& Sons,Inc. 167169 The literature showed literature showed implant MNGCon The accumulation 171 pcfcly rud oe rfig materials, grafting bone around Specifically better understand their role in bone biomaterial bone in role their understand better o eesby hfig hi plrzto from polarization their shifting reversibly to MNGCs) express high levels of cytokines, it cytokines, of levels high express MNGCs) sects fbolss edteil cells, endothelial fibroblasts, osteocytes, small spaces within the oral cavity around cavity oral the within spaces small gration and eventual periimplant bone loss bone periimplant eventual and gration vl o mtra rjcin ih MNGCs with rejection material on avily hg plrzto. neetnl, invading Interestingly, polarization. phage tu fr en et niey ntde yet unstudied entirely left been far thus s Reaction from the fusion of macrophages) are also are macrophages) of fusion the from el otc o prcieatvt) during activity) paracrine or contact cell ipat failure/rejection. implant e acaie (P) a nw ad direct and known a (LPS), saccharides has been performed as it relates to dental to relates it as performed been has polarization. 1 n M mcohg ad MNGC and macrophage M2 and M1 ize immune cells such as macrophages as such cells immune ize is a isa longtermhost equilibrium between e etil be ipiae i bone in implicated been certainly ve hg mres olwn macrophage following markers phage , hi osonerto ad their and osseointegration their s, . In addition, other researchers have researchers other addition, In . omncto ocr between occurs communication ay er floig their following years many tissue vascularization.tissue 170 Hence, it is important to important is it Hence, 167169 ce has now has ce These 175178 19 It

e formed. be polarization towards M2macrophage/M2MNGCs in the the in M2macrophage/M2MNGCs towards polarization UniversityMichigan of Periodontal Graduate Student manusc the in listed information or products the in towards M2 phenotypes and begin to form ectopic bon formectopic to begin phenotypesand M2 towards

hy xrs hg lvl o IFNgamma. of levels high express they arterie of calcification the that shown has disease Conflict of interest: of Conflict during impact their maintenance. and cells) giant multinucleated prominent the out stress also We stability. implant fa responsible potential as discussed are D vitamin syst of effects the Furthermore, healing. of stages preparationliningcel bedbone c implant affects and disease and remains it health attention, much received has both remodeling in implants dental around ad recent the of some highlights review present The Conclusions s and homeostasis. vast a playing macrophages that shown now has Ther formation. bone new dictating are macrophages) It is also interesting to note that more recent res recent more that note to interesting also is It

Accepted Article146 ec, t s neetn t pit u ta i this in that out point to interesting is it Hence, The authors do not have any financial interests, e interests, financial any have not do authors The Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. John Wiley& Sons,Inc. 7, 180 179, t a be son ht arpae polarize macrophages that shown been has It

s is a direct result of macrophages and MNGC and macrophages of result direct a is s ript. This article was partially supported by the by supported partially was article This ript. ls and osteocyte viability and signaling at early at signaling viabilityand osteocyteand ls oe f mue el (.. Otoas and OsteoMacs (e.g., cells immune of role mc ees f hlseo, at ais and acids fatty cholesterol, of levels emic important to better understand how loading how understand better to important Fund. Research vancements in the area of bone remodeling bone of area the in vancements tr fr al ipat os n longterm and loss implant early for ctors e in areas where bone should otherwise not otherwise should wherebone areas in e efore, growing evidence from many fields fields many from evidence growing efore, etl mln osonerto and osseointegration implant dental ac fo te il o cardiovascular of field the from earch btnil oe n oe oeig and modeling bone in role ubstantial niin. hl prmln bone periimplant While onditions. nia aes f reil al where walls arterial of layers intima cnro imn cls sc as (such cells immune scenario, ither directly or indirectly, or directly ither 20 Page 20of38 Page 21of38 BIBLIOGRAPHY Osteoporos Rep Osteoporos . lrni-iv R Sso R SsoCri , Simo E, Sasso-Cerri GR, Sasso Int R, Florencio-Silva That Factors and Function, Structure, Tissue: Bone 8. 3 3Suppl 9. Bonewald LF. The amazing osteocyte. osteocyte. amazing The LF. Bonewald 9. Adulthood. Adulthood. Worthl NA, Ma Dyment a X, Are Wang BG, Cells Matthews Lining I, Bone Matic Quiescent I. Kalajzic D, 15. 7. Clarke B. Normal bone anatomy and physiology. physiology. and anatomy bone Normal B. Clarke 7. 17. Seeman E. Bone modeling and remodeling. remodeling. and modeling Bone E. Seeman 17. R Cl-ocl cmuiain n sebatc netw osteoblastic in function. junction of gap regulation hormonal communication Gr J, Andersen CT, Cell-to-cell Rubin KJ, McLeod HJ, Donahue PR. 18. 19 Res 6 Co J, isn J Cabr T, o S. Mechan SW. Fox TJ, Chambers AJ, Wilson JW, Chow cells lining bone of reactivation by formation bone 16. 0 FazOeda T, al K Wte P. uid a Buried PE. Witten BK, Hall TA, Franz-Odendaal osteocytes. become 10. 11. Miller SC, Bowman BM, Smith JM, Jee WS. Charact WS. adult Jee JM, Smith BM, in Bowman SC, Miller sites bone marrow fatty from cells lining 11. ersn . h bn lnn cl: t rl i clean in role its Tig cell: DC, Jansen lining formation. bone initiating W, bone Korper JM, The Delaisse V, W. Everts Beertsen 19. Clin Implant Dent Relat Dent ResImplant Clin Brea Wennerber P, and Tengvall T, Albrektsson R, Trindade Buildup for Mechanisms On Biomaterials: to 5. 4 Bwa B, ilr C Te rlfrto ad dif and proliferation The SC. Miller BM, Bowman osteogenesis. estrogen-induced in cell lining 14. . evr S Qiye M Rs idctr fr peri- for indicators Risk M. Quirynen S, Renvert review. 4. 12 Suppl . li-ued , iwie J Bre E. Osteocyt EH. Burger PJ, Nijweide J, Klein-Nulend 6. 12. Parfitt AM. Primary osteoporosis. Primaryosteoporosis. AM. Parfitt 12. 173. 3 Mle S, e an-ere L Bwa B, e W Jee BM, Bowman L, Saint-Georges de SC, Miller function. and structure 13. 3. Sanz M, Chapple IL, Working Group 4 of the VEWoP Working 4 of the IL, Chapple Group M, Sanz Group Working of report consensus diseases: implant 3. 1. Davies JE. Understanding peri-implant endosseous peri-implant Understanding JE. Davies 1. 2. Zitzmann NU, Berglundh T, Marinello CP, Lindhe J Lindhe CP, Marinello T, Berglundh NU, Zitzmann man. in mucositis 2. 67

: 219-233. :219-233. : 932-949. :932-949. 2015; 1998; Clin Oral Implants Res Implants Oral Clin : 202-206. :202-206. 2015 : S131-139. :S131-139. Accepted13 Article

Stem Cells Stem : 1760-1767. :1760-1767.

2003; : 421746. 421746. :

J Clin Clin J Periodontol Journal ofBiomedicalMaterialsResearch:PartA DevDyn This article isprotected by copyright. All rights reserved. 2016. 1 : 5-10. 5-10. : Scanning Microsc Scanning J Bone Miner Res Miner Bone J 2016; 2006; 2015; John Wiley& Sons,Inc. 18 235 2001; : 192-203. :192-203. 26 Suppl 11 26Suppl : 176-190. 176-190. : 1989; Lancet 28 2002; : 517-523. :517-523. Bone J Bone Miner Res Miner Bone J J Bone Miner Res Miner J Bone 3 1980; : 953-960; discussion 960-951. 960-951. discussion :953-960; : 15-44. :15-44. 17 1986; beagles. beagles. Crit Rev Eukaryot Gene Eukaryot Rev Crit Expr in 13-week-old rats. rats. 13-week-old in jor Source of Osteoblasts During Osteoblasts of Source jor Influence Bone Cells. Cells. Bone Influence : 77-90. :77-90. 1 4. 4. ing Howship's lacunae and and lacunae Howship's ing : 773-774. :773-774. kdown of Osseointegration. Osseointegration. of kdown 7 erization of endosteal bone- endosteal of erization ine EA, Hertzberg EL, Brink EL, Hertzberg EA, ine . Experimental peri-implant Experimental . Clin J Am Soc Nephrol Soc Am J Clin s J Cri S Booy of Biology PS. Cerri MJ, es hla-utr , atg P, Saftig W, chelaar-Gutter e and bone structure. structure. bone and e orks: cell line-dependent line-dependent cell orks: g A. Foreign Body Reaction Reaction Body Foreign A. g J Clin Periodontol Clin J : 351-357. 351-357. : healing. healing. . Clinical research on peri- on research Clinical . eetain f h bone- the of ferentiation Anat Rec Anat ey DL, Rowe DW, Grcevic Grcevic DW, Rowe DL, ey mlnii. narrative A implantitis. cl odn stimulates loading ical 2011; live: how osteoblasts osteoblasts how live: 1995; S. Bone lining cells: cells: lining Bone S. J Dent Educ J Dent 1980; 26 10 : 229-238. :229-238. : 881-889. :881-889. J J Bone Miner Biomed ResBiomed 198 2012; 2008; 2008; 2009; 2003; : 163- : Curr 39 21

2000; 4 Mnlgs C Brh n dah f oe el: ba cells: bone treatment of death and and pathogenesis Birth the SC. for Manolagas implications and 34. 192. 3 Yn , i , hn , orrt , hmhr G B G, Dhamdhere S, Mouraret T, Chen activation. J, Wnt Li via X, implants Yin oral failed Rescuing 33. Bone Miner Res Miner Bone the sclerostin gene in mice results in increased bo increased in results mice in gene sclerostin the Ke WS, Simonet DL, Lacey PJ, Kostenuik I, Sarosi S, D B, Daugherty N, Sun QT, Niu WarmingtonMS, Ominsky M, Barrero X, F, Li Asuncion J, Gong J, Cao Y, 32. 323. a T, ol W, enne J. PL s ky regul organogenesis key lymph-node a and E, development is lymphocyte OPGL Timms JM. HL, Penninger Tan WJ, Boyle I, TW, Sarosi Mak H, Wake W, Yoshida Khoo A, YY, Itie G, Kong Van AJ, Oliveira-dos-Santos 31. Biophys Res Commun Res Biophys 26. Adachi T, Aonuma Y, Taira K, Hojo M, Kamioka H. Kamioka M, Hojo K, Taira th Y, of Aonuma propagation T, cells: Adachi bone between communication 26. 9 OBin A Nksia , aaaai . Osteocyt H. Takayanagi T, Nakashima CA, O'Brien osteoclastogenesis. 29. simulation. simulation. Fagan l F, Ahwal bone RJ, and Patton osteocyte PG, the Genever M, in Jahani signalling on apoptosis 25. Proc Natl Acad Sci U Acad S ANatl Proc Moonga HK, Datta AS, Alam M, Zaidi I, MacIntyre of nitr action an inhibition: Osteoclastic JR. Vane 30. 7 Hdeok L Hd T Ce A, uts S, Mart SB, Curtiss AA, Chen T, midshafts. tibial rabbit and in density apoptosis remodeli Hadi between NL, associations Hedgecock regional Quantitative 27. 8 Croo , emn C Vrog O Luir , Ma D, Laudier O, Verborgt fatigue. bone BC, intracor Herman of activation L, controls Cardoso apoptosis Osteocyte 28. tra in Janssen form GH, of Lenthe van adaptation R, and Ruimerman R, maintenance Huiskes on forces 20. 21. van Oers RF, Ruimerman R, Tanck E, Hilbers PA, PA, Hilbers E, Tanck R, Ruimerman RF, Oers van remodeling. hemi-osteonal and forosteonal 21. 405 4 Mrti , erti , ula A Plmo , Pa C, Palumbo MA, Muglia tibiae. rabbit M, on Ferretti relationships G, osteoblast-osteocyte Marotti of evaluation 24. 2 Rdn A Mri T. oe f sebat i hor in osteoblasts of Role TJ. Martin GA, Rodan hypothesis. resorption--a 22. 23. Martin RB. Toward a unifying theory of bone rem bone Toward theory of unifying RB. a Martin 23. : 704-706. :704-706. 21

: 115-137. :115-137. Accepted Article J Biomech J

Bone J Bone Miner Res Bone J

2008; 1992; Journal ofBiomedicalMaterialsResearch:PartA Bone This article isprotected by copyright. All rights reserved. 2009; 2012; 23 1991; 2013; : 860-869. :860-869. 13 Calcif Tissue Int Tissue Calcif 389 : 363-368. 363-368. : 45 2009; 88 : 2876-2883. 2876-2883. : John Wiley& Sons,Inc. 54 : 495-500. 495-500. : : 2936-2940. :2936-2940. : 258-263. 258-263. : 24 : 597-605. 597-605. : 1981; Bone 33 Bone ic oxide not mediated by cyclic GMP. GMP. cyclic by mediated not oxide ic 2008; HZ, Paszty C. Targeted deletion of deletion Targeted C. Paszty HZ, ne formation and bone strength. strength. bone and formation ne : 349-351. :349-351. J Clin Periodontol Clin J ia rsrto i rsos to response in resorption tical nn cl ntok a computer a network: cell ining K, Dwyer D, Stolina M, Morony M, Stolina D, Dwyer K, 2007; rwn edsel ufc of surface endosteal growing ham A, Dunstan CR, Lacey DL, Lacey CR, Dunstan A, ham g mdln, n osteocyte and modeling, ng, of osteoporosis. osteoporosis. of e calcium signaling. signaling. calcium e becular bone. bone. becular 42 odeling. odeling. 'Agostin D, Kurahara C, Gao C, Kurahara D, 'Agostin MJ. The effect of osteocyte of effect The MJ. runski JB, Zou S, Helms JA. JA. Helms S, Zou JB, runski Huiskes R. A unified theory theory unified A R. Huiskes sic regulatory mechanisms mechanisms regulatory sic BS, Lidbury PS, Hecker M, M, Hecker PS, Lidbury BS, ator of osteoclastogenesis, osteoclastogenesis, of ator Asymmetric intercellular intercellular Asymmetric . . : 250-259. :250-259. JD. Effects of mechanical mechanical of Effects JD. lazzini S. A quantitative quantitative A S. lazzini Capparelli C, Morony S, S, Morony C, Capparelli 40 Nature monal control of bone bone of control monal ek R, cafe MB. Schaffler RJ, jeska in RB, Hazelwood SJ. SJ. Hazelwood RB, in : 627-637. :627-637. Bone 1999; 1999; 2016; cnrl of control e 2000; Nature Endocr Rev Endocr 397 43 Biochem Biochem 26 2000; 180- : : 315- : : 1-6. :1-6. 22 J

Page 22of38 Page 23of38 J Biomed Mater Res B ApplBiomater B Res Mater Biomed J itmti eauto o ulae nnsbegd im around non-submerged changes unloaded bone mandible. of crestal on evaluation microgap histometric the D, Buser RK, ofSchenk JD, Schoolfield JS, Hermann size 39. 4 Tse M Wle S Kuozs , udrn . Ba T. Lundgren T, Koutouzis S, Wallet M, vi in Tesmer an interface: fixture-abutment implant dental 44. 45. Passos SP, Gressler May L, Faria R, Ozcan M, Bo M, Ozcan R, Faria L, May Gressler SP, Passos signifi Clinical colonization: microbial versus gap 45. 1991-1997. 3 Shit M Nger-ih G Tnnam C Lai HC, Tenenbaum review. systematic G, T Nogueira-Filho (Morse abutment CM, conical of Schmitt Performance J. Nonhoff 43. source a Pan is A, Naito arthritis factor. A, Tsay rheumatoid C, Manning in EM, Gravallese tissue Synovial 35. 7 Cruc , egud T Cmoiin f ua pe human of Composition T. Berglundh O, Carcuac lesions. periodontitis 37. mat f aneac Teay o te rvnin of Prevention the Meta-analysis. and Review Systematic for Therapy Bagrami MA, Alarcon KT, Diaz Maintenance L, Aranda A, Monje of Impact 48. 100 function. pla of years surrounding 0.3-24 after bone retrieved human of G C, Marin M, Suzuki E, Bonfante M, properties Baldassarri Mechanical 47. 2 Brei , aon , aj , mn E, Philippe at EZ, Amine Abutments W, Compatible Kanj and D, Interface. Maroun Original A, of Berberi Evaluation 42. 6 Tms C Tsaoo , al I Wnsrm , No J, Wennstrom I, Caola F, Tessarolo Res Implants Oral Clin C, Tomasi an revisited: mucosa peri-implant of Morphogenesis 36. Oralecon [Microbial O. Etienne literature]. H, the Tenenbaum of S, Baixe Review connections: abutment 41. 0 Isa , oj A Ca H, im N Sak L W L, Shaikh N, Zimmo HL, Chan comput validation. A, histological with cone-beam Monje a A, thickness: Insua membrane Schneiderian 40. 8 Uie , oecn , ais E Pr-mln cr Peri-implant JE. Davies R, Todescan Y, Ujiie mechanism. 38. 9 Wn L Y T Dn L Sa J Q J Zo Q Wei Q, Zhou J, Qi J, Shao L, Deng T, Ye b to L, adjacent bone cortical Wang osteonal in microdamage 49. 6 Km G Ko H, en Y, oe E Le J Han DJ, Lee E, Kosel YH, Jeong d and periods. surrounding HJ, healing treatments different tissues Kwon bone DG, of Kim properties Mechanical 46. e89343. e89343. : 2015-2021. :2015-2021. 2016; Arthritis Rheum Arthritis

J Contemp Dent Pract Dent Contemp J

Accepted ArticlePeriodontol J 117 Int J Dent J Int : 20-25. :20-25. J Biomed Mater Res ARes Mater Biomed J Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. J Dent Res J Dent 2014; 2012; 2000; 2001; Clin Oral Implants Res Implants Oral Clin 25 2012 43 72 2016; John Wiley& Sons,Inc. : 997-1003. 997-1003. : 2014; : 250-258. :250-258. : 1372-1383. :1372-1383. : 742439. :742439. 2013; 17 93 J Dent Res Dent J 2014; : 907-913. 907-913. : : 1083-1088. 1083-1088. : Clin Oral Investig Oral Clin J Biomed Mater Res B Appl Biomater Appl B Res Mater Biomed J 101 : 1321-1328. 1321-1328. : 102 2016; cance based on a literature review. review. literature a on based cance 2016. 2016. tro study. study. tro : 552-574. :552-574. Rev Stomatol Chir Maxillofac Chir Maxillofac Chir Stomatol Rev experimental study in humans. in study experimental one screw. screw. one of osteoclast differentiation differentiation osteoclast of ranato R, Tovar N, Coelho PG. Coelho N, Tovar R, ranato aper) connection implants: a a implants: connection aper) 95 Cochran DL. Influence of the the of Influence DL. Cochran ental implant systems with with systems implant ental ttino MA. Implant-abutment Implant-abutment MA. ttino estal bone loss: a putative putative a loss: bone estal tamination of the implant- the of tamination an RA, Wang HL, Catena A. Catena HL, Wang RA, an eiipat iess A Diseases: Peri-implant , mno , odig SR. Goldring E, Amento C, : 372-379. :372-379. tra clnzto o the of colonization cterial 2016; teau root form implants implants form root teau ed tomography analysis analysis tomography ed iaim mlns A implants. titanium JY, Brito C, Doring H, H, Doring C, Brito JY, plants in the canine canine the in plants the Implant-abutment Implant-abutment the J Periodontol J S Km L Km DJ. Kim HL, Kim JS, , i S Rpi of Repair S. Qiu L, n H. cuay of Accuracy HL. ang l G Brlnh T. Berglundh G, llo A. Micromovement Micromovement A. 20 iipatts and ri-implantitis PLoS OnePLoS : 2211-2220. 2211-2220. : 2009; 2014; 2012; 80 23 9 : :

1989; ag , ag L Avoa Bn Acietr: Syst A B, Architecture: Elnayef P, Bone Analysis. Galindo-Moreno Alveolar HL, HL. Chan Wang A, Monje F, Wang 57. 8 Ro Y Tu T, hr G. lsi poete o properties Elastic GM. Pharr TY, nanoindentatio Tsui by measured JY, bone Rho lamellar trabecular 58. 2013; 59. 59. 1325-1330. 62. Simons WF, De Smit M, Duyck J, Coucke W, Quiryn W, mandible. Coucke of the part posterior the J, Duyck M, Smit De WF, Simons marg early for factor predictive as bone cancellous 62. 5 Le C Sans , alr . oe dpain to adaptation Bone D. Taylor A, Staines TC, Lee remodelling. for stimulus bone 55. 2014; 1 Adre T, begwd E Kitne H, Haug t cells HB, reversal are Kristensen formation: and ME, resorption bone Abdelgawad TL, JM. Andersen Delaisse P, Kjaersgaard-Andersen J, Bollerslev 61. regulation? regulation? MB Schaffler RJ, Majeska NA, Tatton O, Verborgt complem fatigue: bone after osteocytes in Bcl-2 and 54. 1115-1122. 64. Kitamura E, Stegaroiu R, Nomura S, Miyakawa O. O. Miyakawa S, imp Nomura R, osseointegrated Stegaroiu around E, resorption Kitamura bone marginal 64. r-secatgnc inln b dsic osteocyt distinct RJ, by Majeska signaling DM, pro-osteoclastogenic Laudier BC, Herman inv bone OD, fatigue-loaded in Kennedy resorption of Activation 53. 6 Msh E Bn casfcto, riig es to keys training classification, Bone CE. Misch 56. 63. Naert I, Duyck J, Vandamme K. Occlusal overload Occlusal K. Vandamme J, Duyck I, Naert 63. 0 Kitne H, nesn L Mrusn , Roligh N, Marcussen TL, Andersen b cancellous HB, human in routes Kristensen recruitment Osteoblast 60. 1997. p69-111 Lippincott-Raven; York: Ba In risk. fracture of assessment for Implications Oral Implants Res Implants Oral 2 Vsihh , ebrt , iie , cafe MB Schaffler G, Divine O, age. with microcracks Verborgt D, Vashishth is bone cortical human in density lacunar osteocyte 52. 482-490. em J. utsae nlss f h bn-mln i Yin KS, bone-implant Houschyar the AA, Smith of MD, analyses Pereira JY, Multiscale Cha JA. Helms 51. 2010; t insertion high a with design and implant histomorphometrical, experimental Quiryn T, Histological, Ogawa S, Vermeiren I. L, Corpas J, Naert Duyck R, 50. 8 183 184 21 Hayes, W.C., and Bouxsein, M.L. Biomechanics of cor of Biomechanics M.L. Bouxsein, and W.C., Hayes, : 39-44. 39-44. :

: 877-884. :877-884. J Periodontol J

: 235-246. :235-246. Accepted :778-789. Article J Bone Miner Res Miner Bone J 2012; Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. 2015; Bone 23 Suppl 6 23Suppl 2000; 2002; 86 John Wiley& Sons,Inc. J AnatJ : 1231-1248. 1231-1248. : 26 Clin Oral Implants Res Oral Clin 17 : 95-107. :95-107.

: 375-380. :375-380. 2002; : 907-914. 907-914. : 201 : 437-446. :437-446. sic orthopaedic biomechanics. New New biomechanics. orthopaedic sic inal bone loss around implants in in implants around loss bone inal Understanding coupling between between coupling Understanding associated with accumulation of accumulation with associated olves both apoptosis and active active and apoptosis both olves entary roles in bone remodeling remodeling bone in roles entary e populations. populations. e nterface. nterface. ailgcl vlain f an of evaluation radiological he missing link? link? missing he orque. orque. implant success. success. implant one remodeling. remodeling. one and bone/implant loss. bone/implant and at: osdrtos based considerations lants: . Spatial distribution of Bax Bax of distribution Spatial . 2015; en M, Vandamme K, Jacobs Jacobs K, Vandamme M, en X, Mouraret S, Brunski JB, Brunski S, Mouraret X, n. mtc eiw n Meta- and Review ematic load: microdamage as a a as microdamage load: urzLpz e Ao F, Amo del Suarez-Lopez Biomechanical aspects of of aspects Biomechanical tical and trabecular bone: trabecular and tical en M. The proportion of proportion The M. en Fhi D. eln in Decline DP. Fyhrie , Biomaterials hmn otcl and cortical human f Sun HB, Schaffler MB. MB. Schaffler HB, Sun Clin Oral Implants Res Implants Oral Clin J Dent ResDent J 26 d , ease JM. Delaisse L, ed E, oihd L, Rolighed EM, e : 1051-1059. :1051-1059. Bone m Pathol J Am Am J Pathol J Am 1997; Dent Today Dent 2012; 2015; Clin 18 50 94 24 : : : :

Page 24of38 Page 25of38 phenotype and maturation. maturation. and phenotype surf titanium Boya of SL, Hyzy EM, Lotz CH, treatment Lohmann J, Sedlaczek ultrasound low-frequency 78. Dent titanium implant osseointegration by low intensity intensity low by Zhu J, Wang JF, osseointegration rats]. study in Shen experimental WC, Chen YF, implant Hou HB, Zhou titanium 75. 7 Utn , roa O Krc M Aoa , alr I Damlar T, Akova M, Kurkcu O, osseointegratio Erdogan implant Y, dental on Ustun ultrasound pulsed 77. 6 Zo H Hu , h Z Xa W X Q L L L X, Li L, Li Q, Xu W, Xiao Z, Med Ultrasound Zhu Y, Hou H, Osseointegra Implant Zhou on Ultrasound Pulsed Intensity 76. 4 Tii , eadn M Clgoan M Brri D and Berardi M, Histomorphometric Colagiovanni Dent Implant Vivo M, In Berardini An P, Trisi Implants: Titanium 74. modification. modification. ar interactions implant Almeida-Fil bone D, Johnston MC, Andres and de KE, Sisti cell stem Skeletal 73. Clinical Trial. Trial. Clinical Toti P, Tonelli G, Derchi F, Alfonsi A, Barone Outcome Clinical the on Torque Insertion of Effect 67. 769-776. Relat Res Relat imtr n seitgain tlzn smlfe d simplified utilizing osseointegration Co N, Tovar G, Giro C, Marin on MN, Janal R, Jimbo diameter 69. 8 Kaa P, ra H, ora B, enry . Cl L. to Sennerby BI, (up Tourbah torques HM, insertion Arnal high PG, with Khayat placed implants 68. 66. Ottoni JM, Oliveira ZF, Mansini R, Cabral AM. C AM. Cabral R, Mansini ZF, Oliveira JM, Ottoni implants. single-tooth of survival and torque 66. Res analysis. element finite three-dimensional a on 5 Tii , efti , adn E Brri , Cola D, Berardi E, Baldoni G, Perfetti P, Trisi and torque insertion peak to related is micromotion 65. 412. G Ae neto tru ad al osseointegration early and evaluation. torque insertion Ol DZ, Barbosa EA, Bonfante R, Jimbo FE, Are Campos PG. 71. Implants Res Implants f mlns ntle i oe- r ne-rprd si under-prepared dogs. or over- in installed G F,Gonzalez S, Ricci Mintrone Lang NP, M, Rea implants of 70. experimental study in sheep. sheep. study in experimental Biomechan PG. p implant endosteal for Coelho drilling osseodensification L, Jimbo Witek AM, Alifarag N, H, Tovar R, Neiva Freitas B, Lahens M, Cuppini 72. 2009; 2008; Clin Oral Implants Implants ResOral Clin 2013;

Accepted Article20 2 Clin Oral Implants Res Implants Oral Clin 2014; : 254-262. :254-262. 2016; : 467-471. :467-471.

Biochem Biophys Res Commun Res Biophys Biochem Clin Implant Dent Relat Res Relat Dent Implant Clin 2016; 15 : 227-233. 227-233. : Journal ofBiomedicalMaterialsResearch:PartA 25 25 This article isprotected by copyright. All rights reserved. : 1295-1300. 1295-1300. : 35 : 575-580. 575-580. : : 747-754. :747-754. 2015; Clin Oral Implants Res Implants Oral Clin Zhonghua Kou Qiang Yi Xue Za ZhiQiang Za Kou Xue Yi Zhonghua J Mech Behav Biomed Mater Biomed Behav Mech J John Wiley& Sons,Inc. 2015; 26 : 442-446. :442-446. 26 2016; : 1256-1260. :1256-1260. 2016; Int J Oral Maxillofac Implants Oral J Int 18 Clin Oral Implants Res Implants Oral Clin 2016. 2016. : 588-600. :588-600. 473 of Single Implants: A Randomized Randomized A Implants: Single of lacement in low density bone. An bone. density low in lacement bone density. density. bone ehne b LSR titanium LASER by enhanced e P, Marchionni S, Covani U. The The U. Covani S, Marchionni P, ivni , cga . Implant G. Scogna M, giovanni e-a eprmna suy in study experimental tes--an orrelation between placement placement between orrelation onzalez G, Botticelli D. Healing Healing D. Botticelli G, onzalez tion in Ovariectomized Rats. Rats. Ovariectomized in tion n: a preliminary report. report. preliminary a n: : 719-725. 719-725. : elho PG. The effect of implant of effect The PG. elho ho E, Guastaldi AC, Oreffo RO. RO. Oreffo AC, Guastaldi E, ho 176 Ncm). Ncm). 176 ace roughness on osteoblast osteoblast on roughness ace R, Bonfante EA, Bowers MM, MM, Bowers EA, Bonfante R, rprinl A histologic A proportional? rilling protocols. protocols. rilling cl n hsooi bss of basis histologic and ical 2016; iveira MT, Janal MN, Coelho Coelho MN, Janal MT, iveira n BD, Schwartz Z. Effects of Effects Z. Schwartz BD, n , Perfetti G. Laser-Treated Laser-Treated G. Perfetti , hn . fet o Low- of Effects W. Chen Biomechanical Analysis. Analysis. Biomechanical inical outcome of dental dental of outcome inical . Effects of low-intensity low-intensity of Effects . M [h aclrto of acceleration [The ZM. pulsed ultrasound: an an ultrasound: pulsed 2011; 63 : 56-65. :56-65. ln mln Dent Implant Clin Clin Oral Clin Implants 46 2004; : 425-430. :425-430. 2005; ln Oral Clin 15 :401- Eur J Eur 20 25 J J :

Oral Maxillofac Implants Maxillofac Oral 84. Miyata T, Kobayashi Y, Araki H, Ohto T, Shin K. Shin T, Ohto H, Araki Y, Kobayashi a T, 4: part Miyata tissue. peri-implant on overload occlusal 84. 5 Bre S Gnrta K Dqe . a ad oe i bone and Fat G. Duque K, Gunaratnam S, Bermeo 95. Osteoporos Rep Osteoporos 1998; 80. Peri-implant mucositis and peri-implantitis: a a peri-implantitis: and mucositis Peri-implant implications. clinical and diagnoses 80. from the Whitehall II study. study. II fromWhitehall the di drugs, lipid-lowering concentration: Dec cholesterol M. Kivimaki JE, Ferrie T, M Akbaraly Shipley M, Jokela A, Singh-Manoux K, Bouillon AG, Tabak S, 94. 319-324. (II). implants. oral osseointegrated Bi P. ofThomsen U, Lekholm JM, Hirsch M, Esposito failures to 79. 83. Miyata T, Kobayashi Y, Araki H, Ohto T, Shin K. Shin T, Ohto H, Araki Y, Kobayashi T, A 3: Miyata Part tissue. peri-implant on overload occlusal 83. ag P Jnsn . os xesv ocua la af load occlusal excessive S Does Gerber C, dog. the study in J. experimental Weigel B, Jonsson Schmid LJ, NP, Heitz-Mayfield Lang 82. 2010; Oral Maxillofac Implants Maxillofac Oral 2006; 87. Tall AR, Yvan-Charvet L. Cholesterol, inflammat Cholesterol, L. Yvan-Charvet AR, Tall 87. 85. Naert I, Duyck J, Vandamme K. Occlusal overloa K. Vandamme Duyck I, J, Naert 2012; Res Implants Oral Clin. 85. mln tsu hat: sseai rve o anima of review of Effects systematic LA. Lima LA, a Chambrone L, health: Chambrone tissue implant 81. 6 Iio F Ifune f ocs n eiipat b peri-implant on forces of Influence F. Isidor 86. and meta-analysis. meta-analysis. and per of incidence the with CorreKG, Peres LG, Do associated FR, Leite GG, Nascimento gain weight Is 91. 2012; 92. Miettinen TA. Cholesterol production in obesity in production Cholesterol TA. Miettinen 92. in Perth, Western Australia, 1980-1999. 1980-1999. Jamrozik Australia, H, Western Ngo Perth, T, in Briffa MW, Knuiman MS, Hobbs preva rising the despite decline to continue levels 93. 850. Bone Loss in Wistar Rats. Rats. Wistar in Loss Bone M de A, Souza EJ, Gaio Hyp IC, and Macedo Obesity de CK. J, Rosing Cavagni IL, Torres LC, Kucharski 89. bst peit ie o eidna dsae progres M, disease Nunn TT, Fung periodontal C, Apovian to EK, Kaye A, time Gorman predict obesity 90. Rev Immunol Rev 88. Devlin MJ, Rosen CJ. The bone-fat interface: ba interface: bone-fat The CJ. Rosen MJ, Devlin marrowadiposity. 88. 106 81 17 Suppl 2 Suppl 17 39 : 1367-1378. :1367-1378. : 107-114. :107-114.

Accepted Article :721-764.

2015;

2014; : 8-18. :8-18. Lancet Diabetes Endocrinol Diabetes Lancet J Clin Periodontol Clin J Journal ofBiomedicalMaterialsResearch:PartA 15 This article isprotected by copyright. All rights reserved. 12 : 104-116. 104-116. : 2000; 2002; : 235-242. :235-242. J Periodontol J Heart 23 Clin Oral Implants Res Oral Clin 15 17 John Wiley& Sons,Inc. : 95–107 :95–107 2011; : 425-431. :425-431. : 384-390. :384-390. J J Periodontol 2015; 2016; 97 u J adoac rv Rehabil Prev Cardiovasc J Eur 42 : 923-930. :923-930. 87 2015; : 495-505. 495-505. : : e9-17. :e9-17. 2013; lence of obesity: population trends trends population obesity: of lence histologic study in monkeys. monkeys. in study histologic histologic study in monkeys. monkeys. in study histologic Etiopathogenesis. Etiopathogenesis. et, or physical activity? Evidence Evidence activity? physical or et, iodontitis? A systematic review review systematic A iodontitis? 2004; 3 line in low-density lipoprotein lipoprotein low-density in line sion in men. men. in sion erlipidemia Modulate Alveolar Alveolar Modulate erlipidemia current understanding of their their of understanding current : 141-147. 141-147. : sic and clinical implications of implications clinical and sic l-model studies. studies. l-model d and bone/implant loss. dbone/implant and ion and innate immunity. immunity. innate and ion olon RS, Cirelli JA, Hoefel AL, AL, Hoefel JA, Cirelli RS, olon 84 a MB, Demarco FF, Peres MA. Peres FF, Demarco MB, a J, Batty GD, Brunner EJ, Sabia EJ, Brunner GD, Batty J, The influence of controlled controlled of influence The The influence of controlled controlled of influence The . . ological factors contributing contributing factors ological one. one. Bshrt D Jnsn J, Jonsson DD, Bosshardt , Circulation fect osseointegration? An An osseointegration? fect occlusal overload on peri- on overload occlusal Garcia RI. Overweight and and Overweight RI. Garcia : 436-443. 436-443. : 15 K. Plasma cholesterol cholesterol Plasma K. ln rl mlns Res Implants Oral Clin : 259-268. 259-268. : nteractions. nteractions. J Clin Periodontol Clin J 1971; u J rl Sci Oral J Eur J Periodontol J 2008; 44 : 842- : Curr Curr Int JInt Int J Nat Nat 15 26 : :

Page 26of38 Page 27of38 98. Reid IR. Fat and bone. bone. and Fat IR. Reid 98. 106. Sanbe T, Tomofuji T, Ekuni D, Azuma T, Tamaki Tamaki T, Azuma bone D, alveolar rats. in cholesterol dietary Ekuni prevents C T, vitamin Tomofuji of T, administration Sanbe 106. 2008; infarction, and heart failure. heart and infarction, i behavior Leukocyte M. Nahrendorf FK, Swirski 107. 7 Drn A Pnl , adun . nesadn th Understanding P. Hardouin G, Penel A, During physiology. bone 97. 313-319. HDL suppress hematopoietic stem cell proliferation. cell stem hematopoietic suppress HDL ATP-bindin AR. Tall Avagyan HW, EL, Snoeck GJ, Gautier Randolph T, N, Pagler Wang L, Yvan-Charvet 108. and caloric restriction. restriction. caloric and ra and LeBoeu levels C, cholesterol Tang macrophage TS, tissue McMillen adipose EJ, Tarling H, Wei 109. fa marrow Bone B. Cortet V, Pansini P, Hardouin 96. as n oh itidcd n gntc hyperlipidemi H, Huang genetic X, and Ji Y, diet-induced Xie both K, Zhang in C, mass Wang X, Chen 104. 2014; and bone homeostasis. homeostasis. bone and connectio possible a for evidence mineral III: bone type Reduced disease G. Pi A, Parenti Puente Del R, G, Pivonello A, Rossi Andria D, Melis A, Colao 99. T, Nakao K. Increased bone turnover in patients wit patients in turnover bone FukaIncreased K. Nakao N, T, Satoh Y, Komatsu A, Shimatsu T, Majima 105. 112. maac i hmn yecoetrlma n atheros and hypercholesterolemia human monocyte Pro-inflammatory in A. imbalance Avogaro L, Previato N, Vitturi R, S, Cappellari F, Simoni GP, Fadini 111. 1. il A Ri Bls , at A. dcd o p of decade A AH. Hasty W, Bolus Reid biology. macrophage AA, Hill 110. osk T Mygw H Mrkm S Tkhsi , Kaw N, e Takahashi an as S, functions Murakami agonist. adipocyte H, regulates pyrophosphate Miyagawa Taim S, T, Kato YI, Kim K, Egawa H, Hohsaka Nagai T, Goto 100. high-fat diet. high-fatdiet. K AS, e Qadir sclerostin A, upregulates Kwon TNF-alpha HJ, JH. Park Baek HR, GS, Hwang Kim K, Baek 103. 102. Baron R, Kneissel M. WNT signaling in bone hom bone in signaling WNT M. treatments. to mutations human Kneissel R, Baron 102. femoral biomechanics and morphology in low-density low-density knockoutmice. in JA. Camilli morphology JA, and Garcia WR, biomechanics Nakagaki femoral EA, Soares 101. 55 237 Biochem JBiochem : 143-151. :143-151.

: 805-808. :805-808. Accepted Article

J Cell Physiol Cell J

J Bone Miner Metab Miner Bone J Prog Lipid Res Prog 2011; Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. Immunol Rev Immunol J Lipid Res J Bone 438 2014; J Periodontol J 2016; Science : 111-119. 111-119. : Arch Biochem Biophys ArchBiochem John Wiley& Sons,Inc. 2015; 229 Nat Med Nat 2015; 2014; 2012; 86 2013; : 640-650. 640-650. : : 79-85. 79-85. : 59 2007; 56 262 : 126-146. :126-146. 2013; 30 339 : 2337-2347. 2337-2347. : : 419-425. 419-425. : : 134-152. :134-152. 78 : 161-166. 161-166. : 19 : 2165-2170. :2165-2170. : 179-192. :179-192. 2010; Galasso S, Vigili de Kreutzenberg Kreutzenberg de Vigili S, Galasso h hypercholesterolemia. hypercholesterolemia. h n between metabolic imbalance imbalance metabolic between n

Science tio of M1 to M2 cells in obesity in cells M2 to M1 of tio vonello C, Cangemi G, Negri M, M, Negri G, Cangemi C, vonello xpression in obese mice fed a fed mice obese in xpression Yu X. Reduced femoral bone bone femoral Reduced X. Yu a mice. mice. a f RC. ABCG1 regulates mouse mouse regulates ABCG1 RC. f n atherosclerosis, myocardial myocardial atherosclerosis, n fet f yelpdma on hyperlipidemia of Effect atsu A, Sakamoto T, Ebisu S, Ebisu T, Sakamoto A, atsu resorption induced by high high by induced resorption , iy L Hn , ec CL, Welch S, Han RL, Siry S, o A, Ninomiya K, Matsumura Matsumura K, Ninomiya A, o density in glycogen storage storage glycogen in density t. t. g cassette transporters and transporters cassette g eostasis and disease: from from disease: and eostasis e local actions of lipids in in lipids of actions local e iorti rcpo gene receptor lipoprotein mcohg polarization -macrophage 503 Joint Bone Spine Bone Joint ors i aioe tissue adipose in rogress o SH, Woo KM, Ryoo HM, HM, Ryoo KM, Woo SH, o ndogenous PPARgamma PPARgamma ndogenous 2010; clerosis. clerosis. , aaoo . Oral T. Yamamoto N, : 20-27. 20-27. : Bone ada T. Farnesyl Farnesyl T. ada 328 2016; Atherosclerosis : 1689-1693. :1689-1693. 2014; 93 Endocr J 104- : 81 27 :

1. aa S Tkih H Mtuai , aeo , Fu NFATc1suppression. H, osteoclastogenesis Kaneko inhibits D3 K, vitamin 25-dihydroxy Matsuzaki H, Takaishi T Suda T, Taniguchi A, Tanaka K, Saito S, A, Shiraishi Sakai 119. acu mlbopin y iai Didcd inhibiti D-induced vitamin by malabsorption calcium Bonewald maintaine is JQ, Normocalcemia G. Carmeliet Feng R, Bouillon T, Dresselaers MH, Loovere Van S, Lafage-Proust Torrekens R, Masuyama L, Lieben 121. Pathol Oral Radiol Oral Pathol 114. Halfon M, Phan O, Teta D. Vitamin D: a review review a D: Vitamin D. Teta O, Phan frailty. and risk of fall, the strength, M, Halfon 114. Korean Assoc Oral Maxillofac Surg Oral Assoc Korean femur. mouse the hyperlipidemi of effects The T. Aghaloo F, Pirih P, Bezougl G, Kirikian AD, Barroso A, Keuroghlian 112. IH. The effects of high-fat diet on implant osseoin implant on diet high-fat of effects The M, IH. Gul A, Saybak MF, Ozupek F, Yaman S, Dundar 113. hormone, and osteonecrosis of the jaw. Could there there vi Bucal Cir Oral CouldPatol jaw. Bisphosphonates, the of osteonecrosis G. and hormone, Gomez-Moreno Go A, MJ, Aguilar-Salvatierra IO, Sala-Romero Leizaola-Cardesa 120. 1. hu , i , ag , hi , u . 1,25Dihydr J. r Hu osteoporotic X, Shui in X, osseointegration Wang Y, implant Li titanium C, Zhou 118. 115. Holick MF. Vitamin D deficiency. Ddeficiency. Vitamin MF. Holick 115. J Otolsi mtbls o 2(H-iai D: a D3: 25(OH)-vitamin resorption. of bone optimization of metabolism Osteoclastic GJ. V R, Ormsby PH, Anderson DM, Findlay M, Kogawa 116. 1. huru J Kor G Kor F Rse , Test P, Russe D. vitamin serum F, Khoury low-density high implantology: and grafting bone in G, Khoury Two J, E. Choukroun M, Tunali P, Palacci G, Sammartino Choukroun 117. Clin Invest Clin umnain a admzd dul-ln, placebo- double-blind, randomized, a formation bone investigation. - local and Has augmentation K, supplementation Wang C, D Wu T, Dietrich vitamin U, Schulze-Spate 123. stromal cells. cells. stromal and factor differentiation osteoclast of expression MT Gillespie TJ, Martin J, Elliott NJ, Horwood 122. demonstration of vitamin D deficiency in an implant an in deficiency I. Nishimura D S, vitamin Park CJ, of Wang demonstration A, Lin J, Kelly 124. Prosthodont 2. i W Zag , ho , o H Sn , in X, mice. kidneydisease Liang N, of Sun fixation H, the Zou enhances D, supplementation Zhao S, D Zhang Vitamin W, Liu 125.

Accepted2012; Article

2009; Endocrinology Clin Oral Implants Res Implants Oral Clin 122 J Oral ImplantolOral J J Oral Implantol Oral J 2012; 18 Journal ofBiomedicalMaterialsResearch:PartA 2016; This article isprotected by copyright. All rights reserved. PLoS One PLoS : 1803-1815. 1803-1815. : : 473-478. 473-478. : J Bone Miner Metab Miner Bone J 114 21 1998; : S174-178. :S174-178. : e236-240. :e236-240. 2014; John Wiley& Sons,Inc. Endocrinology 2014; 2016; 2015; 139 Biomed Res Int Res Biomed 2016; 9 : e95689. :e95689. : 4743-4746. :4743-4746. N Engl J Med J Engl N 40 42 41 2009; 27 : 110-114. :110-114. : 187-192. :187-192. : e7-e11. :e7-e11. : 701-706. :701-706. 2010; 27 tegration: an experimental study. study. experimental an tegration: 2015; : 643-652. 643-652. : , Miyamoto T, Toyama Y. 1-Alpha, 1-Alpha, Y. Toyama T, Miyamoto , a on implant osseointegration in osseointegration implant on a sepoeei i osteoblastic in osteoprotegerin . Osteotropic agents regulate the regulate agents Osteotropic . Vitamin D and bone physiology: physiology: bone and D Vitamin lipoprotein cholesterol and low low and cholesterol lipoprotein 2007; neglected biologic risk factors factors risk biologic neglected aia O, Tintut Y, Tetradis S, Moy S, Tetradis Y, Tintut O, aia 151 osseointegration rat model. model. rat osseointegration d in mice under conditions of conditions under mice in d through IFN-beta-dependent IFN-beta-dependent through ats. ats. iaim mlns n chronic in implants titanium on of bone mineralization. mineralization. bone of on e msig link? missing a be nzalez-Jaranay M, Moreu G, G, Moreu M, nzalez-Jaranay ad , ase , un Q. Yuan B, Lanske M, Dard Asutay F, Kirtay M, Ozercan Ozercan M, Kirtay F, Asutay oxy vitamin D(3) improves improves D(3) vitamin oxy n R, Schrooten J, Baatsen P, Baatsen J, Schrooten R, n 2015 oeta mcaim for mechanism potential turk H, Dibart S. Systemic Systemic S. Dibart H, turk incent C, Morris HA, Atkins Atkins HA, Morris C, incent : 4613-4625. :4613-4625. F Myr B Pk JW, Pike MB, Meyer LF, on its effects on muscle muscle on effects its on Oral Surg Oral Med Oral Oral Med Oral Surg Oral 357 uaa , iaci Y, Miyauchi M, rukawa tamin D, parathyroid parathyroid D, tamin after maxillary sinus sinus maxillary after ori T, Komiyama Y, Y, Komiyama T, ori : 953241. 953241. : : 266-281. :266-281. controlled clinical clinical controlled Med Oral Oral Med 28 J J J J Page 28of38 Page 29of38 Acta Biomater Acta aotpgahcly ope ipat ufcs n hy Early in JE. Davies surfaces RS, implant Liddell S, complex Bell nano-topographically E, Ajami 134. 135. Carr ME. Diabetes mellitus: a hypercoagulable hypercoagulable a mellitus: Diabetes ME. Carr 135. 2016; 3. acad , akn , ine-ons , Barry A, conditio diabetes: Dionnes-Hornes and A, implants Dental Raskin B. F, Vialettes Marchand 132. 133. Ajami E, Mahno E, Mendes VC, Bell S, Moineddin ost S, on topography Bell surface VC, implant of Mendes effect E, the and Mahno E, Ajami 133. 2012; 3. pe W, ap M Hsen M, ais E Eff JE. Davies MM, Hosseini JM, Karp vitro. in recruitment and migration cell bone WE, Oprea 136. 2001; Implants Placed in 822 Patients. Patients. 822 in Placed Implants Ret C. A Failure? Mangano Implant N, Dental Mangano Early C, with Mortellaro Associated F, Mangano 128. Res Implants Oral lao , agloAbo J CloGiao L Osse JL. Calvo-Guirado Ramirez-Fer p a osteointegration: better for J, implants immediate JE, Gargallo-Albiol Mate-Sanchez de F, O, Alfaro Salomo-Coll 127. 131. Retzepi M, Donos N. The effect of diabetes mel diabetes of effect The N. Res Implants Oral Donos M, Retzepi 131. Res Implants Oral Clin enhance contact bone-to-implant for surface implant Topi JL. Calvo-Guirado J, Ramirez Gargallo-Albiol JE, Val F, de Alfaro Mate-Sanchez O, Salomo-Coll 126. 3. ig , lnbr I Lvne I Brennan-Spera I, Levinger I, placement. implant titanium and Klineberg S, ani of review a osseointegration: on hyperglycaemia King 137. 2. olbrto NDF Wrdie rns n diabe in trends m 4.4 with Worldwide studies population-based 751 of analysis NCDRF. Collaboration 129. elts n is opiain. at : igoi a diagnosis 1: Part consultation. WHO of a report provisional mellitus a complications. diagnosis its Definition, PZ. and Zimmet mellitus KG, Alberti 130. 387 3. ahst D Te oe f h clae mti i matrix collagen the of role The D. Vashishth 138. 2016; Osteoporos Rep Osteoporos 4. oacii , abz E, ext G. h impa The meta-analy GA. and review Peixoto systematic ES, a Barboza failure: V, implant Moraschini 140. utrd os ufatoae bn cls n i rat in and particles. bone devitalized with cells bone unfractionated mouse cultured osteoclast- enhance Maeda products K, Horie end K, glycation Yoshida K, Advanced Notoya T, Miyata 139. : 1513-1530. :1513-1530. 39 38 15 45 : 169-179. :169-179. : 14-19. :14-19. : 44-54. :44-54. : 1237-1245. :1237-1245. Accepted Article

2014; 2007; 2016. 2010; Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. 10 2016; 5 : 62-66. 62-66. : : 394-405. :394-405. 21 : 673-681. :673-681. 27 John Wiley& Sons,Inc. : 896-903. 896-903. : J Am Soc Nephrol Soc Am J Mediators of Inflammation of Mediators ArchOsteoporos J Craniofac Surg Craniofac J 1997; 2016; Diabet Med Diabet cal applications of vitamin D on on D vitamin of applications cal ilot study in foxhound dogs. dogs. foxhound in study ilot eoconduction in hyperglycemia. hyperglycemia. in eoconduction illion participants. participants. illion mal models of diabetes mellitus mellitus diabetes of models mal ns for success. success. for ns bone anchorage to micro- and and micro- to anchorage bone rospective Evaluation on 1625 on Evaluation rospective : a pilot study in dogs part II. part dogs in study pilot a : state. state. idcie lmns around elements oinductive nd classification of diabetes diabetes of classification nd sis. sis. litus on osseous healing. healing. osseous on litus nd classification of diabetes diabetes of classification nd 8 ipatd subcutaneously implanted s nue bn rsrto in resorption bone induced K, Kurokawa K, Taketomi S. Taketomi K, Kurokawa K, 11 perglycemia. perglycemia. -Fernandez MP, Hernandez- MP, -Fernandez : 260-270. :260-270. c o paee rlaae on releasate platelet of ect R, Davies JE. Bone healing healing Bone JE. Davies R, Is Low Serum Vitamin D Vitamin Serum Low Is n skeletal fragility. fragility. skeletal n tes since 1980: a pooled pooled a 1980: since tes Int J Oral Maxillofac Surg Maxillofac Oral J Int : 29. :29. 2016; ct of diabetes on dental dental on diabetes of ct adz P Hernandez- MP, nandez nza TC. The effect of of effect The TC. nza T, Dubois N, Valero R, R, Valero N, Dubois T, J Diabetes Complications Diabetes J 2003; 1998; 2016 14 15 Diabetes Metab Diabetes ca Biomater Acta : 292-300. 292-300. : : 7. Lancet : 539-553. :539-553. 2016; 2016; Curr Curr Clin Clin Clin Clin 29

Acta Biomater Acta 146. Miron RJ, Bosshardt DD. OsteoMacs: Key players Key OsteoMacs: DD. Biomaterials Bosshardt RJ, Miron 146. 2006; sebatlk cls hgcts mtl atce a particles vitro. markerin CD68 metal phagocytose F, cells Alves H, Siggelkow C, osteoblast-like Lohmann DE, Heinemann 147. 4. uz , ee E Vleil-ail M Reyes-B M, ost human Vallecillo-Capilla cultured by E, stimulation Perez cell T C, allogeneic Ruiz 148. 4. uded M Crso L, oaso C, Thomse CB, of review Johansson a wear: LV, of question a Carlsson only not M, loosening, Sundfeldt 145. os dfnd y muoitceia lclzto o localization immunohistochemical by tissu connective associated and of bone macrophages mononuclear The defined S. Gordon JF, Loutit mouse DA, Hume 152. iooa cornt ihbto o osteoclastogenes of phosphate. beta-tricalcium submicrostructured inhibition clodronate Liposomal de H, Yuan P, Layrolle AL, Gamblin NL, Davison 151. of macrophages to titanium particles is determined determined is particles titanium to macrophages of TF, Mandel Li E, Jamsen VP, Kouri J, Pajarinen 144. 5. au M. rmr n h Mtblc oe Disease Bone Metabolic the on Primer Metabolism. MJ. Favus 154. 5. hli , opr F Mlclr seset f o of assessment Molecular LF. Cooper literature. of review current G, Thalji 150. Biochem preceded by macrophage accumulation. accumulation. macrophage by preceded Waterfield H, Murakami S, subcutan polished, not but rough, Ghrebi on formation Bone B, Chehroudi 149. Oral Implants Res Implants Oral aln R Rpl V, ue A Pti A. sel ti lining Osteal bone AR. mouse Pettit and vitro vivo. in in and function osteoblast DA, human Hume throughout VM, intercalated Ripoll J ER, Kuliwaba KA, Alexander LJ, Maylin Raggatt MK, Chang 153. 4. u , lAeal K Rsiedr , b Nader Abi E, study. cohort failure: a implant a Rastikerdar inhibitors K, reuptake serotonin Al-Abedalla Selective F. X, Tamimi Wu 142. knowled current implants: dental 2000Periodontol zirconia Osseointegr D. and Buser V, Chappuis alloy DD, Bosshardt 141. 155. Pettit AR, Chang MK, Hume DA, Raggatt LJ. Oste LJ. Raggatt DA, Hume dynamics. during bone coupling on MK, Chang AR, Pettit 155. 37 5. osr M Ewrs P Epoig h fl spec full the Exploring JP. Edwards DM, activation. Mosser 156. allergy in dental implant patients: a clinical stud clinical a patients: implant dental in allergy Guisas I, Arregui G, Coma S, Cuesta A, Sicilia 143. : 553-554. :553-554. 77 2003; Accepted Article :177-197. Nat Rev Immunol Rev Nat

2016; Revue francaise d endocrinologie clinique nutrition clinique francaised endocrinologie Revue

2013; 13 2017; 2008; : 309-314. 309-314. : Journal ofBiomedicalMaterialsResearch:PartA 82 This article isprotected by copyright. All rights reserved. 9 : 1-19. 1-19. : J Bone Joint Surg Br Surg Joint Bone J : 9229-9240. 9229-9240. : 73 19 : 22-40. :22-40. : 823-835. :823-835. 2008; Int J Oral Maxillofac Implants Oral J Int John Wiley& Sons,Inc. J Dent Res Dent J 8 Bone : 958-969. :958-969. J Immunol J J Biomed Mater Res ARes Mater Biomed J 2008; 2014; 2014; 2000; 43 Biomaterials 93 82 y on 1500 consecutive patients. patients. consecutive 1500 on y 2008; : 976-982. :976-982. ola C, Ruiz E, Maestro A. Titanium Titanium A. Maestro E, Ruiz C, ola : 1054-1061. :1054-1061. : 283-289. 283-289. : in J, Konttinen YT. The response response The YT. Konttinen inJ, different theories. theories. different e. e. eously implanted Ti surfaces is is surfaces Ti implanted eously nd the risk of osseointegrated osseointegrated of risk the nd Bruijn JD, Barrere-de Groot F. F. Groot Barrere-de JD, Bruijn nd express the macrophage macrophage the express nd ols-ie cells. eoblast-like by macrophage polarization. polarization. macrophage by J Cell Sci Cell J al macrophages: a new twist twist new a macrophages: al otella C. Phagocytosis and and Phagocytosis C. otella S, Fazzalari NL, Schroder K, K, Schroder NL, Fazzalari S, 181 is and osteoinduction by by osteoinduction and is around bone biomaterials. biomaterials. bone around to o ttnu, titanium titanium, of ation sseointegration in vitro: a a vitro: in sseointegration 2014; D Oe G Buet DM. Brunette G, Owen JD, and Disorders of Mineral Mineral of Disorders and Engel I, Koster G. Human Human G. Koster I, Engel e n oe questions. open and ge , ail G Nclu B, Nicolau NG, Daniel S, phagocyte system of the the of system phagocyte n P, Gretzer C. Aseptic Aseptic C. Gretzer P, n ssue macrophages are are macrophages ssue 2014; : 1232-1244. 1232-1244. : tissues and regulate regulate and tissues 2010; trum of macrophage macrophage of trum et metabolisme et 1984; 29 f antigen F4/80: F4/80: antigen f : e171-199. :e171-199. 35 93 : 5088-5097. 5088-5097. : 66 : 724-737. :724-737. Acta Orthop Acta Cell Physiol Physiol Cell : 189-194. :189-194. 1996; Clin Clin 30

Page 30of38 Page 31of38 859-864. 859-864. 7. esn S Gue R Bsr , osad D. Os DD. Bosshardt calc D, biphasic Buser observations. microscopical and electron transmission R, mineral bone Gruber bovine SS, deproteinized Jensen 172. ouain f h ifamtr rsos t chitosan to MA mediators. pro-resolution using polarization Barbosa response IF, inflammatory Amaral the M, of Costa Modulation DP, Vasconcelos 171. Res ARes implants. L implants. Houston E, Erickson B, fail with Svensson subjects in factors host immunity Humoral M, Kronström 166. 6. las M, alt M Iaosi . iaim s Titanium S. Ivanovski SM, Hamlet cytokin MA, inflammatory macrophage human the modulates Alfarsi 165. 7. atnz O Sc A Mnoai , oai . Ma M. Locati A, Mantovani A, Sica FO, polarization. Martinez 170. oorpy n 74. mcohg ifamtr cytok inflammatory macrophage production. J774A.1 on LF. Cooper PM, Flood R, Rosado topography L, Qian KS, Tan 163. ufc mdfcto o mcohg ifamtr cyt inflammatory macrophage on Th modification S. Ivanovski R, surface George M, Alfarsi S, Hamlet 164. Oral Maxillofac Surg Clin North AmNorth Clin Surg Maxillofac Oral equilibrium body foreign implants: dental of basis Curre A. Wennerberg T, Albrektsson TrindadeR, 169. Relat Dent ResImplant Clin Brea and Buildup for Mechanisms On Biomaterials: to Wennerb P, Tengvall T, Albrektsson R, Trindade 168. Oral Implants Res Implants Oral 6. lrkso T Dhi C Jm T Sneb L T L, result Sennerby the reaction? implants T, oral Jemt around C, loss Dahlin bone T, marginal Albrektsson 167. 2009; ujkNvkvc . eunil eiey f immunomo scaffolds. bone a of macrophages of transition RR, delivery M1-to-M2 the Anfang facilitate CE, Sequential Witherel S, G. Nassiri KL, Vunjak-Novakovic Spiller 162. 2013; 161. Novak ML, Koh TJ. Macrophage phenotypes during phenotypes Macrophage TJ. Koh ML, Novak 161. 159. MacMicking J, Xie QW, Nathan C. Nitric oxide a oxide Immunol Rev Nitric C. Nathan QW, Xie J, MacMicking 159. 158. Mills CD, Kincaid K, Alt JM, Heilman MJ, Hill Hill MJ, Heilman JM, Alt paradigm. Th1/Th2 K, the Kincaid CD, Mills 158. M Topo R, hee A, ury J Wn T. Ar TA. Wynn PJ, Murray inflammati cytokine-driven AW, Th2 suppress macrophages Cheever RW, Thompson Wils MM, AM, Mentink-Kane TR, Ramalingam JT, Pesce 160. paradigm M2 and M1 The for reassessment. time S. Gordon FO, Martinez 157. 2014; 5 93 : e1000371. e1000371. : : 875-881. :875-881. Clin Implant Dent Relat Res Dent Implant Clin

Accepted periodontologyclinical of Journal Article 102 Biomaterials 1997;

Frontiers in bioscience: a journal and virtual librar and virtual a journal in bioscience: Frontiers Biomaterials : 60-67. :60-67. 2012; Journal ofBiomedicalMaterialsResearch:PartA 15 This article isprotected by copyright. All rights reserved. : 323-350. 323-350. : F1000Prime Rep F1000Prime J Immunol J 23 2006; 2014. 2014. : 584-590. :584-590. 2015; John Wiley& Sons,Inc. 27 2000; : 5170-5177. :5170-5177. 2015; 37 2014; : 194-207. :194-207. 2014; 164 27 2000; 16 : 175-183. 175-183. : Biomaterials : 6166-6173. 6166-6173. : : 155-165. 155-165. : 6 : 13. :13. 27 ing or successful titanium dental dental titanium successful or ing Clin Oral Implants ResImplants Oral Clin : 875-882. :875-882. AM. M-1/M-2 macrophages and and macrophages M-1/M-2 AM. and osseointegration dynamics. dynamics. osseointegration and e effect of hydrophilic titanium titanium hydrophilic of effect e d nac vsuaiain of vascularization enhance nd nd macrophage function. function. macrophage nd erg A. Foreign Body Reaction Reaction Body Foreign A. erg f pooe frin body foreign provoked a of The role of titanium surface surface titanium of role The nt concepts for the biological biological for the concepts nt Ng J, Nakazawa KR, Yu T, T, Yu KR, Nakazawa J, Ng on and fibrosis. fibrosis. and on okine gene expression. expression. gene okine kdown of Osseointegration. Osseointegration. of kdown through M2 macrophage macrophage M2 through ium phosphate: light and and light phosphate: ium e response. response. e 2015; urri A, Wennerberg A. Is Is A. Wennerberg A, urri tissue repair. repair. tissue on MS, El Kasmi KC, Smith KC, Kasmi El MS, on of macrophage activation: activation: macrophage of Baa P Prsn GR. Persson P, Braham , crophage activation and and activation crophage Aus P Broa JN. Barbosa AP, Aguas , dulatory cytokines to to cytokines dulatory ns n nti oxide nitric and ines ecatlk cls on cells teoclast-like urface hydrophilicity hydrophilicity urface y 2007; 37 ginase-1-expressing ginase-1-expressing : 116-123. 116-123. : J Biomed MaterBiomed J 13 PLoS Pathog PLoS J J Leukoc Biol : 453-461. :453-461. 2015; Annu Clin 26 31 : :

2002; Biomaterials o implication local the ceramics: phosphate calcium mesenc human with formation tissue Bone P. Layrolle Le H, Yagita A, Renaud MA, Brennan AL, Gamblin 177. rvn y rmr hmn sebat i cnet with concert in osteoblasts Biomaterials human primary by CJ. driven Kirkpatrick RA, Sader C, Migliaresi Or A, M, Barbeck MJ, Motta Webber P, RE, Unger S, Ghanaati 178. 7. itt , ae J Trio , an T Parhami T, Saini M, Territo J, Patel Y, calcific vascular of regulation Monocyte/macrophage Tintut 179. tumor necrosis factor-alpha and oncostatin M derive M oncostatin and factor-alpha necrosis tumor vascular human in phosphatase alkaline Ko bone-type S, Jono of K, Mori Y, Okuno M, Katagi A, Shioi 180. 105

c and histomorphometrical histological, preliminary substitute bone in regeneration tissue bone Synthetic for material xenogeneic RA. Sader S, CJ, Stuebinger J, Lorenz M, Kirkpatrick Barbeck S, Ghanaati 173. aue oe omto idcd y MC/C/lsa c BMSCs/BCP/plasma by mice. competent immune induced T, Adaptive formation N. Balaguer bone Rochet mature F, JC, Boukhechba Scimeca JF, S, Michiels Bouvet-Gerbettaz 176. 10 oy in Cls ahr hn secat: eut F M, Results Barbeck Osteoclasts: Humans. Than T, Rather Cells Korzinskas Giant Body A, Multinucl TRAP-Positive S. Kubesch Ghanaati CJ, J, Kirkpatrick Lorenz 174. 7. u X Brir D Dvsn , a Y d Bruijn de Y, Yan N, Davison D, in and vitro in induction: bone Barbieri mediates phosphate X, Luo 175. Surg : 477-485. :477-485. : 650-655. :650-655. 2013; 91

: 9-16. :9-16.

Accepted ArticleImplantol Oral J 3 2014; 2011; : 126-138. 126-138. : Tissue Eng Part APart Eng Tissue Journal ofBiomedicalMaterialsResearch:PartA 35 32 This article isprotected by copyright. All rights reserved. : 9660-9667. 9660-9667. : : 8150-8160. 8150-8160. : 2015; John Wiley& Sons,Inc. 41 2014; : e257-266. :e257-266. 20 : 2950-2962. :2950-2962. Scaffold vascularization in vivo vivo in vascularization Scaffold vivo model. model. vivo yama H, Nishizawa Y. Induction Induction Y. Nishizawa H, yama f osteoclasts and macrophages. macrophages. and osteoclasts f oral cancer patients: First and First patients: cancer oral ation in vitro. vitro. in ation ae Gat el Ae Foreign Are Cells Giant eated Seitz O, Landes C, Kovacs AF, Kovacs C, Landes O, Seitz linical results. results. linical d from macrophages. macrophages. from d smooth muscle cells: roles of roles cells: muscle smooth hymal stem cells and biphasic biphasic and cells stem hymal rom a Split-Mouth Study in in Study Split-Mouth a rom JD, Yuan H. Zinc in calcium calcium in Zinc H. Yuan JD, aeil oprbe with comparable material zot F, Heymann D, Trichet V, Trichet D, Heymann F, zot th C, Kirkpatrick JA, Booms Booms JA, Kirkpatrick C, th host inflammatory cells. cells. inflammatory host epne niis ectopic inhibits response Schmid-Antomarchi H, H, Schmid-Antomarchi moie n immune- in omposite Landes C, Sader RA, RA, Sader C, Landes Acta Biomater Acta , ee LL. Demer F, Circulation n Maxillofac Ann Circ Res Circ 2002; 2014; 32

Page 32of38 Page 33of38 bylining cells (Immunofluorescence bone for Tubuli oe Ti gp s ild ih iru tsu. Image tissue. fibrous with filled is gap This bone. iue . oe eoeig iga. ; el involv Cells A; diagram. remodeling Bone 2. Figure Image D: Illustration of compressive strain fields strain compressive of Illustration Image D: induces high that a torque gap without boneimplant observe is (*) gap smaller a and torque low reached pre the with preparation oversized an shows A Image osteotomy the of Schematic : C) B, (A, images Upper K. L. McCauley, & 411425. 11(6), Cancer, Reviews A., Natureattraction. T. Guise, N., K. Weilbaecher, l sinus maxillary of section Histological 1. Figure Cytokines 1. Table released M2 byand macrophage M1 and Figures legends. strai compresive increased of Illustration E: Image pro and bone in engaged thread the of microns 1520 analyses of boneimplantanalysesof the interface. Dent J Res Mouraret X, Yin KS, Houschyar AA, Smith MD, Pereira exce of consequence a as microcracksBone 3. Figure Expr 2009; Expr an modeling Bone E. Seeman from (modified apoptosis osteocy become osteoid the into trapped Osteoblasts Osteoblasts 7) attach. to osteoblasts allows layer BL 5) resorption. osteoclast after debris the clean rem Osteoclasts 3) compartment. remodelingbone the inc damage the bone from recruited are osteoclasts and promotes Osteoblasts torque Excesive 1) torque.

Accepted19 Article

: 219233). : Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. John Wiley& Sons,Inc. around an implant placed with low torque. Only torque. with low placed implant an around 2015; ateral wall with cortical bone surface covered surface bone cortical with wall ateral Cs secrete fibrillar collagen. 6) This collagen This 6) collagen. fibrillar secrete Cs blood, the marrow or from BLCs to populate to BLCs from or marrow the blood, B; Bone remodeling after excessive implant excessive after remodeling Bone B; . . eoi otod o il h cmatet 8) compartment. the fill to osteoid deposit n n DAPI, and 20x). tes or bone lining cells where most undergo most where cells lining bone or tes d. Image C shows an undersized osteotomy undersized an shows C Image d. sos otooy hr te implant the where osteotomy a shows B sive implant torque (modified from Cha JY, JY, Cha from(modified torque implant sive sence of a gap (*) between the implant and implant the between (*) gap a of sence fed aon a ipat lcd under placed implant an around fields n relative to the implant’s external diameter. external implant’s the to relative ove the damaged bone. 4) Bone lining cellslining Bone 4) damagedbone. the ove moted a small region of moderate strain. moderate of region small a moted s. 94 d remodeling. Crit Rev Eukaryot Gene Gene Eukaryot Rev Crit remodeling. d S, Brunski JB, Helms JA. Multiscale JA. Helms JB, Brunski S, : 482490. : d n h poes mdfe from (modified process the in ed uig h otoye ewr. 2) network. osteocyte the luding 21) Cne t bn: fatal a bone: to Cancer (2011). 33

hightorque implant. I F: Image body. implant the and threads the around bon in deeply engaged threads The torque. increased

Accepted Article

Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. John Wiley& Sons,Inc. e and created a larger region of high strain high of region larger a created and e llustration of photoelastic stress around an around stress photoelastic of llustration 34 Page 34of38 Page 35of38

Figure 1. Histological section of maxillary of Figurel sinus Histological 1. section

Accepted Article cells (Immunofluorescence for Tubulin and DAPI, 20x DAPI, cellsforTubulin and (Immunofluorescence Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. 131x126mm(300 300DPI) x John Wiley& Sons,Inc. ateral wall ateral with corticalcovered bone surface byb

). ).

one liningone

includingand 2) Osteoblasts network. osteocyte the Osteoblasts trapped intoOsteoblasts osteoid the become osteocy Guise, T. A., & & A., L. b McCauley, to Guise,T. (2011). K. Cancer 411-425. B; Bone remodeling excessive Bone after 411-425. B; implant from BLCs to populate boneto the fromBLCs remodeling compartme Figure 2. Bone remodeling diagram. A; Cells remodeling involvFigureA; Bone diagram. 2. (modified from Seeman E. Bone(modified E. modeling remodeli fromSeeman and collagen layer allows osteoblasts to attach. 7) Os attach. to collagenlayer allows osteoblasts

Bone lining Bone debris the cells osteoclast after clean Accepted Article Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. 215x279mm(300 300DPI) x John Wiley& Sons,Inc. 233). osteoclasts recruitedare blood, fromthe marr the resorption. 5) BLCs secrete 5)fibrillar BLCs resorption. collagen. 6) one: a fatal attraction. Natureone: 11( fatalReviews attraction. a Cancer, teoblasts deposit compartment. osteoid fill to the ed in the process the (modified edWeilbaecher, in N. from K. tes ortes bone liningundergo apoptos where cells most

torque. 1) Excesive torque promotes bone damage torque.1) bone Excesivedamage torque promotes nt. 3) Osteoclasts remove 3)the Osteoclasts 4)nt. bone. damaged ng. Crit Rev Eukaryot Gene Expr CritRev Eukaryot 2009; 19: 219- ng.

This This ow orow 8) 6), , , is Page 36of38 Page 37of38

Figure 3. Bone microcracks as a consequence microcracks Figurea Bone exce3. of as gap (*) is observed. Image C shows (*)undersized shows gap is observed. an C Image os Smith AA, Houschyar AA, KS, YinMouraret Smith S, X, Brunski filled with fibrous tissue. Image B shows filledshows osteoto with B fibrous a Image tissue. Upper images (A, B, osteotomy : the Schematic B, Upperof C) images (A, shows an oversized an shows preparation withpresence the of Image D: compressive D: of Image Illustration fields strain Illustration of increased of compresive Illustration fields strain threads engaged deeply in bone and created a larger engagedcreated a deeply threads and in bone microns of the thread engaged thread microns the of promoted in bone and

Accepted photoelasticF: of implantImage body. Illustration Article Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. interface. J Dent Res 2015;J interface. Dent 94: 482-490. 220x154mm(300 300DPI) x John Wiley& Sons,Inc. implant. implant. around an implant placed under an increased around torque.Th my where smallmy a torque and implant the reachedlow around an implant placed with lowan 15-2torque.Only around sive implant torque (modified from Cha JY, Pereira sive Cha implant torque (modified from

a gap (*) between the implant and bone. This gap i (*)gap gap This between bone. implanta the and JB,HelmsMultiscale analysesbone-impla the JA. of teotomy that induces high that torque teotomy a bone gap without

relative diameter. Image implant’s the external to region the the higharound of strain and threads a small region of moderate strain. Image E: E: small region a Image moderate strain. of stress around an an high-torquestressaround implant.

e MD, MD, 0 A A er nt nt s s - Page 38of Page 39of38 1: Table

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