tooth-derived bone graft material - koreamed...tooth-derived bone graft material 105 various growth...

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Tooth-derived bone graft material

Young-Kyun Kim1, Junho Lee2, In-Woong Um2, Kyung-Wook Kim3,

Masaru Murata4, Toshiyuki Akazawa5, Masaharu Mitsugi6

1Department of Oral and Maxillofacial Surgery, Section of Dentistry, Seoul National University Bundang Hospital, Seongnam, 2Korea Tooth Bank, Seoul, 3Department of Oral and Maxillofacial Surgery, College of Dentistry, Dankook University, Cheonan, 4Department of Oral and Maxillofacial Surgery, Health Sciences University of Hokkaido, 5Department of Industrial Technology Research, Hokkaido Industrial Research Institute, Sapporo, 6Takamatsu Oral and Maxillofacial Surgery Clinic, Kagawa, Japan

Abstract (J Korean Assoc Oral Maxillofac Surg 2013;39:103-111)

With successful extraction of growth factors and bone morphogenic proteins (BMPs) from mammalian teeth, many researchers have supported development of a bone substitute using tooth-derived substances. Some studies have also expanded the potential use of teeth as a carrier for growth factors and stem cells. A broad overview of the published findings with regard to tooth-derived regenerative tissue engineering technique is outlined. Considering more than 100 published papers, our team has developed the protocols and techniques for processing of bone graft material using extracted teeth. Based on current studies and studies that will be needed in the future, we can anticipate development of scaffolds, homogenous and xenogenous tooth bone grafts, and dental restorative materials using extracted teeth.

Key words: Tooth, Dentin, Demineralized dentin matrix, Bone substitutes, Tissue engineering [paper submitted 2013. 4. 2 / revised 2013. 5. 1 / accepted 2013. 5. 28]

support the intramembranousbone formationpathway

whenintraoralbonegrafting isachieved5,6.Thechemical

compositionsofteeth,especiallydentinandbones,arevery

similar.Enamelconsistsof96%inorganicsubstancesand4%

water,whereasdentinhas65%inorganicsubstances,35%

organicsubstances,andwater.Cementumismadeupof45-

50%inorganicsubstances,50-55%organicsubstances,and

water.Finally,alveolarbonehas65%inorganicand35%

organicsubstances.

In organic parts, dentin and cementum include type

I collagens and various growth factors such as bone

morphogenicproteins (BMPs).TypeIcollagenoccupies

about90%oftheorganicpartsoftissues,withtherestnon-

collagenousproteins (NCP),biopolymers, lipid,citrate,

lactate,etc.NCPs includephosphophoryn, sialoprotein,

glycoprotein,proteoglycan,osteopontin(OPN),osteocalcin,

dentinmatrixprotein-1,osterix,andCbfa1(Runx2).These

proteins are known to trigger thebone resorption and

generationprocesses7-15.

Basedonthepotentialsofosteoconduction,osteoinduction,

andosteogenesisthroughgrowthfactorsintoothandsimilar

histogenesisbetween toothandbone,anovelbonegraft

materialcanbedevelopedutilizingtheinorganicandorganic

I. Introduction

Tooth isacompositestructureconsistingof inorganic

components including thecalciumphosphate lineageand

organiccomponentssuchascollagen.Toothmineralsconsist

of fivebiological calciumphosphates:hydroxyapatite,

tricalciumphosphate(TCP),octacalciumphosphate(OCP),

amorphous calciumphosphate (ACP), and dicalcium

phosphatedehydrate.Interactingreciprocally,thesecalcium

phosphatesarecapableofremodelingtheexistingbonewhen

grafted.Theapatiteexistingwithinthebonetissueisknown

tobeintheformofceramics/high-polymernano-composites.

Teethandbonessharemanysimilarities.Teeth,cartilages,

nerves,andmaxillofacialbonesallembryologicallyoriginated

in theneuralcrest, sharing identicalorigin1-4.Clinicians

REVIEW ARTICLEhttp://dx.doi.org/10.5125/jkaoms.2013.39.3.103

pISSN 2234-7550·eISSN 2234-5930

In-Woong UmKorea Tooth Bank/Seoul In Dental Clinic, Gooahm Building 3rd floor, Nonhyun- dong 249-11, Gang nam-gu, Seoul 135-832, KoreaTEL: +82-2-548-2055 FAX: +82-2-548-2228E-mail: [email protected]

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Copyright Ⓒ 2013 The Korean Association of Oral and Maxillofacial Surgeons. All rights reserved.

J Korean Assoc Oral Maxillofac Surg 2013;39:103-111

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SinceonlyalimitedamountofBMPscanbeextracted

from the teeth,however, theclinicalutilizationmaybe

limited31-33.Therefore,variousrecombinanthumanBMPs

(rhBMP)havebeenrecentlymanufacturedbygenerecombi-

nationbasedonmammalcellsorcolonbacilli34-36.

Dentinandcementumcontainvariousothergrowthfactors

besidesBMPssuchas insulin-likegrowth factor (IGF),

platelet-derivedgrowthfactor (PDGF), fibroblastgrowth

factor(FGF),andtransforminggrowthfactor(TGF)-β37,38.

Finkelmanetal.39reportedtheextractionofTGF-β,IGF-I,

IGF-IIfromhumandentinbutatlowerlevelscomparedto

thosefromhumanbone.

About90%ofdentinalorganiccomponentsareknownto

betypeIcollagens.Thesetriple-helixstructuredcollagens

are themostabundantprotein invertebrates.Collagen-

derivedmaterialshavedemonstratedbiocompatibilityand

interferenceinboneformationattheimplantedsites40-42.

TherestofdentinalorganiccomponentsareNCP.NCPs

thatcontributetomineralizationareosteocalcin,osteonectin,

phosphophoryn,dentinsialoprotein(DSP),dentin-specific

extracellularmatrixprotein,etc.Phosphophoryninparticular,

boundtotypeIcollagen,contributestothemineralization

process;itisofthelargestamountsamongNCPs.Previous

studiesdiscoveredthroughtheimmune-histochemicalstudy

thatOPNandDSPmanifested6-8weeksaftergrafting

thetoothgraftmaterialonalveolarbonedefectsinWistar

rats43.OPNisknownto triggerosteogenesis through the

earlydifferentiationoftheosteoblastsbutalsoleadstobone

resorptionbyallowingadherenceofosteoclaststothebone

surface.DSPhasasignificantroleindentincalcification12,44.

III. Backgrounds of Demineralized Dentin Matrix

1. Biocompatibility

Traditionally,rootswereintentionallyleftforthepreven-tion

ofalveolarboneresorptioninremovableprosthodonticsorin

casesoftoothextractions45,46.Intentionalpartialodontectomy

hasbeensafelypracticedwhenrootsofimpactedthirdmolar

aresituatedclosetotheinferioralveolarnerveorankylosed

sinceonlyacrownportion isdissected, leavingtheroots

behind47.Therootremnantofnon-pathologyinvolvedtooth

inalveolarbonedoesnotinduceanyinflammatoryresponse.

Osteoclastcellsappear in thepulpcavity,with thepulp

replacedbybone,followedbyrootresorption.Afterall,the

remainingrootscompletelyfusewiththesurroundingalveolar

componentsof an extracted tooth. Indeed, autogenous

toothbonegraftmaterial(AutoBT;KoreaToothBankCo.,

Seoul,Korea)hasbeendevelopedfromanextractedtooth.

Anon-restorable toothora thirdmolar tooth isassigned

tobe extracted from thepatient.With fabrication and

demineralizationprocess,AutoBTmaterial ismadefrom

theextractedtooth.ThisAutoBTisgraftedbacktothesame

patientwhenguidedboneregenerationisnecessaryindental

surgeries.Currently,AutoBTiswidelyused inclinics in

KoreaandJapan.

This reviewpaperprovidesoverviewsof thechemical

compositionsofdentindue to itssimilarities to thoseof

alveolarboneandpreviousstudiesondemineralizeddentin

matrix(DDM),aninitial tooth-derivedtissueengineering

application.Finally,wesummarizedrecentapplicationsof

toothasbonegraftingmaterial.

II. Inorganic and Organic Components of Dentin

1. Hydroxyapatite, inorganic component

Dentin consists of70%hydroxyapatite in itsweight

volume.Hydroxyapatite indentin isstructuredwith low-

crystalline calcium phosphate16,making future bone

remodelingpossible.Bonetissuesarealsomainlycomposed

of low-crystallineapatite. Incontrast,hydroxyapatite in

enamelisstructuredashigh-crystallinecalciumphosphate.

Highcrystallinecontentsarenoteasilydecomposedby

osteoclasts, resultinginslowresorptionandconsequently

poorosteoconductivity17.

2. Bone growth factors and type I collagen, organic

component

Growthfactorsaresignalingproteinsthatregulatecellular

growth,proliferation,anddifferentiation18.Urist19 initially

discoveredBMPsandstudied their roles in1965.BMPs

areknowntoexistinthebonematrix,osteosarcomatissue,

anddentinmatrix,functioningtodifferentiateperivascular

mesenchymalstemcellsintocartilageandbonetissues20-23.

Several studieshave successfully isolatedBMPs from

dentin,enamel,andcementumofbovine,rats,guineapigs,

and rabbit teeth8,22-25.Withextensive studiesonBMPs,

researchershaveconfirmedtheosteoinductivityofBMPs

extracted fromanimal teethsuchasbovine, lapine,and

murineteeth8-10,22,23,26-30.


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variousgrowthfactorsandproteins, since the releaseof

thegrowthfactors issometimesblockedby thepresence

ofhydroxyapatitecrystals.Manyauthorsobserved that

heterotrophicbonewas inducedwhenDDMwasgrafted

inthelapine,porcine,andmurinemuscletissues.Assuch,

decalcificationofdentinisbelievedtoinducethereleaseof

BMP,therebyleadingtoosteoinduction52,66-70.Researchers

usevariousdecalcificationmethods.Decalcifieddentinand

boneusing0.6NHClleadtotheinducementofconnective

tissuecellsandformationofendochondralboneinmuscle

andinskinconnectivetissues19,66,71-75.IkeandUrist62partially

demineralizedtherootsoftheteethusing0.6NHCLfor24

hours,andthencutthemin0.5gblockstoproducepartially

demineralizedmatrix (PDM).PDMwas thenwashed in

coldwaterand lyophilized.Analternativeapproachwas

employedbyInoueetal.67; theygraftedthedemineralized

dentin tissuesusing0.6NHCL (pH1) and3M (9N) in

therectalabdominismusclesofWistarrats. Inoueetal.67

reportedfavorablechondrogenesisandosteogenesis,with

theHCL-demineralizeddentinshowingrelativelysuperior

results.Differentapproachesinacidtreatmentprotocolswere

used.DDMwas treatedusing2%HNO3.Severalanimal

studiesshowedfavorableresults,withobservednewbone

formation68,76.

Somestudiesshowedcontraryresults.AccordingtoIkeand

Urist62,whenhumanpartiallydemineralizeddentingranules

weregrafted in the intramuscularpockets,osteoinduction

wasnotobserved.Basedon thequantitativeanalysisof

proliferationanddifferentiationoftheMG-63cell,however,

cellularadhesionandproliferationactivityoftheMG-63cell

onpartiallydemineralizeddentinmatrixwerenoted77.With

differentlyemployedmethods,onemayconjecturethatthe

osteoinductivepropertiesofdentinmaydependondifferent

acidtreatmentprotocols.

IV. Human Tooth as Graft Material

Bonesubstituteshavebeenactivelyused inclinics to

reconstructbonydefects.Therearefourcategoriesofbone

graftmaterials:autograft,allograft,alloplast,andxenograft.

With four typesofgraftmaterials available, theuseof

thesematerialsdependsonclinicalapplications,volume

ofdeficiency, andevidence-based studies52,78,79.Above

all,autograftsareknowntobethegoldstandardduetoits

osteoinductivity,osteoconductivity,andosteogenicity.Still,

autogenousbonegraftsharvestedfromextra-oralsiteshave

bone.Basedontheseclinicalreports,alveolarboneandteeth

canbeinferredtohavehighlevelofaffinitytoeachother48-50.

Homogenous demineralized dentinmatrix (HDDM)

is as aneffectivebiocompatiblebonegraftmaterial as

autogenousdemineralizeddentinmatrix(ADDM)sinceit

inducesheterotopicboneformationwithnohost immune

rejection51,52.ThedemineralizationprocessofHDDMdoes

notdenatureosteopromotiveproperties.HDDMisareservoir

ofbiochemical factors that inducecellularproliferation

aswellascelldifferentiationandchemotaxis53,54. In the

histomorphometricanalysisofHDDMinvitro ,HDDM

resorbsitselfduringtheboneremodelingprocess53.Gomes

et al.54 further evaluated thebone repair process after

implantationofHDDMslicesinsurgicaldefectscreatedinthe

parietalbonesofrabbitswithalloxan-induceddiabetes.They

reportedthatHDDMwasbiocompatible,stimulatingbone

tissueformation.Inthisstudy,HDDMiswellacceptedbythe

hostandistotallyincorporatedintonewlyformedbonetissue.

2. Osteoinduction and release of bone morphogenic

protein

Highlysoluble,BMPsdonotexertosteoinductiveeffects

whenusedalone.ScaffoldsareusedtoforceBMPstostay

attheimplantsite55-57.Scaffoldfunctionsascarrier.Anideal

scaffoldshouldcontrol-releasegrowthfactorsorcellsandcan

preventdegradationandinactivation18.Differentmaterialsare

usedfordifferentpurposes.CollagenandTCPareclinically

usedmostwidely58.ForthedeliveryofBMPsandgrowth

factors,collagen,calciumphosphates,andpolyesterssuchas

polycaprolactonehavebeenused59-61.

DDMwasintroducedasanalternativematerialforscaffold

inreleasingBMPs62-64. IkeandUrist62suggestedthatroot

dentinpreparedfromextractedteethcouldberecycledforuse

ascarrierofrhBMP-2.Althoughthequantityofendogenous

BMPindysfunctionalteethisverysmallornil,activenew

boneformationwasobservedbymanyscientistswhenDDM

wasusedascarrier62,64.Accordingtothebiochemicaland

histomorphometricanalysesofboneandcartilageinducedby

humanDDMandBMP-2,researchersconcludedthathuman

DDMofvitalteethorigininducedboneandcartilage,and

thatBMP-2stronglyacceleratedboneformationintheDDM

carriersystem65.

3. Demineralization

Thedemineralizationprocessisrequiredforfreeingthe


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TheclinicaleffectivenessofADDMwastestedinpocket

preservation.Wistarrat’s incisorswerefrozensoonafter

extraction,and thenmilledwithhydroxypropylcellulose

added.Consequently,earlyhealingandboneformationin

theextractionsocketwereobservedwhengraftedwithmilled

tooth.Thisstudyusedtheextractedtoothasawholewithout

decalcification, includingbothenamelanddentalpulp.

Therefore, theresults indicate thatosteoinductivehealing

maycomefromgrowthfactors indentinordentalpulp91.

Anotherstudywasconductedon thehuman thirdmolar

socketwhereinthegreaterhomogeneityofboneradiopacity

withenhancedhealingprocesswasobserved53,81,84.Periods

of radiographicobservation focusingon thechanges in

radiopacityand in theperipheralboundarybetweengraft

materialandboneandclinicalobservationsconfirmedthatthe

graftwasbiocompatibleandclinicallyeasytouse92.Another

applicationofADDMisonimplantdentistry.Infact,ADDMs

havebeenactively tested in implantosseointegrationand

boneremodelingcapacity;thusenhancingimplantprimary

stability86.

Basedondecadesofresearchandscientificfactsontooth,

Jeongetal.80andKimetal.93suggestedthatAutoBTisan

excellentalternative toautogenousbonegraft.Afterall,

AutoBTwasdevelopedandhasbeeninclinicalusesince

2008inKorea.Withthepatient’sconsent,theextractedteeth

aresenttoKoreaToothBankin75%ethylalcoholstorage

container.(Fig.1.A)Afterdissectionof theanatomical

crown,samplerootportionsaregroundintopowderform,

witheachparticlemeasuring400-800μmindiameter.(Fig.

1.B)Theremainingsoft tissuesandcontaminantsof the

particulateAutoBTareremovedwithdistilledwater.Once

subjected todehydration,defatting, lyophilization, and

ethyleneoxidesterilizationprocesses,AutoBTispacked.A

somelimitations,suchashighmorbidity,potentialresorption,

andhighcosts78,80.Withadvancementsintissueengineering,

researchershaveextensively studiedcompensating the

drawbacksof autografts.Thus,many researcherspaid

attentiontohumantoothasoneoftheintraoraldonorsites

duetoitschemicalsimilaritiestobone.

1. Autogenous demineralized dentin matrix

ExtensivestudiesinvitrohavebeenconductedonADDM

with itsbiocompatibility,osteoinductivity,andosteocon-

ductivity81-84. Inanimalstudies,ADDMinducedbonefor-

mationaccordingtothehistologyanalysis81-83.Forinstance,

Gomesetal.54performedahistologicalevaluationof the

osteoinductivepropertyofADDMoncalvarialbonedefects

inrabbit.Accordingto thestudy,ADDMwasverified to

havechemotacticpropertiesforosteoprogenitorcellsand

osteoblasts,promotingtheaccelerationofbonerepairprocess

at thebonydefect.SlicesofADDMinduceddirectbone

formation,andtheywereincorporatedbythenewlyformed

bonetissueandremodeled82.

ThemechanismsinvolvedintheosteogenesisofADDM

include endochondral and intramembranous bone for-

mation52,85-87.Likewise,theosteogenesisofADDMisinflu-

encedbythesizeandformofgraftmaterials87.Theideal

sizesofgraftmaterialgranulesaredifferentfromauthorto

author,rangingfrom75μmto500μm73,88,89.Someauthors

reducedtheinter-particulatedistancesbyaddingβ-TCPdue

todifficulties inhomogenizing thesizes40.SinceADDM

containsnativegrowthfactorssupportingmesenchymalcell

attachmentandfurtherabsorbsseveralproteinsderivedfrom

bodyfluid,however,someauthorsstatethathomogenizing

theADDMgranulesizeisnotcritical65,90.

Fig. 1. A. Extracted teeth are ready to be fabricated into autogenous tooth bone graft (AutoBT) in either powder form or block form. B. AutoBT powder. C. AutoBT block form. Young-Kyun Kim et al: Tooth-derived bone graft material. J Korean Assoc Oral Maxillofac Surg 2013


107

electronmicrocopy,andhistomorphometricevaluation16,78.

AutoBTconsistsoflow-crystallinehydroxya-patiteandother

calciumphosphatemineralssuchasTCP,ACP,andOCP,

whicharecomponentssimilartothoseofhumanbone16.With

blockformofAutoBTisfabricatedinthesamemanneras

particulatebonegraftexcludingthegrindingsteps.(Fig.1.C)

ThebasiccomponentsandsurfacestructureofAutoBT

havebeenanalyzedusingX-raydiffractionanalyzer,scanning

Fig. 2. A case of sinus bone graft and delayed implant placement in the left maxillary first molar in a 32-year-old female patient. AutoBT powder was used as bone graft material. A. Pre-surgery computed tomography. B. Four months’ post-operative computed tomography. C. Panoramic x-ray soon after implant placement.Young-Kyun Kim et al: Tooth-derived bone graft material. J Korean Assoc Oral Maxillofac Surg 2013

Fig. 3. A case of autogenous tooth bone graft (AutoBT) block socket graft followed by implant placement in a 41-year-old female patient. A. Pre-surgery panoramic x-ray showed bony defect with close proximity to the inferior alveolar nerve after extraction of the left mandibular second molar. B. The AutoBT block form fabricated from the extracted tooth was grafted at the extraction socket. C. Well-formed new bones were observed after raising a flap 5 months after the socket graft. D. Short wide implant was placed at the site. E. Periapical radiograph 6 months after the final prosthesis.Young-Kyun Kim et al: Tooth-derived bone graft ma-terial. J Korean Assoc Oral Maxillofac Surg 2013


108

substituteandscaffold.Asdiscussedinthisreview,ADDM,

withabsenceofantigenicity,enhancesbone-remodeling

capabilities.Amongavarietyofavailablebonegraftmaterials,

choosingtheappropriateoneischallenging.Whilechoosing

thegraftmaterialshouldbedictatedbytheextentofdefects

andtheproceduralpurposes,tooth-derivedbonegraftmay

beconsideredasanoptiongivenitsautogenousoriginand

favorableclinicalandhistologicaloutcomeswhen teeth

extractionisnecessary.Furtherstudiesareneededinevaluating

clinicalefficaciesandcomparingothercommerciallyavailable

bonegraftmaterials.

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Fig. 4. A. High-magnification image of new bone formation around the tooth elements. Marginal scalloping of the implant chip suggested that remodeling was occurring in the new bone-implant chip interface.(H&E staining, ×100) B. Newly formed bone and tooth materials showing remodeling were identified around the implant chip and at the periphery of the implant chip, respectively.(H&E staining, ×100) Images from the article of Kim et al.78 (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010;109:496-503).Young-Kyun Kim et al: Tooth-derived bone graft material. J Korean Assoc Oral Maxillofac Surg 2013


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