103
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]
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J Korean Assoc Oral Maxillofac Surg 2013;39:103-111
104
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.
Tooth-derived bone graft material
105
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
J Korean Assoc Oral Maxillofac Surg 2013;39:103-111
106
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
Tooth-derived bone graft material
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
J Korean Assoc Oral Maxillofac Surg 2013;39:103-111
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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