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Practical whole-tooth restoration utilizing autologous bioengineered tooth germ transplantation in a postnatal canine model

Identifieur interne : 006E83 ( Ncbi/Merge ); précédent : 006E82; suivant : 006E84

Practical whole-tooth restoration utilizing autologous bioengineered tooth germ transplantation in a postnatal canine model

Auteurs : Mitsuaki Ono [Japon] ; Masamitsu Oshima [Japon] ; Miho Ogawa [Japon] ; Wataru Sonoyama [Japon] ; Emilio Satoshi Hara [Japon] ; Yasutaka Oida [Japon] ; Shigehiko Shinkawa [Japon] ; Ryu Nakajima [Japon] ; Atsushi Mine [Japon] ; Satoru Hayano [Japon] ; Satoshi Fukumoto [Japon] ; Shohei Kasugai [Japon] ; Akira Yamaguchi [Japon] ; Takashi Tsuji [Japon] ; Takuo Kuboki [Japon]

Source :

RBID : PMC:5353657

Abstract

Whole-organ regeneration has great potential for the replacement of dysfunctional organs through the reconstruction of a fully functional bioengineered organ using three-dimensional cell manipulation in vitro. Recently, many basic studies of whole-tooth replacement using three-dimensional cell manipulation have been conducted in a mouse model. Further evidence of the practical application to human medicine is required to demonstrate tooth restoration by reconstructing bioengineered tooth germ using a postnatal large-animal model. Herein, we demonstrate functional tooth restoration through the autologous transplantation of bioengineered tooth germ in a postnatal canine model. The bioengineered tooth, which was reconstructed using permanent tooth germ cells, erupted into the jawbone after autologous transplantation and achieved physiological function equivalent to that of a natural tooth. This study represents a substantial advancement in whole-organ replacement therapy through the transplantation of bioengineered organ germ as a practical model for future clinical regenerative medicine.


Url:
DOI: 10.1038/srep44522
PubMed: 28300208
PubMed Central: 5353657

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PMC:5353657

Le document en format XML

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<name sortKey="Ogawa, Miho" sort="Ogawa, Miho" uniqKey="Ogawa M" first="Miho" last="Ogawa">Miho Ogawa</name>
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<name sortKey="Sonoyama, Wataru" sort="Sonoyama, Wataru" uniqKey="Sonoyama W" first="Wataru" last="Sonoyama">Wataru Sonoyama</name>
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<name sortKey="Hara, Emilio Satoshi" sort="Hara, Emilio Satoshi" uniqKey="Hara E" first="Emilio Satoshi" last="Hara">Emilio Satoshi Hara</name>
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<name sortKey="Oida, Yasutaka" sort="Oida, Yasutaka" uniqKey="Oida Y" first="Yasutaka" last="Oida">Yasutaka Oida</name>
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<name sortKey="Shinkawa, Shigehiko" sort="Shinkawa, Shigehiko" uniqKey="Shinkawa S" first="Shigehiko" last="Shinkawa">Shigehiko Shinkawa</name>
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<name sortKey="Nakajima, Ryu" sort="Nakajima, Ryu" uniqKey="Nakajima R" first="Ryu" last="Nakajima">Ryu Nakajima</name>
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<name sortKey="Mine, Atsushi" sort="Mine, Atsushi" uniqKey="Mine A" first="Atsushi" last="Mine">Atsushi Mine</name>
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<country xml:lang="fr">Japon</country>
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<name sortKey="Kasugai, Shohei" sort="Kasugai, Shohei" uniqKey="Kasugai S" first="Shohei" last="Kasugai">Shohei Kasugai</name>
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<name sortKey="Yamaguchi, Akira" sort="Yamaguchi, Akira" uniqKey="Yamaguchi A" first="Akira" last="Yamaguchi">Akira Yamaguchi</name>
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</nlm:aff>
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<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<institution>Oral Health Science Center, Tokyo Dental College</institution>
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<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<name sortKey="Tsuji, Takashi" sort="Tsuji, Takashi" uniqKey="Tsuji T" first="Takashi" last="Tsuji">Takashi Tsuji</name>
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<name sortKey="Kuboki, Takuo" sort="Kuboki, Takuo" uniqKey="Kuboki T" first="Takuo" last="Kuboki">Takuo Kuboki</name>
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<title xml:lang="en" level="a" type="main">Practical whole-tooth restoration utilizing autologous bioengineered tooth germ transplantation in a postnatal canine model</title>
<author>
<name sortKey="Ono, Mitsuaki" sort="Ono, Mitsuaki" uniqKey="Ono M" first="Mitsuaki" last="Ono">Mitsuaki Ono</name>
<affiliation wicri:level="1">
<nlm:aff id="a1">
<institution>Department of Oral Rehabilitation and Regenerative Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University</institution>
, Okayama, 700-8525,
<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="a2">
<institution>Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University</institution>
, Okayama, 700-8525,
<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Oshima, Masamitsu" sort="Oshima, Masamitsu" uniqKey="Oshima M" first="Masamitsu" last="Oshima">Masamitsu Oshima</name>
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<institution>Department of Oral Rehabilitation and Regenerative Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University</institution>
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<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="a3">
<institution>Research Institute for Science and Technology, Tokyo University of Science</institution>
, Noda, Chiba, 278-8510,
<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
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<nlm:aff id="a4">
<institution>RIKEN Center for Developmental Biology</institution>
, Kobe, Hyogo, 650-0047,
<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<name sortKey="Ogawa, Miho" sort="Ogawa, Miho" uniqKey="Ogawa M" first="Miho" last="Ogawa">Miho Ogawa</name>
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, Noda, Chiba, 278-8510,
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<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
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<nlm:aff id="a5">
<institution>Organ Technologies Inc.</institution>
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</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author>
<name sortKey="Sonoyama, Wataru" sort="Sonoyama, Wataru" uniqKey="Sonoyama W" first="Wataru" last="Sonoyama">Wataru Sonoyama</name>
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<institution>Department of Oral Rehabilitation and Regenerative Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University</institution>
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</nlm:aff>
<country xml:lang="fr">Japon</country>
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<name sortKey="Hara, Emilio Satoshi" sort="Hara, Emilio Satoshi" uniqKey="Hara E" first="Emilio Satoshi" last="Hara">Emilio Satoshi Hara</name>
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<country xml:lang="fr">Japon</country>
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<name sortKey="Oida, Yasutaka" sort="Oida, Yasutaka" uniqKey="Oida Y" first="Yasutaka" last="Oida">Yasutaka Oida</name>
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</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
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<author>
<name sortKey="Shinkawa, Shigehiko" sort="Shinkawa, Shigehiko" uniqKey="Shinkawa S" first="Shigehiko" last="Shinkawa">Shigehiko Shinkawa</name>
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<institution>Department of Oral Rehabilitation and Regenerative Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University</institution>
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</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
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<author>
<name sortKey="Nakajima, Ryu" sort="Nakajima, Ryu" uniqKey="Nakajima R" first="Ryu" last="Nakajima">Ryu Nakajima</name>
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<institution>Department of Oral Rehabilitation and Regenerative Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University</institution>
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<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Mine, Atsushi" sort="Mine, Atsushi" uniqKey="Mine A" first="Atsushi" last="Mine">Atsushi Mine</name>
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<nlm:aff id="a1">
<institution>Department of Oral Rehabilitation and Regenerative Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University</institution>
, Okayama, 700-8525,
<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="a6">
<institution>Department of Fixed Prosthodontics, Osaka University Graduate School of Dentistry</institution>
, Yamadaoka, Suita, Osaka 565-0871,
<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Hayano, Satoru" sort="Hayano, Satoru" uniqKey="Hayano S" first="Satoru" last="Hayano">Satoru Hayano</name>
<affiliation wicri:level="1">
<nlm:aff id="a7">
<institution>Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University</institution>
, Okayama, 700-8525,
<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Fukumoto, Satoshi" sort="Fukumoto, Satoshi" uniqKey="Fukumoto S" first="Satoshi" last="Fukumoto">Satoshi Fukumoto</name>
<affiliation wicri:level="1">
<nlm:aff id="a8">
<institution>Division of Pediatric Dentistry, Tohoku University Graduate School of Dentistry</institution>
, Sendai, Miyagi, 980-8575,
<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Kasugai, Shohei" sort="Kasugai, Shohei" uniqKey="Kasugai S" first="Shohei" last="Kasugai">Shohei Kasugai</name>
<affiliation wicri:level="1">
<nlm:aff id="a9">
<institution>Section of Oral Implantology and Regenerative Dental Medicine, Graduate School of Tokyo Medical and Dental University</institution>
, Bunkyo-ku, Tokyo, 113-8549,
<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Yamaguchi, Akira" sort="Yamaguchi, Akira" uniqKey="Yamaguchi A" first="Akira" last="Yamaguchi">Akira Yamaguchi</name>
<affiliation wicri:level="1">
<nlm:aff id="a10">
<institution>Section of Oral Pathology, Department of Oral Restitution, Graduate School of Tokyo Medical and Dental University</institution>
, Chiyoda-ku, Tokyo, 113-8549,
<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="a11">
<institution>Oral Health Science Center, Tokyo Dental College</institution>
, Chiyoda-ku, Tokyo, 101-0061,
<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Tsuji, Takashi" sort="Tsuji, Takashi" uniqKey="Tsuji T" first="Takashi" last="Tsuji">Takashi Tsuji</name>
<affiliation wicri:level="1">
<nlm:aff id="a3">
<institution>Research Institute for Science and Technology, Tokyo University of Science</institution>
, Noda, Chiba, 278-8510,
<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="a4">
<institution>RIKEN Center for Developmental Biology</institution>
, Kobe, Hyogo, 650-0047,
<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="a5">
<institution>Organ Technologies Inc.</institution>
, Tokyo, 105-0001,
<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Kuboki, Takuo" sort="Kuboki, Takuo" uniqKey="Kuboki T" first="Takuo" last="Kuboki">Takuo Kuboki</name>
<affiliation wicri:level="1">
<nlm:aff id="a1">
<institution>Department of Oral Rehabilitation and Regenerative Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University</institution>
, Okayama, 700-8525,
<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
</analytic>
<series>
<title level="j">Scientific Reports</title>
<idno type="eISSN">2045-2322</idno>
<imprint>
<date when="2017">2017</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc>
<textClass></textClass>
</profileDesc>
</teiHeader>
<front>
<div type="abstract" xml:lang="en">
<p>Whole-organ regeneration has great potential for the replacement of dysfunctional organs through the reconstruction of a fully functional bioengineered organ using three-dimensional cell manipulation
<italic>in vitro</italic>
. Recently, many basic studies of whole-tooth replacement using three-dimensional cell manipulation have been conducted in a mouse model. Further evidence of the practical application to human medicine is required to demonstrate tooth restoration by reconstructing bioengineered tooth germ using a postnatal large-animal model. Herein, we demonstrate functional tooth restoration through the autologous transplantation of bioengineered tooth germ in a postnatal canine model. The bioengineered tooth, which was reconstructed using permanent tooth germ cells, erupted into the jawbone after autologous transplantation and achieved physiological function equivalent to that of a natural tooth. This study represents a substantial advancement in whole-organ replacement therapy through the transplantation of bioengineered organ germ as a practical model for future clinical regenerative medicine.</p>
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<pmc article-type="research-article">
<pmc-dir>properties open_access</pmc-dir>
<front>
<journal-meta>
<journal-id journal-id-type="nlm-ta">Sci Rep</journal-id>
<journal-id journal-id-type="iso-abbrev">Sci Rep</journal-id>
<journal-title-group>
<journal-title>Scientific Reports</journal-title>
</journal-title-group>
<issn pub-type="epub">2045-2322</issn>
<publisher>
<publisher-name>Nature Publishing Group</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="pmid">28300208</article-id>
<article-id pub-id-type="pmc">5353657</article-id>
<article-id pub-id-type="pii">srep44522</article-id>
<article-id pub-id-type="doi">10.1038/srep44522</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Article</subject>
</subj-group>
</article-categories>
<title-group>
<article-title>Practical whole-tooth restoration utilizing autologous bioengineered tooth germ transplantation in a postnatal canine model</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name>
<surname>Ono</surname>
<given-names>Mitsuaki</given-names>
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<xref ref-type="aff" rid="a1">1</xref>
<xref ref-type="aff" rid="a2">2</xref>
<xref ref-type="author-notes" rid="n1">*</xref>
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<contrib contrib-type="author">
<name>
<surname>Oshima</surname>
<given-names>Masamitsu</given-names>
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<xref ref-type="aff" rid="a1">1</xref>
<xref ref-type="aff" rid="a3">3</xref>
<xref ref-type="aff" rid="a4">4</xref>
<xref ref-type="author-notes" rid="n1">*</xref>
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<contrib contrib-type="author">
<name>
<surname>Ogawa</surname>
<given-names>Miho</given-names>
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<xref ref-type="aff" rid="a3">3</xref>
<xref ref-type="aff" rid="a4">4</xref>
<xref ref-type="aff" rid="a5">5</xref>
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<contrib contrib-type="author">
<name>
<surname>Sonoyama</surname>
<given-names>Wataru</given-names>
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<xref ref-type="aff" rid="a1">1</xref>
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<name>
<surname>Hara</surname>
<given-names>Emilio Satoshi</given-names>
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<surname>Shinkawa</surname>
<given-names>Shigehiko</given-names>
</name>
<xref ref-type="aff" rid="a1">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Nakajima</surname>
<given-names>Ryu</given-names>
</name>
<xref ref-type="aff" rid="a1">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Mine</surname>
<given-names>Atsushi</given-names>
</name>
<xref ref-type="aff" rid="a1">1</xref>
<xref ref-type="aff" rid="a6">6</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Hayano</surname>
<given-names>Satoru</given-names>
</name>
<xref ref-type="aff" rid="a7">7</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Fukumoto</surname>
<given-names>Satoshi</given-names>
</name>
<xref ref-type="aff" rid="a8">8</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Kasugai</surname>
<given-names>Shohei</given-names>
</name>
<xref ref-type="aff" rid="a9">9</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Yamaguchi</surname>
<given-names>Akira</given-names>
</name>
<xref ref-type="aff" rid="a10">10</xref>
<xref ref-type="aff" rid="a11">11</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Tsuji</surname>
<given-names>Takashi</given-names>
</name>
<xref ref-type="aff" rid="a3">3</xref>
<xref ref-type="aff" rid="a4">4</xref>
<xref ref-type="aff" rid="a5">5</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Kuboki</surname>
<given-names>Takuo</given-names>
</name>
<xref ref-type="corresp" rid="c1">a</xref>
<xref ref-type="aff" rid="a1">1</xref>
</contrib>
<aff id="a1">
<label>1</label>
<institution>Department of Oral Rehabilitation and Regenerative Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University</institution>
, Okayama, 700-8525,
<country>Japan</country>
</aff>
<aff id="a2">
<label>2</label>
<institution>Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University</institution>
, Okayama, 700-8525,
<country>Japan</country>
</aff>
<aff id="a3">
<label>3</label>
<institution>Research Institute for Science and Technology, Tokyo University of Science</institution>
, Noda, Chiba, 278-8510,
<country>Japan</country>
</aff>
<aff id="a4">
<label>4</label>
<institution>RIKEN Center for Developmental Biology</institution>
, Kobe, Hyogo, 650-0047,
<country>Japan</country>
</aff>
<aff id="a5">
<label>5</label>
<institution>Organ Technologies Inc.</institution>
, Tokyo, 105-0001,
<country>Japan</country>
</aff>
<aff id="a6">
<label>6</label>
<institution>Department of Fixed Prosthodontics, Osaka University Graduate School of Dentistry</institution>
, Yamadaoka, Suita, Osaka 565-0871,
<country>Japan</country>
</aff>
<aff id="a7">
<label>7</label>
<institution>Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University</institution>
, Okayama, 700-8525,
<country>Japan</country>
</aff>
<aff id="a8">
<label>8</label>
<institution>Division of Pediatric Dentistry, Tohoku University Graduate School of Dentistry</institution>
, Sendai, Miyagi, 980-8575,
<country>Japan</country>
</aff>
<aff id="a9">
<label>9</label>
<institution>Section of Oral Implantology and Regenerative Dental Medicine, Graduate School of Tokyo Medical and Dental University</institution>
, Bunkyo-ku, Tokyo, 113-8549,
<country>Japan</country>
</aff>
<aff id="a10">
<label>10</label>
<institution>Section of Oral Pathology, Department of Oral Restitution, Graduate School of Tokyo Medical and Dental University</institution>
, Chiyoda-ku, Tokyo, 113-8549,
<country>Japan</country>
</aff>
<aff id="a11">
<label>11</label>
<institution>Oral Health Science Center, Tokyo Dental College</institution>
, Chiyoda-ku, Tokyo, 101-0061,
<country>Japan</country>
</aff>
</contrib-group>
<author-notes>
<corresp id="c1">
<label>a</label>
<email>kuboki@md.okayama-u.ac.jp</email>
</corresp>
<fn id="n1">
<label>*</label>
<p>These authors contributed equally to this work.</p>
</fn>
</author-notes>
<pub-date pub-type="epub">
<day>16</day>
<month>03</month>
<year>2017</year>
</pub-date>
<pub-date pub-type="collection">
<year>2017</year>
</pub-date>
<volume>7</volume>
<elocation-id>44522</elocation-id>
<history>
<date date-type="received">
<day>03</day>
<month>12</month>
<year>2015</year>
</date>
<date date-type="accepted">
<day>10</day>
<month>02</month>
<year>2017</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright © 2017, The Author(s)</copyright-statement>
<copyright-year>2017</copyright-year>
<copyright-holder>The Author(s)</copyright-holder>
<license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/4.0/">
<pmc-comment>author-paid</pmc-comment>
<license-p>This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit
<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>
</license-p>
</license>
</permissions>
<abstract>
<p>Whole-organ regeneration has great potential for the replacement of dysfunctional organs through the reconstruction of a fully functional bioengineered organ using three-dimensional cell manipulation
<italic>in vitro</italic>
. Recently, many basic studies of whole-tooth replacement using three-dimensional cell manipulation have been conducted in a mouse model. Further evidence of the practical application to human medicine is required to demonstrate tooth restoration by reconstructing bioengineered tooth germ using a postnatal large-animal model. Herein, we demonstrate functional tooth restoration through the autologous transplantation of bioengineered tooth germ in a postnatal canine model. The bioengineered tooth, which was reconstructed using permanent tooth germ cells, erupted into the jawbone after autologous transplantation and achieved physiological function equivalent to that of a natural tooth. This study represents a substantial advancement in whole-organ replacement therapy through the transplantation of bioengineered organ germ as a practical model for future clinical regenerative medicine.</p>
</abstract>
</article-meta>
</front>
<floats-group>
<fig id="f1">
<label>Figure 1</label>
<caption>
<title>Generation of a bioengineered tooth using embryonic canine tooth germ-derived cells under subrenal capsule transplantation.</title>
<p>(
<bold>A</bold>
) Schematic representation of the generation of reconstituted tooth germ. (Illustration by R.N.) (
<bold>B</bold>
) Photograph (
<italic>left</italic>
) and histological image obtained by HE staining (
<italic>centre</italic>
) of permanent first molar tooth germ (M1) and phase contrast image of reconstituted tooth germ on organ culture day 2 (
<italic>right</italic>
). Epi, epithelial tissue; Mes, mesenchymal tissue. (
<bold>C</bold>
) Micro-CT images of natural tooth germ at 8 and 12 weeks after subrenal capsule transplantation. Three-dimensional (3D) images are shown in the upper column, and cross-sectional views are shown in the lower column (
<italic>left</italic>
). Histological analysis of the bioengineered tooth 12 weeks after subrenal capsule transplantation (
<italic>right</italic>
). Boxes indicate the area shown at higher magnification in the lower panels. (
<bold>E</bold>
), enamel; (
<bold>D</bold>
), dentin. (
<bold>D</bold>
) Bioengineered tooth germ was reconstituted using single cells derived from molar tooth germ. Micro-CT images (
<italic>left</italic>
) and histological image (
<italic>right</italic>
) of the bioengineered tooth 8 weeks after subrenal capsule transplantation. 3D images are shown in the upper column, and cross-sectional views are show in the lower column. Boxes indicate the area shown at higher magnification in the lower panels. (
<bold>E</bold>
), enamel; (
<bold>D</bold>
), dentin.</p>
</caption>
<graphic xlink:href="srep44522-f1"></graphic>
</fig>
<fig id="f2">
<label>Figure 2</label>
<caption>
<title>Development of bioengineered tooth using postnatal canine-derived tissue in the autologous transplantation model.</title>
<p>(
<bold>A</bold>
) Schematic representation of autologous transplantation methods for the bioengineered tooth using postnatal canine-derived tissue. (Illustration by R.N.) (
<bold>B</bold>
) Photograph of the extracted deciduous molar (dM) with permanent premolar tooth germ (
<italic>left</italic>
) and isolation of the permanent premolar tooth germ (
<italic>right</italic>
). White arrowhead, extracted deciduous molar; Red arrowhead, permanent premolar tooth germ. (
<bold>C</bold>
) Photograph (
<italic>left</italic>
) and histological image by HE staining (
<italic>right</italic>
) of the isolated permanent premolar tooth germ. Epi, epithelial tissue; Mes, mesenchymal tissue. (
<bold>D</bold>
) Phase contrast image of the reconstituted canine tooth germ using epithelial tissue and mesenchymal cells derived from permanent premolar tooth germ after 2 days in organ culture. (
<bold>E</bold>
) Photograph of the autologous transplantation of bioengineered tooth germ into canine lower jawbone. Red arrowhead, bioengineered tooth germ. (
<bold>F</bold>
) Oral photographs and CT images of the erupted bioengineered tooth at 180 days after transplantation: no transplantation group (
<italic>left</italic>
), natural tooth germ transplantation group (
<italic>centre</italic>
), and bioengineered tooth germ transplantation group (
<italic>right</italic>
). Red arrowhead, erupted tooth. (
<bold>G</bold>
) Micro-CT images and histological analysis of the natural tooth group (
<italic>upper</italic>
), the natural tooth germ transplantation group (
<italic>middle</italic>
), and the bioengineered tooth germ transplantation group (
<italic>lower</italic>
). Histological analysis of the bioengineered tooth over the crown area and the periodontal tissue area. (
<bold>E</bold>
) enamel; (
<bold>D</bold>
) dentin; (
<bold>C</bold>
) cementum; PDL, periodontal ligament; (
<bold>A</bold>
,
<bold>B</bold>
) alveolar bone.</p>
</caption>
<graphic xlink:href="srep44522-f2"></graphic>
</fig>
<fig id="f3">
<label>Figure 3</label>
<caption>
<title>SEM and EDX analysis in the bioengineered tooth.</title>
<p>SEM image of enamel (
<bold>A</bold>
) and dentin (
<bold>B</bold>
) of the natural tooth, the erupted tooth formed by the transplantation of natural tooth germ and the bioengineered tooth. Boxes indicate the area shown at higher magnification in the centre panels. To analyse the structure of the enamel rod and dentin tube, the tooth was treated with 40% phosphoric acid for 10 sec and sodium hypochlorite for 15 sec. The surface composition of each tooth was analysed by EDX. C, carbon; O, oxygen; P, phosphorus; Ca, calcium.</p>
</caption>
<graphic xlink:href="srep44522-f3"></graphic>
</fig>
<fig id="f4">
<label>Figure 4</label>
<caption>
<title>Experimental tooth movement in the canine model.</title>
<p>(
<bold>A</bold>
) Schematic representation of orthodontic movement of the natural tooth, the erupted tooth formed by transplantation of natural tooth germ and the bioengineered tooth. (Illustration by R.N.) (
<bold>B</bold>
) Oral photograph of the orthodontic appliance designed for the canine jawbone. The erupted teeth were continuously loaded with 10 gf of horizontal orthodontic force (from the buccal side to the lingual side) for 30 days using an orthodontic appliance. Arrowhead, erupted tooth; arrow, direction of orthodontic force. (
<bold>C</bold>
) CT images of the tooth movement of the erupted tooth formed by transplantation of natural tooth germ and the bioengineered tooth before orthodontic treatment (
<italic>left panels</italic>
, blue) and after orthodontic treatment (
<italic>centre panels</italic>
, red). Merged images before and after orthodontic treatment are shown (
<italic>right panels</italic>
).</p>
</caption>
<graphic xlink:href="srep44522-f4"></graphic>
</fig>
<table-wrap position="float" id="t1">
<label>Table 1</label>
<caption>
<title>Frequency of bioengineered tooth germ development under the various reconstructing conditions.</title>
</caption>
<table frame="hsides" rules="groups" border="1">
<colgroup>
<col align="left"></col>
<col align="center"></col>
</colgroup>
<thead valign="bottom">
<tr>
<th align="left" valign="top" charoff="50">Reconstructing condition</th>
<th align="center" valign="top" charoff="50">Frequency of reconstructed tooth germ development</th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td align="left" valign="top" charoff="50">Epithelial tissue and Mesenchymal tissue</td>
<td align="center" valign="top" charoff="50">100% (6/6)</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">Epithelial tissue and Mesenchymal cells</td>
<td align="center" valign="top" charoff="50">100% (6/6)</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">Epithelial cells and Mesenchymal tissue</td>
<td align="center" valign="top" charoff="50">100% (6/6)</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">Epithelial cells and Mesenchymal cells</td>
<td align="center" valign="top" charoff="50">16.7% (3/18)*</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn id="t1-fn1">
<p>*
<italic>P</italic>
 < 0.001 (chi-square test).</p>
</fn>
</table-wrap-foot>
</table-wrap>
</floats-group>
</pmc>
<affiliations>
<list>
<country>
<li>Japon</li>
</country>
</list>
<tree>
<country name="Japon">
<noRegion>
<name sortKey="Ono, Mitsuaki" sort="Ono, Mitsuaki" uniqKey="Ono M" first="Mitsuaki" last="Ono">Mitsuaki Ono</name>
</noRegion>
<name sortKey="Fukumoto, Satoshi" sort="Fukumoto, Satoshi" uniqKey="Fukumoto S" first="Satoshi" last="Fukumoto">Satoshi Fukumoto</name>
<name sortKey="Hara, Emilio Satoshi" sort="Hara, Emilio Satoshi" uniqKey="Hara E" first="Emilio Satoshi" last="Hara">Emilio Satoshi Hara</name>
<name sortKey="Hayano, Satoru" sort="Hayano, Satoru" uniqKey="Hayano S" first="Satoru" last="Hayano">Satoru Hayano</name>
<name sortKey="Kasugai, Shohei" sort="Kasugai, Shohei" uniqKey="Kasugai S" first="Shohei" last="Kasugai">Shohei Kasugai</name>
<name sortKey="Kuboki, Takuo" sort="Kuboki, Takuo" uniqKey="Kuboki T" first="Takuo" last="Kuboki">Takuo Kuboki</name>
<name sortKey="Mine, Atsushi" sort="Mine, Atsushi" uniqKey="Mine A" first="Atsushi" last="Mine">Atsushi Mine</name>
<name sortKey="Mine, Atsushi" sort="Mine, Atsushi" uniqKey="Mine A" first="Atsushi" last="Mine">Atsushi Mine</name>
<name sortKey="Nakajima, Ryu" sort="Nakajima, Ryu" uniqKey="Nakajima R" first="Ryu" last="Nakajima">Ryu Nakajima</name>
<name sortKey="Ogawa, Miho" sort="Ogawa, Miho" uniqKey="Ogawa M" first="Miho" last="Ogawa">Miho Ogawa</name>
<name sortKey="Ogawa, Miho" sort="Ogawa, Miho" uniqKey="Ogawa M" first="Miho" last="Ogawa">Miho Ogawa</name>
<name sortKey="Ogawa, Miho" sort="Ogawa, Miho" uniqKey="Ogawa M" first="Miho" last="Ogawa">Miho Ogawa</name>
<name sortKey="Oida, Yasutaka" sort="Oida, Yasutaka" uniqKey="Oida Y" first="Yasutaka" last="Oida">Yasutaka Oida</name>
<name sortKey="Ono, Mitsuaki" sort="Ono, Mitsuaki" uniqKey="Ono M" first="Mitsuaki" last="Ono">Mitsuaki Ono</name>
<name sortKey="Oshima, Masamitsu" sort="Oshima, Masamitsu" uniqKey="Oshima M" first="Masamitsu" last="Oshima">Masamitsu Oshima</name>
<name sortKey="Oshima, Masamitsu" sort="Oshima, Masamitsu" uniqKey="Oshima M" first="Masamitsu" last="Oshima">Masamitsu Oshima</name>
<name sortKey="Oshima, Masamitsu" sort="Oshima, Masamitsu" uniqKey="Oshima M" first="Masamitsu" last="Oshima">Masamitsu Oshima</name>
<name sortKey="Shinkawa, Shigehiko" sort="Shinkawa, Shigehiko" uniqKey="Shinkawa S" first="Shigehiko" last="Shinkawa">Shigehiko Shinkawa</name>
<name sortKey="Sonoyama, Wataru" sort="Sonoyama, Wataru" uniqKey="Sonoyama W" first="Wataru" last="Sonoyama">Wataru Sonoyama</name>
<name sortKey="Tsuji, Takashi" sort="Tsuji, Takashi" uniqKey="Tsuji T" first="Takashi" last="Tsuji">Takashi Tsuji</name>
<name sortKey="Tsuji, Takashi" sort="Tsuji, Takashi" uniqKey="Tsuji T" first="Takashi" last="Tsuji">Takashi Tsuji</name>
<name sortKey="Tsuji, Takashi" sort="Tsuji, Takashi" uniqKey="Tsuji T" first="Takashi" last="Tsuji">Takashi Tsuji</name>
<name sortKey="Yamaguchi, Akira" sort="Yamaguchi, Akira" uniqKey="Yamaguchi A" first="Akira" last="Yamaguchi">Akira Yamaguchi</name>
<name sortKey="Yamaguchi, Akira" sort="Yamaguchi, Akira" uniqKey="Yamaguchi A" first="Akira" last="Yamaguchi">Akira Yamaguchi</name>
</country>
</tree>
</affiliations>
</record>

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