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5.1 Introduction
The tooth is of ectodermal organ whose development is regulated by reciprocal
epithelial-mesenchymal interactions (Jussila et al. 2013 ; Tucker and Sharpe 2004 )
and has characteristic hard tissues that include enamel, dentin and cementum. To
maintain tooth homeostasis, a tooth also has soft connective tissues including pulp
and a periodontal ligament (PDL) that contains nerve fibres and blood vessels
(Avery 2002 ; Nanci 2012 ). Thus, tooth has a three-dimensional multicellular struc-
ture that establishes functional cooperation with the maxillofacial region (Avery
2002 ; Nanci 2012 ). Tooth loss or the onset of oral disease, such as dental caries,
periodontal disease and traumatic injury, causes fundamental problems for oral
function, e.g. enunciation, mastication, occlusion and associated general health
issues (Peoffit et al. 2004 ). To restore the occlusal function after tooth loss, several
dental therapies that replace the tooth with artificial materials, such as fixed dental
bridges or removable dentures, have been widely performed as the conventional
dental treatment (Rosenstiel et al. 2015 ; Ponkorny et al. 2008 ). Currently, osseoin-
tegrated dental implants that can stand alone in the jawbone without affecting the
adjacent teeth have been used to treat tooth loss (Brenemark and Zarb 1985 ; Burns
et al. 2003 ). Although these artificial therapies have been widely applied to rehabili-
tation of tooth loss, further technological improvements based on biological find-
ings are expected to restore tooth physiological functions (Huang et al. 2008 ).
Recent advances in future regenerative therapies have been influenced by many
previous research fields in embryonic development, stem-cell biology and tissue
engineering technology (Brockes and Kumar 2005 ; Langer and Vacanti 1999 ; Atala
2005 ; Madeira et al. 2015 ). As an attractive regenerative concept, stem-cell trans-
plantations using tissue-derived stem cells, embryonic stem (ES) cells or induced
pluripotent stem (iPS) cells have been attempted for repairing damaged tissues due
to structural and functional diseases (Trounson et al. 2013 ; Takebe et al. 2013 ; Addis
and Epstein 2013 ; Kamao et al. 2014 ). Also, cytokine therapy is considered to have
the potential to induce the activation and differentiation of stem/progenitor cells in
various tissues (Gurtner et al. 2008 ). In the dental field, tooth tissue-derived stem
cells and the cytokine network that regulates tooth development have been identi-
fied/characterised at the molecular level (Huang et al. 2009 ). These advances can be
applied to the regenerative approach of dental pulp and periodontal tissues and con-
tributed to the functional repair of partial tooth-tissue damage (Huang et al. 2009 ).
Ideally, the regenerative therapy is to develop fully functional bioengineered tis-
sues/organs that can replace lost or damaged organs following disease, injury or
ageing (Ikeda and Tsuji 2008 ). Organ replacement regenerative therapy, unlike
stem-cell transplantation, has great potential for the replacement of dysfunctional
organ by a fully functional bioengineered organ, which is reconstructed by in vitro
three-dimensional cell manipulation using candidate stem cells (Atala 2005 ; Purnell
2008 ). In dentistry, tooth regenerative therapy would involve replacement with a
bioengineered tooth built using stem cells that have the capacity to form a functional
tooth unit containing periodontal tissue (Yen and Sharpe 2008 ; Volponi et al. 2010 ;
M. Oshima and T. Tsuji