Submit Manuscript | http://medcraveonline.com Abbreviations: DPSCs, dental pulp stem cells; SHEDs, stem cells from human exfoliated deciduous teeth; PDLSCs, periodontal ligament stem cells; SCAPs, stem cells of apical papilla; 1BA, frst branchial arch; PEK, primary enamel knot; SEK, secondary enamel knot; FGFs, fbroblast growth factors; BMPs, bone morphogenetic proteins; FGFs, fbroblast growth factors; BMPs, bone morphogenetic protein; Lhx, lim/homeobox protein; Barx-1, barh-like homeobox 1; Msx, msh homeobox; Dlx, homeobox protein dlx; Shh, sonic hedge- hog; Wnt, wingles-related integration site homeobox; Lef-1, lymphoid enhancer-binding factor 1; p21, cyclin-dependent kinase inhibitor 1 Introduction Rapid increase of knowledge in stem cell research, bioengineering technology and molecular basis of odontogenesis has fnally lead us to the point where it is possible to develop approaches for treatment of tooth loss with bioengineered teeth, which one day might supplement and replace conventional prosthodontics and dental implants. 1,2 What puts tooth bioengineering in the forefront of bio-regenerative medicine are the very features of tooth as an organ. Teeth are easily accessible, non-essential for life organs of relatively simple structure with their own complement of various stem cells niches. 2 There are at least three possible ways to bioengineer tooth - to build and then to assemble individual tooth components crown, root; putting aggregates of dental stem cells to spontaneously re-organize within tooth-shape customized scaffolds; and to transplant artifcially created tooth germs into adult jaws until they develop into functional teeth. 3–5 From strictly clinical point of view in the treatment of tooth loss, tooth crown is of less importance than tooth root because the crown itself if there is a viable root can be easily replaced by the artifcial one with adequate morphology following conventional prosthodontic treatment protocols. In deciduous and permanent teeth, researchers have already identifed, cultivated and manipulated cellular elements needed to synthesize hard and soft tissue elements of tooth crown and root - DPSCs and SHEDs, for dentine PDLSCs, and SCAPs for cementum and alveolar bone anchoring periodontal ligament fbres. 6–8 Even though these cells show huge potential in regenerative treatment of dental pulp injuries and periodontal ligament defects, their odontogenic potential for tooth bioengineering has been less apparent. 6 In numerous attempts to bioengineer whole-tooth or tooth components by seeding dental stem cells onto bio-degradable scaffolds moulded in the shape of teeth, dentin-like or cementum-like structures with incorporated cellular elements were indeed produced, however, those chips and globules of mineralized tissue were still far cry from what resembles to normal crown, root, or especially the whole tooth. 3,9 One of the main reasons why such an approach in tooth bioengineering does not yield as expected, is that scaffolds represent an over-simplifcation of micro-environment in which the tooth development normally takes place where stem cells only represent a niche, but not a full cellular complement. Another reason is that dental stem cells might be too lineage committed and thus have more limited proliferation, differentiation and self-organization potential in comparison to embryonic tooth germ cells. 10,11 Research of properties of various dental stem cell populations is still under way and it will J Stem Cell Res Ther. 2016;1(3):117‒123. 117 © 2016 Kero et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and build upon your work non-commercially. Odontogenesis - a masterful orchestration of functional redundancy or what makes tooth bioengineering an intrinsically diffcult concept Volume 1 Issue 3 - 2016 Darko Kero, 1 Mirna Saraga Babic 2 1 Study Programme of Dental Medicine, University of Split, Croatia 2 Department of Anatomy, Histology and Embryology, University of Split, Croatia Correspondence: Darko Kero, Study Programme of Dental Medicine, School of Medicine, University of Split, Soltanska 2, 21000 Split, Croatia, Tel +385 21 557 846, Fax +385 21 557 811, Email dkero@mefst.hr Received: July 02, 2016 | Published: August 05, 2016 Abstract Rapid increase of knowledge in stem cell research, bioengineering technology and molecular basis of odontogenesis has finally lead us to the point where it is possible to develop approaches for treatment of tooth loss with bioengineered teeth, which one day might completely replace conventional prosthodontics and dental implants. By holding onto the premise that in order to bioengineer teeth, full understanding of how teeth develop is required, it must be acknowledged that there are certain features of odontogenesis which create obstacles in gaining that understanding. One such feature is the functional redundancy in genetic networks responsible for molecular control of odontogenesis. Abundant data imply that having functional redundancy of various elements in regulatory genetic networks is more than just a failsafe built into the odontogenic sequence in order to secure unhindered development of teeth. This phenomenon plays important roles in determination of tooth numbers and positioning, and is increasingly recognized as important for enabling sufficient plasticity of regulatory genetic networks through which the appearance of tooth-type specific and species-specific diversity of mammalian tooth morphology can be explained. Unfortunately, most of what we know about molecular basis of odontogenesis, comes from studies of mouse molars. This represents a serious gap which has to be bridged by the novel insights from developmental biology, stem cell research, and bioengineering technology, if we ever want to make de novo tooth bioengineering a clinically viable method for treatment of tooth loss Keywords: odontogenesis, tooth bioengineering, dental stem cells, morphogenesis, patterning, homeobox genes, growth factors, primary enamel knot Journal of Stem Cell Research & Terapeutics Mini Review Open Access