Plos One - Functional Tooth Regeneration Using a Bioengineered Tooth Unit as a Mature Organ Replacement Regenerative Therapy
We here demonstrate the successful transplantation of a bioengineered tooth unit, which is a model for a bioengineered mature organ, into a missing tooth region in vivo and the subsequent restoration of tooth function by this graft. We also show that this transplantation can restore the bone volume in both the vertical and horizontal dimensions in a missing tooth mouse model with a serious extensive bone defect. These findings indicate that whole tooth regenerative therapy is feasible through the transplantation of a bioengineered mature tooth unit. This study also provides the first reported evidence of entire organ regeneration through the transplantation of a bioengineered tooth.
Organ replacement regenerative therapy, but not stem cell transplantation regenerative therapy for tissue repair, holds great promise for the future replacement of a dysfunctional organ with a bioengineered organ reconstructed using three-dimensional cell manipulation in vitro. In previous reports, however, artificial organs, which were constructed with various cells and artificial materials could not restore functionality and thus are not a viable option for long-term organ replacement in vivo. Previously, it has been shown that a bioengineered organ can be grown in vivo in amphibian models in which activin-treated cell aggregates could form a secondary heart with pumping function and also regenerate eyes that were light responsive and connected with the host nervous system. Recently, we have also regenerated bioengineered organ germs, including tooth germs and whisker follicles, and successfully achieved a fully functioning tooth replacement in an adult mouse through the transplantation of a bioengineered tooth germ in the lost tooth region. It has been anticipated that replacement therapies will be developed in the future through the transplantation of a bioengineered mature organ with full functionality and long-term viability. In our present experiments, we successfully generated a size-controlled bioengineered mature tooth unit, a strategy we adopted because the growth of functional organs in vitro is not yet possible. Organs require a sufficient mass (cell number) and proper shape to function and the tooth has unique morphological features, such as the tooth crown width and length (macro-morphology), and cusp and root shape (micro-morphology). However, the technology to regulate tooth morphogenesis for whole tooth regeneration remains unexplored. We recently developed a novel organ germ method to regulate the crown width by regulating the contact area between epithelial and mesenchymal cell layers. In our previous work, we demonstrated that the length of the bioengineered tooth is equivalent to that of natural tooth after the transplantation of the bioengineered tooth germ into oral environment. In this study, the length of the bioengineered tooth unit could be controlled longitudinally, which would be provided by the limited space of the device. These findings provide the first evidence that the bioengineered tooth can be controlled in three-dimensions using a specialized device. It is also thought that bioengineered teeth could be generated with a controlled crown width through cell manipulation and tooth length by placement in a size-controlling device, which places a three-dimensional spatial limitation on size.