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Functional Tooth Regrowth Demonstrated in a Canine Model

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Posted 21 March 2017 - 12:17 AM

There has been considerable progress over the past decade towards the regrowth or tissue engineering of adult teeth via a number of different mechanisms. These include growing a tooth entirely outside the body, starting from a few cells, an approach that has a range of associated challenges regarding how to guide the growing tissues to form the right shape. Some years back researchers demonstrated a fairly brute force method of providing that guidance in tissue engineered mouse teeth, to pick one example. Then there is the alternative approach in which researchers attempt to create the seed of a tooth, the tooth germ, a collection of cells as similar as possible to those that occur naturally when a tooth grows. The idea here is to enlist the existing environment of the jaw and gum to guide growth of a new tooth; if the artificial seed is close enough to the natural equivalent, then the end result will be a correctly formed tooth. The paper quoted below is an example of the state of the art in this latter approach to adult tooth regrowth: researchers have pushed towards larger animal models, and can now fairly reliably induce the growth of functional replacement adult teeth in canines.

If you read the paper closely, the researchers are still relying heavily on natural tissues to source the relevant cells to make up the seed for a new tooth. They report on mining the naturally grown teeth of animal models in order to demonstrate that suitably arranged cell combinations will then go on to grow new teeth in those same animals when implanted into the jaw. Future work will involve establishing reliable methods of creating patient-matched cells to order, such as via reprogramming of a patient cells sample into induced pluripotent stem cells, and then differentiating the needed cell types from that pluripotent lineage. Not all of the required recipes for the cell types of interest have yet been established, however, so there is a significant amount of work left to be accomplished. Once done, however, that will open the doors to further progress.

How long before we humans will benefit from this sort of approach to tooth regeneration? Dentistry is somewhat less oppressively regulated than the rest of medicine in much of the world, the consequence of a long history of somewhat arbitrary separation of disciplines, and so new innovations in dentistry tend to arrive in clinics more rapidly. If researchers are just now growing new teeth in dogs after ten years of work in bioreactors and rodents, then another decade to reach clinical applications is a fair guess. It is an open question as to how well it will work in older individuals, however. Do old people still exhibit enough of the same guiding signals and cellular behavior in gums and jaw bones? It is well known that regeneration in general declines with age, for reasons that include failing stem cell activity and altered cell signaling that occurs in reaction to rising levels of molecular damage in tissues. The fastest way to find out is to try and see, but we can also survey the sort of work on aging and stem cell biochemistry that is currently taking place in relation to the development of stem cell therapies. That will provide some idea of the additional time and cost imposed by trying to make things work well in older people. There are differences between old tissues and young tissues, and in many cases they are significant enough to require a modified or alternative approach.

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

In this study, we demonstrated functional tooth restoration after transplanting bioengineered tooth germ in a postnatal large-animal model. The bioengineered tooth, which was reconstructed using canine permanent tooth germ, developed with the correct tooth structure after autologous transplantation into the jawbone. We also determined that the bioengineered tooth erupted into the oral cavity with the features of proper tooth tissue formation and restored physiological tooth function, such as the response to orthodontic mechanical force. This study represents a substantial advancement in organ replacement therapy through the transplantation of bioengineered organ germ as a practical model for future whole-organ regeneration.

Whole-tooth replacement therapy holds great promise for the replacement of lost teeth by reconstructing a fully functional bioengineered tooth using three-dimensional cell manipulation in vitro. It is anticipated that bioengineering technology will ultimately enable the reconstruction of fully functional organs in vitro through the proper arrangement of epithelial and mesenchymal cell components. Many researchers have attempted to generate bioengineered tooth germ using epithelial and mesenchymal cells from embryonic tooth germ or postnatal tooth germ from various species, including mice, rats and swine. With the goal of precisely replicating the developmental processes that occur in organogenesis, the study of an in vitro three-dimensional cell manipulation method called the bioengineered organ germ method has been recently reported. However, additional evidence of the practical application to human medicine is required to demonstrate the generation of bioengineered tooth germ using postnatal cell sources in a large-animal model.

To achieve whole-tooth restoration in humans, it is desirable to autologously transplant bioengineered tooth germ reconstructed using a patient's own stem cells to prevent immunological rejection, and it is necessary to first establish an autologous tooth germ transplantation system in a large-animal model. We therefore investigated whether the canine bioengineered tooth germ reconstructed using epithelial and mesenchymal components isolated from individual tooth germs could develop after autologous transplantation into the jawbone. We demonstrated that a bioengineered tooth reconstructed from canine permanent tooth germ reproduced the correct tooth structure, including calcified components and enamel and dentin microstructure. Furthermore, the erupted bioengineered tooth had a single-root shape with the proper periodontal tissue structure, and it achieved physiological tooth function in terms of biological response to mechanical stress equivalent to the function of a natural tooth.

If a large-scale culture of epithelium/mesenchymal tooth germ cells were to be established in future, this bioengineered tooth technology would be able to treat a large number of missing teeth. Elderly patients, however, do not have a developing tooth germ that can be used for the reconstruction of bioengineered tooth germ in the patient's own jaw. In the dental field, recent stem cell biology studies have led to the identification of dental stem cells based on tooth organogenesis for tooth tissue regeneration and tooth regenerative therapy. Although these stem cells would be valuable cell sources for stem cell transplantation therapy aimed toward dental tissue regeneration, the tooth inductive potential cells, which can replicate an epithelial-mesenchymal interaction for whole-tooth replacement, has not yet been identified.

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