Whole-tooth regeneration: it takes a village of scientists, clinicians, and patients

Abstract

A team of senior scientists was formed in 2006 to create a blueprint for the regeneration of whole human teeth along with all of the supporting structure of the dentition. The team included experts from diverse fields, each with a reputation for stellar accomplishment. Participants attacked the scientific issues of tooth regeneration but, more importantly, each agreed to work collaboratively with experts from other disciplines to form a learning organization. A commitment to learn from one another produced a unique interdisciplinary and multidisciplinary team. Inspired by the Kennedy space program to send a man to the moon, with its myriad of problems and solutions that no one discipline could solve, this tooth regeneration team devised an ambitious plan that sought to use stem cell biology, engineering, and computational biology to replicate the developmental program for odontogenesis. In this manner, team members envisioned a solution that consisted of known or knowable fundamentals. They proposed a laboratory-grown tooth rudiment that would be capable of executing the complete program for odontogenesis when transplanted to a suitable host, recreating all of the dental tissues, periodontal ligament, cementum, and alveolar bone associated with the canonical tooth. This plan was designed to bring regenerative medicine fully into the dental surgery suite, although a lack of funding has so far prevented the plan from being carried out.

Figure 1. Canonical tissues integrated into the organ

The target of the regeneration strategy was to create a single rooted tooth. This hybrid cartoon-radiograph illustrates the complexity of a single tooth.

Figure 2. Overarching plan for development of a regenerated human tooth

The central blueprint of the tooth would provide all of the production specifications obtained from measurements of canonical teeth and would be used to design a regenerated tooth and measure its fidelity. A biological approach using cell biology, developmental biology, and stem cell biology principles would be married to engineering design and bioactive matrices created by nanotechnology to provide the basis of regenerating a cap stage tooth that could be engrafted to a host. A biomimetic approach was envisioned as a complement to the biological approach and would provide an alternative should the biological approach meet irreconcilable roadblocks. Compliance with FDA regulations was deemed vital for the project in order to move it towards safety trials in animals and then into clinical trials with select patients.

Figure 3. Rationale for regenerating a human tooth

Panel A defines the reciprocal signals occurring between all epithelial-mesenchymal interacting tissues. Fundamental to organogenesis is the ability of one tissue to induce in another tissue the expression of previously quiescent genes that determines the induced tissue to acquire a new identity. Panel B describes the use of growth factors, transcription factors, and matrix factors to provide the signals inducing a naïve stem cell population to adopt odontogenic potential. Panel C is a strategy for screening a variety of stem cell populations, such as mesenchymal stem cells (MSC), embryonic stem cells (ESC), and epithelial stem cells (EpSC) for their ability to adopt odontogenic capacity under the influence of an odontogenic tissue, such as porcine dental epithelia (pDE) or porcine dental mesenchyme (pDM). Panel D is the time line required to bring the laboratory steps together for the in vitro manipulation of stem cell populations to regenerate a cap stage tooth bud and to initiate clinical training with release to the dental community within a decade.