In dentistry, regenerative therapies are often thought of as a future, rather than a current, modality. However, dentists have been using regenerative therapies for decades, one example being vital pulp therapy. Vital pulp therapy was first introduced in the 17th century, and it relies on the regenerative and reparative capabilities of the tooth (2). More recently, clinicians have used other regenerative approaches. For instance, oral surgeons, periodontists, and implantologists have used bone grafting and guided tissue regeneration (GTR) therapies, well-validated techniques that use biocompatible scaffolds to aid tissue regeneration, for many years (3). Moreover, although less well-evidenced, regenerative endodontic therapies, which aim to revitalize the damaged dental pulp, have now to some extent been clinically translated and have been used by many endodontists and pediatric dentists worldwide (4). The application of regenerative therapies still produces fairly unpredictable outcomes; thus, clinicians and researchers are required to keep abreast of advances in evidence-based regenerative materials.

Advances in regenerative dentistry research over recent years have seen whole tooth bioengineering and the use of dental stem cells in a wide array of promising therapies. The discovery of how epithelial and mesenchymal cells interact to initiate a cascade of developmental processes to generate whole organs initiated many efforts to exploit these processes. These pioneering innovations include the first bioengineered tooth via embryonic and adult cell recombination, the characterization of dental pulp stem cells (DPSCs), the first bioengineered tooth grown in a rat jaw, to more recent experiments fabricating bi-layered hydrogel tooth buds (5–8). Tooth primordium can be formed by combining both adult and embryonic stem cells from humans and mice. Furthermore, these constructs, when surgically transplanted in edentulous areas in mice, were shown to develop and erupt into fully functional teeth (9–14). Thus, in principle, tooth organ bioengineering is already a reality.

Humans, like most mammals, are diphyodonts; that is, they only have two sets of teeth (primary and permanent) (15). However, other animals possess an almost an unlimited capacity to regenerating their teeth (polyphyodonty) (15). These animals include, but are not limited to, crocodiles, alligators, a wide variety of fish, and geckos. For instance, sharks have a set of 300 teeth in both jaws that can be replaced 30,000 times during their lifetimes (16). They replace their teeth in a “vending machine-like” or “conveyer belt-like” manner. Erupted teeth have successors, and underneath these successors lie dormant stem cells. Therefore, when one tooth is shed, it is replaced by its successors and the stem cells start differentiating into tooth buds ready to take their place. Shark teeth were first studied in the 18th century (17), which prompted a series of studies to understand the mechanism behind their regenerative potential. Recent studies have demonstrated that specific sets of genes, mainly from hedgehog, Wnt/β-catenin, bone-morphogenic protein, and fibroblast growth factor signaling pathways, are responsible for this phenomenon (18, 19). These signaling cascades orchestrate the development of the dental lamina which, in return, regenerates the tooth (18, 19).

Other studies have focused on crocodiles, which also possess an exceptional capacity to regenerate teeth. In each jaw quadrant, crocodiles have a set of 20 teeth which can be replaced 50 times during their lifetimes (20). As with sharks, specific sets of genes in different signaling pathways have been shown to be central to tooth regeneration (19, 20). Humans also possess these genes, although during evolution they have been “switched off.” Understanding the function of these genes and the underlying physiological processes might allow their “re-activation” and the potential to regenerate teeth in patients who have lost their teeth due to an underlying condition or aging.

Although the ultimate goal in regenerative dentistry is to regenerate a whole tooth, studies into tooth regeneration also provide other new therapeutic opportunities (21). Some focus on regenerating specific dental tissues such as dentine, pulp tissues, or enamel using either cell-based approaches, scaffold-based approaches, or both (21). One recent example is the demonstration that certain compounds developed for Alzheimer's disease, namely the small molecule GSK-3 inhibitor tideglusib, can activate dentine reparative mechanisms (21). Low concentrations of these molecules were embedded into injectable collagen sponges which, when placed in contact with vital pulp tissues, stimulated intracellular signaling, stem cell differentiation into odontoblasts, and eventually the production of reparative dentine in its former configuration. This is of particular importance since current materials, mainly tricalcium silicate-based cements, replace dentine rather than regenerating it. As noted above, pulp regeneration can be regarded as a regenerative endodontic therapy that has already clinically translated and documented (4). With respect to enamel, the cell that form it, ameloblasts, die after producing it, making enamel rather difficult to regenerate. However, considerable efforts are being made to mimic or regenerate enamel hydroxyapatite crystals either via biologically-inspired materials or cell-based approaches (22–24).

While these are some examples of many aiming to regenerate specific dental tissues, other groups have focused on exploiting the regenerative potential of DPSCs, a highly pluripotent and accessible cell type. These studies have so far primarily focused on neural repair, smooth muscles regeneration, bladder tissue repair, retinal tissue repair, and bone regeneration, to name a few (25–28).

Many clinical treatments have emerged from an in-depth understanding of the underlying molecular biology and genetics, so exposing young dentists to these principles is of prime importance. Currently, dental undergraduates are forced to primarily focus on the clinical aspects of dentistry and skills acquisition, which are, of course, very important. However, due to the current rapid pace of innovation and advances in regenerative dentistry, dentists should be exposed to at least its basics at an early stage. Failing to do so will only make it harder for future dentists to catch up.

One of the authors' personal experiences of studying Regenerative Dentistry at King's College London highlight some of the salient issues. All first and second year dental undergraduates are taught basic biology, but later years at dental school mainly focus on the clinical aspects of dentistry, leaving basic science marginalized. Students applying for the Regenerative Dentistry Program are expected to have a moderate understanding of molecular biology, genetics, and biomaterial sciences. Due to the lack of early exposure to these subjects as undergraduates, graduate students enrolled in these postgraduate programs are likely to experience difficulties with the course materials, which eventually hinders their progress and diverts time away from applying knowledge to research. If, however, undergraduate students were provided with sufficient knowledge of the underlying principles of regenerative dentistry, they would have more time to focus on research and innovation.

Dentists should no longer solely be clinicians, but instead physicians that put the mouth back to where it belongs, in the body. With recent advances in genomics, not least next-generation sequencing technologies, new genetic disorders are constantly being added to the literature. There are now over 6,500 known inherited conditions, 700 of which are craniofacial and dental-related syndromes (29). Individuals can now have their genomes sequences for as little as $300. These personalized genetic reports provide individuals with data that may predict their predisposition to a specific disease (e.g., cancer or neurodegenerative disease), meaning that patients are becoming more knowledgeable about their own genetic risk factors and will expect answers and clarification from their healthcare providers.

General dentists could be the first to encounter patients with a genetic disease and, if diagnosed correctly, they could offer the ideal referral. Moreover, pediatric dentists are often the first to receive these referrals, since they diagnose and manage a wide range of genetic defects such as amelogenesis imperfecta (AI), dentinogenesis imperfecta, hypodontia, and supernumerary teeth, amongst other craniofacial syndromes such as orofacial clefts. AI does not necessarily affect the teeth alone, in some cases also manifesting with enamel-renal syndrome, a rare genetic disease associated with nephrocalcinosis that affects premature infants (30). These conditions can be detrimental to the health of the child and require immediate intervention. Another example is cleidocranial dysplasia, a rare autosomal dominant skeletal syndrome that is apparent at birth and characterized by dental anomalies and bone abnormalities (31). Its characteristics include clavicle aplasia (absence of the clavicles) and late cranial suture closure. Due to insufficient closure of the cranial vault, part of these children's brains are exposed, mandating head protection such as helmets to avoid brain injuries. Since these conditions are associated with dental anomalies, dentists encounter them relatively frequently and could be the first to provide life-saving advice.

Therefore, dentists may identify numerous genetic diseases as incidental findings. Some genetic defects, if not detected early, could be lethal, so dentists must have a good working knowledge of genetics to be able to diagnose and deal with such cases. The discovery of new mutations will continue to accelerate, and if dentists are not knowledgeable about them they may not be able to detect, diagnose, or manage them.

Unlike regenerative medicine, regenerative dentistry is a relatively new field, albeit one that has recently gained a lot of attention. Over the past 5 years, postgraduate programs in “Regenerative Dentistry” have been established in five leading institutions worldwide. The first to pioneer the program was King's College London, followed by the University of Sheffield, Trinity College Dublin, the University of Michigan, and Tokyo Medical and Dental University. The proactive integration of these programs into these dental schools indicates how crucial these programs are for future dentists globally.

This has led to and coincided with studies evaluating levels of knowledge about regenerative dentistry in undergraduate dental students. The outcomes commonly assessed in these studies included knowledge about stem cells; sources of knowledge; interest in continuous education; interest in pursuing graduate education in regenerative dentistry; and clinical applications of stem cells (32). A multicenter study of 231 final year dental students reported that the majority of students had a “poor” level of knowledge with respect to stem cells (33). Nevertheless, 80% of dental students expressed an interest in pursuing continuing education in stem cells and exploring its clinical applications in regenerative dentistry (33). Similarly, another study of a smaller sample of 80 final year dental students found that 70% were only able to provide a definition of stem cells and that knowledge about the types and clinical applications of stem cells was poor (34). This corroborates findings from a more recent multicenter study that aimed to evaluate the knowledge and clinical applications of regenerative dentistry in dentists, specialist pediatric dentists, and endodontists (35). In this study, despite disparities among participants, the basic level of knowledge was still poor with respect to stem cells and the clinical applications of regenerative dentistry. However, most of these studies were confined to asking the participants to merely provide a definition of stem cells; a classification of stem cells; and the clinical applications of regenerative dentistry.