In this blog post, we’ll start by examining the characteristics of animals—such as sharks and crocodiles—that continuously regenerate their teeth, then explore the principles of tooth regeneration technology using stem cells and dental buds, along with its research achievements, limitations, and future potential.
Can We Regrow Teeth?
Even the lion, the king of beasts, finds it difficult to survive on its own if it loses or breaks a tooth due to old age or a fierce fight. Similarly, humans experience significant inconvenience in daily life without teeth. However, sharks and crocodiles have little need to worry about this, even though their teeth aren’t particularly hard. What is their secret? Sharks and crocodiles do not fear broken or lost teeth because their teeth regenerate continuously. The old proverb, “If you have no teeth, you live by your gums,” may one day become a thing of the past if tooth regeneration technology advances. Until now, dentures and implants have served as artificial teeth for people without teeth, but tooth regeneration technology aims to create new teeth from the patient’s own tissue instead of using artificial materials. Therefore, if this technology advances sufficiently, it has the potential to solve the problem of tooth loss in a way that differs from current tooth replacement treatments. However, we have not yet reached the stage where an entire tooth can be regenerated in a human and used for daily life; research and clinical development are still ongoing.
Tooth regeneration, as the term suggests, is the process of recreating teeth. Rather than creating structures resembling teeth using artificial materials, the goal is to biologically regenerate the tissues and structures that make up teeth. Sharks and crocodiles, known as prime examples of animals capable of continuously producing teeth, possess biological systems related to tooth development that allow them to regenerate teeth over multiple generations. However, since humans have a limited ability to continuously produce teeth throughout their lives, efforts are being made to develop tooth regeneration technology through different approaches. Current research on human tooth regeneration is exploring various methods, including stem cells, tissue engineering, and organoids, and the regeneration of dental tissue using stem cells is one of the key areas of study. In particular, recent research has focused on induced pluripotent stem cells (iPSCs) and tooth-derived stem cells, with efforts underway not only to create complete teeth but also to regenerate individual tissues that make up the tooth, such as the pulp, dentin, and periodontal tissues.
The Seed That Forms Teeth: The Dental Germ
Most of a tooth is composed of dentin. Dentin is not a single type of cell but a hard tissue produced by cells within the pulp, and it accounts for a significant portion of the tooth. Therefore, just like with other organs in the body, it is extremely difficult to directly create an entire tooth simply by culturing stem cells. Instead, by creating the dental germ—the foundation of the tooth—researchers can gain insight into the process of tooth formation. The tooth bud is a structure that exists before a tooth is fully formed; it serves as the starting point for the development of both primary and permanent teeth. The tooth bud can be described as both the soil and the seed that produce the fruit known as a tooth.
Therefore, if we use stem cells to create a tooth bud, we can guide it to develop into a tooth as it matures. The formation of teeth relies on the intricate interaction between epithelial and mesenchymal cells. Mesenchymal cells are involved in the formation of the pulp and dentin, while epithelial cells play a crucial role in the enamel formation process. Ultimately, ensuring that these two cell lineages interact and differentiate appropriately during tooth development is one of the key challenges in tooth regeneration. Recent research has been actively investigating the specific types and roles of dental stem cells. In 2026, GLDN-positive odontogenic stem cells—which appear to play a crucial role in the development and regeneration of the pulp and dentin—were reported to be present in the human dental papilla.
How Are Reprogrammed Stem Cells Created?
So, how are stem cells created? One of the methods currently attracting attention in dental regeneration research is the technology for creating reprogrammed stem cells, or induced pluripotent stem cells (iPSCs). This method involves subjecting fully differentiated adult cells to a specific process to revert them to a state where they can differentiate into various cell types. The iPSC technology, which became widely known through research by Shinya Yamanaka’s team in 2006, uses four factors—KLF4, OCT4, c-MYC, and SOX2—to reprogram adult cells. By using these four factors to reprogram adult cells, it is possible to create iPSCs capable of differentiating into cells of various tissues. However, for practical clinical application, there are many issues that need to be resolved, such as the safety of gene delivery methods, the potential for tumor formation, and ensuring stable cell differentiation and function.
In early iPSC research, viral vectors such as retroviruses were used to deliver these four factors into cells. Retroviruses have the ability to insert their own genetic material into the host cell’s genome; the human immunodeficiency virus (HIV) is also a type of retrovirus. Therefore, by inserting the necessary genes into these viral vectors and delivering them to adult cells, the factors required to reprogram the cells can be expressed. Subsequently, various non-integrating methods—such as Sendai virus, episomal vectors, and mRNA—were developed to reduce the risk of permanent integration of foreign genes into the genome.
When induced pluripotent stem cells (iPSCs) created in this manner are cultured under appropriate conditions and provided with the necessary signals, they can be differentiated into epithelial and mesenchymal cells involved in tooth formation. Furthermore, by combining these cells through tissue engineering under appropriate conditions, it is possible to form structures similar to tooth buds or to guide them toward regenerating dental tissue. Recent studies are not only focused on dental tissue regeneration using stem cells but also on utilizing three-dimensional organoids to mimic the structure and function of teeth. However, such research is still largely confined to the laboratory and preclinical stages, and significant technological advancements are required before it can reach the level of producing fully functional teeth in humans.
The Potential for Tooth Regeneration Confirmed in Animal Studies
A research team in Japan previously conducted tooth regeneration studies using epithelial and mesenchymal cells in mice, demonstrating the potential for tooth formation. The researchers extracted the cells necessary for tooth formation, cultured them in a collagen gel, and transplanted the resulting tooth buds into mice. As a result, actual tooth tissue was observed forming from the transplanted tooth buds. This study was one of the important preclinical studies demonstrating the potential to biologically regenerate damaged or lost teeth.
However, the mere fact that teeth formed in animals does not necessarily mean that human teeth can regenerate in the same way. For application in humans, not only must the size and shape of the tooth be correct, but various tissues—including the pulp, dentin, enamel, periodontal ligament, blood vessels, and nerves—must also form in the precise positions and sequence. In recent tooth regeneration research, methods for regenerating not only the entire tooth but also parts of it—such as the tooth root, pulp, and periodontal tissues—are being actively studied. In fact, research has been reported on creating organoids resembling tooth roots using human pulp stem cells and periodontal ligament stem cells.
Remaining Challenges in Tooth Regeneration
Unfortunately, however, the path to tooth regeneration remains arduous. First, the process by which teeth form from the dental bud is extremely complex, requiring the precise interaction of various cells and signaling pathways at the right time and place. While the basic developmental process of tooth formation has been largely elucidated, a method for reliably producing teeth of the desired shape and position in humans has not yet been fully established. In particular, regenerated teeth must match the size and shape of the original teeth. While current research has made significant progress in creating the tissues that make up teeth or tooth-like structures, accurately reproducing the unique size and shape of each patient’s teeth and ensuring their natural integration with the jawbone and surrounding tissues remains a major challenge. Even if a tooth can be created, it must be properly connected to the periodontal tissues, blood vessels, and nerves to function normally within the mouth.
Even if technical issues are resolved, major obstacles remain in the form of productivity and safety. Since the shape and size of teeth vary from person to person—and even within a single person, individual teeth differ in shape and size depending on their location and function—tooth regeneration can present challenges similar to making dozens of custom-tailored suits for each person. It would be ideal if teeth could be mass-produced and used just like ready-to-wear clothing; however, unlike with ready-to-wear clothing—where a certain degree of discrepancy between the body and the garment is tolerable—teeth can cause occlusal problems or significant discomfort if the shape and position of the new tooth do not properly align with the existing teeth. In addition, issues such as the stable differentiation of stem cells, the potential for abnormal cell proliferation and tumor formation, long-term safety, immunological concerns, and the connection of blood vessels and nerves must also be addressed. In fact, a systematic review on stem cell-based tooth regeneration published in 2025 noted that many studies remain limited to animal experiments and concluded that randomized clinical trials to confirm long-term safety and clinical efficacy are still needed before the method can be widely applied to humans.
Nevertheless, research on tooth regeneration is steadily advancing. Recently, studies have been conducted to regenerate teeth and surrounding tissues by combining various technologies—including not only stem cells but also organoids, biomaterials, hydrogels, tissue engineering, and 3D bioprinting. As of 2026, clinical development is underway in Japan to induce tooth regeneration using an antibody therapy targeting USAG-1, and the developer, Torezem Biopharma, has announced that it is proceeding with a Phase 2 clinical trial of TRG035 in Japan. This demonstrates that research is expanding beyond the stage of relying solely on animal experiments, as in the past, to a stage where the potential for tooth regeneration therapy in actual human subjects is being verified. However, this treatment is not yet an established therapy that patients with general tooth loss can readily receive at a hospital.
Despite these obstacles, if the safety and efficacy of tooth regeneration are proven in the future and technical issues are resolved, allowing for its use in actual clinical practice, treatment approaches for tooth loss could change significantly. This is because we may be entering an era that goes beyond simply replacing lost teeth with artificial substitutes, such as dentures or implants, to one where new teeth and dental tissues are generated by harnessing the patient’s own tooth development process and regenerative capacity. Although there are still many hurdles to overcome, research on tooth regeneration continues to advance as an interdisciplinary field at the intersection of life sciences, dentistry, stem cell research, and tissue engineering. A day may come when losing a tooth is far less daunting than it is today. Research aimed at developing tooth regeneration into a viable treatment option will continue to play a crucial role in improving humanity’s oral health and quality of life.
