The ability to regrow teeth after a certain age would be monumental to solving most of our dental problems. Unlike other animals like sharks and alligators that can replace their teeth dozens of times, or the kangaroos and elephants – all polyphyodonts – humans are diphyodonts capable of having only two successive sets of teeth. Most people lose their first tooth between the ages of 6 and 12 and have them all replaced by age 21. Edentulous problems (meaning lacking teeth) occurring after that age are aided by artificial fittings as tooth regeneration has stayed out of our reach for a long time.
A Japanese research team, led by Katsu Takahashi, head of dentistry and oral surgery at the Medical Research Institute Kitano Hospital in Osaka, was able to stimulate new tooth growth in mice with tooth agenesis. The monumental achievement has not only redefined dental care but also opened new horizons for regenerative medicine and tissue engineering. In this blog post, we will delve into the scientific journey that led Dr. Takahashi to this momentous breakthrough.
Dr. Takahashi has been working on regrowing teeth since 1991, when he was a molecular biology graduate student. The driving force behind his work was the desire to develop a novel approach that could trigger the body’s natural regenerative abilities to regrow teeth with all their original characteristics. This ambitious goal demanded an in-depth understanding of tooth development, stem cell biology, and tissue regeneration. In 2018, he and his team discovered the medicine that can induce new teeth growth and ran experiments with it on mice and ferrets. The results were published in renowned U.S scientific journals in 2021.
Clinical trials and research findings
In his research, Dr. Takahashi stated that teeth could be formed mainly by two mechanisms. Here is the first: rescue of tooth rudiments via targeted molecular therapy by stimulating arrested tooth germs. While it is well known that humans grow two sets of teeth in their lifetimes, recent research has shown the presence of a potential third set of germs. When the second successional lamina forms, the third dentition starts to develop but regresses via apoptosis (programmed cell death). By reactivating the development of tooth germs that have been halted, targeted molecular therapy can be utilized to help patients with congenital tooth agenesis grow teeth.
The second mechanism is by the contribution of odontogenic epithelial stem cells (the ones involved in tooth development) in adults. These stem cells are differentiated from the enamel epithelial stem cells and form the odontogenic mesenchymal stem cells through epithelial-mesenchymal transition. Both the odontogenic epithelial and odontogenic mesenchymal stem cells have been induced to form supernumerary teeth in adults.
In his research, Dr. Takahashi and his co-authors dove into an in-depth characterization of these unique stem cells. They identified key molecular markers that distinguished odontogenic stem cells from other cell types, enabling their isolation and cultivation.
However, Dr. Takahashi’s medicine is based on targeted molecular therapy. Manabu Sugai of the University of Fukui, a co-author, said that “Conventional tissue engineering is not suitable for tooth regeneration. Our study shows that cell-free molecular therapy is effective for a wide range of congenital tooth agenesis.”
Targeted molecular therapy to rescue tooth rudiments
The growth of a tooth depends on various molecular interactions, including major signaling pathways regulating tooth development: the BMP(bone morphogenetic protein) and Wnt signaling. The molecules responsible for tooth development have been identified as RunX2, USAG-1 Spry-4. While at Kyoto University and in the U.S. afterwards, Dr. Talahashi made the deletion of these genes, the USAG-1, the focal point of his research.
Uterine sensitization-associated gene-1 (USAG-1) is a bone morphogenetic protein (BMP) antagonist gene that controls the number of teeth by inhibiting development of potential tooth germs. It’s very active in people with congenital tooth agenesis and missing teeth. Congenital tooth agenesis, otherwise referred to as anodontia, is a congenital condition characterized by the absence of one or more teeth. It is caused by the cessation of tooth development due to the deletion of the causative gene and suppression of its function.
Now, inhibition of tooth regression has been proven to cause development of rudimentary maxillary incisors in USAG-1 deficient mice. As USAG-1 is a BMP-7 antagonist, its inhibition would naturally increase BMP signaling as observed in Usag-1-deficient mice, an improvement that prevents apoptosis and leads to supernumerary teeth formation. These results suggest that inactivation or inhibition of single molecules such as Usag-1 have the potential to regenerate whole teeth through the rescue of the rudimental tooth germ.
Application in congenital anodontia
Dr. Takahashi et al tested whether blocking Usag-1 expression locally could reverse arrested tooth formation in Runx2-deficient mice. Runx2-deficient mice were used to mimic congenital anodontia. Runx2 is a transcription factor that plays a crucial role in tooth development and bone formation. When Runx2 is deficient, it can lead to defects in the formation of dental epithelial cells and mesenchymal cells that can result in the absence of teeth or severe tooth agenesis in mice, similar to the condition seen in congenital anodontia in humans.
Furthermore, they also tested a drug-delivery system using cationized gelatin-loaded siRNA to the mandibles of the mice, and it effectively delivered the treatment.
The study demonstrated that application of Usag-1 siRNA partially rescued arrested tooth development in Runx2-deficient mice, showing potential for regenerating teeth in cases of congenital tooth agenesis. These findings have important implications for developing treatments for this condition in humans.
Dr. Takahashi’s tooth regrowth medicine will be particularly relevant for young children aged 2 to 6 who display signs of anodontia. Current treatment options for these children are often complex and involve orthodontic procedures and dental prosthetics. The regenerative approach could potentially provide a less invasive and more natural solution, allowing these children to develop a complete set of teeth without the need for extensive interventions.
Besides congenital anodontia, the medication also benefits a wide array of dental challenges. Here’s how:
For tooth regeneration in individuals with dental pathologies, one of the primary beneficiaries of this innovation includes those who have lost teeth due to severe dental cavities, diseases or trauma. Traditional solutions such as dentures and dental implants have limitations, both functionally and aesthetically. However, the tooth regrowth medicine offers a promising alternative by stimulating the natural regrowth of teeth. This medicine has the potential to improve the quality of life for those dealing with tooth loss, restoring both the appearance and function of their natural dentition.
As an alternative to conventional interventions, the medicine offers the possibility of preventing or reducing the need for conventional dental interventions like extractions, dental bridges or implants. This preventive aspect could significantly enhance oral health outcomes and reduce the overall burden of dental treatments for individuals.
For enhanced aesthetics and functionality, dental implants and dentures are effective but may not always perfectly replicate the aesthetics and functionality of natural teeth. The tooth regrowth medication has the potential to yield teeth that closely resemble the patient’s original dentition in terms of appearance, strength and functionality. This can have a positive impact on self-esteem, confidence and overall quality of life.
Dental interventions can be costly, particularly for procedures involving implants and orthodontics. If the tooth regrowth medication becomes a viable and cost-effective solution, it could potentially reduce the economic burden on individuals and health-care systems alike.
Dr. Takahashi’s research extends beyond dentistry, contributing to the broader field of regenerative medicine. The principles and techniques developed in this research could have implications for other regenerative therapies targeting various tissues and organs.
Challenges and obstacles in development and implementation
BMP and the Wnt pathways also play important roles in more than just tooth development. They control the development of organs and tissue growth during early embryonic development. This highlights the need to be cautious about using drugs that affect these processes, as they could have widespread effects on the entire body.
Other challenges with its development and implementation include the targeted regeneration complexities, rigorous clinical trials, regulatory approval demands, potential high costs, patient variability, long-term effect uncertainties, public acceptance, and ethical considerations. Overcoming these obstacles during and after human clinical trials, and ensuring the medicine’s safety and efficacy in humans, would preclude successful integration into dental practices.
Availability
The human clinical trials would commence July 2024, with the hope of making the medication available for widespread use by 2030. “In any case, we’re hoping to see a time when tooth-regrowth medicine is a third choice alongside dentures and implants,” Takahashi said, outlining his ambitious vision for the future of dentistry.
Peace Chukwu
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How can i contact this institute? I am not a drug taker but for sure i will give this a shot
Our blogger writes that the medication won’t be available until 2030, assuming the clinical trials go well. Reaching out to your dentist is probably your best option.
How can I get the treatment for this, I am in desperate need for this treatment.
Please consult with your doctor or dentist.
How can I get involved in these trials?
Your doctor/dentist, local hospitals or clinicaltrials.gov may have information about clinical trials.
I am very interested in clinical trials in Colorado, my name is Stephen Bausch. My cell phone number is 720-226-1857.
Hi Stephen,
Your doctor/dentist, local hospital or clinicaltrials.gov may know about relevant clinical trials in your area. Good luck.