THE THIRD DENTITION: Could We Be Approaching an Era When Lost Teeth Grow Back?

Japan’s experimental tooth-regeneration drug, TRG035, brings one of dentistry’s oldest dreams closer to clinical reality.

By DentistryUnited | November 2026

Imagine a future in which a patient loses a permanent tooth and, instead of discussing an implant, bridge or removable denture, the dentist discusses the possibility of growing a biological replacement.

For generations, dentistry has concentrated on restoring what nature has lost. We have developed increasingly sophisticated dentures, implant systems, bone grafting techniques, digital workflows and prosthetic materials. Yet, despite these remarkable advances, we have not been able to routinely regenerate an entire natural human tooth.

That could eventually change.

A Japanese research programme has brought an experimental tooth-regeneration drug called TRG035 into human clinical development. It targets a protein known as USAG-1, which normally acts as a brake on tooth development.

The development is significant not simply because of the possibility of growing teeth, but because it represents a different philosophy of treatment: instead of replacing a missing biological structure with an artificial one, can we activate the body’s own developmental machinery to rebuild it?

The science is promising. The clinical journey, however, is still unfolding.

1. The Japanese breakthrough: What exactly is happening?

The research involves scientists associated with Kyoto University, Kitano Hospital and Toregem BioPharma, a Japanese biotechnology company.

The experimental drug, TRG035, is a monoclonal antibody designed to neutralise USAG-1 (uterine sensitisation-associated gene-1), a protein that regulates signalling pathways involved in tooth development.

The first human study was registered in Japan under clinical trial identifier jRCT2051240154.

It was a Phase I, randomised, double-blind, placebo-controlled, dose-escalation study.

The registered protocol included:

* A target of 30 healthy adult male participants.
* Participants aged 30 to under 65 years.
* At least one missing molar.
* A single intravenous administration of TRG035 or placebo.
* Five planned dose levels, ranging from 0.4 mg/kg to 24 mg/kg.
* Primary assessment of safety, with pharmacokinetics and antibody formation as secondary outcomes.

An important clarification: although participants had missing teeth, this first study was primarily a safety investigation. It was not designed to demonstrate that missing teeth could be regrown in these adults.

The Japanese clinical development programme subsequently reported completion of Phase I in September 2025.

The Japanese Agency for Medical Research and Development (AMED) records that the study evaluated safety, tolerability and dose selection.

2. The science: Why target USAG-1?

To understand why this approach is so interesting, we need to look at how teeth develop.

Tooth formation is not a random process. It is regulated by a complex interaction between epithelial and mesenchymal tissues, with several molecular signalling pathways controlling the initiation, development, shape and number of teeth.

Two particularly important pathways are:

BMP – Bone Morphogenetic Protein signalling

BMP signalling participates in the regulation of tooth development and the differentiation of dental tissues.

WNT – WNT signalling pathway

WNT signalling is another essential regulator of embryonic development and odontogenesis.

USAG-1, also known as SOSTDC1, acts as an inhibitor of these developmental signals.

In simple terms, it functions partly as a biological brake on tooth formation.

The researchers hypothesised that inhibiting USAG-1 could release this brake and allow otherwise suppressed tooth-development potential to become active.

TRG035 is designed to achieve this through a targeted antibody-based approach.

It is not a conventional growth supplement, stem-cell injection or artificial tooth implant. It is a molecular intervention intended to influence the biological signalling mechanisms responsible for tooth formation.

3. What did the animal experiments demonstrate?

The foundation of this research was published in 2021 in Science Advances.

The paper was titled:

Anti–USAG-1 therapy for tooth regeneration through enhanced BMP signaling.

DOI: 10.1126/sciadv.abf1798

The research team investigated whether neutralising USAG-1 could restore tooth development in animal models.

The findings were particularly interesting:

* In genetically modified mice, the absence of USAG-1 was associated with the development of additional teeth.
* Administration of selected USAG-1-neutralising antibodies restored tooth formation in certain mouse models of congenital tooth agenesis.
* In wild-type mice, antibody administration promoted the formation of additional teeth.
* In ferrets, researchers observed additional tooth formation resembling a third dentition.

The ferret findings were particularly relevant because ferrets, like humans, are diphyodont animals: they normally develop two generations of teeth.

However, there are important scientific qualifications. The ferret experiments required higher antibody exposure, repeated administration and immunosuppression. The results should not be interpreted as proof that the same treatment will produce predictable, functional replacement teeth in humans.

The research nevertheless established an important principle: molecular signalling pathways may provide a route to activating dormant tooth-development potential.

4. The next milestone: Moving from healthy adults to children

One of the most important developments occurred in 2026.

According to Japan’s AMED programme documentation, the Phase I study was completed in September 2025. In April 2026, the research team completed a consultation with Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) concerning a Phase II study involving children aged 2–12 years with congenital tooth agenesis.

On 17 August 2026, Toregem BioPharma announced that the PMDA had completed its investigation of the clinical trial notification for the Phase IIa programme.

The next study is intended to investigate the drug in patients with the condition it is initially being developed to treat.

This is an important transition. The programme is moving from assessing the safety of an investigational drug in healthy adults towards investigating its potential therapeutic application in patients.

It is not yet evidence of successful human tooth regeneration.

The company is also preparing for possible clinical development in the United States.

5. Here is the most important distinction: Congenitally missing teeth versus extracted teeth

This is where headlines and social-media posts can become misleading.

The initial clinical programme is directed at congenital tooth agenesis.

This means that a person is born without one or more teeth because the corresponding tooth development did not occur normally.

It includes conditions such as:

* Hypodontia: congenitally missing teeth in smaller numbers.
* Oligodontia: six or more congenitally missing teeth.
* Severe congenital tooth agenesis, which may involve extensive absence of the permanent dentition.

The proposed treatment seeks to activate tooth-development potential that may have been arrested or suppressed.

But what about the much larger population of people who lose teeth because of:

* Dental caries?
* Periodontitis?
* Trauma?
* Failed endodontic treatment?
* Extraction of non-restorable teeth?
* Complications involving previously placed implants?

These are different biological situations.

In an individual who loses a permanent tooth through extraction, the original tooth germ may no longer be present. The surrounding bone and soft tissues may also have undergone significant remodelling.

We cannot assume that a drug capable of rescuing arrested tooth development in congenital agenesis will automatically regenerate an extracted permanent tooth.

The research team has expressed an interest in eventually extending this technology to acquired tooth loss. However, this remains a future development objective, not an established clinical indication.

This distinction is essential when communicating the research to patients and dental professionals.

6. Does this mean dentures and dental implants will become obsolete?

Certainly not at this stage.

Dental implants have transformed modern restorative dentistry. With appropriate case selection, planning, placement, maintenance and management of biological complications, implants can provide excellent long-term outcomes.

Likewise, removable prostheses and fixed dental bridges remain important treatment options for patients with different clinical and financial needs.

It is also misleading to suggest that every implant or denture has a predetermined expiry date.

Implants can function for decades, although prosthetic components, restorations and surrounding tissues may require maintenance or intervention.

What TRG035 potentially introduces is an entirely different category of treatment.

If biological tooth regeneration becomes clinically successful, dentists may eventually have another therapeutic option alongside conventional prosthodontics and implant dentistry.

The question may no longer be exclusively how to replace a missing tooth, but whether the patient’s own biology can be encouraged to produce a replacement.

That is a profound change in the way we think about restorative dentistry.

7. The scientific challenges that still need to be overcome

Growing something that resembles a tooth is only the beginning.

For a regenerated tooth to become a meaningful clinical replacement, it must demonstrate:

1. Correct positioning: The tooth must develop in an anatomically appropriate location.
2. Appropriate morphology: Its crown dimensions and shape must be compatible with the patient’s occlusion.
3. Root development: It must develop adequate roots and appropriate periodontal support.
4. Periodontal integration: The tooth must establish a functional relationship with the periodontal ligament and surrounding alveolar bone.
5. Neural and vascular development: Pulpal tissues must develop with appropriate vascular and neural components.
6. Functional eruption: The tooth must erupt into a useful position and establish a stable occlusal relationship.
7. Long-term safety: The treatment must demonstrate predictable outcomes without inappropriate or excessive tooth formation or other unintended biological effects.

There is another important challenge: tooth development is a highly regulated process. BMP and WNT pathways participate in many biological functions beyond dentistry.

An intervention that modifies these pathways must therefore be carefully controlled, particularly when being developed for young children.

The long-term behaviour of regenerated teeth will be just as important as their initial formation.

8. When could this treatment become available?

The Japanese research programme has publicly stated an ambition to make the treatment available in Japan by 2030.

That is a development target, not a guaranteed launch date.

The drug still needs successful clinical evaluation, further regulatory review and eventual marketing authorisation.

The initial programme is focused on congenital tooth agenesis. Wider application to acquired tooth loss would require additional research and clinical trials.

Patients should therefore continue to receive established treatment based on their current clinical needs rather than postponing necessary care in anticipation of an experimental therapy.

9. What could this mean for the future of dentistry?

For dental professionals, this development deserves attention beyond the excitement of a possible new drug.

It raises questions about the future relationship between several disciplines:

* Oral and maxillofacial biology.
* Molecular dentistry.
* Developmental biology.
* Regenerative medicine.
* Orthodontics.
* Periodontics.
* Implantology.
* Prosthodontics.

It may also eventually change the way dental education approaches tooth development and missing teeth.

Imagine a future clinical assessment involving not just radiographs, CBCT and digital scans, but also an understanding of the patient’s genetic and developmental background to determine whether biological regeneration is possible.

That future is not here yet, but the research gives us a reason to take it seriously.

For implantologists and restorative dentists, the message is not that their profession is disappearing. It is that the definition of a treatment option may expand.

For researchers, the opportunity is even greater: to understand how the developmental potential of the human dentition can be safely activated.

Conclusion: From replacing teeth to regenerating them

Dentistry has travelled a remarkable distance.

From removable dentures to osseointegrated implants, from conventional impressions to intraoral scanners, and from manual laboratory procedures to digitally designed restorations, our profession has continually reinvented the way we restore oral function.

Yet, one fundamental limitation has remained: we have been unable to routinely make a lost natural permanent tooth grow again.

The Japanese TRG035 programme challenges that limitation.

It is still experimental. Human tooth regeneration has not yet been demonstrated through this treatment, and its initial clinical target is congenital tooth agenesis rather than ordinary tooth loss.

Nevertheless, the science is compelling.

Perhaps the next major revolution in dentistry will not be another improvement in implant surfaces, ceramic materials or aligner technology.

Perhaps it will be the ability to persuade the human body to do something it was once thought incapable of doing: grow another tooth.

The future question may not simply be which implant to place, which bridge to design or which denture to fabricate. It may be whether we can help nature complete what it once started.

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References and further reading

1. Murashima-Suginami A, et al. Anti–USAG-1 therapy for tooth regeneration through enhanced BMP signaling. Science Advances. 2021;7(7):eabf1798. DOI: 10.1126/sciadv.abf1798.
2. Japan Registry of Clinical Trials. Phase I Single-Administration Study of TRG035 in Healthy Adults. Trial registration: jRCT2051240154.
3. Japan Agency for Medical Research and Development (AMED). Development of a novel antibody drug to regenerate missing teeth in patients with congenital tooth agenesis. 2025–2026 programme documentation.
4. Toregem BioPharma. Announcement regarding completion of the PMDA investigation of the Clinical Trial Notification for the TRG035 Phase IIa trial. 17 August 2026.
5. Kitano Hospital. Tooth Regeneration Research Programme – Frequently Asked Questions and clinical development information.
6. Murashima-Suginami A, et al. Development of a new antibody drug to treat congenital tooth agenesis. Journal of Oral Biosciences. 2024. DOI: 10.1016/j.job.2024.10.002.