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The possibility of naturally regenerating human teeth—long believed biologically impossible after the loss of developmental potential in adulthood—has become increasingly plausible due to advances in developmental biology, dental stem-cell research, and molecular modulation of signalling pathways. Emerging reports from South Korean research groups describe progress toward a microneedle-delivered regenerative therapy, potentially capable of activating dormant human odontogenic pathways. While full clinical validation remains ongoing, the mechanistic underpinnings are strongly supported by established research in Wnt signalling, GSK-3 inhibition, and dental stem-cell biology.

This article synthesizes available peer-reviewed evidence on tooth regeneration, situating recent South Korean developments within the broader scientific context of regenerative dentistry.

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1. Why Adult Humans Stop Growing Teeth

Humans generate only two sets of teeth because odontogenic signalling programs are silenced after permanent dentition forms, leaving only quiescent epithelial and mesenchymal stem-cell niches in the periodontal ligament and dental pulp (Vidovic et al., 2017). In contrast, some mammals possess continuously renewing dental lamina, enabling lifelong tooth replacement.

A critical molecular barrier to human tooth regeneration is GSK-3, which inhibits the Wnt/β-catenin pathway—a pathway essential for tooth initiation, morphogenesis, cusp patterning, and odontoblast differentiation (Lohi et al., 2010).

Other developmental pathways suppressed in adulthood include:

• BMP and FGF pathways normally active in enamel-knot signalling (Hou et al., 2021),

• Stem-cell proliferation markers that decline with aging (Vidovic et al., 2017),

• Matrix-forming programmes necessary for enamel and dentin deposition (Huang et al., 2021).

Thus, reactivating tooth development requires coordinated stimulation of Wnt signalling, mesenchymal proliferation, enamel-matrix deposition, and extracellular mineralization.

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2. GSK-3 Inhibition and the Tideglusib Breakthrough

The breakthrough that re-ignited the field occurred in 2017, when researchers at King’s College London showed that tideglusib, a small-molecule GSK-3 inhibitor, could stimulate dental pulp stem cells (DPSCs) to regenerate dentin after injury (Neves et al., 2017).

Preclinical findings (Neves et al., 2017):

• Tideglusib activated Wnt/β-catenin signalling in DPSCs.

• A collagen sponge carrying tideglusib led to complete dentin bridge formation in vivo.

• Newly formed dentin integrated seamlessly with native tooth structure.

This provided the first proof that pharmacological reactivation of odontogenesis could surpass conventional restorative dentistry, which relies on inert foreign materials.

Mechanistically, inhibiting GSK-3 releases the suppression on Wnt pathways that govern tooth morphogenesis, effectively reawakening developmental programmes (Lohi et al., 2010; Hou et al., 2021).

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3. Microneedle Patches for Localized Regeneration

Microneedle delivery systems are emerging as powerful tools for targeted, minimally invasive drug delivery. Their ability to bypass epithelial barriers and release regenerative agents directly into deep tissue layers has made them attractive for dental applications (Jin et al., 2023).

South Korean groups have reported developing dissolvable polymer microneedles capable of delivering:

• Tideglusib for pulp and dentin regeneration (building on Neves et al., 2017),

• Growth factors such as BMP-2, FGF-10, and Wnt agonists, all of which play confirmed roles in early tooth initiation and enamel-knot signalling (Hou et al., 2021; Park et al., 2021),

• Enamel matrix derivatives capable of stimulating ameloblast-like activity (Lee et al., 2022).

Microneedle patches offer a strategic advantage in regenerative dentistry: precise spatial delivery of molecules that must remain localized to avoid systemic Wnt activation, which carries oncogenic risks.

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4. Mechanisms of Hard-Tissue Regeneration4.1 Regenerating Dentin

4.1 Regenerating Dentin

Dentin is formed by odontoblasts, which originate from DPSCs. Tideglusib-driven activation of these cells stimulates:

• Proliferation,

• Differentiation (upregulation of DSPP and DMP-1),

• Tubular dentin formation with morphology approaching native tissue (Neves et al., 2017).

4.2 Regenerating Enamel

Enamel is more complex: adult teeth have no ameloblasts, which undergo apoptosis after eruption. However, recent advances include:

• Biomimetic enamel-matrix peptides,

• Calcium-phosphate nanomineralization systems,

• Microneedle-delivered enamel-inducing compounds (Huang et al., 2021; Lee et al., 2022).

These approaches have produced enamel-like microstructures in animal and in vitro models.

4.3 Inducing New Tooth Buds

The most ambitious aim—inducing de novo tooth germs—is supported by mammalian models:

• Forced Wnt activation induces extra teeth in mice (Järvinen et al., 2018).

• Bioengineered tooth germs transplanted into animals can erupt with full functionality (Ikeda et al., 2009).

Although such results have not yet been confirmed in humans, they form the biological foundation for the claim that Wnt-modulating therapies may one day enable true tooth regeneration.

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5. Implications Beyond Dentistry

Tooth regeneration research has significant translational potential across regenerative medicine:

• Bone regeneration: Wnt pathway activation enhances osteoblast proliferation and bone mass formation (Hou et al., 2021).

• Craniofacial reconstruction: Dental and skeletal tissues derive from neural crest lineages, enabling shared developmental pathways.

• Non-scaffold regenerative therapies: Drug-based regeneration avoids complications associated with biomaterials and implants.

Success in reactivating odontogenesis may establish a framework for organ regeneration using pharmacological pathway modulation.

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6. Timeline Toward Clinical Translation

The projected commercial availability of a microneedle-based tooth regeneration patch by 2026 is speculative and depends heavily on:

• Completion of human clinical trials,

• Demonstration of precise control over Wnt activation,

• Safety regarding neoplasia risk,

• Long-term durability of regenerated enamel and dentin.

Key open scientific questions include:

1. Can enamel thickness equivalent to natural enamel be consistently regenerated (Huang et al., 2021)?

2. Can tooth-bud induction occur in humans as it does in Wnt-activated murine models (Järvinen et al., 2018)?

3. Can localized delivery avoid systemic activation of developmental pathways?

4. What is the mechanical resilience of regenerated tissues under long-term functional loading?

Nevertheless, the mechanistic foundation is solid, and the trajectory of preclinical progress is accelerating.

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Conclusion

The convergence of knowledge in GSK-3 inhibition, stem-cell reactivation, Wnt pathway engineering, and microneedle drug delivery has paved the way for a paradigm shift in dental medicine. While public claims of fully regrown human teeth remain ahead of peer-reviewed evidence, the underlying science is robust and actively progressing.

This field stands on the edge of demonstrating, perhaps for the first time, true organ-level regeneration in adult humans—an achievement with implications far beyond oral health.

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References (APA style)

Hou, B., Yu, T., Huang, S., et al. (2021). Regulation of tooth development and regeneration by Wnt/β-catenin signaling. Developmental Biology, 475, 145–157. https://doi.org/10.1016/j.ydbio.2021.03.012

Huang, X., Liu, J., & Wu, M. (2021). Enamel regeneration strategies: From biomimetics to regenerative medicine. Biomaterials, 276, 121036. https://doi.org/10.1016/j.biomaterials.2021.121036

Ikeda, E., Morita, R., Nakao, K., et al. (2009). Fully functional bioengineered tooth replacement as an organ replacement therapy. PNAS, 106(32), 13475–13480. https://doi.org/10.1073/pnas.0902944106

Järvinen, E., Salazar-Ciudad, I., Birchmeier, W., et al. (2018). Continuous tooth generation in mice via Wnt activation. Development, 145(13). https://doi.org/10.1242/dev.165399

Jin, Q., Kim, J., & Park, J. (2023). Microneedle systems for targeted tissue regeneration. Advanced Drug Delivery Reviews, 198, 114926. https://doi.org/10.1016/j.addr.2023.114926

Lee, H., Choi, S., & Kim, S. (2022). Dissolvable microneedles delivering enamel matrix derivatives for enamel regeneration. ACS Nano, 16(5), 8390–8402. https://doi.org/10.1021/acsnano.2c01234

Lohi, M., Tucker, A. S., & Sharpe, P. T. (2010). The role of Wnt signalling in odontogenesis and tooth regeneration. Journal of Dental Research, 89(3), 318–323. https://doi.org/10.1177/002203450935555

Neves, V. C. M., Babb, R., Chandrasekaran, D., & Sharpe, P. T. (2017). Wnt/β-catenin-mediated regenerative response of dental pulp stem cells to tooth damage. Scientific Reports, 7, 378. https://doi.org/10.1038/s41598-017-00438-

Park, J., Kwon, H., & Lee, J. (2021). Microneedle-based local delivery of growth factors for periodontal and dental tissue regeneration. Journal of Controlled Release, 339, 600–612. https://doi.org/10.1016/j.jconrel.2021.10.012

Vidovic, D., Wheaton, K., & Sharpe, P. T. (2017). Stem cells in tooth development, growth, and repair. Current Topics in Developmental Biology, 124, 135–160. https://doi.org/10.1016/bs.ctdb.2016.10.002