Tooth regeneration

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A set of human teeth under an orthopantomogram

Introduction

Tooth regeneration is an emerging approach in regenerative medicine that aims to replace missing or damaged teeth through the bioengineering of new dental tissues using autologous stem cells.[1] In this process, somatic cells are reprogrammed into induced pluripotent stem cells (iPSCs), which possess embryonic-like pluripotency and can differentiate into multiple cell lineages. These cells can subsequently be directed toward odontogenic differentiation and seeded either within the native tooth-forming region (dental lamina) or onto a resorbable biopolymer scaffold designed to mimic tooth architecture.[2][3]

This approach represents a paradigm shift from conventional restorative dentistry, which relies on artificial replacements such as fillings, dentures, and implants, toward biologically based regeneration of functional tooth structures. Experimental models, particularly rodents such as mice and rats, have been extensively used to study tooth development due to their continuously growing incisors, which provide valuable insight into epithelial–mesenchymal interactions and stem cell maintenance during odontogenesis.[4]

The clinical significance of tooth regeneration lies in the limitations of current treatment modalities for tooth loss, which primarily restore structure rather than biological function. Although conventional prosthetic and implant-based therapies are effective, they do not replicate the regenerative capacity or native physiology of natural teeth. Tooth loss remains highly prevalent globally, affecting a substantial proportion of adults, particularly older populations. While no clinically available therapy currently enables complete human tooth regeneration, advances in stem cell biology, including embryonic stem cells, induced pluripotent stem cells, RNA-based technologies, and biomineralisation strategies, indicate growing potential for future clinical translation.[5]

Clinical Need for Tooth Regeneration

Tooth loss remains a significant clinical problem because current dental treatments are unable to fully restore the natural structure and biological function of teeth. [6]Although restorative materials, dentures, and osseointegrated dental implants can replace missing teeth and improve oral function, they rely on inert materials and do not replicate the complex biology of natural teeth, particularly the presence of the periodontal ligament. The absence of the periodontal ligament eliminates its physiological role in shock absorption and force distribution during mastication, which may contribute to alveolar bone resorption over time.[7][8] Given the high prevalence of tooth loss caused primarily by dental caries, periodontal disease, and genetic conditions, with dental caries being the most common disease worldwide[9], there is a clear need for alternative approaches that go beyond conventional restoration.

Natural teeth are composed of multiple specialized hard and soft tissues, including enamel, dentin, cementum, pulp, and the periodontal ligament, each of which plays a distinct biological role[10]. Current dental therapies can restore external form but cannot replace the biological functions of these tissues, such as vascularization, innervation, and physiological remodeling. To overcome these limitations, research in regenerative dentistry focuses on understanding the mechanisms of tooth development, particularly the interactions between dental epithelium and dental mesenchyme that guide tissue formation. Knowledge of these developmental processes supports the design of biologically based strategies for regenerating dental tissues and potentially whole teeth, while also providing a valuable model for broader studies in organ development and regenerative medicine.

Basic Biology of Tooth Development

Tooth development, known as odontogenesis, occurs in several stages and applies to both deciduous and permanent teeth. Although permanent teeth develop later and replace primary teeth, both follow the same basic process. Development begins before birth with the bud stage, when dental epithelium grows from the dental lamina to form the tooth germ. This progresses to the cap stage, where the tooth germ differentiates into three main components: the enamel organ , the dental papilla, and the dental follicle. These structures establish the basic organization of the developing tooth.[11]

In the bell stage, the enamel organ takes on a bell shape, tooth shape is determined, and cells specialize to carry out specific functions in enamel formation. This is followed by crown and root formation, during which dentin forms first, followed by enamel, while the root develops with the guidance of Hertwig’s epithelial root sheath. Finally, in the eruption stage, the tooth moves toward the oral cavity as bone and connective tissues remodel to allow eruption. Primary teeth erupt first, usually beginning around six months of age, while permanent teeth develop later and erupt over several years, with some, such as third molars, completing development much later in life.[12]

Sources of stem cells for tooth regeneration

Tooth regeneration research relies on several major types of stem cells, each offering unique advantages and limitations:

  1. Embryonic stem cells (ESCs)
    • ESCs are pluripotent cells, meaning they can make any type of cell in the body.[1]
    • They are derived from cells found in very early human embryos, before they have implanted in the uterus.[13]
    • They grow indefinitely in the lab and have been shown to form tissues like gum lining, jawbone, and periodontal structures, and can even activate early tooth-forming genes.
    • However, ESCs face serious challenges, including ethical concerns, possible immune rejection, and the risk of forming tumors, which currently prevent their clinical use in patients.
  2. Adult stem cells found naturally in dental tissues [1]
    • Several types of dental-derived stem cells have been identified, including:
    • These stem cells can produce dentin, pulp-like tissues, bone, ligament, and, under experimental conditions, even enamel-like structures .
  3. Adult stem cells from non-dental tissues [1]
    • Mesenchymal stem cells (MSCs), particularly from bone marrow, can respond to odontogenic signals from dental epithelium.
    • They have been shown to express tooth-related genes (e.g., Pax9, Msx1, Lhx7) and form tooth crown-like structures in animal models.
    • This shows that tooth development can be triggered even in cells from outside the mouth.
  4. Induced pluripotent stem cells (iPSCs)
    • They are created by reprogramming normal body cells back into a pluripotent state. [14]
    • This technology, first developed by Yamanaka in 2006, allows scientists to produce ESC-like cells without using embryos. [14]
    • In dentistry, iPSCs can be generated from many accessible tissues such as dental pulp, baby teeth, gum tissue, and periodontal ligaments.
    • iPSCs share the same powerful abilities as ESCs in which they can become nearly any cell type and grow long-term, but without the ethical concerns. [15]
    • They still carry risks like tumor formation and may retain “memory” from the original tissue, but they remain one of the most promising sources for creating fully functional, patient-specific bioengineered teeth in the future. [1]

Approaches to tooth regeneration

A few approaches are going on for tooth regeneration, including:

  1. Clinical or Near-Clinical Approaches
    • USAG-1 antibody therapy: Blocks USAG-1 to activate natural tooth growth; currently in early human trials. [16]
    • Dentin–pulp regeneration (DPSCs / Human Exfoliated deciduous teeth stem cell (SHED) ): Uses dental stem cells with scaffolds and growth factors to restore dentin, pulp, blood vessels, and nerves in damaged teeth.[17]
  2. Experimental / Preclinical Approaches
    • Bioengineered tooth-germ transplantation: Lab-grown early tooth structures transplanted into the jaw form complete teeth in animals.[1]
    • Signaling pathway modulation: Adjusts signaling pathways to stimulate tooth formation.[17]
    • Tissue engineering: Use stem cells with or without biodegradable scaffolds to guide forming new teeth. [17]
    • Component-specific regeneration: Focuses on regenerating individual tooth tissues such as enamel, dentin, or periodontal ligament. [17]

History

Young et al first demonstrated in 2002 that teeth could be regenerated from cells.[18]

The first clinical trial on tooth regeneration started in 2023 in Japan, for a medicine stimulating tooth regrowth by inhibition of USAG-1.[19][20][21]

In April 2025, researchers in the UK successfully grew human teeth in a lab, offering a potential alternative to dental implants and fillings.[22]

Lab-grown tooth-like structures

In 2025, researchers at King's College London led by Ana Angelova Volponi reported the laboratory generation of early tooth-like structures using a hydrogel scaffold designed to support interactions between odontogenic cells. The engineered matrix was shown to encourage the organization of developing tooth tissue precursors, suggesting a possible way toward biological tooth replacement. Researchers noted that the constructs do not yet replicate the full morphology or function of natural teeth in humans, and the approach remains at an experimental preclinical stage. However, the development was described as a meaningful advance in regenerative dentistry and tooth repair research.[23][24][25] Researchers note that significant challenges remain before lab-grown teeth can be used clinically in humans. The lab work aims to improve interactions between cells involved in tooth formation, but methods for reliably replacing embryonic model cells with adult human cells have not yet been known. Possible future approaches if the research succeeded in humans, include partially growing a tooth in vitro before implantation into the tooth socket to complete development, or fully growing a tooth in the laboratory prior to surgical implantation. Researchers emphasize that these applications remain experimental and are not yet ready for clinical use.[26]

Challenges

The majority of stem cell studies have stopped at the stage of animal studies and have not proceeded to clinical trials due to numerous safety and ethical concerns. The potential risks of undesired tissue formation, tumourigenesis, and metastasis have not yet been resolved.[27]

See also

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References

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