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Tooth regeneration

Tooth regeneration is the process of biologically restoring or regrowing damaged, diseased, or congenitally missing teeth through regenerative medicine techniques, including stem cell therapies, tissue engineering, and modulation of developmental signaling pathways, aiming to replace traditional restorative methods like fillings, crowns, or implants with functional, living dental tissues.^[1]^[2]^[3] This field draws on the principles of odontogenesis, the natural embryonic development of teeth, which involves reciprocal interactions between dental epithelial and mesenchymal cells to form enamel, dentin, pulp, and supporting structures.^[1]^[3] These interactions are regulated by conserved signaling pathways, including Wnt, bone morphogenetic protein (BMP), fibroblast growth factor (FGF), Sonic hedgehog (Shh), and inhibitors like uterine sensitization-associated gene-1 (USAG-1), which control cell proliferation, differentiation, and morphogenesis.^[1]^[2] In adults, teeth lack the innate regenerative capacity seen in continuously replacing structures like skin or fish teeth, but research has identified latent potential in a "third dentition" mechanism, where genetic mutations or interventions can induce supernumerary tooth formation.^[2] Key strategies for tooth regeneration encompass direct induction of stem cells using growth factors, multicellular recombination to mimic embryonic tooth buds, and scaffold-based tissue engineering that integrates biomaterials with dental stem cells such as dental pulp stem cells (DPSCs), stem cells from human exfoliated deciduous teeth (SHED), and periodontal ligament stem cells (PDLSCs).^[1]^[3] Pharmacological approaches, notably anti-USAG-1 antibodies, have shown promise by antagonizing BMP-Wnt inhibition to promote tooth outgrowth in animal models like mice and ferrets, with human clinical trials commencing in 2025.^[2]^[4] Notable advances include several clinical studies and trials demonstrating vital pulp-dentin complex regeneration with vascularization and innervation, as well as bioengineered whole-tooth replacement in pigs using decellularized extracellular matrix scaffolds.^[1]^[3] Enamel regeneration remains in early stages, focusing on epitaxial growth via novel biomaterials, while challenges like scalability, immunogenicity, and integration with jawbone persist.^[1] These developments hold potential to address global oral health burdens, including the 22.3 million annual endodontic procedures in the US and edentulism affecting approximately 20% of Americans aged 75 and older (as of 2020).^[3]^[5]

Biological Foundations

Tooth Development and Structure

Teeth are complex organs composed of multiple specialized tissues that form a functional unit for mastication, phonation, and aesthetics. The outermost layer, enamel, is the hardest substance in the human body, consisting primarily of hydroxyapatite crystals arranged in rods, and is acellular and avascular once formed. It is produced by ameloblasts, which are derived from the inner enamel epithelium and secrete an organic matrix that mineralizes through a process called amelogenesis, involving sequential shifts in pH to promote crystal formation.^[6] Beneath the enamel lies dentin, a resilient, tubular tissue that constitutes the bulk of the tooth crown and root, comprising approximately 70% mineralized hydroxyapatite, 20% organic material (mainly collagen type I), and 10% water. Dentin is secreted by odontoblasts, elongated cells of mesenchymal origin that line the periphery of the dental pulp and extend cytoplasmic processes into dentinal tubules, enabling sensory responses to stimuli. Mineralization of dentin, known as dentinogenesis, begins with the deposition of unmineralized predentin, which then calcifies into structured layers through the formation and coalescence of mineral globules.^[6] The central pulp is a soft, vascularized connective tissue housed within the pulp chamber and root canals, containing fibroblasts, undifferentiated mesenchymal cells, blood vessels, and nerves that provide nutrition and innervation to the tooth. It is organized into zones, including an outermost odontoblastic layer, a cell-rich zone with immune cells, and a central core with larger vessels. The cementum, a thin, mineralized layer covering the root surface, resembles bone in composition (with cementocytes embedded in lacunae) and facilitates attachment to the alveolar bone via the periodontal ligament, a collagenous fibrous connective tissue that absorbs occlusal forces and houses proprioceptive nerves, cementoblasts, and fibroblasts.^[6] Tooth development, or odontogenesis, originates from reciprocal interactions between ectodermal epithelium and neural crest-derived mesenchyme, forming teeth as ectodermal appendages. Primary teeth initiate at 6 to 8 weeks of gestation, while permanent teeth begin forming later, with their buds appearing from the 20th week of gestation through the first few postnatal years. The process unfolds in distinct embryological stages, beginning with the initiation stage around the 6th week of gestation, where the oral epithelium thickens into the dental lamina, a band of ectodermal cells that invaginates into the underlying mesenchyme to specify tooth-forming sites through epithelial-mesenchymal signaling.^[7] In the bud stage (8th to 9th weeks), epithelial buds protrude from the dental lamina into the mesenchyme, surrounded by condensing mesenchymal cells that form the dental papilla (future pulp and dentin) and dental follicle (future supporting tissues). This stage involves initial epithelial-mesenchymal interactions mediated by signaling pathways such as fibroblast growth factor (FGF), which promotes mesenchymal condensation and epithelial proliferation.^[7]^[8] The cap stage (9th to 10th weeks for primary teeth) features further invagination of the enamel organ, creating a cap-like structure with a concave inner enamel epithelium that induces the underlying dental papilla to differentiate. Here, bone morphogenetic protein (BMP) signaling from the mesenchyme patterns tooth identity and initiates ameloblast differentiation in the epithelium. The dental follicle differentiates into the periodontal ligament precursors.^[7]^[8] During the bell stage (11th to 12th weeks), the enamel organ fully encircles the dental papilla, forming distinct layers: the outer enamel epithelium, stellate reticulum, stratum intermedium, and inner enamel epithelium. Epithelial-mesenchymal interactions intensify, with Wnt signaling activating genes for enamel knot formation—a transient signaling center that expresses Sonic hedgehog (Shh) and other factors to regulate cusp patterning, inhibit epithelial proliferation, and shape the tooth crown. Odontoblasts differentiate under epithelial influence via BMP and FGF, initiating dentin deposition, followed by ameloblasts forming enamel. The tooth germ at this stage comprises the trilaminar structure of enamel organ, dental papilla, and dental follicle, with mineralization processes commencing as odontoblasts secrete predentin and ameloblasts produce enamel matrix for subsequent calcification. Root development follows crown formation via Hertwig's epithelial root sheath, derived from the cervical loop.^[7]^[8]^[9]

Natural Regeneration in Animals

In non-mammalian vertebrates such as fish, reptiles, and amphibians, polyphyodonty enables the continuous replacement of teeth throughout an animal's life, contrasting with the limited dentition in most mammals. This regenerative capacity relies on persistent epithelial structures that support multiple generations of teeth, providing models for understanding evolutionary adaptations in dental renewal.^[10]^[11] Sharks exemplify polyphyodonty among fish, where teeth are replaced continuously in organized rows through the activity of the dental lamina, an epithelial band that generates successive tooth primordia while functional teeth are shed lingually.^[10] In reptiles, such as alligators, teeth renew annually, with each position capable of up to approximately 50 replacements over a lifespan of about 50 years, facilitated by tooth family units consisting of a functional tooth, a successor, and a remnant dental lamina.^[12] Amphibians, including species like Xenopus laevis and Rana pipiens, also display lifelong tooth succession, where the dental lamina maintains connections between developing teeth and the oral epithelium, allowing conical or bicuspid teeth to form and replace without significant interruption.^[11] Among mammals, exceptions to diphyodonty include continuous eruption of incisors in rodents like mice, driven by stem cell niches at the cervical loop, which houses epithelial progenitors in the outer enamel epithelium and stellate reticulum to sustain growth at rates of about 365 microns per day.^[13] In mice, incisor regeneration occurs rapidly after experimental cutting, with quiescent mesenchymal stem cells mobilizing to replenish progenitors and restore tooth length, whereas molars lack this capacity and remain non-regenerative.^[14] Some marsupials exhibit limited replacement, with only one tooth per jaw—the deciduous premolar—replaced postnatally, a pattern ancestral to the group and linked to their reproductive biology.^[15] Key mechanisms underlying these regenerative processes involve specialized stem cell niches and signaling pathways that differ across species. In polyphyodont animals, epithelial stem cells reside in the dental lamina, enabling perpetual renewal through label-retaining progenitors on the lingual side.^[10] In rodents, the cervical loop niche maintains incisor stem cells via repression of Hox genes (such as Hoxa9 and Hoxc9) by Bmi1, preventing premature differentiation, while Sonic hedgehog (Shh) signaling, marked by Gli1 expression, drives progenitor proliferation and ameloblast formation essential for cycling.^[16] These differences in Hox expression and Shh pathway activity contribute to the evolutionary shift from continuous tooth cycling in non-mammals to limited renewal in mammals.^[16]

Historical Overview

Early Discoveries and Concepts

In ancient Greece, Hippocrates documented observations on tooth growth and teething in his fourth-century BC treatise On Dentition, describing symptoms such as itching gums, fever, convulsions, and diarrhea associated with primary tooth eruption in children.^[17] These early accounts represented foundational conceptualizations of tooth development as a natural, albeit challenging, physiological process, influencing subsequent medical thought on dental emergence.^[18] The 18th century marked a shift toward understanding the internal vitality of teeth, with Scottish surgeon John Hunter's The Natural History of the Human Teeth (1771) providing the first detailed description of the dental pulp as a living, vascular, and sensitive tissue essential for tooth nutrition and repair, challenging prior views of teeth as inert structures.^[19] By the mid-19th century, advances in microscopy enabled deeper insights into tooth histology; Swiss anatomist Rudolf Albert von Kölliker utilized these techniques to elucidate the cellular composition of dental tissues, including dentin and enamel formation, in works such as his 1854 studies on tissue microstructure, laying groundwork for recognizing regenerative-like processes in dental hard tissues.^[20] In the early 20th century, experimental histology advanced concepts of dental repair, with Bernhard Gottlieb's 1930s investigations in Vienna demonstrating the potential for vital pulp preservation in root canal treatments and highlighting epithelial attachment mechanisms that supported tissue regeneration ideas in periodontics.^[21] Complementing this, Rudolf Kronfeld's 1931 paper on repair following tooth fracture detailed the formation of reparative dentin as a response to injury, illustrating how odontoblasts could bridge defects and restore pulp-dentin integrity, serving as an early precursor to broader regenerative theories.^[22] Post-World War II, dentistry increasingly emphasized the "regenerative potential" of dental tissues, spurred by wartime experiences with trauma and the establishment of institutions like the National Institute of Dental Research in 1948, which promoted vital pulp therapies and tissue repair strategies as alternatives to extraction.^[23] Concurrently, 1950s embryology studies, building on Clifford Grobstein's work on inductive tissue interactions, introduced hypotheses on epithelial-mesenchymal induction in tooth development, positing reciprocal signaling between these layers to orchestrate organogenesis and inspire later regeneration models.^[24]

Major Advancements in the 20th and 21st Centuries

In the mid-20th century, researchers began exploring the regenerative potential of dental tissues through transplantation experiments in animal models. During the 1960s and 1970s, studies demonstrated that dental papilla cells could induce tooth structure formation when recombined with epithelial tissues, marking an early shift toward understanding mesenchymal-epithelial interactions in odontogenesis. For instance, experiments involving the transplantation of mouse dental papilla with non-dental epithelium resulted in the regeneration of dentin and enamel-like structures, highlighting the inductive capacity of dental mesenchyme.^[25]^[26] The 1990s and early 2000s saw pivotal advancements in identifying stem cell sources within dental tissues. In 2000, Songtao Shi and colleagues isolated dental pulp stem cells (DPSCs) from human third molars, revealing their ability to differentiate into dentin-pulp complexes both in vitro and in vivo after transplantation into immunocompromised mice. This discovery established DPSCs as a key postnatal stem cell population for tooth regeneration, with high proliferative capacity and odontogenic potential. Building on this, the identification of stem cells from the apical papilla (SCAPs) in 2006 further expanded accessible sources, as these cells supported root formation and dentin regeneration in preclinical models.^[27]^[28]^[29] A landmark achievement occurred in 2007 when Japanese researchers, including those from Takashi Tsuji's laboratory, successfully bioengineered functional tooth germs from dissociated embryonic mouse cells, which were transplanted into adult mouse alveolar bone to form mature teeth capable of erupting and responding to stimuli. This organ germ method represented a breakthrough in tissue engineering, enabling the reconstitution of complex tooth structures from single-cell suspensions. Concurrently, Paul Sharpe's laboratory at King's College London advanced re-aggregation techniques using adult stem cells, laying groundwork for scalable tooth bioengineering.^[30]^[31] The 2010s marked a conceptual transition from gross transplantation to precise molecular interventions, incorporating gene editing tools like CRISPR-Cas9 to manipulate tooth organoids. Early applications in the late 2010s demonstrated CRISPR's utility in editing genes within dental stem cell-derived organoids, enhancing odontogenic differentiation and modeling tooth development defects. This molecular approach complemented pharmacological strategies, such as the 2018 Japanese preclinical studies on USAG-1 inhibition, where antibody blockade in mice and ferrets promoted supernumerary tooth formation by modulating BMP signaling.^[32]^[33]^[34] In 2021, researchers advanced cell reprogramming techniques, including efforts to convert oral epithelial cells into pluripotent states for dental applications, though direct Harvard-affiliated studies focused more on stem cell characterization for dentin repair. International collaborations, such as the EuroGCT consortium, have facilitated cross-European efforts in gene and cell therapies, supporting advancements in dental regeneration through shared protocols and ethical frameworks for stem cell-based interventions. In 2024, Japanese researchers initiated the world's first human clinical trials of an anti-USAG-1 antibody drug at Kyoto University Hospital, aiming to induce supernumerary tooth growth in patients with congenital tooth agenesis or post-extraction loss, with trials expected to conclude by 2030.^[35]^[36]^[37]^[38] Concurrently, U.S. researchers at Tufts University reported successful bioengineered tooth formation in adult minipigs using decellularized tooth bud extracellular matrix scaffolds seeded with human dental pulp cells, producing tooth-like structures with root development after 4 months implantation, advancing toward potential human investigational applications.^[39] These milestones underscore the progression toward clinically viable tooth regeneration strategies.

Regenerative Approaches

Stem Cell Therapies

Stem cell therapies represent a cornerstone of regenerative dentistry, leveraging the multipotent capabilities of various stem cell populations to restore tooth structure and function. Dental-derived stem cells, such as dental pulp stem cells (DPSCs), stem cells from human exfoliated deciduous teeth (SHED), and periodontal ligament stem cells (PDLSCs), are isolated from oral tissues and exhibit high proliferative potential and differentiation capacity toward odontogenic lineages.^[40]^[41] Non-dental alternatives, including induced pluripotent stem cells (iPSCs) reprogrammed from somatic cells, offer ethical advantages and broad accessibility for generating dental-specific progenitors.^[42] These cells can be directed to form dentin-pulp complexes, addressing congenital defects, trauma-induced loss, or age-related degeneration. The primary mechanism underlying stem cell-based tooth regeneration involves the directed differentiation of these cells into odontoblasts and ameloblasts, the key cellular builders of dentin and enamel, respectively. Growth factors such as bone morphogenetic protein-2 (BMP-2) and transforming growth factor-β (TGF-β) play pivotal roles in this process; BMP-2 promotes mesenchymal condensation and odontoblastic differentiation by activating Smad signaling pathways in dental mesenchymal stem cells, while TGF-β enhances proliferation and matrix mineralization in pulp-derived cells.^[43]^[44] Culturing can occur in scaffold-free systems, where cell aggregates or sheets self-assemble via cell-cell interactions to mimic natural tissue architecture, or scaffold-based approaches that provide biomechanical support for enhanced vascularization and deposition, though the former emphasizes intrinsic cellular potency.^[45] Isolation of these stem cells typically employs enzymatic digestion protocols to extract viable populations from dental tissues. For DPSCs and SHED, pulp tissue is minced and treated with collagenase type I and dispase for 30-60 minutes at 37°C, followed by filtration and plating in culture media supplemented with fetal bovine serum, yielding mesenchymal-like colonies within 7-14 days.^[46]^[47] PDLSCs are similarly isolated from periodontal ligaments using trypsin-EDTA digestion. In vitro studies demonstrate high efficacy, with SHED achieving approximately 82% successful isolation under odontogenic induction media containing dexamethasone and ascorbic acid.^[48]^[49] A notable example of translational potential is the use of SHED in pulp regeneration, as reported in early clinical case studies where autologous SHED transplants into immature permanent teeth with necrotic pulp resulted in radiographic evidence of root development and vitality restoration over 12-24 months, highlighting their safety and regenerative efficacy without adverse events.^[50]

Tissue Engineering Techniques

Tissue engineering techniques for tooth regeneration involve the design and fabrication of biomimetic scaffolds that provide a three-dimensional framework to guide cellular organization, proliferation, and differentiation toward functional dental structures such as dentin, pulp, and enamel. These approaches emphasize non-cellular constructs, including biomaterials that mimic the extracellular matrix (ECM) to support tissue ingrowth without relying on exogenous cells as the primary driver. Scaffolds are engineered to possess porosity for nutrient diffusion, biocompatibility to avoid immune rejection, and bioresorbability to allow gradual replacement by native tissue.^[51] Key scaffold materials include natural hydrogels like collagen and alginate, which offer high biocompatibility and mimic the native ECM to facilitate cell attachment and migration. Collagen-based hydrogels, derived from animal sources, provide a soft, fibrous network that supports dental pulp regeneration by promoting vascularization and dentin formation, with enzymatic degradation via collagenase ensuring controlled resorption. Alginate hydrogels, often crosslinked with calcium ions, serve as injectable matrices for dentin-pulp complexes, enabling periodontal and pulp regeneration through their mild gelling properties and ability to encapsulate bioactive cues. Synthetic polymers such as poly(lactic-co-glycolic acid) (PLGA) are fabricated via 3D printing to create precise architectures, offering tunable porosity and mechanical strength suitable for load-bearing dental tissues. Decellularized extracellular matrices (dECM), processed from porcine or bovine dental tissues, retain native biochemical signals and hierarchical structures, enhancing regeneration of complex interfaces like the dentin-enamel junction when combined with hydrogels for improved handling.^[51]^[51]^[52] Advanced fabrication techniques include bioprinting, which enables the layer-by-layer deposition of bioinks containing scaffold materials to form tooth bud-like structures that recapitulate embryonic tooth development. This method allows spatial control over material composition, such as gradient scaffolds transitioning from soft pulp-like hydrogels to rigid dentin-mimicking polymers, fostering organized tissue assembly. For pulp-dentin complexes, vascularization integration is critical; scaffolds incorporate angiogenic motifs or perfusable channels to promote endothelial cell infiltration and neovascular networks, ensuring nutrient supply in avascular dental cores. These techniques often briefly integrate stem cells for enhanced outcomes, but the scaffold itself drives structural fidelity.^[53]^[54] Scaffolds are optimized with mechanical properties matching native dentin, exhibiting elastic moduli of 15-20 GPa to withstand occlusal forces while permitting flexibility for pulp vitality. Degradation rates are tailored to 6-12 months via copolymer ratios in PLGA or crosslinking density in hydrogels, aligning scaffold resorption with tissue maturation to prevent fibrous encapsulation.^[55]

Pharmacological and Gene-Based Methods

Pharmacological approaches to tooth regeneration focus on administering agents that modulate signaling pathways to stimulate endogenous tooth formation, bypassing the need for exogenous cell or tissue implantation. A prominent example is the use of monoclonal antibodies targeting USAG-1 (also known as SOSTDC1), a protein that antagonizes bone morphogenetic protein (BMP) and Wnt signaling during tooth development. By neutralizing USAG-1, these antibodies enhance BMP activity, promoting the initiation and progression of tooth buds in models of congenital tooth agenesis.^[56] In preclinical studies using mice with mutations in genes like Eda or Msx1, a single systemic intraperitoneal injection of anti-USAG-1 antibody at 16 μg/g body weight rescued approximately 75% of missing mandibular molars, restoring normal tooth development.^[56] Similar results were observed in ferrets, a diphyodont model more akin to human dentition, where three injections at 80 μg/g induced supernumerary incisor formation resembling a third dentition.^[56] Delivery of these pharmacological agents typically involves localized or systemic injections to target jaw regions, minimizing off-target effects on other BMP-regulated tissues like bone. For instance, in postnatal ferrets, targeted administration around the incisor area led to tooth bud eruption within months, demonstrating the potential for precise dosing in clinical translation. Growth factors such as vascular endothelial growth factor (VEGF) complement these efforts by promoting vascularization essential for regenerated dental pulp viability. Recombinant VEGF, when incorporated into scaffolds or applied directly, has been shown to increase microvessel density and support pulp regeneration in rodent models of dental injury, with concentrations around 10-50 ng/mL enhancing angiogenesis without inhibiting cell proliferation.^[57] Gene-based methods leverage molecular tools to alter genetic expression in situ, aiming to correct developmental defects or activate regenerative pathways. RNA interference techniques, such as small interfering RNA (siRNA) targeting USAG-1, have demonstrated efficacy in rescuing arrested tooth development. In Runx2-deficient mice, local application of USAG-1 siRNA via cationized gelatin hydrogel achieved approximately 50% knockdown of USAG-1 mRNA, resulting in 42% of explants showing partial tooth growth, including odontogenic epithelial structures.^[58] Delivery through hydrogels allows sustained release over 10 days, improving targeting to mandibular tissues.^[58] Viral vector-mediated gene therapy offers a strategy to deliver key odontogenic genes like Pax9 and Msx1, which are implicated in non-syndromic tooth agenesis when mutated. Adeno-associated virus (AAV) vectors, prized for their long-term expression and low immunogenicity, can transduce dental mesenchymal cells to overexpress these transcription factors, potentially stimulating dormant tooth germs. Feasibility studies indicate AAV's suitability for postnatal in vivo delivery to induce supernumerary teeth by modulating BMP/Wnt pathways, with Msx1 enhancement linked to increased tooth bud formation in USAG-1-deficient models.^[59] For Runx2, a master regulator of osteogenic and odontogenic differentiation, CRISPR/Cas9 editing has been explored to fine-tune its expression in dental stem cells, promoting differentiation toward tooth-forming lineages without full agenesis. In vitro applications show CRISPR-mediated Runx2 knockdown enhances osteogenic potential in periodontal ligament stem cells, suggesting broader utility for editing in tooth repair contexts.^[60] These methods converge toward clinical application, exemplified by preparations for human trials of anti-USAG-1 antibody at Kyoto University. Phase 1 trials, initiated in September 2024 and completed by August 2025, involved intravenous administration to 30 healthy adult males aged 30–64 with at least one missing tooth, primarily assessing safety and dosing for congenital partial anodontia. Phase 2 efficacy trials for children are planned to begin in 2025, with potential drug availability by 2030.^[61]^[62]

Current Research and Applications

Preclinical Studies

Preclinical studies on tooth regeneration have primarily utilized in vitro and in vivo animal models to establish proof-of-concept for various regenerative techniques, focusing on the development of functional tooth structures from stem cells and scaffolds. In vitro approaches, such as organoid cultures, have enabled the simulation of tooth development outside living organisms. For instance, a 2020 study developed a porcine tooth in situ organ culture model using a bioreactor to maintain dental and periodontal tissues, demonstrating viable epithelial-mesenchymal interactions essential for odontogenesis. These organoids provide a controlled environment to study cellular differentiation and tissue assembly prior to in vivo testing.^[63] In vivo experiments in small animal models like mice and rats have shown promising results for tooth implantation and eruption. Bioengineered tooth germs transplanted into mouse jawbones have developed into mature teeth that erupt into the oral cavity within 4-6 weeks, exhibiting crown and root formation with dentin and enamel layers. Similarly, in rat models, scaffolds seeded with dental stem cells have led to structured tooth-like tissues observable after 4 weeks of subcutaneous growth followed by orthotopic implantation. Micro-computed tomography (micro-CT) imaging has been instrumental in these studies, allowing non-invasive assessment of regenerated tooth volume and microstructure, such as root length and pulp chamber dimensions.^[64]^[65]^[66] Larger animal models, particularly swine, have tested scalability and functionality of regenerated teeth. In miniature pigs, allogeneic mesenchymal stem cell-based bio-root regeneration has achieved approximately 50% success in forming functional tooth structures capable of supporting artificial crowns, with crown-root formation confirmed histologically. These outcomes highlight the potential for periodontal integration but also reveal variability in eruption and vascularization.^[67] A notable example involves pharmacological approaches to stimulate third-generation teeth in ferrets, a model with dental anatomy closer to humans. Japanese researchers demonstrated that neutralizing the USAG-1 protein via antibody therapy enhanced BMP signaling, leading to the regeneration of supernumerary teeth in ferrets, as reported in a 2021 study building on earlier gene inactivation work. This approach induced full tooth development, including enamel and dentin, without surgical implantation.^[56] Induced pluripotent stem cell (iPSC)-derived models have advanced toward more complex innervation in higher mammals. Although primate-specific tooth studies remain limited, iPSC technologies have generated dental organoids showing neural integration in rodent hosts. These findings suggest potential for sensory restoration in regenerated teeth. Despite these successes, preclinical translation faces challenges in scaling from rodents to humans, primarily due to size mismatches in tooth dimensions and jaw architecture, which affect nutrient diffusion and mechanical loading in larger models. Rodent teeth, being smaller, regenerate more uniformly but fail to replicate human occlusal forces, necessitating larger animals like pigs for better predictive validity.^[68]^[69]

Clinical Trials and Human Applications

Clinical trials for tooth regeneration have primarily focused on regenerative endodontics and stem cell-based approaches to restore dental pulp vitality and promote root development in immature teeth, serving as alternatives to traditional apexification procedures. In these Phase I and II trials, techniques such as pulp revascularization have demonstrated success rates of approximately 84-88% in achieving continued root maturation and apical closure, with radiographic evidence of dentin bridge formation observed in pediatric patients treated for necrotic pulps. For instance, a systematic review of revascularization procedures in immature necrotic teeth reported an 88.3% success rate, including significant root elongation and thickening, alongside pain reduction in over 90% of cases. These outcomes position regenerative endodontics as a viable clinical application for preserving avulsed or traumatized teeth, where case studies of delayed reimplantation have shown functional healing and reduced periapical lesions through induced tissue regeneration.^[70]^[71]^[72] Stem cell therapies, particularly using dental pulp stem cells (DPSCs), have advanced to early human trials for treating irreversible pulpitis and pulp necrosis. A pilot clinical study involving five patients with irreversible pulpitis demonstrated the safety and feasibility of autologous DPSC transplantation, with monitoring up to 24 weeks showing pulp regeneration without adverse events and improved clinical symptoms such as reduced sensitivity to percussion. Larger randomized controlled trials have confirmed these findings, reporting positive pulp responses in 71-86% of cases treated with DPSCs or stem cells from human exfoliated deciduous teeth (SHED) combined with scaffolds like hyaluronic acid, highlighting their potential for vital pulp therapy in mature teeth. These Phase I/II efforts underscore the translation of preclinical stem cell research into human applications, with ongoing trials evaluating long-term efficacy in endodontic regeneration.^[73]^[74]^[75] A landmark development in full tooth replacement is the Japanese Phase I clinical trial of an anti-USAG-1 antibody (TRG-035) to stimulate tooth regrowth in patients with congenital anodontia, initiated in September 2024 at Kyoto University Hospital, with follow-up completed in August 2025. This safety trial involved 30 healthy adult males aged 30-64 who were missing at least one tooth, aiming to assess tolerability and preliminary efficacy through intravenous administration. In September 2025, TRG-035 received orphan drug designation from Japan's Ministry of Health, Labour and Welfare for the treatment of severe congenital anodontia.^[76] Building on preclinical success in ferrets, the trial targeted suppression of the USAG-1 protein to reactivate dormant tooth buds, paving the way for Phase II efficacy studies in children with tooth agenesis and potential Phase III expansion for broader applications like post-extraction regeneration by 2030. Initial reports indicate no major safety concerns in the early cohort, marking the first human evaluation of pharmacological tooth induction.^[77]^[61]^[78]

Challenges and Future Prospects

Biological and Technical Barriers

One of the primary biological hurdles in tooth regeneration is the immune rejection of allogeneic cells, which triggers T-cell, B-cell, and natural killer cell responses due to major histocompatibility complex disparities, often leading to graft failure without tolerance induction strategies such as regulatory T-cell therapy or immunosuppressive biomaterials.^[79] This risk is particularly pronounced in dental applications, where limited autologous tooth germ cell sources necessitate allogeneic or xenogeneic cells, complicating whole-tooth bioengineering despite successful demonstrations in minipig models.^[80] Additionally, bioengineered enamel frequently exhibits incomplete hardness, with mineral density significantly lower than natural enamel's 95% by weight, limiting mechanical durability and long-term functionality in restorative contexts.^[81] Technical challenges further impede progress, notably vascularization failure in engineered constructs, where nutrient diffusion is restricted to small scales of 1-2 mm, resulting in central necrosis beyond this threshold due to inadequate oxygen and metabolite exchange in avascular scaffolds.^[82] Innervation deficits also pose a barrier, as sensory nerve denervation disrupts dental pulp stem cell migration and reparative dentin formation, yielding non-functional sensation and impaired pulp homeostasis in regenerated tissues.^[83] These issues are exacerbated by high apoptosis rates in scaffolds, often reaching 20-30% under suboptimal conditions like increased collagen stiffness, which reduces cell viability and hinders tissue integration.^[84] Size scaling from laboratory models to clinical applications remains problematic, with inconsistent regeneration observed in larger animal teeth (e.g., ferrets or dogs with 15-17 mm canines) due to poor blood supply in narrow root canals and complex multirooted structures, contrasting reliable outcomes in smaller rodent models.^[68] Specific examples include failures in large animal trials, such as dogs, where ectopic mineralization—chaotic calcified clusters rather than organized dentin—arises from sensory innervation deficits, leading to misplaced odontoblastic differentiation and incomplete functional restoration.^[83]^[85]

Ethical Considerations and Potential Impacts

Ethical considerations in tooth regeneration encompass equity in access and informed consent, particularly given the potential for high costs associated with these therapies. Regenerative treatments may initially be expensive, limiting availability to affluent populations and exacerbating disparities between cosmetic enhancements and essential medical applications for conditions like congenital tooth defects. For instance, stem cell-based approaches could prioritize aesthetic improvements over restorative needs in low-resource settings, raising concerns about healthcare justice. Additionally, obtaining informed consent in pediatric trials for congenital anomalies poses challenges, as guardians must weigh long-term benefits against unknown risks in growing children, necessitating robust ethical oversight to protect vulnerable participants.^[86] Regulatory frameworks for tooth regeneration therapies, especially those involving stem cells and biologics, are guided by stringent guidelines from bodies like the FDA and EMA. The FDA's Cellular and Gene Therapy Guidances, updated in 2024, emphasize expedited programs for regenerative medicine while requiring rigorous safety and efficacy data for dental applications, including stem cell products derived from dental pulp; in September 2025, the FDA issued additional guidance on innovative clinical trial designs for cellular and gene therapy products in small populations, facilitating faster development for rare dental conditions.^[87]^[88] Similarly, the EMA's biological guidelines outline requirements for marketing authorization of biologics, focusing on quality control and non-clinical testing, though specific dental endorsements remain limited as of 2024.^[89] Intellectual property issues in gene-edited teeth, such as CRISPR-based modifications for enhanced dental structures, are complicated by ongoing patent disputes over editing technologies, potentially hindering innovation and access if exclusive rights dominate commercialization.^[90] The potential societal and economic impacts of tooth regeneration are profound, with implications for public health and industry growth. Societally, successful regeneration could diminish the demand for traditional orthodontics and prosthetics by addressing congenital and acquired tooth loss, thereby improving quality of life, self-esteem, and social participation for affected individuals. Economically, the global tooth regeneration market is projected to reach approximately USD 7.3 billion by 2030, driven by rising incidences of tooth loss and aesthetic demands, though this growth underscores the need to balance profitability with equitable distribution.^[91] Debates on "designer teeth" enhancements highlight bioethical tensions, as cosmetic applications risk promoting unnecessary interventions and overtreatment, echoing broader concerns in aesthetic dentistry about patient autonomy versus professional responsibility.^[92]^[93]

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Jun 23, 2017 · Bernhard Gottlieb (1885-1950) who was the Director of the Dental. Institute at the University of Vienna Austria. Gottlieb continued the.
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In the 1930s he began to address in the European sector, root canal treatment in teeth with a vital pulp; following his immigration to the United States, he ...Missing: transplantation experiments
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Perspectives on Tissue Interactions in Development and Disease
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Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo
In this study, we isolated a clonogenic, rapidly proliferative population of cells from adult human dental pulp.
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Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo
This study isolates postnatal human DPSCs that have the ability to form a dentin/pulp-like complex.
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Feb 4, 2014 · Stem cells from the apical papilla (SCAPs) are found in the papilla tissue in the apical part of the roots of developing teeth. The third ...
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Feb 22, 2007 · Sharpe's lab is looking for adult stem cells, including those found in bone marrow and dental gum, as possible candidates for regrowing teeth.
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About EuroGCT
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TGF-β promotes the proliferation and osteogenic differentiation of ...
The pooled data showed that TGF-β could promote the proliferation and ossification of dental pulp stem cells.
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Polymeric Scaffolds Used in Dental Pulp Regeneration by Tissue ...
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Biofunctionalization of silk fibroin scaffolds with enamel matrix ...
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Anti–USAG-1 therapy for tooth regeneration through enhanced BMP ...
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Evaluation of vascular endothelial growth factor – A release from ...
Jan 16, 2021 · Previous studies have shown that recombinant VEGF promoted angiogenesis and increased the microvessel density of dental pulp.
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Local application of Usag-1 siRNA can promote tooth regeneration ...
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Feasibility of Gene Therapy for Tooth Regeneration by Stimulation of ...
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Developing a Tooth in situ Organ Culture Model for Dental and ...
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Insulin-like growth factor 1 modulates bioengineered tooth ... - Nature
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Whole-Tooth Regeneration by Allogeneic Cell Reassociation in Pig ...
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Clinical and radiographic outcomes of non-surgical retreatment of ...
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Tooth Formation: Are the Hardest Tissues of Human Body Hard to ...
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Next-Generation Strategies for Enamel Repair and Regeneration
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Current overview on challenges in regenerative endodontics - PMC
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Sensory nerves drive migration of dental pulp stem cells via the ...
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3D culturing of human dental pulp stem cells at different strengths of ...
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Animal Model for Regenerative Endodontology ... - Karger Publishers
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Regenerative Strategies in Dentistry: Harnessing Stem Cells ...
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Cellular & Gene Therapy Guidances - FDA
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Dental Regeneration Market Size Worth $7.8 Billion By 2030
The global dental regeneration market size is expected to reach USD 7.8 billion by 2030, expanding at 6.1% CAGR from 2023 to 2030, according to a new report ...
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Tooth Regeneration Communicating Dental Research Responsibly
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Jan 27, 2025 · This study aims to explore the ethical dimensions of marketing practices and the phenomenon of overtreatment in cosmetic dental procedures.