Regenerative Dentistry

Current Research and Upcoming Advances

By Carrie Pallardy

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What if you could grow entirely new teeth for patients instead of relying on fillings, root canals and implants? That is just one of the possibilities within the multidisciplinary field of regenerative dentistry. Regenerative therapies focus on the repair and restoration of soft and hard tissues like dental pulp, enamel, dentin, gingiva, bone and other supporting tissues.

Researchers specializing in tissue engineering, biomaterials, genetics and nanotechnology are making progress in their labs that could translate into myriad clinical applications in general dentistry, endodontics, periodontics and oral surgery.(1)

Where is the field of regenerative dentistry today? And what advances could it bring in the future?

Stem Cells and Regenerative Dentistry

Stem cells, along with bioactive molecules and bioactive scaffolds, are an essential part of regenerative medicine.(2) These cells have the ability to self-renew and differentiate. Dental pulp stem cells (DPSCs) and periodontal ligament stem cells, for example, can play a role in regenerating dental, bone and periodontal tissues.(3) In the past, research involving stem cells has been clouded by controversy, particularly relating to embryonic stem cell research.(4)

“Now, we can isolate stem cells from many different tissues in adults. They are in dental pulp, for example,” said Luisa A. DiPietro, DDS, PhD, professor and director of the University of Illinois Chicago (UIC) Center for Wound Healing & Tissue Regeneration.

Researchers can also take cell-free approaches. Rather than implanting stem cells, they can use in situ tissue regeneration, which involves using biomaterials to direct stem cells already in the body to promote the repair and replacement of diseased or damaged tissue.(5)

How are some researchers using stem cells in their labs to push the field of regenerative dentistry forward?

Sriram Ravindran, PhD, an associate professor of oral biology at UIC, is currently conducting research that makes use of mesenchymal stem cells found in dental pulp, bone marrow and adipose tissue. His lab aims to develop a biomimetic approach to stem cell differentiation using cell type-specific extracellular matrices and exosomes. Ultimately, his lab is focused on regenerating dental pulp, cartilage and bone.

Mildred Embree, DMD, PhD, MS, principal investigator at Embree Lab, and Dr. Edwin S. Robinson associate professor of dental medicine (orthodontics) at Columbia University College of Dental Medicine, and her team are using the temporomandibular joint (TMJ) as a model for studying skeletal stem cells and how cartilage repairs itself.

“We use this as a foundation for developing minimally invasive therapeutics that target either the niche of cartilage or the progenitor cells themselves,” she shared. “We developed a couple of candidate drugs that ameliorate degeneration of the joint.”

They have shown that StemJEL®, a drug developed in Embree Lab, can be used as a therapy for osteoarthritis.(6) “It can be used in the TMJ and in the knee joint. So, we’re starting to look at its effectiveness in multiple joints,” said Embree.

Regenerative Approaches in Endodontics and Periodontics

Regenerative endodontics leverages tissue engineering to restore root canals in damaged or necrotic teeth to a healthy state, ultimately preserving the tooth.(7) Regenerative techniques are widely used in endodontics today. In a survey published in the Journal of Endodontics last year, 85.4% of respondents reported performing regenerative endodontic procedures in their practice.(8)

“With regenerative endo, there’s this paradigm shift where we’re not only trying to disinfect what’s inside the canal and eliminate the bacteria — the goal of regenerative endodontics is also to regenerate the pulp tissue, including the nerve and vasculature structures within the canal,” said Gordon Lai, DDS, MSD, an endodontist and clinical assistant professor at the University of the Pacific Arthur A. Dugoni School of Dentistry and one of the survey authors.

A typical regenerative endodontic procedure might be conducted over the course of two visits. The goal of the first visit is to disinfect the canal. Endodontists often use sodium hypochlorite as a disinfecting irrigant and calcium hydroxide as an intracanal medicament.(8)

On the second visit, the endodontist may irrigate the canal with ethylenediaminetetraacetic acid. “Once we disinfect the canal, we intentionally try to induce bleeding at the apex, and that creates a blood clot within the canal,” said Lai. “That blood clot acts as a natural scaffold for the tooth to attract stem cells and growth factors to induce hard tissue formation, and increased root length and thickness. Then the ideal goal is, eventually, to regenerate the nerve cells as well.”

Endodontists leverage bioceramic materials to seal the pulp canal space, with the intention of inducing a hard tissue barrier and revascularization. Regenerative endodontics — also referred to as revascularization endodontics — is not yet at the point of regenerating the whole pulp-dentin complex and restoring sensitivity in teeth, but there are exciting developments in the field.

Biomaterial scaffolds serve as the framework that facilitates tissue regeneration. A study published in the Journal of Endodontics last year found promise in antimicrobial silk scaffolds.(9) Other researchers are 3D-printing scaffolds.(10) Platelet-rich plasma and platelet-rich fibrin are also useful tools in creating scaffolds and promoting tissue regeneration in endodontic procedures.

“How can we engineer certain stem cells for direct insertion into the root canal? Or how might we incorporate them into a 3D-printed bioscaffold? These are some of the exciting innovations that are emerging right now in this field,” said Lai.

Lai also sees some challenges in the field of regenerative endodontics. One is the issue of standardization. Treatment protocols, such as those published by the American Association of Endodontists, serve as guides for endodontists.(11) But there are still plenty of variations to consider.

“For example, when we’re disinfecting the root canal during the first visit, what concentration of sodium hypochlorite should we use? We have to use sodium hypochlorite to eliminate the bacteria, but, at the same time, if we use too strong of a concentration, we might be simultaneously killing the stem cells we want to recruit inside the root canal,” said Lai.

Lai also sees the need for more long-term research. “What we’re missing right now is those long-term studies, 10 or 15 years out. Are these regenerative endo procedures still successful at that time — or are they failing?” he said.

Regenerative techniques can also be applied to preserve and restore tissue, like periodontal ligaments and bone, that can fall prey to periodontal disease.(12)

Guided bone regeneration (GBR) and guided tissue regeneration (GTR) are two of the primary therapies in regenerative periodontics.(13) Periodontists leverage GBR to regenerate alveolar bone around areas affected by disease. GTR, on the other hand, is used to regenerate periodontal ligaments, cementum and bone. Both procedures involve the use of a barrier membrane to promote regeneration while inhibiting the growth of undesirable tissue.

Researchers are also studying how DPSCs can be put to work in the regeneration of periodontal tissues and the dentin-pulp complex.(3) They have leveraged different strategies, such as biochemical interventions and small-molecule therapies, to amplify the therapeutic value of DPSCs.(3)

Regenerative dentistry research can have applications that go beyond the mouth. In her lab at UIC, DiPietro, also a professor of periodontics, is studying wound healing in the oral mucosa and skin.(14) “We’re focused on understanding the difference between these two tissues and trying to determine if we can really improve skin healing and model it after the oral cavity,” DiPietro explained.

Challenges in Regenerative Research

Regenerative research is an exciting field, but it is not without its scientific and logistical obstacles. The prospect of regrowing complex biological structures — like an entire tooth — is a major goal in the field. Scientists can look to examples of that capability elsewhere in the natural world.

Take axolotls. These amphibians can regrow entire limbs.(15) Understanding and replicating that regenerative capability is of obvious interest. “Many scientists have asked if we can find a way to get humans to adopt that regenerative phenotype and mechanism,” said DiPietro.

We don’t yet fully understand axolotls’ natural regenerative capabilities. Even if we reach the point of translating that capability to humans, how long would it take for us to regrow natural tissue?

In all likelihood, it would take a significant amount of time. There is a possibility that restorative materials will outpace the clinical applications of regenerative dentistry. “Robotic and material replacements for tissues are getting better and better. These advances may leapfrog regeneration strategies,” DiPietro said.

Bioinspired materials, for example, mimic the structure and function of naturally-occurring tissue material. Ana Bedran-Russo, DDS, MS, PhD, associate dean for research and head of the Department of Oral Biology at UIC, is leveraging natural compounds to create these kinds of materials to improve tooth restoration and strengthen tooth structure.

Researchers exploring bioengineering tissue must grapple with the sheer complexity of the human body.

“What we’re learning is that the human body is a lot more complicated than just putting stuff together and engineering it. It’s not just regenerating and engineering the tissue; it’s making it last,” said Embree. “It’s really hard to build a house on sand, so to speak. You really have to have a clear foundation of how tissues work and how they’re maintained.”

That’s why, in recent years, Embree has observed a greater push for a multidisciplinary approach to regenerative research in dentistry. Engineers, researchers who specialize in the microbiome, immune system specialists — many different experts are needed to push the field forward. “It really takes a lot of different teams to understand how to not only prepare the tissue, but also how to maintain it. Because we also have to make sure it lasts,” she said.

For all of the exciting possibilities unfolding in the lab, there is a major external difficulty to be managed: funding. Every researcher knows how competitive, and often demoralizing, securing grants for their work can be.

Peer reviewers can be harsh. And work that researchers pour countless hours into may not secure a necessary grant. DiPietro shared her perspective on the process, acknowledging both the difficulty and opportunity that can come from it.

“It can be very difficult at times. Reviewer comments can be hard to read because people are harshly criticizing your work, but, a lot of times, you can read those reviews and get good ideas out of them,” she said. “Most of us, as scientists, demand the very best of ourselves: our very best ideas, our very best effort, and that’s how I approach every grant that I write.”

Today, funding challenges are further complicated by significant cuts to the National Institutes of Health (NIH), which funds billions of dollars of medical research.(16) While industry can be a source of funding, the private sector tends to focus on work that can be commercialized on a shorter timeline.

“We need public support and public funds — namely NIH support — to really see a lot of these advances through to fruition,” said Embree. “A lot of industry doesn’t do foundational, basic science because it takes way too long. Sometimes, the science takes 15 years before it gets to the point where it can be translated to patients.”

When researchers do reach the point where their work can be prepared for clinical use, there are then many regulatory hurdles to clear.

“There are so many nuances in commercializing and translating your drug or technology to patients,” Embree noted.

NIH support can play a role here as well. Embree co-founded biotechnology company WNT Scientific to help bring StemJEL to patients.(6) That company secured support from the NIH’s National Institute of Dental and Craniofacial Research and NIH’s Commercialization Readiness Pilot program.(17)

“They partnered us with a team of regulatory consultants, which was phenomenal because I had no idea how to do this,” said Embree. “There must have been 15 people on the call helping prepare us for our Food and Drug Administration meeting.”

The Future of Regenerative Dentistry

Dentists have access to many aspects of regenerative dentistry in clinical practice today: bioactive materials, endodontic revascularization, GBR and GTR. Research continues, and, with it, the hope of more clinical applications.

New generations of researchers and clinicians have opportunities to learn about regenerative dentistry and figure out how they can incorporate that work into their labs and practices. The University of Michigan, for example, has a 12-month postgraduate program dedicated to regenerative dentistry.(18)

The competitive, intensive program accepts three or four students per intake. Students can come from a variety of backgrounds. “Dentistry, medicine and veterinary medicine, as well as physicists and engineers — we are all are trying to bridge engineering with biology and clinical applications of these biomaterials for regenerative applications,” Marco Bottino, DDS, MSc, PhD, FADM, the program director, told AGD Impact.

Approximately a quarter of the program is dedicated to coursework in foundational areas of regenerative medicine, like stem cell biology and biomaterials science. Another quarter gives students the opportunity to participate in clinical shadowing based on their particular interests. The other half of the program is focused on hands-on research.

Many students join Bottino in his lab. “My lab focuses on the development of biomaterials and drug delivery therapies for reconstructing damaged dental and craniofacial tissues,” he said.

A number of different projects are underway in the lab. For example, Bottino and his team are exploring ways to 3D-print antimicrobial dental implants and to 3D-print tissue-specific grafts and scaffolds for the reconstruction of bone and periodontal ligaments. They are also examining ways to reconstruct alveolar bone for posterior implant placement.

Bottino’s lab is also working on dental pulp tissue regeneration. “We are trying to understand potential strategies in terms of transplanting stem cells in teeth that are now devitalized. How can we make these teeth feel pain and become responsive to stimuli?” he said.

Another area of research is the fabrication of soft tissue grafts. By using biomaterials and cells from the gingiva or oral mucosa, researchers could potentially grow a graft outside of the body.

“We want to use the cells from the patient, and then this tissue can mature in the lab,” Bottino explained. “Then, we transplant it back into the patient after it has grown, without the patient suffering a pretty significant mutilation from taking a full-sized tissue graft from one site, the donor area, and applying it to the area of need.”

Right now, the University of Michigan program grants a one-year certificate. But Bottino is hopeful that it will grow into a two-year master’s degree program. He envisions the program branching out into more specialties, like periodontics, and expanding to offer students more opportunities for hands-on experience in treating patients.

Research in regenerative dentistry continues to push the field forward in other ways as well. At the end of 2024, researchers with the Tufts University School of Dental Medicine published a study in Stem Cells Translational Medicine. They successfully bioengineered tooth buds with human cells and implanted them in minipigs. Toothlike tissue grew over the course of two or four months.(19) While that end product doesn’t yet look like a natural human tooth, the research appears to be an exciting step toward living tooth replacements.(20)

Of course, that is just one study. Plenty of other researchers are hard at work exploring possibilities in regenerative dentistry. And one area that could open a lot of doors for them? Vast, complex sets of information from a variety of sources — big data.

Machine learning models, often referred to as artificial intelligence, could be applied to data sets to drive more efficient “… analysis of factors that define cells’ differentiation, creating an optimal scaffold for cell growth, and predicting the effectiveness of the treatment.”(21)

“What’s often called ‘big data’ is really advancing the field very rapidly,” said DiPietro. “Because of the advancement of genomic and transcriptomic analysis, we’re able to learn so much about what genes are being turned on and utilized in different circumstances.”

“I’m very excited about the possibility of people doing more computational modeling. That approach will help us make predictions about things that we can’t easily test in the lab,” DiPietro added. “It really could be helpful in any regenerative field — not just in the oral cavity or the craniofacial complex, but the whole body.”

Carrie Pallardy is a freelance writer and editor based in Chicago. To comment on this article, email impact@agd.org.

References

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14. UIC College of Dentistry. “Perfect Wound Healing: Lessons from the Mouth.” YouTube, uploaded by UIC Dentistry, 24 May 2024, youtube.com/watch?v=clyt_0I2ieY.

15. McCusker, Catherine, et al. “The Axolotl Limb Blastema: Cellular and Molecular Mechanisms Driving Blastema Formation and Limb Regeneration in Tetrapods.” Regeneration (Oxford, England), vol. 2, no. 2, 11 May 2015, pp. 54-71.

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20. Gordemer, Barry, and Obed Manuel. “Scientists Grew Human-like Teeth in Pigs. Could It Lead to Living Tooth Replacements?” NPR, 10 Feb. 2025, npr.org/2025/02/10/nx-s1-5290022/scientists-grow-human-like-teeth-in-pigs.

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