UB oral biology researchers receive NIH grant to create miniature tooth model

BUFFALO, N.Y. — About 1 in 10 children are born with at least one missing permanent tooth due to congenital anomalies. And a much higher percentage of adults lose teeth from decay or injury over their lifetimes.

Implants and bridges, which can be expensive and involve risks to surrounding teeth, are the only remedy. Unlike bones, teeth do not regrow. 

Two researchers in the University at Buffalo School of Dental Medicine have received funding to work toward an alternative. They are growing miniature teeth in a lab from induced pluripotent stem cells (iPSCs), which are reprogrammed adult stem cells.

Laertis Ikonomou, PhD, associate professor of oral biology, is the principal investigator of a two-year, $435,167 R21 grant from the National Institute of Dental and Craniofacial Research to better understand how human teeth form at their very earliest stages and how to replicate them.

He is working with Hyuk-Jae (Edward) Kwon, DDS, PhD, associate professor of oral biology, who has examined how specific genes affect the development of tooth enamel in mice. Kwon received international recognition for his research in June when he won second place in the International Association for Dental Research (IADR) Joseph Lister Award for New Investigators Competition in Barcelona, Spain.

The two researchers will use a process called directed differentiation to guide the stem cells through the same type of steps that occur when a tooth is developing in a human embryo.

“The goal is to develop a powerful new tool for understanding why some children are born with missing or defective teeth, and eventually, to open the door to regenerative dental therapies,” Kwon said. 

Complementary research interests

Ikonomou met Kwon when he interviewed at UB in 2019. 

“I realized that we had a confluence of research interests,” Ikonomou said. “During my interview and presentation, I sketched out some ideas of how we can make teeth from pluripotent cells. Researchers have tried for many years but haven’t quite been successful.” 

Ikonomou, who has a background in stem cell biology, came to UB in 2020 from Boston University School of Medicine, where he researched how to make respiratory cells from iPSCs. He also has extensive expertise in the bioethics of cell and gene therapies.

“We use human embryonic stem cells less and less in research due to a lot of issues, including ethical issues,” Ikonomou says. “What we are mostly using in our research are induced pluripotent stem cells. We can take cells from any individual and turn back the clock to return them to their pluripotent state. It’s pretty amazing.”

Facilitating formation of early organoids in mice

For their project, Ikonomou and Kwon will first create “reporter” stem cells.

The cells start glowing in certain colors when specific genes are activated, which will help in tracking and isolating early tooth progenitors. At the same time, they will map the genetic instructions that guide normal tooth initiation in mice, using advanced single-cell and spatial technologies. Tooth progenitors derived from iPSCs can then form 3D structures in a dish  called organoids.

“You can also put the cells under the kidney capsule in mice because it’s highly vascularized,” Ikonomou explains. “It’s a permissive environment that will facilitate the formation and maturation of this early organoid, which doesn’t resemble a mature tooth.”

Finally, they will combine all this information with previous research to try to recreate the process to make efficient and accurate early dental cells.

With a better understanding of why some humans are born with dental anomalies, researchers can then start looking for therapeutic targets to directly address those birth defects — and eventually replace implants for a number of patients, including those who lose teeth due to injury or decay.

Long process to get to bioartificial teeth

There is no quick fix, however.

“Scientists started doing research in the early 2000s with pluripotent stem cells for lungs,” Ikonomou says, “and still we have no therapies.” 

With more understanding and research, the door could open to surgically implanting cells for organic teeth inside the mouth or growing cells in an animal host, which would create a finished tooth to be implanted in the mouth.

“The challenge is that you would have to do microsurgeries to connect the tooth to the existing nervous system and the circulatory system so that the tooth is receiving the nutrition it needs to be healthy,” Kwon says.

Ikonomou points to other successful uses of transplanted stem cell products such as in Type 1 diabetes patients, many of whom remain insulin-independent for months. Yet questions remain, he says, including, How do the cells stay in place? How do they remain functional? How are they not attacked by the immune system of the recipient?

While doing their investigations under this grant, Ikonomou says they will apply for additional grants to continue conducting research toward the ultimate goals.

 “I think it will take a long time to develop something that can essentially make an artificial tooth,” he says. “We are hoping to work on this for a long time.”