Periodontal Disease: Engineering the Future of Care

In the 1950s, soon after NIDCR’s founding, millions of Americans often flipped on their black-and-white tube televisions and watched commercials that warned of a tongue-twisting condition called gingivitis. As the ads warned, gingivitis was step one on the road to chronic gum, or periodontal, disease and tooth loss.

Today, researchers now know that gingivitis does not necessarily lead to advanced periodontal disease. However, a confluence of factors can induce chronic inflammation of the gingiva in some people. These factors include lifestyle choices, such as an addiction to tobacco; diabetes or another underlying health condition that compromises one’s ability to heal; a susceptibility to gingival infections; and an over reactive immune system. If left unchecked, periodontal disease gradually will degrade the four tooth-supporting tissues of the periodontium – gingiva, periodontal ligament, cementum, and bone. As the television ads from the 1950s correctly concluded, advanced periodontal disease will lead to tooth loss.

Today, a trip to the periodontist typically entails anti-infective therapy coupled with scaling and planing of the inflamed tissue. Periodontists also have been eager to employ the latest biological discoveries to regenerate damaged gingiva, ligament, and bone. Although today’s tissue regeneration techniques remain works in progress, research on this front continues to progress nicely. Most scientists are optimistic that tissue engineering, with its sophisticated mix of biology and chemistry, will be more predictable in the years ahead. To present the research themes are two scientists with long and productive track records in this area: Dr. William Giannobile, a researcher at the University of Michigan in Ann Arbor; and Dr. Pamela Robey, an NIDCR scientist in Bethesda, Maryland.

William Giannobile

You oversee your own laboratory and head a clinical research center at the University of Michigan. You also find the time to see patients in private practice?

I’m also a practicing periodontist, and I continue to treat patients in a private practice here in Ann Arbor.

So you’ve both seeded and directly benefited from the research?

I think so. As a practitioner, I’ve benefited from the advancements in biomaterials research, various bone grafting techniques, guiding tissue membranes that separate the bone from the connective tissues, and anti-infective therapies to arrest or slow the progression of periodontal disease.

But there’s still a ways to go?

That’s right. Periodontal treatment today remains fairly unpredictable in terms of getting stable, long-term results. That’s especially true for regenerating the various parts of the periodontium - bone, ligament, cementum, and mucosa. But there have been some nice advancements, and I just mentioned a few of them. I think the combination of research progress and the continued unpredictability of treatment has, to some extent, shifted the periodontist’s role.

How so?

About 20 years ago, most restorative dentists would contact periodontists with referrals and say, “Do your best. See how many more years you can help this patient eke out of these teeth.” Now, the mindset is much different. Because of the unpredictability of regeneration and the challenge of controlling a chronic immune response, many practitioners don’t want to run the risk of trying to save the teeth. Many advise their patient to have the questionable teeth removed and replaced with dental implants. But as a researcher and periodontist, I continue to support the profession’s founding principles to save teeth whenever possible. For that reason, I see a lot of areas that we need to explore to develop more predictable therapies, especially when regenerating the damaged tissues of the periodontium.

And the biology is there for the taking?

I think so. You can see it in the scientific literature each and every month. You also can see it in the ideas that have entered the clinical research pipeline.

For example?

Growth factors. Platelet derived growth factor and the bone morphogenetic proteins are both now FDA approved and have entered into the clinical arena over the last two years. Although these growth factors have sometimes incorrectly been held up as a panacea for tissue regeneration, they are indeed very important advancements. Keep in mind, though, periodontal disease is an extremely complex condition. Tissue regeneration alone is not the answer. We need to push the anti-infective/host modulation side, too, and ensure that the patient’s immune response doesn’t turn chronic and self-destructive.

And that self destruction is of an inherently complex environment?

Absolutely. We essentially have a tooth – an avascular mineralized tissue - that protrudes through soft tissue, where it is under constant microbial attack. The tooth is rooted in bone, anchored by ligament, and dependent on supportive tissues in dentin and cementum. These tissues have specific geographic junctions, abilities to bond, and load-bearing qualities. What’s more, all of this complexity is rolled into a tight biologic space. We often talk about millimeters of eroded bone. Millimeters are very significant in the support of teeth. There’s just nothing like the periodontium in the rest of the body.

So how do you make tissue regeneration more predictable?

I think interdisciplinary collaborations hold the key. We need scientists with training in infectious disease, biomedical engineering, molecular and cell biology, genetics, and clinical research.

What about technology development?

Discovery and technology development typically go hand in hand. A good example is the progress in high resolution imaging techniques. They produce images of bone damage that are so accurate, we literally can construct in the laboratory three dimensional scaffolds that fit perfectly into the periodontal pockets and deliver regenerative factors. This hasn’t yet reached the clinic, but it suggests the following scenario. The surgeon images the tooth/bone lesion and says to the patient, “Okay, I can quickly make this scaffold, and it will be loaded with growth factors or stem cells. We’ll just drop it into the defect.” Right now, the surgeons carve out the decalcified bone as best they can. It’s just not efficient.

We talked a moment ago about the biology being there for the taking. If the scaffolds and their growth-promoting cargo now can be more precisely delivered, that raises the issue of timing. You need to drop in the growth factors at the right time and in the right sequence.

That’s an important point. Researchers have begun to look at the process in a more systematic way. But defining the biology is even more important from a diagnostic standpoint. Patients respond differently to treatment.

Right, it drives periodontists crazy.

But it makes perfect sense. Periodontal disease represents a spectrum of disease. Patients are infected with various pathogens, their immune system reacts differently to the infection, and they arrive in the periodontist’s office with various underlying conditions and habits. If informative protein markers could be identified in patients, at the front end of the visit, we could begin to tailor treatment to their specific needs.

This broader biology base takes us back to the clinical pipeline that you mentioned a moment ago. With greater diagnostic specificity, periodontal patients no longer would be lumped together in clinical trials. It would be possible to subcategorize them and begin to customize treatment.

That’s why I think we’re going to be looking more at these designer therapies for patients. With different molecular diagnostic approaches, we’ll have certain patients who really respond well to a given treatment; whereas we have others who have always been lumped together into this non-responder group. Why are they considered to be non-responders? That’s where the diagnostic side would really benefit them. These therapies open up the future use of pharmacogenomics, or individualizing treatment to the patient’s specific form of periodontal disease.

Pamela Robey

You’ve said if five people of different scientific backgrounds were chatting, it’s possible they’d arrive at five different definitions of the term “stem cell.” I know this is an issue that you’ve thought long and hard about. What is a stem cell?

I think any definition must be based on a stem cell’s activity in the body, not necessarily its traits in a culture dish. So, starting there, I think everyone would agree on two broad defining features. One, a stem cell must give rise to more mature daughter, or progenitor, cells that can differentiate into cell types that are needed to maintain a tissue structure. For example, in the hierarchy of bone formation in adults, stromal stem cells reside in the bone marrow. When prompted to repair, they beget not only the osteo-chondro-progenitor daughter cells that form bone or cartilage, depending on the tissue microenvironment. They also beget the stroma that supports blood formation and marrow fat cells.

It’s kind of like reading the Old Testament Book of Numbers. The patriarchal stem cell begets sublineages of cells.

Right, and this theme is played out throughout the body. We see it in bone and cartilage, and we see it in dentin.

What’s the second defining feature?

Self renewal. A stem cell must have the ability to produce a new generation of stem cells. So, as they churn out more mature daughter cells, they also must produce daughter cells that remain stem cells. Without self renewal, the stem cells that populate a given tissue would die their natural deaths and take with them the ability to regenerate and maintain a tissue structure.

Why has the definition of stem cell gone off in all directions?

It’s the vagaries of cell culture. Because scientists typically study stem cells in a culture dish, they describe certain characteristics that may or may not relate back to what they do in the body.

For example?

Well, two things come to mind. A lot of people say that a stem cell is undifferentiated. But that may be a misnomer. It may be that a fully differentiated cell, under the proper conditions, can revert back and become a precursor cell or maybe even a more primitive cell like a stem cell. As long as a cell has an intact nucleus, nothing is really impossible.

Secondly, some say a stem cell has the ability to replicate almost endlessly. But that isn’t necessarily the case either. Even the best characterized stem cell - the hematopoietic stem cell - is not immortal. Each hematopoietic stem cell can only repopulate blood cells a certain number of times before it becomes exhausted.

How does this “stemness” translate to the periodontium? Let’s start with the periodontal ligament.

We know it’s possible to take a periodontal ligament, and treat it with enzymes to release single cells. Within that mixed population of cells, there are some that have the ability to recreate fibers that look a lot like those in a periodontal ligament. Whether the fibers can function as a periodontal ligament I think is still on the table for discussion. These cells were discovered here at NIDCR about four years ago, and this lead is actively being pursued. It’s also not clear where the cell comes from, and whether it’s truly a stem cell or a useful progenitor cell. I think that is something that we need to take into consideration.

What do you mean?

Having a stem cell is a wonderful thing. Knowing about it is a wonderful thing. But the slightly more committed progenitors also can do wonderful things. We shouldn’t dismiss them just because they don’t self renew or produce more than one cell type. If they’re useful in a regenerative way, that’s fine. They don’t have to be a stem cell to be useful.

What about alveolar bone of the tooth socket?

Stem cells that make bone have been under study since the mid 1990s. Obviously, they have great potential in regenerating the periodontium. If you don’t have bone to anchor the tooth, you have no foundation. But we really need to know how this type of bone is different from the axial and appendicular bone found elsewhere in the body. They have a different embryonic origin, and their properties appear to be slightly different. We don’t know how that is. Nor do we know the impact of these differences. For example, can we take bone marrow from the iliac crest of the pelvis and use it to regenerate craniofacial bone, including alveolar bone? That’s a huge question, and we really don’t know much about it.

What about cementum?

Well, I just mentioned the periodontal ligament cells. They also make something that appears to be cementum. In addition, a number of years ago, we took shavings of cementum and could get cells to grow out of those shavings in a clonal fashion. When we took the cells, put them in a scaffold, and transplanted them into our animal model, they formed tissue that resembled cementum. The problem is we don’t really know whether cementum is different from bone. We don’t have any cementum specific markers to answer that question. It may just be that osteogenic cells form a cementum-like structure when they are in close proximity to dentin-forming cells. So, the boundaries between cementum and bone are very subtle. It’s difficult to say that they are truly two distinct entities. Maybe under the right conditions, cells that normally would be osteogenic could be made to be cementogenic.

Are you confident that the regeneration of the periodontium will be doable down the road?

I am confident. We have cells that we can begin to use to try and create a viable tooth. But there is a major hurdle in trying to construct a root that will provide a solid anchor within the jawbone. And we need to bring a broader array of expertise to the table. We need more people with expertise in bioinformatics, biomaterials, biochemistry, and clinicians to help us design appropriate animal models that mimic a given human disease. There can be a perception that it’s only a tooth. It’s not going to kill you, if you don’t have one. But try to tell that to somebody with a bad tooth ache. Dental problems cut across all aspects of society, and their solutions potentially benefit everyone. Secondly, the mouth is readily accessible, unlike the body’s internal organs such as the pancreas or liver. The lessons learned in the oral cavity might not be a perfect fit in learning to better treat osteoporosis or kidney cancer, but they will have applicability.