Regenerative Potential of Carious Lesions – A Literature Review

It seems increasingly I have been approached by both patients and dental colleagues and asked to give an opinion regarding some aspect of regenerative dentistry; from regrowing pulp and dentin to 3D printing or growing a whole new tooth for the purpose of intention replantation.  This trending prevalence can be attributed directly to the increase in research in these areas, but also to the increased availability of select articles through social media.  It is the social media aspect I find that has a potentially combative air about it as if practitioners will be trapped between either hiding information from the public or not being on the cutting edge of technology to offer this treatment.  Obviously, this could not be further from the truth and I have found that asking for the original article can be an effective way of directing the conversation back to rational discussion.  There are common pitfalls, either in the research itself or in the inferences to practical application, that usually result in headline-grabbing statements and titles that make their way to newsfeeds.  A fantastic example of this was in an article presented to me by a study club asking for comment, and so I thought it would be a good time to review Neves, V. C. M. et al. Promotion of natural tooth repair by small molecule GSK3 antagonists. Sci. Rep. 7, 39654; doi: 10.1038/srep39654 (2017).

In the introduction summary, Vitor Neves comments that dentin lost by a carious lesion is commonly restored by an inorganic calcium or silicon-based cement and that this material does not degrade over time thus the mineral volume of the tooth is never fully restored.  Translated to dentistry, they are describing the use of either a calcium hydroxide like Dycal or a mineral trioxide aggregate (MTA) in examples of carious exposures.  In their research, they do not distinguish between a carious exposure and a near exposure. Their summary goes on to say that use of a glycogen synthase kinase (GSK-3) antagonist soaked into a collagen sponge will, “promote the natural processes of reparative dentin formation to completely restore dentin,” and concluding that this could provide a new way of restoring teeth.

In their background introduction, they bring up that odontoblasts are responsible for dentin formation and that the pulp contains stem cells that are capable of differentiating into odontoblasts.  They illustrate nicely the exact intracellular signaling pathway and transcription factors that are up-regulated following tooth damage and preceding differentiation and dentin formation.  They hypothesize that use of one of three commercially available GSK-3 antagonists will allow for an increase in Wnt signaling agonists and therefore produce even more dentin than under normal conditions.  They argue that this will give the pulp a greater ability to recover from an exposure by producing even more dentin (for large carious lesions) and that if a collagen sponge is used it will be absorbed and replaced by dentin resulting in complete regeneration of the carious lesion by dentin.

Following cell culture testing of effective concentrations and cytotoxicity of the drugs, theGraph researchers drilled holes in the molar teeth of mice and placed a collagen sponge soaked with the appropriate concentration of the drug in contact with the pulp.  They then covered the sponges with glass ionomer and analyzed the expression levels after 24 hours and 5 days and compared it with MTA.  The graph they published showed a 3-fold increase in axin-2 expression after 1 day for the GSK-3 antagonists with no change from control for MTA.  They did comment but chose not to show the graph, that axin-2 levels were the same for MTA and the GSK-3 after 5 days meaning the levels of odontoblast differentiation were the same after the setting time for MTA which is 24-48 hours.  Also interesting was the failure to note the inherent differences in inflammation between a carious exposure and an acute mechanical exposure with no history of disease.

In the next phase of their research, Neves et al reproduced the same mechanical exposure but allowed dentin formation for 4-6 weeks before performing micro-CT and decalcified histologic analysis.

Dentin formation for 4-6 weeks before performing micro CT and decalcified histologic analysis

Their headline conclusion was that there was a 1.7x more mineralization in the GSK-3 sponges than compared to the MTA groups. More importantly, they state, was that reparative dentin in the GSK-3 groups filled the entire space from exposure to occlusal surface and the pulp remained vital. While the micro CT slices provided may seem promising, the histology slides paint a clear picture of what is really happening. The ‘injury’ site may be ‘filled’ but the mineralization is porous and structurally very different from the natural dentinal tubules directly adjacent to it. This is consistent with our understanding of natural dentin formation during development compared with reactive dentin deposition in response to an exposure.

Graph

Restoration of a carious lesion involves replacing lost hard tissues, prevention of disease and returning a tooth to functioning structural integrity.  While the science of many articles focused on regeneration may be sound, the politics of grant funding rely on researchers making sometimes large leaps to practical applicability.  Remembering that the embryologic development of enamel and dentin formation is a complex process that we are far from replicating, and that inflammation in the presence of disease changes laboratory studies in unpredictable ways, are just two of the important points to apply to this type of research.  Using this lens to critically evaluate the progress of research will enable appropriate and worthwhile discussions with colleagues and patients.

Dr. Jason Conn

Dr, Jason Conn, DMD, CAGS, FRCD(C)

About Dr. Jason Conn, Langley Endodontics

Dr. Conn was born and raised in Langley. He completed a Bachelors in Chemistry at Simon Fraser University before receiving his DMD and Certificate of Advanced Graduate Study in Endodontics at Boston University where he wrote a thesis in clinical decision making and another in odontogenic stem cell differentiation.

Dr. Conn has maintained an active practice alongside Dr. Bittner since 2012 while teaching as a part-time clinical assistant professor at the University of British Columbia.

In his free time, Dr. Conn is a Cub Scout leader, long-distance runner, back-country hiker, snowboarder, and yogi-in-training

On April 25, 2018, posted in: News for Doctors by

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