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Translating Basic Science to Clinical Research

By Drs. Anil Kishen and Mo K. Kang

Clinical practice of dentistry has witnessed several technological advancements in recent decades. In general, these advancements relied upon in-vitro testing and sometimes controlled clinical assessments prior to being marketed for clinical practice. The aim of these advancements was mainly to improve clinical efficiency and a desire to enhance treatment predictability. There were few advances aimed at producing a major paradigm shift in the science and/or therapeutic aspects of endodontics. Currently, root canal treatment benefits from rapidly evolving technologies including instruments, sound energy, light energy, chemicals, adhesive materials and tissue regeneration. Notwithstanding these improvements in the provision of endodontic treatment, epidemiological data suggests that up to 38% of root treated teeth showed persistent endodontic disease. The presence of surface-adherent root canal biofilm within complex root canal anatomy and the ability of organic root canal components to neutralize the efficacy of disinfectants have been cited as major causes for limited therapeutic effectiveness. Ten percent of root-filled teeth may also be lost due to root fractures. Loss of fracture resistance has been attributed to physiological, pathological and iatrogenic risk factors in root-filled teeth.

My research program at the University of Toronto focuses on developing cost-effective and safe treatment strategies that promote health and retention of previously infected natural teeth. These include taking advantage of principles of tissue engineering using bioactive nanoparticles. For such technologies to be adopted into clinical practice, they must be subjected to rigorous in-vitro, ex-vivo, in-vivo and clinical research, to demonstrate their safety, efficacy and, most importantly, effectiveness in clinical trials. Laboratory based in -vitro, ex-vivo and in-vivo investigations followed by translational research forms a continuum of research activity extending from basic science discoveries to their clinical applications. Translational research plays a vital role in scientific inventions that would impact endodontics as a major paradigm shift.

Translational research has several important roles in a research enterprise. Primarily, it bridges knowledge gaps between basic science (lab-based inventions), clinical research (knowledge), and clinical application. Translational research also helps to develop strategies to promote adoption of best practices in clinical settings and for policy development. It is mostly considered to be unidirectional, particularly in the course of basic research from the lab translated into clinically relevant studies. But, translational research can also be applied in other directions. This transpires when the basic researcher desires to examine elements of a multifaceted treatment program in the laboratory, under controlled conditions with high internal validity for meaningful clinical advancement. Currently the research from my lab is in this phase.

In closing, translating basic science to clinical research through well-planned translational research is key for meaningful advances in endodontics. Basic researchers, clinician scientists and clinicians should work as a team to achieve the set goals. Today’s academic community face the challenges of teaching, research, publishing and competing for limited sources of funding, combined with pursuing their individual career goals, which can be daunting. Nonetheless, it can be a deeply satisfying and fulfilling endeavour, when fruits of laboratory-based discoveries are translated into new therapeutic tools and improve healthcare practices for our patients.  –Dr. Anil Kishen

Missing Piece in Endodontic Research: ‘Back to Basics’

Inflamed pulp is considered as dispensable tissue that we endodontists happily remove on a daily basis to treat our patients. Dental pulp on the other hand is an incredible organ that is capable of diverse biological processes, including tissue regeneration, inflammation resolution, immune surveillance, mineralization, neovascularization, neurogenesis, just to name a few. Structurally too, pulp-dentin complex is an amazing feat for the Designer of such micro-structure with exquisite delicacy for the maximal functionality within such minuscule space.  Since the same biological processes occur in the dental pulp as in other organ systems yet at much minute scale, this adds to the complexity with which we have to explore the biological and diseases processes in the dental pulp.  In the recent past, especially in the mid to late 1900s, there had been significant expansion in our understanding of how dental pulp functions in health and how bacteria cause pulpitis and periapical diseases. This expansion in our understanding of dental pulp came about through basic science research contributed by our predecessors in endodontics, whom I will not dare to name because I cannot name every one of them. Nonetheless, our understanding of dental pulp pathophysiology at present is the result of the ingenuity and tremendous effort of the past.

Science and technology continually evolves, and it seems to occur at an ever-accelerating rate as time advances. That is evident in almost all parts of our lives, including personal computing, communication, healthcare, imaging, and even charting our entries for patient care. Perhaps less noted by the public, scientific advancement has already gone beyond our imagination in basic biomedical research. This can be exemplified in the way we understand gene regulation. In the recent past, identifying a single gene differentially regulated in a biological process was a monumental task that involved laborious benchtop assays and would suffice awarding a Ph.D. degree. With the introduction of multiplex DNA hybridization, also known as “microarray,” in the early 90s, scientists are able to identify hundreds and thousands of genes differentially regulated in a single experiment. More recently, advancement in nucleotide sequencing technologies have allowed for sequencing of every single RNA molecules expressed in cells comparatively to identify the full spectrum of differentially expressed genes in the genome. This, so called next-generation sequencing, is the newest platform by which scientists today study gene regulation, protein-DNA interactions, mutations, deletions, etc.

With the advancing technologies today, we are able to address questions in pulp biology that we had not even thought of in the past. For instance, histological and ultrastructural studies of the late-’80s revealed the snapshot of endodontic pathosis and the disease process. Subsequent functional and genetic (knockout) studies in the ’90s elucidated the cellular and molecular elements of periapical inflammation using the animal models. These prior studies gave us the list of cytokines, e.g., IL-1b, IL-6, and TNF-a, which exacerbate periapical inflammation and bone destruction.  The remaining questions are … what are the regulatory mechanisms by which these cytokines or other inflammatory mediators are expressed in the event of periapical inflammation? How does chromatin structure is altered in the inflammatory cells to allow for the expression of these cytokines during pulpitis or periapical abscess?  What is the molecular mechanism of inflammation resolution in the pulp after direct pulp capping? Which cellular entities and molecular mechanisms are responsible for dentin regeneration during regenerative endodontic therapies? We endodontists today are in a unique position to harness the available technologies in biomedical science to address these (and much more) questions so that our successors in the future can innovate new therapeutic modalities to save more teeth and restore function.

While the technological advances in clinical endodontics is at the full speed, the scientific literature in endodontics today seem to indicate dimming light on the torch, in terms of basic research in endodontics, especially in the U.S.  Scientific rigor in endodontics is critically important for all aspects of our specialty and will define our specialty as an academic discipline of dentistry. We shall refocus our efforts on our basic understanding of how dental pulp works and how periapical disease occurs, using the new insights, new tools, and the new technologies that have only become available today.  This will require capturing the resources that are currently available and cultivating the next generation of impactful endodontic junior investigators, who are so scarce these days. In doing so, we may be able to recycle the inflamed pulp tissues rather than disposing of them. –Dr. Mo K. Kang

Anil Kishen B.D.S., MDS, Ph.D. is professor, Endodontic Program; graduate coordinator, Graduate Education; principal investigator, Dental Research Institute; Faculty of Dentistry, at University of Toronto. He can be reached anil.kishen@dentistry.utoronto.ca. Mo K. Kang, D.D.S., Ph.D., is professor and chair; Jack Weichman Endowed Chair, Section of Endodontics, at UCLA School of Dentistry. He can be reached at mkang@dentistry.ucla.edu.