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Regenerative Endodontics Research: Seven Years in the Making

 

In late 2013, the Foundation approved grants to three research teams who responded to a Request for Application, to investigate different aspects of stem cell regeneration. The research investment was made to help endodontics to ride the tide that promised sweeping changes in clinical practice for both dentistry and medicine. The following grants were paid over a seven-year period. 

Institutions (at time of application) Investigators Project Title Total Funding Received
University of North Carolina at Chapel Hill

University of Washington

New York University

 Asma A. Khan, B.D.S., Ph.D.

Natasha M. Flake, D.D.S., Ph.D.

Jennifer L. Gibbs, D.D.S., Ph.D.

 Prospective and Retrospective Treatment Analysis of Regenerative Outcomes in Immature Teeth $200,000
University of Texas Health Science Center at San Antonio

University of Maryland

Loma Linda University

 Kenneth M. Hargreaves, D.D.S., Ph.D.

Ashraf F. Fouad, B.D.S., D.D.S., M.S.

Mahmoud Torabinejad, D.M.D., M.S.D., Ph.D.

 Regeneration of Pulp Dentin Development in Teeth with Necrotic Pulps and Immature Roots $1.7 million
University of California at Los Angeles

University of Southern California

Yonsei University Dental College

Kyung Hee University College of Dentistry

 Mo K. Kang, D.D.S., Ph.D., M.S.

Songtao Shi, D.D.S., M.S., Ph.D.

Euiseong Kim, D.D.S., M.S.D., Ph.D.

San Hyuk Park, D.M.D., M.S.D., Ph.D.

 Cell Based Approaches to Endodontic Regeneration $300,000

 

 

Since funding began in 2014, researchers have shifted institutions and projects have developed, resulting in a wide variety of presentations, manuscripts, publications, and additional accomplishments. The Foundation looks forward to reporting additional results from this investment as they become available. 

Prospective and Retrospective Treatment Analysis of Regenerative Outcomes in Immature Teeth

The goal of this project is to compare clinical and radiographic outcomes of regenerative endodontic treatment (REGENDO) versus apexification (APEX). We will recruit a multi-centered cohort of previously treated patients by completing a comprehensive chart review to identify eligible patients. This will allow us to identify a retrospective cohort of subjects in an unbiased systematic manner, as well as evaluate documented clinical outcomes and attempt to bring eligible subjects in for an additional follow up visit for clinical evaluation. 

Resulting Presentations:

  • A multi-centered retrospective evaluation of clinical and radiographic outcomes of revascularization/revitalization therapy in immature teeth: Study design and recruitment. Abstract submitted and accepted for presentation at AAE15 in Seattle, Washington.
  • Clinical Outcomes of Endodontic Treatment in Children with Immature Permanent Teeth: An Interim Analysis. Abstract submitted and accepted for presentation at AAE16 in San Francisco, California.
  • Retrospective Study of Radiographic Outcomes of Endodontic Treatment of Immature Teeth with Necrotic Pulps. Abstract submitted and accepted for presentation at AAE16 in San Francisco, California.

Manuscripts in Preparation:

  • Final touches are being put on the first manuscript which will accomplish the goals of Aim1. Planning to submit this manuscript in spring of 2021
  • The second manuscript will accomplish the goals of Aim2. Anticipating a publication time frame of the summer or fall of 2021 for this manuscript.

 

Regeneration of Pulp Dentin Development in Teeth with Necrotic Pulps and Immature Roots

This exploratory clinical trial is a randomized multi-center clinical trial designed to compare the clinical and radiographic outcomes of a regenerative endodontic procedure using tissue engineering principles (REGENDO), or a revascularization endodontic procedure (REVASC) – both using a triple antibiotic paste, to that of an apexification treatment using a mineral trioxide aggregate barrier (APEX) for the treatment of permanent teeth with pulpal necrosis and immature apexes.

Presentations of Preliminary Study Results – In addition to the preliminary Analysis of Microbiological Data for the trial which was presented at AAE19 in Montreal, Canada, the three additional presentations have been made:

  • The Role of Infection and Disinfection in Dental Pulp Regeneration. (Keynote Address) J Dent Res 2018, 97, Section A, Abstract #0862, AADR/CADR 47th Annual Meeting, Fort Lauderdale, Fla., USA.
  • Contemporary Microbial and Antimicrobial Analysis in Regenerative Endodontic Therapy. (Keynote Speaker) June 24, 2019:, Pulp Biology and Regeneration Satellite Symposium following IADR Meeting in Vancouver, CA:. Portland, OR.
  • The following poster presentation at UNC Research Day on February 12, 2020. This poster was awarded First Place for the Derek T. Turner Student Research Award at Research Day at UNC. It has not been presented nationally yet due to COVID-19:
    • Fouad AF, Roening C, Diogenes A, Torabinejad M, Hargreaves K. Geographical Variations in Microbiota from Immature Teeth with Necrotic Pulp.

Manuscripts in Preparation:

  • Fouad AF, Diogenes A, Torabinejad M, Hargreaves KM. Microbiome changes during regenerative endodontic treatment
  • Fouad AF, Roening C, Diogenes A, Torabinejad M, Hargreaves KM. Geographical variations in microbiota from immature teeth with necrotic pulp
  • Diogenes A, Fouad AF, Torabinejad M, Locke E, Hargreaves KM.  A multi-center randomized clinical trial evaluating regenerative endodontic treatments.
  • Hargreaves KM, Fouad AF, Diogenes A, Locke E, Sanns W, Torabinejad M.  Development of a web-based registration system to support multi-center endodontic clinical trials

Additional Study Accomplishments:

  • Microbiological Sample Analysis – Microbiological sample analysis continues; however preliminary analysis has provided exciting information. The microbiological analyses of the data have changed from how it was originally envisioned in the grant due to advances in the technology. One area that may become clinically important in future is metagenomic analyses of the endodontic microbiome to predict microbial virulence and response to antimicrobial treatment. This area of research has not been reported in endodontic research yet.  
  • Resident Study Participation – Residents at all study sites played a critical role in the recruitment and execution of study procedures for enrolled subjects. They benefited by performing the endodontic therapy utilizing the research related canal disinfection procedure, performing post-procedure clinical analysis of the treated tooth, and assisting in documentation of their findings at the one- and two-year recall visits. Additionally, because of their work with the study, graduating endodontists gained enhanced knowledge on canal disinfection that will be carried forward in their own practices.

 

Cell Based Approaches to Endodontic Regeneration

The goal of this study is to test whether autologous dental pulp stem cell (DPSC) transplantation is capable of de novo regeneration of pulp-dentin complex and restoration of normal pulp physiology in teeth with necrotic pulp. We will test our hypothesis, “that functional dental pulp restoration and regeneration of pulp-dentin complex in vivo necessitates cell-based therapies utilizing DPSC transplantation.”

Resulting Presentations:

  • 2016 West China Dental Exhibition and Symposium. “Regenerative Endodontics: Current State and Future Prospects.” April 25, 2016. Chengdu, China.
  • PENN, UCLA, Yonsei “Present and Future of Endodontics” International Symposium in Endodontics. Invited Lecture titled, “BioCeramics: New Material for New Approaches in Regenerative Endodontics.” June 26, 2016. Seoul, Korea. 
  • PENN Stem Cell and Regenerative Dentistry Conference. “Pulp Revascularization: Limitations and Future Directions.” October 20-21, 2017, Philadelphia, PA.
  • American Association of Endodontists Annual Meeting. “Minced Pulp Tissue as Source of Mesenchymal Stem Cells.” April 2018. Denver, CO.
  • 96th International Association for Dental Research (IADR). Symposium, “Pulp Regeneration Key Issues: Scaffolds, Vascularization and What’s Next?” Titled, “Minced Pulp Tissues as Source of Mesenchymal Stem Cells.” July 2018, London, UK.
  • 11th International Federation of Endodontics Association (IFEA). “Pulp-dentin regeneration: Updates and Challenges.” October 6, 2018. Seoul, Korea.
    • Complete Pulp Tissue Regeneration Using Pulp Tissue Fragment. Abstract submitted and accepted for presentation virtually at AAE21.
    • SARS-CoV-2 Entry Factors are Regulated by Grainyhead-like 2 in Oral Mucosal Epithelium. Abstract submitted and accepted for presentation virtually at AAE21.
  • Role of Platelet Rich Fibrin in Vasculogenic Potential of Minced Pulp-derived Mesenchymal Stem Cells. Abstract submitted and accepted for presentation virtually at AAE21.

Publications

  • Cao Y, Song M, Kim E, Shon WJ, Chugal N, Bogen G, Lin L, Kim RH, Park NH, and Kang MK. (2015) Pulp-dentin regeneration: Current state and future prospects. Journal of Dental Research, 94:1544-1551.
  • Cao Y, Bogen G, Lim J, Shon WJ, and Kang MK. (2016) Changing concepts in vital pulp therapy: Bioceramics in Endodontics. Journal of California Dental Association, 44:278-290.
  • Song M, Cao Y, Shin SJ, Shon WJ, Chugal N, Kim RH, Kim E, and Kang MK. (2017) Revascularization-associated intracanal calcification (RAIC): Assessment of prevalence and contributing factors. Journal of Endodontics, 43:2025-2033. PMC In Process. Honorable mention for JOE Publication Award, Regenerative Endodontics Category.
  • Liang Z, Kawano S, Chen W, Sadrkhani MS, Lee C, Kim E, Moshaverinia A, Kim RH, Kang MK. (2018) Minced pulp as source of pulpal MSCs with odontogenic differentiation capacity. Journal of Endodontics, 44:80-86. PMC In Process. JOE Publication Award 2018, Regenerative Endodontics Category.
  • Kim S, Lee S, Jung HS, Kim SY, Shin SJ, Kang MK, and Kim E. (2018) Evaluation of the biodistribution of human dental pulp stem cells transplanted into mouse. J. Endod., 44:592- 598. PMC Processing. PMID 29370943.

Manuscript in Preparation:

  • Lee CH, Sadrkhani MS, Moshaverinia A, Kim E, Kang MK. (2019) Minced gingiva as an alternative source of mesenchymal stem cells for pulp-dentin regeneration. Manuscript In Preparation.