By Avina K. Paranjpe, BDS, M.S., MSD, Ph.D.
There has been an ongoing debate about Regenerative Endodontic (RegEndo) procedures and if they actually work. This ongoing debate stems from the success rates for this procedure, which varies. However, the question always remains: do we know everything about this procedure? The answer is “no”.
The success of Tissue Engineering is based on a triad of stem cells, a scaffold and growth factors (1). However, one main difference in regenerating tissue within the tooth versus other parts of the body is the presence of various species of bacteria within the canal space. When performing non-surgical root canal treatments the canals are chemomechanically debrided with the help of endodontic files and various irrigants. However, when a tooth has an immature, open apex and the clinician plans to perform a RegEndo procedure, the main considerations should be adequate disinfection. This could prove challenging as the canal walls are thin and cannot be instrumented. Hence, the clinician needs to rely on irrigation, irrigation techniques and intracanal medicaments for disinfection. However, is this enough? This procedure additionally requires stem cells for tissue formation. These stem cells are present in the apical portion of the tooth and are the Stem Cells of the Apical Papilla (SCAP). SCAP are expected to survive the various procedures and then differentiate in the root canal space into a different cell type. Can they do this effectively and efficiently?
Current research has focused heavily on various aspects of RegEndo procedures. The research various from systematic reviews to bench-top studies. However, the literature still reports a high number of failures to about 39%, two years after initiation of treatment (2). The failures ranged from tooth discoloration to fracture to signs of periapical pathosis and presence of symptoms. Other studies have demonstrated success rates of up to 91% in these cases (3). These numbers are varied and depend on the type study conducted (systematic reviews, cohort studies etc.) and the factors that were considered (success, failure, outcomes etc.) (2-6)
The varied success and failures rates could be attributed to various reasons some of which include 1) no standardized technique 2) inadequate disinfection, 3) insufficient knowledge about the SCAP and 4) scaffolds used (2, 7).
A recent web-based survey demonstrated clinicians use various irrigants and intracanal medicaments for disinfection during these procedures. Clinicians used various irrigants like Chlorhexidine (CHX- concentrations ranging from 0.12% -0.2%), NaOCl (concentrations ranging from 1%-5.25%) and not all clinicians used EDTA at the second appointment (2, 7). CHX is cytotoxic to SCAP (8, 9). EDTA is essential to release the growth factors from the dentin, which in turn would help the SCAP to differentiate (8, 10, 11). However, a recent study demonstrated that a final rinse with EDTA prior to inducing bleeding causes a decrease in clot formation and recommended the use of saline after EDTA (12).
Clinicians use various intracanal medicaments during the procedure, which include calcium hydroxide, or antibiotics are varied concentrations (7). However, is this enough to disinfect the root canal space? Persistent infection has been attributed to 79% of failed RegEndo cases (2). Other studies have demonstrated that residual bacteria in the canal could affect treatment outcomes significantly by either affecting the release of growth factors from the dentin, the differentiation of the SCAP and the survival of the SCAP once they are introduced into the root canal space (13-16). Bacteria can activate the immune system present in the blood clot and this activated immune system could be cytotoxic to the SCAP. Hence, disinfection of the canal space is imperative to the success of these procedures (15).
The cellular properties of SCAP play an important role in RegEndo procedures. A recent study demonstrated that SCAP are less resistant to cell death and have a lower differentiation potential as compared to some other oral stem cells, which could make them more vulnerable to the immune cells (17). It is a possibility that the SCAP do not survive due to these reasons, thereby contributing to the failure of some RegEndo procedures.
The traditional blood clot has been the scaffold of choice until date. However, some studies have demonstrated that the blood clot may not be necessary or may not be the ideal scaffold for these procedures (2, 18, 19). Research studies related to various scaffolds and their effectiveness during RegEndo procedures have been published and are ongoing (20-22).
“Life isn’t black or white, it’s a million gray areas.”- Ridley Scott
Although RegEndo is an important treatment alternative when treating permanent teeth with open apices, it should be noted that there are many gray areas that need to be investigated. Research is ongoing and it is possible that developments in the near future will enable the clinician to perform these procedures with more desirable and predictable outcomes.
Dr. Avina Paranjpe, Diplomate, American Board of Endodontics, is associate professor, Department of Endodontics, University of Washington, School of Dentistry. She can be reached at firstname.lastname@example.org.
- Cao Y, Song M, Kim E, Shon W, Chugal N, Bogen G, et al. Pulp-dentin Regeneration: Current State and Future Prospects. J Dent Res 2015;94(11):1544-1551.
- Almutairi W, Yassen GH, Aminoshariae A, Williams KA, Mickel A. Regenerative Endodontics: A Systematic Analysis of the Failed Cases. J Endod 2019;45(5):567-577.
- Torabinejad M, Nosrat A, Verma P, Udochukwu O. Regenerative Endodontic Treatment or Mineral Trioxide Aggregate Apical Plug in Teeth with Necrotic Pulps and Open Apices: A Systematic Review and Meta-analysis. J Endod 2017;43(11):1806-1820.
- Alobaid AS, Cortes LM, Lo J, Nguyen TT, Albert J, Abu-Melha AS, et al. Radiographic and clinical outcomes of the treatment of immature permanent teeth by revascularization or apexification: a pilot retrospective cohort study. J Endod 2014;40(8):1063-1070.
- Bose R, Nummikoski P, Hargreaves K. A retrospective evaluation of radiographic outcomes in immature teeth with necrotic root canal systems treated with regenerative endodontic procedures. J Endod 2009;35(10):1343-1349.
- Jeeruphan T, Jantarat J, Yanpiset K, Suwannapan L, Khewsawai P, Hargreaves KM. Mahidol study 1: comparison of radiographic and survival outcomes of immature teeth treated with either regenerative endodontic or apexification methods: a retrospective study. J Endod 2012;38(10):1330-1336.
- Lee JY, Kersten DD, Mines P, Beltran TA. Regenerative Endodontic Procedures among Endodontists: A Web-based Survey. J Endod 2018;44(2):250-255.
- Trevino EG, Patwardhan AN, Henry MA, Perry G, Dybdal-Hargreaves N, Hargreaves KM, et al. Effect of irrigants on the survival of human stem cells of the apical papilla in a platelet-rich plasma scaffold in human root tips. J Endod 2011;37(8):1109-1115.
- Widbiller M, Althumairy RI, Diogenes A. Direct and Indirect Effect of Chlorhexidine on Survival of Stem Cells from the Apical Papilla and Its Neutralization. J Endod 2019;45(2):156-160.
- Galler KM, Widbiller M, Buchalla W, Eidt A, Hiller KA, Hoffer PC, et al. EDTA conditioning of dentine promotes adhesion, migration and differentiation of dental pulp stem cells. Int Endod J 2016;49(6):581-590.
- Schmalz G, Widbiller M, Galler KM. Signaling Molecules and Pulp Regeneration. J Endod 2017;43(9S):S7-S11.
- Taweewattanapaisan P, Jantarat J, Ounjai P, Janebodin K. The Effects of EDTA on Blood Clot in Regenerative Endodontic Procedures. J Endod 2019;45(3):281-286.
- Cameron R, Claudia E, Ping W, Erin S, Ruparel NB. Effect of a Residual Biofilm on Release of Transforming Growth Factor beta1 from Dentin. J Endod 2019;45(9):1119-1125.
- Vishwanat L, Duong R, Takimoto K, Phillips L, Espitia CO, Diogenes A, et al. Effect of Bacterial Biofilm on the Osteogenic Differentiation of Stem Cells of Apical Papilla. J Endod 2017;43(6):916-922.
- Latham J, Fong H, Jewett A, Johnson JD, Paranjpe A. Disinfection Efficacy of Current Regenerative Endodontic Protocols in Simulated Necrotic Immature Permanent Teeth. J Endod 2016;42(8):1218-1225.
- Verma P, Nosrat A, Kim JR, Price JB, Wang P, Bair E, et al. Effect of Residual Bacteria on the Outcome of Pulp Regeneration In Vivo. J Dent Res 2017;96(1):100-106.
- Whiting D, Chung WO, Johnson JD, Paranjpe A. Characterization of the Cellular Responses of Dental Mesenchymal Stem Cells to the Immune System. J Endod 2018;44(7):1126-1131.
- Murray PE. Platelet-Rich Plasma and Platelet-Rich Fibrin Can Induce Apical Closure More Frequently Than Blood-Clot Revascularization for the Regeneration of Immature Permanent Teeth: A Meta-Analysis of Clinical Efficacy. Front Bioeng Biotechnol 2018;6:139.
- Ulusoy AT, Turedi I, Cimen M, Cehreli ZC. Evaluation of Blood Clot, Platelet-rich Plasma, Platelet-rich Fibrin, and Platelet Pellet as Scaffolds in Regenerative Endodontic Treatment: A Prospective Randomized Trial. J Endod 2019;45(5):560-566.
- Nosrat A, Kolahdouzan A, Khatibi AH, Verma P, Jamshidi D, Nevins AJ, et al. Clinical, Radiographic, and Histologic Outcome of Regenerative Endodontic Treatment in Human Teeth Using a Novel Collagen-hydroxyapatite Scaffold. J Endod 2019;45(2):136-143.
- Murray PE. Constructs and scaffolds employed to regenerate dental tissue. Dent Clin North Am 2012;56(3):577-588.
- Bottino MC, Pankajakshan D, Nor JE. Advanced Scaffolds for Dental Pulp and Periodontal Regeneration. Dent Clin North Am 2017;61(4):689-711.