A REVIEW OF REGENERATIVE ENDODONTICS: CURRENT PROTOCOLS AND FUTURE DIRECTIONS

Abstract

This review outlines the biological basis and clinical protocols currently used in regenerative endodontic procedures (REPs) and discuss future directions in pulp regeneration approaches. The treatment of immature teeth with REPs has been described as a ‘paradigm shift’ as there is the potential for further root maturation. Clinically, REPs involve disinfection of the root canal system without damaging the endogenous stem cell potential present in the apical papilla and other tissues. These stems cells are introduced into the root canal space by inducing a blood clot followed by placement of an intracanal barrier to prevent microleakage. The biological concept of REPs involves the triad of stem cells, scaffold and signalling molecules. Currently, repair rather than true regeneration of the ‘pulp-dentine complex’ is achieved and further root maturation is variable. However, may clinicians consider the treatment of teeth with REPs as the optimal treatment approach for immature teeth with pulp necrosis.

Keywords

• Regenerative endodontic protocols,immature teeth; pulp necrosis; root maturation; triple antibiotic paste; calcium hydroxide

References

1. Chueh LH, Huang GT. Immature teeth with periradicular periodontitis or abscess undergoing apexogenesis: A paradigm shift. J Endod 2006;32(12):1205-1213.
2. Huang GT. A paradigm shift in endodontic management of immature teeth: Conservation of stem cells for regeneration. J Dent 2008;36(6):379-386.
3. Huang GT, Sonoyama W, Liu Y, Liu H, Wang S, Shi S. The hidden treasure in apical papilla: The potential role in pulp/dentin regeneration and bioroot engineering. J Endod 2008;34(6):645-651.
4. Diogenes A, Ruparel NB, Shiloah Y, Hargreaves KM. Regenerative endodontics: A way forward. J Am Dent Assoc 2016;147(5):372-380.
5. Bezgin T, Sonmez H. Review of current concepts of revascularization/revitalization. Dent Traumatol 2015;31(4):267-273.
6. Diogenes A, Henry MA, Teixeira FB, Hargreaves KM. An update on clinical regenerative endodontics. Endod Topics 2013;28(1):2-23.
7. Galler KM. Clinical procedures for revitalization: Current knowledge and considerations. Int Endod J 2016;49(10):926-936.
8. Hargreaves KM, Giesler T, Henry M, Wang Y. Regeneration potential of the young permanent tooth: What does the future hold? J Endod 2008;34(7 Suppl):S51-56.

9. Kontakiotis EG, Filippatos CG, Tzanetakis GN, Agrafioti A. Regenerative endodontic therapy: A data analysis of clinical protocols. J Endod 2015;41(2):146-154.
10. Murray PE, Garcia-Godoy F, Hargreaves KM. Regenerative endodontics: A review of current status and a call for action. J Endod 2007;33(4):377-390.
11. Alobaid AS, Cortes LM, Lo J, Nguyen TT, Albert J, Abu-Melha AS, Lin LM, Gibbs JL. 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.
12. Kahler B, Rossi-Fedele G, Chugal N, Lin LM. An evidence-based review of the efficacy of treatment approaches for immature permanent teeth with pulp necrosis. J Endod 2017;43(7):1052-1057.
13. 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.
14. Andreasen JO, Andreasen FM. Textbook and color atlas of traumatic injuries to the teeth. Copenhagen: Munsgaard, 1994.
15. Huang GT, Lin LM. Letter to the editor: Comments on the use of the term "revascularization" to describe root regeneration. J Endod 2008;34(5):511; author reply 511-512.
16. Banchs F, Trope M. Revascularization of immature permanent teeth with apical periodontitis: New treatment protocol? J Endod 2004;30(4):196-200.
17. Iwaya SI, Ikawa M, Kubota M. Revascularization of an immature permanent tooth with apical periodontitis and sinus tract. Dent Traumatol 2001;17(4):185-187.
18. Becerra P, Ricucci D, Loghin S, Gibbs JL, Lin LM. Histologic study of a human immature permanent premolar with chronic apical abscess after revascularization/revitalization. J Endod 2014;40(1):133-139.
19. Martin G, Ricucci D, Gibbs JL, Lin LM. Histological findings of revascularized/revitalized immature permanent molar with apical periodontitis using platelet-rich plasma. J Endod 2013;39(1):138-144.
20. Wang X, Thibodeau B, Trope M, Lin LM, Huang GT. Histologic characterization of regenerated tissues in canal space after the revitalization/revascularization procedure of immature dog teeth with apical periodontitis. J Endod 2010;36(1):56-63.
21. Lenzi R, Trope M. Revitalization procedures in two traumatized incisors with different biological outcomes. J Endod 2012;38(3):411-414.
22. Kumar V, Abbas AK, Aster J. Robbins and cotran pathologic basis of disease. Philadelphia, PA: Saunders, 9th ed. 2014.
23. Majno G, Joris I. Cells, tissues, and disease. Oxford, London: Oxford University Press, 2nd ed. 2004.
24. Shi S, Bartold PM, Miura M, Seo BM, Robey PG, Gronthos S. The efficacy of mesenchymal stem cells to regenerate and repair dental structures. Orthod Craniofac Res 2005;8(3):191-199.
25. Galler KM, Buchalla W, Hiller KA, Federlin M, Eidt A, Schiefersteiner M, Schmalz G. Influence of root canal disinfectants on growth factor release from dentin. J Endod 2015;41(3):363-368.
26. Nakashima M, Nagasawa H, Yamada Y, Reddi AH. Regulatory role of transforming growth factor-beta, bone morphogenetic protein-2, and protein-4 on gene expression of extracellular matrix proteins and differentiation of dental pulp cells. Dev Biol 1994;162(1):18-28.
27. Rutherford RB, Wahle J, Tucker M, Rueger D, Charette M. Induction of reparative dentine formation in monkeys by recombinant human osteogenic protein-1. Arch Oral Biol 1993;38(7):571-576.
28. Sloan AJ, Smith AJ. Stimulation of the dentine-pulp complex of rat incisor teeth by transforming growth factor-beta isoforms 1-3 in vitro. Arch Oral Biol 1999;44(2):149-156.
29. Tzaifas D AA, Papadimitrious S, Gasic J, Komnenou A. 1998;43(6):431-444. Effects of recombinant basic fibroblast growth factor, insulin-like growth factor-11 and transforming growth factor-β1 on dog dental pulp cells in vivo. Arch Oral Biol 1998;43(6):431-444.
30. Lovelace TW, Henry MA, Hargreaves KM, Diogenes A. Evaluation of the delivery of mesenchymal stem cells into the root canal space of necrotic immature teeth after clinical regenerative endodontic procedure. J Endod 2011;37(2):133-138.
31. da Silva LA, Nelson-Filho P, da Silva RA, Flores DS, Heilborn C, Johnson JD, Cohenca N. Revascularization and periapical repair after endodontic treatment using apical negative pressure irrigation versus conventional irrigation plus triantibiotic intracanal dressing in dogs' teeth with apical periodontitis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010;109(5):779-787.
32. Lei L, Chen Y, Zhou R, Huang X, Cai Z. Histologic and immunohistochemical findings of a human immature permanent tooth with apical periodontitis after regenerative endodontic treatment. J Endod 2015;41(7):1172-1179.
33. Shimizu E, Ricucci D, Albert J, Alobaid AS, Gibbs JL, Huang GT, Lin LM. Clinical, radiographic, and histological observation of a human immature permanent tooth with chronic apical abscess after revitalization treatment. J Endod 2013;39(8):1078-1083.
34. Yamauchi N, Yamauchi S, Nagaoka H, Duggan D, Zhong S, Lee SM, Teixeira FB, Yamauchi M. Tissue engineering strategies for immature teeth with apical periodontitis. J Endod 2011;37(3):390-397.
35. Lin LM, Rosenberg PA. Repair and regeneration in endodontics. Int Endod J 2011;44(10):889-906.
36. Simon SR, Tomson PL, Berdal A. Regenerative endodontics: Regeneration or repair? J Endod 2014;40(4 Suppl):S70-75.
37. American Association of Endodontists. AAE Clinical Considerations for a Regenerative Procedure. Available at: www.aae.org/Dental_Professional/Considerations for Regenerative Procedures.aspx.
38. Ostby BN. The role of the blood clot in endodontic therapy. An experimental histologic study. Acta Odontol Scand 1961;19:324-353.
39. Jung IY, Lee SJ, Hargreaves KM. Biologically based treatment of immature permanent teeth with pulpal necrosis: A case series. J Endod 2008;34(7):876-887.
40. Thomson A, Kahler B. Regenerative endodontics--biologically-based treatment for immature permanent teeth: A case report and review of the literature. Aust Dent J 2010;55(4):446-452.
41. Cotti E, Mereu M, Lusso D. Regenerative treatment of an immature, traumatized tooth with apical periodontitis: Report of a case. J Endod 2008;34(5):611-616.
42. Kahler B, Mistry S, Moule A, Ringsmuth AK, Case P, Thomson A, Holcombe T. Revascularization outcomes: A prospective analysis of 16 consecutive cases. J Endod 2014;40(3):333-338.
43. Shah N, Logani A, Bhaskar U, Aggarwal V. Efficacy of revascularization to induce apexification/apexogensis in infected, nonvital, immature teeth: A pilot clinical study. J Endod 2008;34(8):919-925; discussion 1157.
44. Thibodeau B, Trope M. Pulp revascularization of a necrotic infected immature permanent tooth: Case report and review of the literature. Pediatr Dent 2007;29(1):47-50.
45. Paryani K, Kim SG. Regenerative endodontic treatment of permanent teeth after completion of root development: A report of 2 cases. J Endod 2013;39(7):929-934.
46. Saoud TM, Martin G, Chen YH, Chen KL, Chen CA, Songtrakul K, Malek M, Sigurdsson A, Lin LM. Treatment of mature permanent teeth with necrotic pulps and apical periodontitis using regenerative endodontic procedures: A case series. J Endod 2016;42(1):57-65.
47. Wang Y, Zhu X, Zhang C. Pulp revascularization on permanent teeth with open apices in a middle-aged patient. J Endod 2015;41(9):1571-1575.
48. Geisler TM. Clinical considerations for regenerative endodontic procedures. Dent Clin North Am 2012;56(3):603-626.
49. Lin LM, Shimizu E, Gibbs JL, Loghin S, Ricucci D. Histologic and histobacteriologic observations of failed revascularization/revitalization therapy: A case report. J Endod 2014;40(2):291-295.
50. Fouad AF, Nosrat A. Pulp regeneration in previously infected root canal space. Endod Topics 2013;28(1):24-37.
51. Chaniotis A. The use of a single-step regenerative approach for the treatment of a replanted mandibular central incisor with severe resorption. Int Endod J 2016;49(8):802-812.
52. McCabe P. Revascularization of an immature tooth with apical periodontitis using a single visit protocol: A case report. Int Endod J 2015;48(5):484-497.
53. Shin SY, Albert JS, Mortman RE. One step pulp revascularization treatment of an immature permanent tooth with chronic apical abscess: A case report. Int Endod J 2009;42(12):1118-1126.
54. Galler KM, D'Souza RN, Federlin M, Cavender AC, Hartgerink JD, Hecker S, Schmalz G. Dentin conditioning codetermines cell fate in regenerative endodontics. J Endod 2011;37(11):1536-1541.
55. Galler KM, Widbiller M, Buchalla W, Eidt A, Hiller KA, Hoffer PC, Schmalz G. Edta conditioning of dentine promotes adhesion, migration and differentiation of dental pulp stem cells. Int Endod J 2016;49(6):581-590.
56. Martin DE, De Almeida JF, Henry MA, Khaing ZZ, Schmidt CE, Teixeira FB, Diogenes A. Concentration-dependent effect of sodium hypochlorite on stem cells of apical papilla survival and differentiation. J Endod 2014;40(1):51-55.
57. Trevino EG, Patwardhan AN, Henry MA, Perry G, Dybdal-Hargreaves N, Hargreaves KM, Diogenes A. 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.
58. Sato T, Hoshino E, Uematsu H, Noda T. In vitro antimicrobial susceptibility to combinations of drugs on bacteria from carious and endodontic lesions of human deciduous teeth. Oral Microbiol Immunol 1993;8(3):172-176.
59. Takushige T, Cruz EV, Asgor Moral A, Hoshino E. Endodontic treatment of primary teeth using a combination of antibacterial drugs. Int Endod J 2004;37(2):132-138.
60. Hoshino E, Kurihara-Ando N, Sato I, Uematsu H, Sato M, Kota K, Iwaku M. In-vitro antibacterial susceptibility of bacteria taken from infected root dentine to a mixture of ciprofloxacin, metronidazole and minocycline. Int Endod J 1996;29(2):125-130.
61. Sato I, Ando-Kurihara N, Kota K, Iwaku M, Hoshino E. Sterilization of infected root-canal dentine by topical application of a mixture of ciprofloxacin, metronidazole and minocycline in situ. Int Endod J 1996;29(2):118-124.
62. Ruparel NB, Teixeira FB, Ferraz CC, Diogenes A. Direct effect of intracanal medicaments on survival of stem cells of the apical papilla. J Endod 2012;38(10):1372-1375.
63. Althumairy RI, Teixeira FB, Diogenes A. Effect of dentin conditioning with intracanal medicaments on survival of stem cells of apical papilla. J Endod 2014;40(4):521-525.
64. 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.
65. Diogenes AR, Ruparel NB, Teixeira FB, Hargreaves KM. Translational science in disinfection for regenerative endodontics. J Endod 2014;40(4 Suppl):S52-57.
66. Torabinejad M, Parirokh M. Mineral trioxide aggregate: A comprehensive literature review--part ii: Leakage and biocompatibility investigations. J Endod 2010;36(2):190-202.
67. Yoldas SE, Bani M, Atabek D, Bodur H. Comparison of the potential discoloration effect of bioaggregate, biodentine, and white mineral trioxide aggregate on bovine teeth: In vitro research. J Endod 2016;42(12):1815-1818.
68. Kontakiotis EG, Filippatos CG, Agrafioti A. Levels of evidence for the outcome of regenerative endodontic therapy. J Endod 2014;40(8):1045-1053.
69. Chen YP, Jovani-Sancho Mdel M, Sheth CC. Is revascularization of immature permanent teeth an effective and reproducible technique? Dent Traumatol 2015;31(6):429-436.
70. Chen MY, Chen KL, Chen CA, Tayebaty F, Rosenberg PA, Lin LM. Responses of immature permanent teeth with infected necrotic pulp tissue and apical periodontitis/abscess to revascularization procedures. Int Endod J 2012;45(3):294-305.
71. Kahler B, Rossi-Fedele G. A review of tooth discoloration after regenerative endodontic therapy. J Endod 2016;42(4):563-569.
72. Ioannidis K, Mistakidis I, Beltes P, Karagiannis V. Spectrophotometric analysis of coronal discolouration induced by grey and white mta. Int Endod J 2013;46(2):137-144.
73. Cordeiro MM, Dong Z, Kaneko T, Zhang Z, Miyazawa M, Shi S, Smith AJ, Nor JE. Dental pulp tissue engineering with stem cells from exfoliated deciduous teeth. J Endod 2008;34(8):962-969.
74. Huang GT, Yamaza T, Shea LD, Djouad F, Kuhn NZ, Tuan RS, Shi S. Stem/progenitor cell-mediated de novo regeneration of dental pulp with newly deposited continuous layer of dentin in an in vivo model. Tissue Eng Part A 2010;16(2):605-615.
75. Iohara K, Murakami M, Takeuchi N, Osako Y, Ito M, Ishizaka R, Utunomiya S, Nakamura H, Matsushita K, Nakashima M. A novel combinatorial therapy with pulp stem cells and granulocyte colony-stimulating factor for total pulp regeneration. Stem Cells Transl Med 2013;2(7):521-533.
76. Ishizaka R, Iohara K, Murakami M, Fukuta O, Nakashima M. Regeneration of dental pulp following pulpectomy by fractionated stem/progenitor cells from bone marrow and adipose tissue. Biomaterials 2012;33(7):2109-2118.
77. Murakami M, Horibe H, Iohara K, Hayashi Y, Osako Y, Takei Y, Nakata K, Motoyama N, Kurita K, Nakashima M. The use of granulocyte-colony stimulating factor induced mobilization for isolation of dental pulp stem cells with high regenerative potential. Biomaterials 2013;34(36):9036-9047.
78. Nakashima M, Iohara K. Mobilized dental pulp stem cells for pulp regeneration: Initiation of clinical trial. J Endod 2014;40(4 Suppl):S26-32.
79. Rosa V, Zhang Z, Grande RH, Nor JE. Dental pulp tissue engineering in full-length human root canals. J Dent Res 2013;92(11):970-975.
80. Gronthos S, Mankani M, Brahim J, Robey PG, Shi S. Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo. Proc Natl Acad Sci U S A 2000;97(25):13625-13630.
81. Miura M, Gronthos S, Zhao M, Lu B, Fisher LW, Robey PG, Shi S. Shed: Stem cells from human exfoliated deciduous teeth. Proc Natl Acad Sci U S A 2003;100(10):5807-5812.
82. Sonoyama W, Liu Y, Yamaza T, Tuan RS, Wang S, Shi S, Huang GT. Characterization of the apical papilla and its residing stem cells from human immature permanent teeth: A pilot study. J Endod 2008;34(2):166-171.
83. Huang GT, Al-Habib M, Gauthier P. Challenges of stem cell-based pulp and dentin regeneration: A clinical perspective. Endod Topics 2013;28(1):51-60.
84. Mao JJ, Kim SG, Zhou J, Ye L, Cho S, Suzuki T, Fu SY, Yang R, Zhou X. Regenerative endodontics: Barriers and strategies for clinical translation. Dent Clin North Am 2012;56(3):639-649.
85. Conde MC, Chisini LA, Demarco FF, Nor JE, Casagrande L, Tarquinio SB. Stem cell-based pulp tissue engineering: Variables enrolled in translation from the bench to the bedside, a systematic review of literature. Int Endod J 2016;49(6):543-550.