Regenerative Endodontic Procedures: Management of Immature Necrotic Permanent Teeth

Conventionally, to create an apical hard-tissue barrier prior to root canal filling, these types of cases have been treated with the apexification technique that requires long-term application of calcium hydroxide (Ca[OH]₂) with multiple visits or one-step apexification with placement of a mineral trioxide aggregate (MTA) as an apical barrier with one or two visits. These treatments often result in the resolution of clinical symptoms of diseases and the healing of periapical lesions. However, they fail to stimulate further root development and strengthen root structure.¹ Therefore, immature teeth remain with thin dentin walls and poor crown-to-root ratios, making them susceptible to cervical fractures and increasing the potential for early loss of the entire tooth.

In recent years, biologically based treatment in the form of regenerative endodontic procedures (REPs) has been proposed as a better alternative to conventional treatment modalities for the management of immature necrotic teeth.² REPs are used to replace damaged or necrotic pulp tissues with a revitalized, healthy pulp-dentin complex, allowing for continued root development and apical closure and leading to enhanced long-term survival. Evidence has been accumulated to support the clinical feasibility of this biological approach and its inclusion as part of the endodontic treatment spectrum.³

Tissue engineering aims to generate functional tissues that enable the restoration, maintenance, or improvement of damaged tissues or whole organs. Generally, three essential elements are involved in the tissue engineering process: stem/progenitor cells, biomaterial scaffold, and bioactive molecules such as growth factors. Based on this concept, REPs have incorporated tissue engineering principles.³

In REPs of immature necrotic permanent teeth with apical periodontitis, over-instrumentation beyond the apices irritates the periapical tissues and evokes blood flow into the canal space.² This step plays a key role in achieving treatment goals as it similarly introduces several components of tissue engineering. Induced bleeding during REPs provokes the migration of undifferentiated mesenchymal stem cells from the apical papilla in immature teeth or from the bone marrow of the jaw into the canal space.^3,4 Furthermore, blood clots in the canal space act as a 3-dimensional fibrin matrix and suitable microenvironment for these stem cells. In addition, blood contains abundant chemotactic factors and platelet-derived growth factors, which are necessary for cell proliferation and differentiation.³

Disinfection of the root canal is a critical step in REPs for immature necrotic teeth with apical periodontitis. Mechanical instrumentation is not considered an effective method to facilitate debridement of wide infected root canals, and is contraindicated due to these canals' fragile, thin root walls. Therefore, the primary form of disinfection in REPs is restricted to the use of irrigation solutions and intracanal medications.

Sodium hypochlorite (NaOCl) has been widely used in concentrations between 2.5% to 5.25% for chemical debridement and antimicrobial action in conventional endodontic treatments. In REPs, lower concentrations (1.25% to 2.5%) of NaOCl are advised to prevent the denaturalization of growth factors embedded in the dentin matrix and minimize cytotoxicity to stem/progenitor cells in the periapical tissues.^5,6 The irrigation needle should be positioned about 2 mm short of the root end to prevent periapical extrusion of the irrigant and damage of stem/progenitor cells in the apical tissue. After copious irrigation with NaOCl (20 mL/canal), intracanal medicament, Ca(OH)₂, or triple antibiotic paste (TAP) (the combination of metronidazole, ciprofloxacin, and minocycline with a ratio of 1:1:1) needs to be placed in the root canals.⁷ Due to tooth discoloration issues, minocycline may be excluded from TAP, and either the use of double antibiotic paste or utilizing an alternative for minocycline such as amoxicillin, clindamycin, or cefaclor is recommended. After mixing these antibiotic powders with saline, the resulting thick, creamy mixture needs to be diluted to 0.01-0.1 mg/ml to avoid stem cell toxicity while retaining the desirable antibacterial effect.⁸ Additionally, the widely available intracanal medicament Ca(OH)₂ may be used in REPs, as its antimicrobial concentrations do not induce stem cell toxicity.⁸

Following disinfection control at the first visit, patients could be recalled in 2 to 4 weeks to confirm the absence of clinical signs and symptoms. At the second visit, local anesthesia needs to be achieved with 3% mepivacaine with no vasoconstrictor, which may be helpful to facilitate stimulation of periapical bleeding. After removing antimicrobial medicaments, root canals need to be irrigated with 17% ethylenediaminetetraacetic acid (EDTA). In REPs, EDTA plays a pivotal role in inducing the release of bioactive growth factors embedded in the dentin matrix during dentinogenesis and creating the dentin condition for the survival, differentiation, and attachment of stem/progenitor cells.⁹ Upon completion of the final irrigation with 17% EDTA (20 mL/canal), a pre-curved hand file is introduced 2 mm beyond the apical foramen and rotated to evoke bleeding from periapical tissues. After 15 minutes, blood would clot in the canal and stop at the level of the cementoenamel junction. Three-millimeter-thick MTA or BC-RRM Fast-Set Putty^™ (Brasseler, brasselerusadental.com) is gently placed over the blood clot, and the access cavity is sealed with permanent filling materials.

Numerous studies have shown that REPs result in better outcomes for the management of immature necrotic teeth with apical periodontitis compared to the traditional treatment, apexification, promoting physiological root maturation (increased root canal wall thickness and root length) as well as the elimination of clinical symptoms and the resolution of apical periodontitis.^1,3 A retrospective study revealed that all included teeth survived and were functional; 75% of cases showed complete resolution of apical periodontitis with continued root formation; 14% of cases presented ongoing healing of the periapical lesions during observation. However, 11% of cases demonstrated persistent apical periodontitis due to coronal leakage from fractured restoration or persistent inflammatory root resorption.¹⁰

According to previous case reports, the healing progression following REPs might vary depending on preoperative conditions, such as root development stage and degree of trauma, and variations in the clinical protocols.³ Additionally, radiographic assessment of the outcome revealed varying degrees of canal calcification and apical closure. Radiographic evidence of complete apical closure and root maturation most likely will take more than 2 years.^1,10

However, several histological studies reported that there was cementum-, bone-, or periodontal ligament-like tissues and absence of pulp-like tissue in the canals following REPs. Therefore, clinicians need to be aware of variable predictability of continued or inconsistent root development and evidence that the newly formed tissues may not present full root regeneration of the native pulp-dentin complex.^1,3

REPs are recognized as a potential treatment modality to bring diseased teeth back to life rather than leave a dead tooth in the oral cavity. Future studies are needed to develop suitable scaffolds that enhance stem cell proliferation and differentiation and specific bioactive molecules that direct stem/progenitor cells from periapical tissues to differentiate into odontoblast-like cells. Moreover, biocompatible disinfection methods need to be evaluated to create an optimal microenvironment of the root canal for the healing of periapical lesions and regrowth of host tissues in the canal by stem/progenitor cells from periapical tissues. These improvements in REPs would be a necessary step conducive to the optimal regeneration of destroyed pulp-dentin tissues in necrotic teeth.

The author has no conflicts of interest related to this report.

Su-Min Lee, DDS, MSD, DScD
Assistant Professor, Department of Endodontics, University of Pennsylvania School of Dental Medicine, Philadelphia, Pennsylvania