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Outcome of Revascularization Procedure: A Retrospective Case Series
Basic Research—Biology
Outcome of Revascularization Procedure: A Retrospective Case Series Sarah Bukhari, BDS, Meetu R. Kohli, BDS, DMD, Frank Setzer, DMD, PhD, MS, and Bekir Karabucak, DMD, MS Abstract Introduction: The purpose of this retrospective case series was to investigate the outcome of the revascularization procedure in necrotic immature teeth. Methods: The residents and faculty members at the University of Pennsylvania endodontic department were invited to submit consecutive revascularization cases treated by them, irrespective of the outcome, during the time period of 2009 to 2012. Twenty-eight of 35 submitted necrotic immature teeth met the inclusion criteria. The treatment protocol included minimal instrumentation and irrigation with 3% sodium hypochlorite and 17% EDTA. Triple antibiotic paste was placed for a minimum of 21 days. After blood clot induction, either EndoSequence Bioceramic Putty (Brasseler, Savannah, GA) or mineral trioxide aggregate was placed below the cementoenamel junction, and composite was used as a final restoration. The follow-up period ranged from 7 to 72 months. The outcome was assessed as complete healing (the absence of clinical signs and symptoms, complete resolution of periradicular radiolucency, increase in the root dentin thickness/length, and apical closure), incomplete healing (the absence of clinical signs and symptoms, the periapical lesion completely healed without any signs of root maturation or thickening, the periapical lesion either reduced in size or unchanged with/without radiographic signs of increasing root dentin thickness/length, or apical closure), and failure (persistent clinical signs and symptoms and/or increased size of the periradicular lesion). Results: Twenty-one of 28 cases (75%) healed completely, 3 cases (10.7%) failed during the observation period and needed further treatment, and 4 cases (14%) presented with incomplete healing. Conclusions: Within the limitation of this study, the outcome of revascularization, wherein healing of periapical periodontitis and maturation of roots occurs, is fairly high, making it a viable treatment option in comparison with apexification. (J Endod 2016;-:1–8)
Key Words Apical periodontitis, BioCeramic, mineral trioxide aggregate, outcome, revascularization, success
C
onventional endodonSignificance tic treatment of necRevascularization outcome analysis should rotic immature teeth with include both the radiographic healing of apical periapical periodontitis preodontitis and the radiographic signs of further root sents a certain set of chaldevelopment. The outcome of revascularization lenges. Open apices make wherein healing of periapical periodontitis and achieving an adequate maturation of roots occur is high. seal during endodontic therapy difficult (1). Disinfection of necrotic immature teeth with traditional mechanical instrumentation and irrigation with sodium hypochlorite have been reported to be not as effective (2), necessitating placement of an intracanal medicament. Although this treatment protocol of apexification has reported high endodontic clinical success, these teeth are prone to post-treatment fracture because of thin fragile root canal walls (3). Calcium hydroxide apexification has traditionally been the treatment of choice for necrotic immature teeth (4). The goal of this treatment is to induce a hard tissue barrier apically to facilitate root canal filling. However, the treatment protocol calls for multiple visits and hence a compliant patient. Prolonged contact with calcium hydroxide weakens root dentin resistance to mechanical forces, thereby rendering the tooth further susceptible to fracture (5, 6). To reduce the time for treatment execution, a 1-step apexification technique with mineral trioxide aggregate (MTA) was proposed (7). Nevertheless, this treatment modality does not not promote root canal wall thickening or apical closure. This necessitates the need for an alternative treatment protocol conducive to continued root maturation with deposition of hard tissue, thereby strengthening the tooth and protecting against future loss to root fracture. Revascularization is a regenerative treatment that is biologically based to allow for root maturation by continued deposition of dentin and a cementumlike structure along the root walls. The foundation of revascularization was laid down in the early 60s by Nygaard-Østby and Hjortdal (8, 9), but the concept behind the contemporary revascularization procedure comes from the trauma literature. It was observed that when an avulsed immature tooth was reimplanted within a certain set of circumstances, revascularization occurred. The main requirements being absence of bacterial challenge, thereby having a necrotic/ischemic but uninfected pulp tissue in the root canal system acting as a scaffold into which new tissue can grow through the large open apical foramina (10). It was postulated that creating a similar
From the Department of Endodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Address requests for reprints to Dr Bekir Karabucak, Department of Endodontics, School of Dental Medicine, University of Pennsylvania, 240 South 40th Street, Philadelphia, PA 19104. E-mail address: [email protected] 0099-2399/$ - see front matter Copyright ª 2016 American Association of Endodontists. http://dx.doi.org/10.1016/j.joen.2016.06.021
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Basic Research—Biology environment when treating necrotic immature teeth with apical periodontitis should result in revascularization and subsequent root development. The first case treated with this approach was published in 2001 with promising results (11). An overwhelming number of case reports have been published since. However, the literature lacks outcome studies evaluating the probability of long-term success. Case reports are generally an accumulation of cases that present a successful outcome of the intended procedure. There are very few studies that describe success and failure rates for revascularization. The objective of this retrospective case series was to report the outcome of consecutive revascularization procedures in necrotic immature teeth treated in the endodontic department at the University of Pennsylvania from 2009 to 2012 by faculty and residents regardless of outcome. A set of outcome criteria was established to describe clinical and radiographic success and failure.
Materials and Methods The University of Pennsylvania endodontic department has a prescribed methodology for the revascularization procedure based on the recommendations of the American Association of Endodontics (AAE) (12). The residents and faculty were invited to participate in this study by submitting consecutive cases treated by them with this protocol during the time period of 2009 to 2012 regardless of the outcome. The resident dental charts for these cases were retrieved via an electronic search using Dentrix software (Henry Schein Inc, Melville, NY). The faculty members were asked to fill out a similar electronic chart with radiographic and other examination notes for submission. Patient’s personal information was masked in accordance with the Health Insurance Portability and Accountability regulations. Each case that fulfilled the following criteria was included in the outcome analysis: 1. An immature permanent tooth with clinical diagnosis of necrotic pulp with or without radiographic signs of apical pathology and the cause of necrosis clearly indicated 2. A tooth treated with the prescribed revascularization protocol 3. A preoperative, postoperative, and follow-up radiograph of at least 6 months after the treatment along with documented clinical signs and symptoms at each of the previous appointments
The preoperative radiographs were checked for immature apices, either blunderbuss canals or wide canals with parallel walls, and in a few cases a moderately developed root but with an open apex. Patient age, sex, tooth number, dental history, presence or absence of periapical radiolucency, treatment and follow-up periods, and the details of the clinical procedure and any variation were also recorded. Thirty-five cases were treated and submitted by the residents and faculty during the previously stated treatment duration. A total of 28 immature teeth out of 35 (in 23 patients) between the ages of 8 and 31 years met the inclusion criteria. Seven cases were excluded because of 1 or more of the following reasons: lack of a detailed description of the treatment protocol, less than a 6-month follow-up or no follow-up, and less than ideal radiographic documentation. The revascularization protocol used was as follows. The treatment was completed in 3 visits; the first visit consisted of the administration of local anesthesia, rubber dam isolation, access preparation, copious irrigation with 3% sodium hypochlorite, minimal or no instrumentation, and placement of triple antibiotic paste (TAP) (metronidazole, ciprofloxacin, and ciprofloxacin [equal parts mixed in distilled water in a 3:1 powder:liquid ratio]; Skywalk Pharmacy, Milwaukee, WI) as an interappointment dressing. An open apex was also verified clinically with a size 100 K-file. Minocycline was replaced with clindamycin in this composition to reduce the risk of tooth discoloration (12). The access opening was temporarily sealed for these cases for an average of 37 days with a temporary restoration material (Cavit; 3M ESPE, St Paul, MN). At the second appointment, 3% mepivacaine without a vasoconstrictor (Dentsply Pharmaceutical, York, PA) was the local anesthetic of choice. After removal of temporary filling under rubber dam isolation, TAP was flushed out by copious irrigation with 3% sodium hypochlorite and a final rinse with 17% EDTA. The blood clot was induced using a #10 K-file to lacerate the apical tissues. After the blood clot was formed, either EndoSequence Bioceramic Putty (Brasseler, Savannah, GA) or MTA (Dentsply, York PA) was placed below the cementoenamel junction and either over the blood clot directly or using a matrix barrier (Collaplug; Zimmer Dental, Carlsbad, CA) based on the clinician’s judgment. The access opening was again temporarily sealed with Cavit. At the final appointment, the setting of bioceramic putty or the MTA was confirmed before placing the permanent composite restoration (3M Filtek P60; 3M ESPE, St Paul, MN). The majority of the follow-up period ranged between 7 and 31 months, with 2 cases being the longest at 4 and 6 years.
TABLE 1. A Summary of Patient Demographics and the Clinical Characteristics and Outcome of the Study Population Variable Tooth type Anterior Premolar Molar Location Maxilla Mandible Cause Caries Anatomical/caries Trauma Signs and Symptoms Absent Present Radiolucency Absent Present
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Teeth, n = 28 (%)
Complete healing, n = 21 (%)
Incomplete healing, n = 4 (%)
Failure, n = 3 (%)
21 (75) 5 (18) 2 (7)
17 (80.9) 3 (60) 1 (50)
2 (9.5) 2 (40) 0
2 (9.5) 0 1 (50)
22 (79) 6 (21)
17 (77) 4 (66.6)
3 (14) 1 (16.6)
2 (9) 1 (16.6)
5 (18) 3 (11) 20 (71)
3 (60) 2 (67) 16 (80)
1 (20) 1 (33) 2 (10)
1 (20) 0 2 (10)
18 (64) 10 (36)
15 (83) 7 (70)
2 (11) 2 (20)
1 (6) 1 (10)
6 (21) 22 (79)
4 (66.6) 17 (77)
1 (16.6) 3 (14)
1 (16.6) 2 (9)
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Basic Research—Biology
Figure 1. Complete healing category. Lower right first molar. Increased thickening of the canal walls and continued root maturation after revascularization. (A) Postoperative radiograph. (B) Follow-up radiograph at 18 months.
The outcome was assessed using the radiographic healing of the apical periodontitis, the clinical signs and symptoms, and the radiographic signs of continued root development. Each case was assigned to 1 of the following criteria at follow-up. 1. Complete healing: The absence of clinical signs and symptoms, complete resolution of periradicular radiolucency, and an increase in the root dentin thickness/length and apical closure 2. Incomplete healing: The absence of clinical signs and symptoms, the periapical lesion completely healed without any signs of root maturation or thickening, the periapical lesion either reduced in size or unchanged with/without radiographic signs of increasing root dentin thickness/length, or apical closure 3. Failure: Persistent clinical signs and symptoms and/or increased size of the periradicular lesion Three calibrated examiners, who were experienced endodontists familiar with the revascularization procedure, reviewed all the images (F.S., M.R.K., and B.K.). The examiners were calibrated by being given a detailed description of the outcome criteria used for evaluation in this study. The examiners were also shown radiographs representing each outcome category for normalization. Once calibrated, the 3 examiners reviewed all the images. Periapical radiographs were projected on a big screen in a dark room and were displayed in random order. A specific healing category was assigned for each radiograph when all 3 examiners
agreed or achieved a consensus after discussion. Healing was determined as complete, incomplete, or failure according to the criteria established previously.
Results Residents and faculty members submitted 35 cases. The retrospective chart review of these cases resulted in 28 cases meeting the inclusion criteria. These 28 cases included 21 anterior teeth, 5 premolars, and 2 molars. Table 1 summarizes the patient demographics and the clinical information available from the chart review. Based on the criteria previously stated, 21 of 28 cases (75%) healed completely; 3 cases (10.7%) failed during the observation period and needed further treatment; and another 4 cases (14%) showed incomplete healing, which were rescheduled for the next follow-up visit before a decision on further intervention could be made. Representative cases of each category (ie, complete healing, incomplete healing, and failure) are presented in Figures 1–3, respectively. Cases were further analyzed for potential prognostic factors that may determine outcome. The effect of the primary etiologic factor of necrosis in these cases was analyzed. The cause was trauma, pulp exposure with anatomic anomaly such as dens invaginatus or evaginatus (talons cusp), or caries in itself. It was found that 20 of 28 (71%) cases reviewed in the study were associated with a history of
Figure 2. Failure category. Upper right central incisor. Failed case, patient was symptomatic 22 months after completing the treatment. (A) Preoperative radiograph. (B) Follow-up radiograph at 1 month. (C) Apexification procedure was performed 22 months after revascularization.
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Figure 3. Incomplete healing category. Maxillary left central incisor. Size of apical radiolucency considerably decreased but did not completely resolve with slight increase in the root length along mesial walls. (A) Preoperative radiograph. (B) Follow-up radiograph at 9 months. Mandibular right second premolar. Size of apical radiolucency decreased considerable with no further root growth in length or thickness. (C) Preoperative radiograph. (D) Follow-up radiograph at 10 months.
trauma; 80% (n = 15) of these showed complete healing. Caries and anatomic anomaly occurred in 18% (n = 5) and 11% (n = 3) of the cases, respectively, with a complete healing of 60% in case of caries and 67% in the 3 cases that were associated with a fractured talon cusp. The presence of signs and symptoms at the time of treatment was also analyzed; 10 (36%) cases were symptomatic when the revascularization procedure was initiated, 70% of which healed, whereas 18 (64%) cases were asymptomatic and had an 83% (n = 16) healing rate. The impact of apical pathology at the time of treatment was also evaluated; it was found that in the presence of apical radiolucency (22 cases), 77% had completely healed at the time of follow-up versus a 66.6% success rate in cases in which there was no apical radiolucency (6 cases). Because of the small sample size in this study, no statistical analysis was conducted.
Discussion Because of the promising radiographic and clinical results of the revascularization procedure shown by several case reports and case series, it has become a viable option for the treatment of immature non4
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vital teeth. However, there are 3 important issues associated with this treatment modality: 1. The lack of randomized clinical outcome studies to validate its longterm efficacy 2. The lack of a standardized treatment protocol, which hinders a proper comparison between different studies to gain more information about prognostic factors affecting the outcome 3. The lack of a clear definition of success and failure as an outcome in revascularization studies (13) In order to have a comprehensive definition of success and failure of revascularization, the objectives of the treatment have to be clearly defined. In the case of conventional nonsurgical root canal therapy, the elimination and/or prevention of apical periodontitis is the primary goal. However, in revascularization procedures, along with elimination of the disease, the promotion of further root development, and hence preventing future complications (ie, root fracture), can be viewed as a secondary goal. This secondary outcome is what makes it a superior option over apexification. In this case, it is fair to say that outcome analysis should include both the radiographic healing of apical periodontitis JOE — Volume -, Number -, - 2016
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Figure 4. Maxillary left central incisor failure, due to inflammatory resorption following avulsion. (A) Preoperative radiograph. (B) Follow-up radiograph at 1 month.
and the radiographic signs of further root development and that they should not be analyzed as separate entities, which is the case in the published literature on revascularization so far (14–19). To our knowledge, this is the first study that attempts to create outcome criteria that would fulfill both (ie, the healing process of periapical periodontitis and the continuation of root development demonstrated as 1 or all of the following: increased root length, increased dentinal wall thickness, and/or apical closure). Three distinct categories in outcome are defined: complete healing, incomplete healing, and failure. Complete healing was defined as the absence of clinical signs and symptoms, complete resolution of periradicular radiolucency, an increase in the root dentin thickness/length, and apical closure. Incomplete healing was defined as the absence of clinical signs and symptoms, the periapical lesion either reduced in size or unchanged with/without radiographic signs of increasing root dentin thickness/length, or apical closure. Finally, ‘‘failure’’ was defined as persistent clinical signs and symptoms and/or increased size of the periradicular lesion. Even though the goals of the regenerative endodontic procedures presented in this study are similar to the goals defined and accepted by the AAE, the success criteria vary. Success defined by the AAE is categorized by achieved goals including the primary goal (the elimination of symptoms and the evidence of bony healing), the secondary goal (increased root wall thickness and/or root length [desired but perhaps not essential]), and the tertiary goal (a positive response to vitality testing) (12). When the cases are evaluated by the AAE’s criteria, our data reveal that the primary goal was achieved in 78.5% of cases, whereas 71% met the secondary goal. The tertiary goal was not evaluated in this study. Unsuccessful cases with persistent clinical signs and symptoms and/or increased size of the periradicular lesion should be reevaluated. If the overall treatment plan allows, the disinfection protocol should be followed, and either a second attempt for regenerative treatment or the apexification procedure should be initiated in order to treat apical periodontitis, maintain the patient’s natural dentition, and restore function.
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In the incomplete healing group, the periapical pathology has decreased in size significantly in all cases, hence satisfying at least 1 goal of the treatment—elimination of the disease process. Healing of periapical tissues and root development may take longer in some cases. Additional follow-ups for these cases are recommended and may lead to complete healing and an increased success rate. Slightly more than half of the cases (52%) were followed up for more than 2 years; 2 were followed up even longer for 4 and 6 years. There are very few published case reports that show the long-term success of revascularization at a follow-up period ranging from 4 to 6 years (20–22). In the case report by Nosrat et al (22), 2 anterior teeth after 6 years of revascularization treatment had to be reaccessed for internal bleaching because the patient was not satisfied esthetically with the teeth discoloration, which likely resulted from either minocycline in TAP or from MTA. In the present study, minocycline was replaced with clindamycin in the TAP, and the majority of cases were sealed with bioceramic putty instead of MTA (23). Collectively and including the 2 cases in this study, there are 7 cases of revascularization with a follow-up period greater than 4 years reported in the literature (20–22). Although it is a small number to draw any conclusions, it validates sustained longterm success of revascularization; however, a larger sample size in a controlled environment is required to confirm this finding. Several limitations are associated with the present study. First, it is a retrospective evaluation and hence presents a lower level of evidence compared with a prospective randomized controlled trial. However, it still sheds light on the probability of success or failure because the submission process in the current study included all cases performed in the given period, irrespective of outcome. A retrospective study by Bose et al (19) examined published and unpublished endodontic regenerative cases that were considered to be successful, whereas Cheuh et al (17) presented only those cases that showed improvement in the clinical signs and symptoms, radiographic evidence of root development, and regression of apical radiolucency. Some researchers have attempted to mathematically quantify the changes in dentin thickness and root development using computer software. Although electronic evaluation of root development could be a
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Figure 5. Maxillary left lateral incisor. Increased thickening of the canal walls and apical closure after revascularization. (A) Preoperative radiograph. (B) Followup radiograph at 5 years. (C) Follow-up radiograph at 6 years. (D) CBCT at 5 years. Note the apical closure evident labiopalatally (arrows).
valuable research tool, it may not be practical for daily clinical practice. In contrast to Bose et al (19) and Jeeruphan et al (15), in the present study no mathematical demonstration of root development was obtained. Although an attempt was made to use an approach previously described (19, 24, 25), it was unsuccessful in the majority of cases because of a lack of stable landmarks. These landmarks are necessary for mathematical transformation of nonstandardized preoperative and postoperative radiographs for superimposition to produce corrected output images from which the increase in root length or thickness can be calculated. This mathematical modeling depends largely on finding 3 widely spaced landmarks on both pre6
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and postoperative images such as the cementoenamel junction or the root apex of the adjacent tooth as reference points for correcting the distortion in the image in comparison with the image with the least visible distortion among the set. If the tooth in question was surrounded by erupting teeth or teeth with immature apices, then image correction would not be possible because of a lack of stable reference points, which was the case in 17 teeth included in this study. Fourteen of those were anterior teeth in young children, which means that the neighboring teeth are immature and still erupting unlike those in the study by Bose et al (19) in which three quarters of the cases were of second premolars (33 cases) and the rest were
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Figure 6. Maxillary central incisors associated with history of trauma, presented with pulpal necrosis and chronic apical abscess (A). (B) Preoperative radiograph with sinus tract tracing and root resorption. (C) Follow-up radiograph at 13 months showing resolution of apical radiolucency and arrested resorption.
anterior teeth in adolescent patients (17, 18, 20, 26–29). Therefore, in the present study, the determination of further root growth had to be made subjectively by 3 experienced endodontists despite that this method has its own set of inherent limitations. An attempt was made to analyze different prognostic factors and relate their impact on the outcome (Table 1), but because of the small sample size, no statistical significance could be drawn; hence, the results presented in Table 1 should be interpreted cautiously. The reasons for the failures of the procedure were also investigated; 1 case showed coronal leakage because of restorative failure, which could have potentially led to endodontic failure. Another case had inflammatory root resorption within a month from initiating the revascularization, which could be attributed to the injury as a result of avulsion (Fig. 4). In the third failed case, the probable cause could not be clearly identified. Nonetheless, it is noteworthy that even though the previously mentioned avulsed tooth failed within a month of initiation of treatment, another avulsed tooth in this case series responded favorably to revascularization for up to 6 years (Fig. 5). It seems that the outcome of avulsion cases treated with revascularization depends largely on other factors like the traumatic injury caused by the avulsion itself. Petrino et al (30) reported a successful outcome in 2 avulsed teeth that presented with pulpal necrosis and asymptomatic apical periodontitis without resorption that were treated with revascularization 6 months after reimplantation. Another case report showed revascularization as a viable treatment option for an avulsed immature permanent tooth with root resorption, which was successfully arrested as a result of the treatment (31). A recent report that included 3 cases of external inflammatory root resorption treated with revascularization showed that it was effective in arresting external inflammatory root resorption (32). A successful cessation of apical resorption was also observed in the present study in 2 maxillary incisors associated with a history of dental trauma (Fig. 6). Revascularization is potentially a stem cell–based procedure. A substantial increase in the mesenchymal stem cell markers, up to 700-fold, has been shown after intracanal bleeding induction (33). However, there is an overall decline in tissue regenerative potential with age; it is unknown whether this is because of the intrinsic aging of stem cells or the impairment of stem cell function in the aged tissue environment (34). Three adult patients between the ages of 20 and 31 years with immature teeth because of untreated infection during root development were included in this study. One of these cases JOE — Volume -, Number -, - 2016
showed complete healing, whereas the other 2 cases showed incomplete healing up to 9 and 26 months of follow-up, respectively. This could be attributed to the low regenerative potential and less healing capacity in adults compared with young patients although Shah and Logani (35) have demonstrated favorable results in treating mature teeth with apical periodontitis in 18 adults with a mean age of 44.7 years by a novel, nonobturation technique based on the concept of regeneration. Further research with a larger sample size is needed to explore the probability of success of revascularization in adult patients. The success rate in this study (75%) was comparable with the Mahidol study (80%) (15) and the study by Shah et al (18) (78.5%), which indicates that revascularization is a viable treatment option for immature necrotic teeth with apical periodontitis. However, it is noteworthy that in the incomplete healing group, the periapical pathology has decreased in size significantly in all cases, hence satisfying at least 1 goal of the treatment, elimination of the disease process. Moreover, 3 of 4 cases in this category were followed up for a maximum of 10 months only. A longer follow-up period may result in complete healing of these cases and an increased success rate. In conclusion, within the limitation of this study, outcome of revascularization, wherein healing of periapical periodontitis and maturation of roots occur, is fairly high, making it a viable treatment option in comparison with apexification. However, further investigation with a larger sample size for valid statistical analysis is needed to determine which factors have a detrimental impact on the outcome and hence are considered to be of prognostic value. A more standardized treatment protocol and outcome criteria are also needed to permit such a comparison via a meta-analysis.
Acknowledgments The authors deny any conflicts of interest related to this study.
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20. Jung YI, Lee SJ, Hargreaves KM. Biologically based treatment of immature permanent teeth with pulpal necrosis: a case series. J Endod 2008;34:876–87. 21. Kottoor J, Velmurugan N. Revascularization for a necrotic immature permanent lateral incisor: a case report and literature review. Int J Pediatr Dent 2013;23: 310–6. 22. Nosrat A, Homayounfar N, Oloomi K. Drawbacks and unfavorable outcomes of regenerative endodontic treatments of necrotic immature teeth: a literature review and report of a case. J Endod 2012;38:1428–34. 23. Kohli MR, Yamaguchi M, Setzer FC, Karabucak B. Spectrophotometric analysis of coronal tooth discoloration induced by various bioceramic cements and other endodontic materials. J Endod 2015;41:1862–6. 24. Matteson SR, Deahl ST, Alder ME, Nummikoski PV. Advanced imaging methods. Crit Rev Oral Biol Med 1996;7:346–95. 25. Webber RL, Ruttimann UE, Groenhuis RA. Computer correction of projective distortions in dental radiographs. J Dent Res 1984;63:1032–6. 26. Chueh LH, Huang GT. Immature teeth with periradicular periodontitis or abscess undergoing apexogenesis: a paradigm shift. J Endod 2006;32:1205–13. 27. Thibodeau B, Trope M. Pulp revascularization of a necrotic infected immature permanent tooth: case report and review of the literature. Pediatr Dent 2007;29:47–50. 28. Banchs F, Trope M. Revascularization of immature permanent teeth with apical periodontitis: new treatment protocol? J Endod 2004;30:196–200. 29. Petrino JA. Revascularization of necrotic pulp of immature teeth with apical periodontitis. Northwest Dent 2007;86:33–5. 30. Petrino JA, Boda KK, Shambarger S, et al. Challenges in regenerative endodontics: a case series. J Endod 2010;36:536–41. 31. Miller EK, Lee JY, Tawil PZ, et al. Emerging therapies for the management of traumatized immature permanent incisors. Pediatr Dent 2012;34:66–9. 32. Santiago CN, Pinto SS, Sassone LM, et al. Revascularization technique for the treatment of external inflammatory root resorption: a report of 3 cases. J Endod 2015; 41:1560–4. 33. 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;37:133–8. 34. Rando TA. Stem cells, ageing and quest for immortality. Nature 2006;441:1080–6. 35. Shah N, Logani A. SealBio: a novel, non-obturation endodontic treatment based on concept of regeneration. J Conserv Dent 2012;15:328–32.
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Outcome of Revascularization Procedure: A Retrospective Case Series Sarah Bukhari, BDS, Meetu R. Kohli, BDS, DMD, Frank Setzer, DMD, PhD, MS, and Bekir Karabucak, DMD, MS Abstract Introduction: The purpose of this retrospective case series was to investigate the outcome of the revascularization procedure in necrotic immature teeth. Methods: The residents and faculty members at the University of Pennsylvania endodontic department were invited to submit consecutive revascularization cases treated by them, irrespective of the outcome, during the time period of 2009 to 2012. Twenty-eight of 35 submitted necrotic immature teeth met the inclusion criteria. The treatment protocol included minimal instrumentation and irrigation with 3% sodium hypochlorite and 17% EDTA. Triple antibiotic paste was placed for a minimum of 21 days. After blood clot induction, either EndoSequence Bioceramic Putty (Brasseler, Savannah, GA) or mineral trioxide aggregate was placed below the cementoenamel junction, and composite was used as a final restoration. The follow-up period ranged from 7 to 72 months. The outcome was assessed as complete healing (the absence of clinical signs and symptoms, complete resolution of periradicular radiolucency, increase in the root dentin thickness/length, and apical closure), incomplete healing (the absence of clinical signs and symptoms, the periapical lesion completely healed without any signs of root maturation or thickening, the periapical lesion either reduced in size or unchanged with/without radiographic signs of increasing root dentin thickness/length, or apical closure), and failure (persistent clinical signs and symptoms and/or increased size of the periradicular lesion). Results: Twenty-one of 28 cases (75%) healed completely, 3 cases (10.7%) failed during the observation period and needed further treatment, and 4 cases (14%) presented with incomplete healing. Conclusions: Within the limitation of this study, the outcome of revascularization, wherein healing of periapical periodontitis and maturation of roots occurs, is fairly high, making it a viable treatment option in comparison with apexification. (J Endod 2016;-:1–8)
Key Words Apical periodontitis, BioCeramic, mineral trioxide aggregate, outcome, revascularization, success
C
onventional endodonSignificance tic treatment of necRevascularization outcome analysis should rotic immature teeth with include both the radiographic healing of apical periapical periodontitis preodontitis and the radiographic signs of further root sents a certain set of chaldevelopment. The outcome of revascularization lenges. Open apices make wherein healing of periapical periodontitis and achieving an adequate maturation of roots occur is high. seal during endodontic therapy difficult (1). Disinfection of necrotic immature teeth with traditional mechanical instrumentation and irrigation with sodium hypochlorite have been reported to be not as effective (2), necessitating placement of an intracanal medicament. Although this treatment protocol of apexification has reported high endodontic clinical success, these teeth are prone to post-treatment fracture because of thin fragile root canal walls (3). Calcium hydroxide apexification has traditionally been the treatment of choice for necrotic immature teeth (4). The goal of this treatment is to induce a hard tissue barrier apically to facilitate root canal filling. However, the treatment protocol calls for multiple visits and hence a compliant patient. Prolonged contact with calcium hydroxide weakens root dentin resistance to mechanical forces, thereby rendering the tooth further susceptible to fracture (5, 6). To reduce the time for treatment execution, a 1-step apexification technique with mineral trioxide aggregate (MTA) was proposed (7). Nevertheless, this treatment modality does not not promote root canal wall thickening or apical closure. This necessitates the need for an alternative treatment protocol conducive to continued root maturation with deposition of hard tissue, thereby strengthening the tooth and protecting against future loss to root fracture. Revascularization is a regenerative treatment that is biologically based to allow for root maturation by continued deposition of dentin and a cementumlike structure along the root walls. The foundation of revascularization was laid down in the early 60s by Nygaard-Østby and Hjortdal (8, 9), but the concept behind the contemporary revascularization procedure comes from the trauma literature. It was observed that when an avulsed immature tooth was reimplanted within a certain set of circumstances, revascularization occurred. The main requirements being absence of bacterial challenge, thereby having a necrotic/ischemic but uninfected pulp tissue in the root canal system acting as a scaffold into which new tissue can grow through the large open apical foramina (10). It was postulated that creating a similar
From the Department of Endodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Address requests for reprints to Dr Bekir Karabucak, Department of Endodontics, School of Dental Medicine, University of Pennsylvania, 240 South 40th Street, Philadelphia, PA 19104. E-mail address: [email protected] 0099-2399/$ - see front matter Copyright ª 2016 American Association of Endodontists. http://dx.doi.org/10.1016/j.joen.2016.06.021
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Basic Research—Biology environment when treating necrotic immature teeth with apical periodontitis should result in revascularization and subsequent root development. The first case treated with this approach was published in 2001 with promising results (11). An overwhelming number of case reports have been published since. However, the literature lacks outcome studies evaluating the probability of long-term success. Case reports are generally an accumulation of cases that present a successful outcome of the intended procedure. There are very few studies that describe success and failure rates for revascularization. The objective of this retrospective case series was to report the outcome of consecutive revascularization procedures in necrotic immature teeth treated in the endodontic department at the University of Pennsylvania from 2009 to 2012 by faculty and residents regardless of outcome. A set of outcome criteria was established to describe clinical and radiographic success and failure.
Materials and Methods The University of Pennsylvania endodontic department has a prescribed methodology for the revascularization procedure based on the recommendations of the American Association of Endodontics (AAE) (12). The residents and faculty were invited to participate in this study by submitting consecutive cases treated by them with this protocol during the time period of 2009 to 2012 regardless of the outcome. The resident dental charts for these cases were retrieved via an electronic search using Dentrix software (Henry Schein Inc, Melville, NY). The faculty members were asked to fill out a similar electronic chart with radiographic and other examination notes for submission. Patient’s personal information was masked in accordance with the Health Insurance Portability and Accountability regulations. Each case that fulfilled the following criteria was included in the outcome analysis: 1. An immature permanent tooth with clinical diagnosis of necrotic pulp with or without radiographic signs of apical pathology and the cause of necrosis clearly indicated 2. A tooth treated with the prescribed revascularization protocol 3. A preoperative, postoperative, and follow-up radiograph of at least 6 months after the treatment along with documented clinical signs and symptoms at each of the previous appointments
The preoperative radiographs were checked for immature apices, either blunderbuss canals or wide canals with parallel walls, and in a few cases a moderately developed root but with an open apex. Patient age, sex, tooth number, dental history, presence or absence of periapical radiolucency, treatment and follow-up periods, and the details of the clinical procedure and any variation were also recorded. Thirty-five cases were treated and submitted by the residents and faculty during the previously stated treatment duration. A total of 28 immature teeth out of 35 (in 23 patients) between the ages of 8 and 31 years met the inclusion criteria. Seven cases were excluded because of 1 or more of the following reasons: lack of a detailed description of the treatment protocol, less than a 6-month follow-up or no follow-up, and less than ideal radiographic documentation. The revascularization protocol used was as follows. The treatment was completed in 3 visits; the first visit consisted of the administration of local anesthesia, rubber dam isolation, access preparation, copious irrigation with 3% sodium hypochlorite, minimal or no instrumentation, and placement of triple antibiotic paste (TAP) (metronidazole, ciprofloxacin, and ciprofloxacin [equal parts mixed in distilled water in a 3:1 powder:liquid ratio]; Skywalk Pharmacy, Milwaukee, WI) as an interappointment dressing. An open apex was also verified clinically with a size 100 K-file. Minocycline was replaced with clindamycin in this composition to reduce the risk of tooth discoloration (12). The access opening was temporarily sealed for these cases for an average of 37 days with a temporary restoration material (Cavit; 3M ESPE, St Paul, MN). At the second appointment, 3% mepivacaine without a vasoconstrictor (Dentsply Pharmaceutical, York, PA) was the local anesthetic of choice. After removal of temporary filling under rubber dam isolation, TAP was flushed out by copious irrigation with 3% sodium hypochlorite and a final rinse with 17% EDTA. The blood clot was induced using a #10 K-file to lacerate the apical tissues. After the blood clot was formed, either EndoSequence Bioceramic Putty (Brasseler, Savannah, GA) or MTA (Dentsply, York PA) was placed below the cementoenamel junction and either over the blood clot directly or using a matrix barrier (Collaplug; Zimmer Dental, Carlsbad, CA) based on the clinician’s judgment. The access opening was again temporarily sealed with Cavit. At the final appointment, the setting of bioceramic putty or the MTA was confirmed before placing the permanent composite restoration (3M Filtek P60; 3M ESPE, St Paul, MN). The majority of the follow-up period ranged between 7 and 31 months, with 2 cases being the longest at 4 and 6 years.
TABLE 1. A Summary of Patient Demographics and the Clinical Characteristics and Outcome of the Study Population Variable Tooth type Anterior Premolar Molar Location Maxilla Mandible Cause Caries Anatomical/caries Trauma Signs and Symptoms Absent Present Radiolucency Absent Present
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Teeth, n = 28 (%)
Complete healing, n = 21 (%)
Incomplete healing, n = 4 (%)
Failure, n = 3 (%)
21 (75) 5 (18) 2 (7)
17 (80.9) 3 (60) 1 (50)
2 (9.5) 2 (40) 0
2 (9.5) 0 1 (50)
22 (79) 6 (21)
17 (77) 4 (66.6)
3 (14) 1 (16.6)
2 (9) 1 (16.6)
5 (18) 3 (11) 20 (71)
3 (60) 2 (67) 16 (80)
1 (20) 1 (33) 2 (10)
1 (20) 0 2 (10)
18 (64) 10 (36)
15 (83) 7 (70)
2 (11) 2 (20)
1 (6) 1 (10)
6 (21) 22 (79)
4 (66.6) 17 (77)
1 (16.6) 3 (14)
1 (16.6) 2 (9)
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Figure 1. Complete healing category. Lower right first molar. Increased thickening of the canal walls and continued root maturation after revascularization. (A) Postoperative radiograph. (B) Follow-up radiograph at 18 months.
The outcome was assessed using the radiographic healing of the apical periodontitis, the clinical signs and symptoms, and the radiographic signs of continued root development. Each case was assigned to 1 of the following criteria at follow-up. 1. Complete healing: The absence of clinical signs and symptoms, complete resolution of periradicular radiolucency, and an increase in the root dentin thickness/length and apical closure 2. Incomplete healing: The absence of clinical signs and symptoms, the periapical lesion completely healed without any signs of root maturation or thickening, the periapical lesion either reduced in size or unchanged with/without radiographic signs of increasing root dentin thickness/length, or apical closure 3. Failure: Persistent clinical signs and symptoms and/or increased size of the periradicular lesion Three calibrated examiners, who were experienced endodontists familiar with the revascularization procedure, reviewed all the images (F.S., M.R.K., and B.K.). The examiners were calibrated by being given a detailed description of the outcome criteria used for evaluation in this study. The examiners were also shown radiographs representing each outcome category for normalization. Once calibrated, the 3 examiners reviewed all the images. Periapical radiographs were projected on a big screen in a dark room and were displayed in random order. A specific healing category was assigned for each radiograph when all 3 examiners
agreed or achieved a consensus after discussion. Healing was determined as complete, incomplete, or failure according to the criteria established previously.
Results Residents and faculty members submitted 35 cases. The retrospective chart review of these cases resulted in 28 cases meeting the inclusion criteria. These 28 cases included 21 anterior teeth, 5 premolars, and 2 molars. Table 1 summarizes the patient demographics and the clinical information available from the chart review. Based on the criteria previously stated, 21 of 28 cases (75%) healed completely; 3 cases (10.7%) failed during the observation period and needed further treatment; and another 4 cases (14%) showed incomplete healing, which were rescheduled for the next follow-up visit before a decision on further intervention could be made. Representative cases of each category (ie, complete healing, incomplete healing, and failure) are presented in Figures 1–3, respectively. Cases were further analyzed for potential prognostic factors that may determine outcome. The effect of the primary etiologic factor of necrosis in these cases was analyzed. The cause was trauma, pulp exposure with anatomic anomaly such as dens invaginatus or evaginatus (talons cusp), or caries in itself. It was found that 20 of 28 (71%) cases reviewed in the study were associated with a history of
Figure 2. Failure category. Upper right central incisor. Failed case, patient was symptomatic 22 months after completing the treatment. (A) Preoperative radiograph. (B) Follow-up radiograph at 1 month. (C) Apexification procedure was performed 22 months after revascularization.
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Figure 3. Incomplete healing category. Maxillary left central incisor. Size of apical radiolucency considerably decreased but did not completely resolve with slight increase in the root length along mesial walls. (A) Preoperative radiograph. (B) Follow-up radiograph at 9 months. Mandibular right second premolar. Size of apical radiolucency decreased considerable with no further root growth in length or thickness. (C) Preoperative radiograph. (D) Follow-up radiograph at 10 months.
trauma; 80% (n = 15) of these showed complete healing. Caries and anatomic anomaly occurred in 18% (n = 5) and 11% (n = 3) of the cases, respectively, with a complete healing of 60% in case of caries and 67% in the 3 cases that were associated with a fractured talon cusp. The presence of signs and symptoms at the time of treatment was also analyzed; 10 (36%) cases were symptomatic when the revascularization procedure was initiated, 70% of which healed, whereas 18 (64%) cases were asymptomatic and had an 83% (n = 16) healing rate. The impact of apical pathology at the time of treatment was also evaluated; it was found that in the presence of apical radiolucency (22 cases), 77% had completely healed at the time of follow-up versus a 66.6% success rate in cases in which there was no apical radiolucency (6 cases). Because of the small sample size in this study, no statistical analysis was conducted.
Discussion Because of the promising radiographic and clinical results of the revascularization procedure shown by several case reports and case series, it has become a viable option for the treatment of immature non4
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vital teeth. However, there are 3 important issues associated with this treatment modality: 1. The lack of randomized clinical outcome studies to validate its longterm efficacy 2. The lack of a standardized treatment protocol, which hinders a proper comparison between different studies to gain more information about prognostic factors affecting the outcome 3. The lack of a clear definition of success and failure as an outcome in revascularization studies (13) In order to have a comprehensive definition of success and failure of revascularization, the objectives of the treatment have to be clearly defined. In the case of conventional nonsurgical root canal therapy, the elimination and/or prevention of apical periodontitis is the primary goal. However, in revascularization procedures, along with elimination of the disease, the promotion of further root development, and hence preventing future complications (ie, root fracture), can be viewed as a secondary goal. This secondary outcome is what makes it a superior option over apexification. In this case, it is fair to say that outcome analysis should include both the radiographic healing of apical periodontitis JOE — Volume -, Number -, - 2016
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Figure 4. Maxillary left central incisor failure, due to inflammatory resorption following avulsion. (A) Preoperative radiograph. (B) Follow-up radiograph at 1 month.
and the radiographic signs of further root development and that they should not be analyzed as separate entities, which is the case in the published literature on revascularization so far (14–19). To our knowledge, this is the first study that attempts to create outcome criteria that would fulfill both (ie, the healing process of periapical periodontitis and the continuation of root development demonstrated as 1 or all of the following: increased root length, increased dentinal wall thickness, and/or apical closure). Three distinct categories in outcome are defined: complete healing, incomplete healing, and failure. Complete healing was defined as the absence of clinical signs and symptoms, complete resolution of periradicular radiolucency, an increase in the root dentin thickness/length, and apical closure. Incomplete healing was defined as the absence of clinical signs and symptoms, the periapical lesion either reduced in size or unchanged with/without radiographic signs of increasing root dentin thickness/length, or apical closure. Finally, ‘‘failure’’ was defined as persistent clinical signs and symptoms and/or increased size of the periradicular lesion. Even though the goals of the regenerative endodontic procedures presented in this study are similar to the goals defined and accepted by the AAE, the success criteria vary. Success defined by the AAE is categorized by achieved goals including the primary goal (the elimination of symptoms and the evidence of bony healing), the secondary goal (increased root wall thickness and/or root length [desired but perhaps not essential]), and the tertiary goal (a positive response to vitality testing) (12). When the cases are evaluated by the AAE’s criteria, our data reveal that the primary goal was achieved in 78.5% of cases, whereas 71% met the secondary goal. The tertiary goal was not evaluated in this study. Unsuccessful cases with persistent clinical signs and symptoms and/or increased size of the periradicular lesion should be reevaluated. If the overall treatment plan allows, the disinfection protocol should be followed, and either a second attempt for regenerative treatment or the apexification procedure should be initiated in order to treat apical periodontitis, maintain the patient’s natural dentition, and restore function.
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In the incomplete healing group, the periapical pathology has decreased in size significantly in all cases, hence satisfying at least 1 goal of the treatment—elimination of the disease process. Healing of periapical tissues and root development may take longer in some cases. Additional follow-ups for these cases are recommended and may lead to complete healing and an increased success rate. Slightly more than half of the cases (52%) were followed up for more than 2 years; 2 were followed up even longer for 4 and 6 years. There are very few published case reports that show the long-term success of revascularization at a follow-up period ranging from 4 to 6 years (20–22). In the case report by Nosrat et al (22), 2 anterior teeth after 6 years of revascularization treatment had to be reaccessed for internal bleaching because the patient was not satisfied esthetically with the teeth discoloration, which likely resulted from either minocycline in TAP or from MTA. In the present study, minocycline was replaced with clindamycin in the TAP, and the majority of cases were sealed with bioceramic putty instead of MTA (23). Collectively and including the 2 cases in this study, there are 7 cases of revascularization with a follow-up period greater than 4 years reported in the literature (20–22). Although it is a small number to draw any conclusions, it validates sustained longterm success of revascularization; however, a larger sample size in a controlled environment is required to confirm this finding. Several limitations are associated with the present study. First, it is a retrospective evaluation and hence presents a lower level of evidence compared with a prospective randomized controlled trial. However, it still sheds light on the probability of success or failure because the submission process in the current study included all cases performed in the given period, irrespective of outcome. A retrospective study by Bose et al (19) examined published and unpublished endodontic regenerative cases that were considered to be successful, whereas Cheuh et al (17) presented only those cases that showed improvement in the clinical signs and symptoms, radiographic evidence of root development, and regression of apical radiolucency. Some researchers have attempted to mathematically quantify the changes in dentin thickness and root development using computer software. Although electronic evaluation of root development could be a
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Figure 5. Maxillary left lateral incisor. Increased thickening of the canal walls and apical closure after revascularization. (A) Preoperative radiograph. (B) Followup radiograph at 5 years. (C) Follow-up radiograph at 6 years. (D) CBCT at 5 years. Note the apical closure evident labiopalatally (arrows).
valuable research tool, it may not be practical for daily clinical practice. In contrast to Bose et al (19) and Jeeruphan et al (15), in the present study no mathematical demonstration of root development was obtained. Although an attempt was made to use an approach previously described (19, 24, 25), it was unsuccessful in the majority of cases because of a lack of stable landmarks. These landmarks are necessary for mathematical transformation of nonstandardized preoperative and postoperative radiographs for superimposition to produce corrected output images from which the increase in root length or thickness can be calculated. This mathematical modeling depends largely on finding 3 widely spaced landmarks on both pre6
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and postoperative images such as the cementoenamel junction or the root apex of the adjacent tooth as reference points for correcting the distortion in the image in comparison with the image with the least visible distortion among the set. If the tooth in question was surrounded by erupting teeth or teeth with immature apices, then image correction would not be possible because of a lack of stable reference points, which was the case in 17 teeth included in this study. Fourteen of those were anterior teeth in young children, which means that the neighboring teeth are immature and still erupting unlike those in the study by Bose et al (19) in which three quarters of the cases were of second premolars (33 cases) and the rest were
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Figure 6. Maxillary central incisors associated with history of trauma, presented with pulpal necrosis and chronic apical abscess (A). (B) Preoperative radiograph with sinus tract tracing and root resorption. (C) Follow-up radiograph at 13 months showing resolution of apical radiolucency and arrested resorption.
anterior teeth in adolescent patients (17, 18, 20, 26–29). Therefore, in the present study, the determination of further root growth had to be made subjectively by 3 experienced endodontists despite that this method has its own set of inherent limitations. An attempt was made to analyze different prognostic factors and relate their impact on the outcome (Table 1), but because of the small sample size, no statistical significance could be drawn; hence, the results presented in Table 1 should be interpreted cautiously. The reasons for the failures of the procedure were also investigated; 1 case showed coronal leakage because of restorative failure, which could have potentially led to endodontic failure. Another case had inflammatory root resorption within a month from initiating the revascularization, which could be attributed to the injury as a result of avulsion (Fig. 4). In the third failed case, the probable cause could not be clearly identified. Nonetheless, it is noteworthy that even though the previously mentioned avulsed tooth failed within a month of initiation of treatment, another avulsed tooth in this case series responded favorably to revascularization for up to 6 years (Fig. 5). It seems that the outcome of avulsion cases treated with revascularization depends largely on other factors like the traumatic injury caused by the avulsion itself. Petrino et al (30) reported a successful outcome in 2 avulsed teeth that presented with pulpal necrosis and asymptomatic apical periodontitis without resorption that were treated with revascularization 6 months after reimplantation. Another case report showed revascularization as a viable treatment option for an avulsed immature permanent tooth with root resorption, which was successfully arrested as a result of the treatment (31). A recent report that included 3 cases of external inflammatory root resorption treated with revascularization showed that it was effective in arresting external inflammatory root resorption (32). A successful cessation of apical resorption was also observed in the present study in 2 maxillary incisors associated with a history of dental trauma (Fig. 6). Revascularization is potentially a stem cell–based procedure. A substantial increase in the mesenchymal stem cell markers, up to 700-fold, has been shown after intracanal bleeding induction (33). However, there is an overall decline in tissue regenerative potential with age; it is unknown whether this is because of the intrinsic aging of stem cells or the impairment of stem cell function in the aged tissue environment (34). Three adult patients between the ages of 20 and 31 years with immature teeth because of untreated infection during root development were included in this study. One of these cases JOE — Volume -, Number -, - 2016
showed complete healing, whereas the other 2 cases showed incomplete healing up to 9 and 26 months of follow-up, respectively. This could be attributed to the low regenerative potential and less healing capacity in adults compared with young patients although Shah and Logani (35) have demonstrated favorable results in treating mature teeth with apical periodontitis in 18 adults with a mean age of 44.7 years by a novel, nonobturation technique based on the concept of regeneration. Further research with a larger sample size is needed to explore the probability of success of revascularization in adult patients. The success rate in this study (75%) was comparable with the Mahidol study (80%) (15) and the study by Shah et al (18) (78.5%), which indicates that revascularization is a viable treatment option for immature necrotic teeth with apical periodontitis. However, it is noteworthy that in the incomplete healing group, the periapical pathology has decreased in size significantly in all cases, hence satisfying at least 1 goal of the treatment, elimination of the disease process. Moreover, 3 of 4 cases in this category were followed up for a maximum of 10 months only. A longer follow-up period may result in complete healing of these cases and an increased success rate. In conclusion, within the limitation of this study, outcome of revascularization, wherein healing of periapical periodontitis and maturation of roots occur, is fairly high, making it a viable treatment option in comparison with apexification. However, further investigation with a larger sample size for valid statistical analysis is needed to determine which factors have a detrimental impact on the outcome and hence are considered to be of prognostic value. A more standardized treatment protocol and outcome criteria are also needed to permit such a comparison via a meta-analysis.
Acknowledgments The authors deny any conflicts of interest related to this study.
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Basic Research—Biology 4. Rafter M. Apexification: a review. Dent Traumatol 2005;21:1–8. 5. Andreasen JO, Farik B, Munksgaard EC. Long term calcium hydroxide as a root canal dressing may increase the risk of root fracture. Dent Traumatol 2002;18:134–7. 6. Doyon GE, Dumsha T, von Fraunhofer JA. Fracture resistance of human root dentin exposed to intracanal calcium hydroxide. J Endod 2005;3:895–7. 7. Torabinejad M, Chivian N. Clinical applications of mineral trioxide aggregate. J Endod 1999;25:197–205. 8. Nygaard-Østby B. The role of the blood clot in endodontic therapy: an experimental histologic study. Acta Odont Scand 1961;19:323–53. 9. Nygaard-Østby B, Hjortdal O. Tissue formation in the root canal following pulp removal. Scand J Dent Res 1971;79:333–49. 10. Kling M, Cvek M, Mejare I. Rate and predictability of pulp revascularization in 10 therapeutically reimplanted permanent incisors. Endod Dent Traumatol 1986;2: 83–9. 11. Iwaya SI, Ikawa M, Kubota M. Revascularization of an immature permanent tooth with apical periodontitis and sinus tract. Dent Traumatol 2001;17:185–7. 12. American Association of Endodontics, Clinical considerations for regenerative procedures. Available at: www.aae.org/regenerativeendo/. Accessed July 31, 2013. 13. Diogenes A, Henry MA, Teixeira FB, Hargreaves KM. An update on clinical regenerative endodontics. Endod Topics 2013;28:2–23. 14. Jadhav G, Shah N, Logani A. Revascularization with and without platelet-rich plasma in nonvital, immature, anterior teeth: a pilot clinical study. J Endod 2012;38:1581–7. 15. Jeeruphan T, Jantarat J, Yanpiset K, et al. 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;38:1330–6. 16. Chen MY, Chen KL, Chen CA, et al. Responses of immature permanent teeth with infected necrotic pulp tissue and apical periodontitis/abscess to revascularization procedures. Int Endod J 2012;45:294–305. 17. Chueh LH, Ho YC, Kuo TC, et al. Regenerative endodontic treatment for necrotic immature permanent teeth. J Endod 2009;35:160–4. 18. 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;34:919–25. 19. 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;35:1343–9.
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JOE — Volume -, Number -, - 2016