Evaluation of the apical infiltration after root canal disruption and obturation

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www.fob.usp.br/jaos or www.scielo.br/jaos J Appl Oral Sci. 2008;16(5):345-9 EVALUATION OF THE APICAL INFILTRATION AFTER ROOT CANAL DISRUPTION AND OBTURATION João Eduardo GOMES-FILHO1, Renato Nicolás HOPP2, Pedro Felício Estrada BERNABÉ3, Mauro Juvenal NERY1, José Arlindo OTOBONI FILHO1, Elói DEZAN JÚNIOR1 1- DDS, MSc, PhD, Associate Professor, Department of Endodontics, Dental School of Araçatuba, State University of São Paulo, Araçatuba, SP, Brazil. 2- DDS, Department of Endodontics, Dental School of Araçatuba, State University of São Paulo, Araçatuba, SP, Brazil. 3- DDS, MSc, PhD, Chairman, Dental School of Araçatuba, State University of São Paulo, Araçatuba, SP, Brazil. Corresponding address: Dr. Renato Nicolás Hopp - Rua Simoneto Biagioni, 653 - Jardim Esplanada, 18550-000 Boituva, SP, Brasil. Phone; +55-15-3363-2905. e-mail: renhopp@gmail.com Received: August 31, 2007 - Modification: March 4, 2008 - Accepted: April 7, 2008 ABSTRACT The aim of this study was to evaluate two root canal filling techniques used in teeth that had their apical foramen disrupted and compare the apical infiltration with an ideal clinical situation. Twenty-seven freshly extracted single-rooted teeth were selected and radiographed to confirm the existence of a single and straight root canal. The crowns were removed at a mean distance of 11 mm from the apex. The teeth had the root canals instrumented and were randomly assigned to 3 groups (n=9): ND group - root canals were filled using the lateral compaction technique and no disruption was performed; DRF group - the apical constriction was disrupted by advancing a #40 K-file 1 mm beyond the original working length, the canals were reinstrumented to create an apical ledge at 1 mm from the apical foramen and were obturated with a master gutta-percha cone with same size as the last file used for reinstrumentation; DF group - the teeth had the apical constriction disrupted and the canals were obturated with a master gutta-percha cone that fit at 1 mm from the apex. The teeth were submitted to dye leakage test with Rhodamine B for 7 days, using vaccum on the initial 5 min. The teeth were sectioned longitudinally and the leakage was measured in a linear fashion from apex to crown. There was no statistically significant difference (p>0.05) between the groups that had the apical foramen disrupted (DF, DRF), but significant difference was found between the disrupted groups and the non-disrupted one (p<0.01). In conclusion, none of the evaluated techniques was able to prevent apical infiltration, so working length so the working length determination has to be established and maintained carefully. Key words: Root canal filling. Apical infiltration. Apical disruption. INTRODUCTION Resorption or iatrogenic enlargement during instrumentation can result in disruption of the apical constriction. Iatrogenic perforation of the apical constriction can be caused by erroneous determination of the working length (WL). Instrumentation beyond the apical foramen causes damage to the periapical tissues due to extrusion of debris and irrigating solution, and impairs or prevents the adequate seal of the apical foramen, increasing the risk of extrusion of the filling material to the periapical space. If the main objective of endodontic therapy is to create means that lead to the repair of the cementum over the apical foramen, the filling material should not be extruded beyond the root canal into the periapical region21,22, although the limit of obturation should be set as close as possible from its termination19. Since the exact location of the apical constriction is not determined 345 clinically but histologically, clinicians must be extremely careful not to extrude material beyond it, in order to maintain the integrity of the periapical tissues. It is well accepted that optimal results are obtained when the limit of root canal instrumentation and obturation is set 1 mm short of the radiographic apex22. Lateral condensation is the most frequently used technique to prevent overfilling. Silva, et al.20 observed less overfilling using lateral condensation than thermoplastic techniques, such as Thermafill or backfilling. Al Dewani, et al.1 also found less chance of material extrusion and better radiographic quality using cold lateral condensation compared to thermoplasticized techniques. Two techniques can be used to correct the problem of iatrogenic disruption: the canal can be either reinstrumented to create a new apical ledge, or obturated with a master gutta-percha cone that adapts on the disrupted foramen. The first involves a new determination EVALUATION OF THE APICAL INFILTRATION AFTER ROOT CANAL DISRUPTION AND OBTURATION of the WL with thicker files and subsequent obturation. Obturation in these cases can go trough several difficulties, which can lead to extrusion of the filling material into the periapical region. The second technique uses a master gutta percha cone that adapts on the original WL and is thick enough to get stuck on the disrupted foramen. The aim of the present study was to evaluate these two techniques and compare the apical infiltration with an ideal clinical situation, using the lateral compaction technique, in teeth with enlarged apical constriction. MATERIALAND METHODS Tooth Selection and Preparation Twenty-seven single-rooted teeth freshly extracted for periodontal reasons were selected and stored in neutral formaldehyde until use. No attempt was made to identify the patient’s age or gender. The teeth were radiographed confirm the existence of a single straight root canal. The crowns were sectioned at a mean distance of 11 mm from the apex and discarded. Tooth Instrumentation and Obturation Instrumentation was held by a single operator. A #10 K-file (FKG Dentaire, La Chaux-de-Fonds, Switzerland) was introduced into the root canal until it was visible at the apical foramen and the WL was determined at 1 mm short of this length. Root canal instrumentation was performed using #0.02 K-files. The canals were irrigated with sodium hypochlorite at each change of file. After instrumentation, the teeth were randomly assigned to 3 groups of 9 specimens each: Non-disrupted (ND) group - the root canals were filled according to the lateral compaction technique and the apical constriction was not disrupted; Disrupted-reinstrumented-filled (DRF) group - the apical constriction was disrupted by advancing a #40 K-file 1 mm beyond the original WL. A new root canal instrumentation was performed to create a new ledge at 1 mm short of the apex (original WL), starting with a file that fit the new diameter up to a file three sizes greater. Canals were irrigated with sodium hypochlorite at each change of instrument and EDTA was applied for 5 min as a chelating agent at the end of instrumentation. Root canal filling was performed using the lateral condensation technique with a master gutta-percha cone of the same diameter of the last K-file used for instrumentation, accessory gutta-percha points and Sealapex (Sybron Endo, USA). Filling was considered satisfactory when no accessory gutta-percha point could advance more than 1 mm into the canal; Disrupted-filled (DF) group – The apical constriction was disrupted in the same way as described for the DRF group. However, the canals were not reinstrumented, but only filled with a master gutta-percha cone that fit into the original WL (1 mm short of the apex), accessory gutta-percha points and Sealapex. Filling was considered satisfactory when no accessory gutta-percha point could advance more than 1 mm into the canal. Apical Infiltration - Dye Leakage Test After instrumentation, the teeth were sealed with nail varnish leaving only the apex free for the dye penetration and were submitted to dye leakage test with Rhodamine B for 7 days, using vacuum in the first 5 min. Thereafter, the teeth were dried, cut longitudinally and the leakage was measured in a linear fashion from apex to crown. Two measures were taken: (1) the distance from the filling to the apex and (2) the penetration of the dye along the filling. Data were analyzed by ANOVA, using Microsoft Excel and Student’s t-test to verify the statistical significance of the results ( α= 5%) . RESULTS The distance between root apex and filling material and dye leakage extent in the groups are shown in Tables 1, 2, and 3. The ND group had a mean apex-to-filling distance of 1.29 ± 0.56 mm, which fits in the original WL, and a dye leakage mean value of 0.13 ± 0.17mm. Five specimens in this (55%) presented no leakage (Tables 1 and 4). The DRF group had a mean apex-to-filling distance of 1.43 ± 0.24 mm, and a dye leakage mean value of 0.44 ± 0.33 mm. Two specimens (22.2%) presented no leakage (Tables 2 and 5). The DF group had a mean apex-to-filling distance of 1.24 ± 0.54 mm and a dye leakage mean value of 0.39 ± 0.21 mm. All specimens showed apical leakage (Tables 3 and 6). There was no statistically significant difference between the groups that had the apical constriction disrupted (DF, DRF), but significant difference was found between the disrupted groups and the non-disrupted one (p<0.05) TABLE 1- Apex-to-filling distance (mm) and leakage extent (mm) in the non-disrupted (ND) group ND Apex-to-filling distance (mm) Leakage (mm) 1 2 3 4 5 6 7 8 9 Mean 1.9992 1.2936 0.9408 1.764 0.1176 1.764 1.2936 1.4112 1.0584 1.2936 0 0 0.4704 0.2352 0 0.2352 0.2352 0 0 0.130666667 346 GOMES-FILHO J E, HOPP R N, BERNABÉ P F E, NERY M J, OTOBONI FILHO J A, DEZAN JÚNIOR E TABLE 2- Apex-to-filling distance (mm) and leakage extent (mm) in the disrupted-reinstrumented-filled (DRF) group DRF Apex-to-filling distance (mm) Leakage (mm) 1 2 3 4 5 6 7 8 9 Mean 1.0584 1.6464 1.764 1.6464 1.2936 1.2936 1.176 1.4112 1.6464 1.4373 0.2352 0.588 0.4704 0 0.9408 0.8232 0.588 0.3528 0 0.4442 TABLE 3- Apex-to-filling distance (mm) and leakage extent (mm) in the disrupted-filled (DF) group DF Apex-to-filling distance (mm) Leakage (mm) 1 2 3 4 5 6 7 8 9 Mean 1.5288 1.6464 0.3528 2.1168 1.176 1.5288 1.2936 0.7056 0.8232 1.2413 0.2352 0.4704 0.2352 0.2352 0.2352 0.2352 0.8232 0.588 0.4704 0.392 TABLE 4- Statistical data for the non-disrupted (ND) group ND Apex-to-filling distance (mm) Leakage Mean SD ANOVA 1.2936 0.5609 0.3146 0.1307 0.1709 0.0291 347 TABLE 5- Statistical data for the disrupted-reinstrumentedfilled (DRF) group DRF Apex-to-filling distance (mm) Leakage Mean SD ANOVA 1.4373 0.2479 0.0615 0.4443 0.3315 0.1099 TABLE 6- Statistical data for the disrupted-filled (DF) group DF Apex-to-filling distance (mm) Leakage Mean SD ANOVA 1.2413 0.5425 0.2943 0.3920 0.2120 0.0449 DISCUSSION The present study focused on the role of the obturation technique when the apical foramen is disrupted, which can clinically occur when the WL is erroneously established or not maintained during the root canal instrumentation. All procedures were performed by a single operator in order to avoid inter-operator discrepancies. Only teeth with a single straight root canal were used because they offer a more standardized method for evaluation of apical leakage. In addition, evaluating the difficulties on management of curved canals was not within the scope of this study. There is a lot of skepticism regarding the significance of in vitro leakage studies and the limitations of their results25. Even so, they are widely used to evaluate and compare the sealability of materials and have an important role for testing prior to clinical use in patients. Although the intensity of the coloration produced after apical infiltration was not an issue in the present experimentation, Rhodamine B was used because it does not suffer discoloration by calcium hydroxide-based materials as occurs with methylene blue25. Vacuum was used based on studies that showed greater infiltration when vacuum was used compared to its nonuse, probably due to formation of air pockets in the filling mass, which hinders dye penetration but not bacteria6. Apical constriction disruption mostly happens when WL determination is done in an erroneous way11. The WL can be determined either radiographically or electronically4. It has been shown that root apex locators offer a more accurate WL determination because not all apical foramens are localized on the root apex, and can be sometimes on the side of the root. The anatomic apex may or may not coincide with the apical foramen. In most cases (50-98% of all roots), the foramen deviates from the long axis of the tooth15. Weine24 stated that the ideal apical limit should be at the EVALUATION OF THE APICAL INFILTRATION AFTER ROOT CANAL DISRUPTION AND OBTURATION cemento-dentinal junction (apical constriction) and the practical limit at 1 mm short of the apex; while other researchers have mentioned only the practical limit of instrumentation and obturation, setting them between 0.5 and 1 mm short of the apex16, 1 mm short of the apex7 or at the apical constriction9,12,23,. Schaeffer, et al.19, observed that teeth obturated 0-1 mm short of the radiographic apex had better healing than those obturated more than 1 mm from the apex. The results of the present study showed a mean apexto-filling distance acceptable based the literature, with little deviation from 1 mm short of the apex. However, given some of apex-to-filling distances had means that were the same, it may be assumed that the greater dye leakage occurred in the disrupted groups was due the diameter of the apical foramen after disruption. Little has been published about the correlation between apical foramen diameter and apical infiltration, which impairs a direct comparison of the present results to previous ones. The results of this study showed a poorer sealing when the apical foramen was disrupted, probably due to a larger diameter of the apical foramen after disruption, which allowed deeper leakage. Mente, et al.13 evaluated the influence of apical enlargement on the sealing ability and observed a positive correlation between apex diameter and more leakage was found in extremely large canals compared smaller ones. When the apical foramen is disrupted, canal shape can be changed and cause apical misfit of the master cone to the canal walls with formation of voids that create paths for dye leakage. El Ayouti, et al.5 showed that despite the correct radiographic determination of WL, overinstrumentation occurred in 51% of premolars and in 22% of molars.Although root apex locators are provide a more accurate WL determination than radiographs, the latter are still widely used and neither of the techniques can avoid the WL is lost due to inadvertent disruption of this area. When the apex constriction is disrupted and lateral condensation technique is used, the master gutta-percha must fit to the region of constriction. The master cone can fit a new apical ledge or the dentinal walls without creation of a new apical ledge. Various techniques are described in the literature to avoid overfilling. The use of dentin chips, calcium hydroxide apical plugs and master cone customization are described in order to maintain the filling material inside of the canal and prevent it from invading the periapical tissues. Allison, et al.2, showed that the master cone does not have to get stuck in the apical constriction, which is a clinically difficult maneuver under certain situations. Standardization with calibrating rulers is a fast, practical and useful method. Modeling of the apical end of the gutta-percha master cone can be done with xylol or chloroform, and is a useful technique even though they are considered carcinogenic. However, it was not within the scope of the present study to evaluate the role of cone modeling filling techniques in disrupted teeth. Lateral condensation is the most frequently used technique to prevent overfilling. Silva, et al.20 found less overfilling using lateral condensation than thermoplastic techniques such as Thermafill or backfilling. Another study1 also found less possibility of material extrusion and better radiographic quality using cold lateral condensation compared to thermoplasticized techniques. Pérez Heredia, et al.18 showed that cold lateral condensation was effective in sealing the apex and presented a greater depth of spreader penetration compared to the thermoplastic technique. Another study8 found a larger area of sealer when cold lateral condensation was used compared to the use of Thermafil. Peng L, et al.17 found a higher chance of extruding material when warm gutta-percha is used when compared to the lateral compaction technique, but showed no differences in the outcomes of those fillings, while another study10 showed that fillings with continuous wave of obturation were more likely to extrude than the cold lateral compaction. Other researchers25 demonstrated that there is a higher fluid movement when teeth are filled by the vertical compaction technique that those filled by lateral condensation. In the present study, we also used #0.02 master gutta-percha cones, which have been shown to allow the spreader to advance to a depth significantly closer to the WL3. In another study, cold lateral compaction achieved a better apical sealing than thermoplasticized techniques14. Still, the diameter of the apical foramen cannot be considered as the only factor for greater leakage. No obturation technique, even if performed as accurately as possible, is still flawless. When the root canal is disrupted, the presence of apical voids is somehow increased because of factors such as dislocation of the obturation, difficulty to get the cone stuck on a newly prepared apical ledge and even canal transportation produced in the moment of disruption, altering the canal shape. One of the most difficult points of the endodontic treatment is to achieve regularity and equilibrium value of MeCpG steps (,+14 deg.) [31,44]. In comparison, methylation has a significantly lower stability cost when happening at major groove positions, such as 211 and 21 base pair from dyad (mutations 9 and 12), where the roll of the nucleosome bound conformation (+10 deg.) is more compatible with the equilibrium geometry of MeCpG steps. The nucleosome destabilizing effect of cytosine methylation increases with the number of methylated cytosines, following the same position dependence as the single methylations. The multiple-methylation case reveals that each major groove meth- PLOS Computational Biology | www.ploscompbiol.org 3 November 2013 | Volume 9 | Issue 11 | e1003354 DNA Methylation and Nucleosome Positioning ylation destabilizes the nucleosome by around 1 kJ/mol (close to the average estimate of 2 kJ/mol obtained for from individual methylation studies), while each minor groove methylation destabilizes it by up to 5 kJ/mol (average free energy as single mutation is around 6 kJ/mol). This energetic position-dependence is the reverse of what was observed in a recent FRET/SAXS study [30]. The differences can be attributed to the use of different ionic conditions and different sequences: a modified Widom-601 sequence of 157 bp, which already contains multiple CpG steps in mixed orientations, and which could assume different positioning due to the introduction of new CpG steps and by effect of the methylation. The analysis of our trajectories reveals a larger root mean square deviation (RMSD) and fluctuation (RMSF; see Figures S2– S3 in Text S1) for the methylated nucleosomes, but failed to detect any systematic change in DNA geometry or in intermolecular DNA-histone energy related to methylation (Fig. S1B, S1C, S4–S6 in Text S1). The hydrophobic effect should favor orientation of the methyl group out from the solvent but this effect alone is not likely to justify the positional dependent stability changes in Figure 2, as the differential solvation of the methyl groups in the bound and unbound states is only in the order of a fraction of a water molecule (Figure S5 in Text S1). We find however, a reasonable correlation between methylation-induced changes in hydrogen bond and stacking interactions of the bases and the change in nucleosome stability (see Figure S6 in Text S1). This finding suggests that methylation-induced nucleosome destabilization is related to the poorer ability of methylated DNA to fit into the required conformation for DNA in a nucleosome. Changes in the elastic deformation energy between methylated and un-methylated DNA correlate with nucleosomal differential binding free energies To further analyze the idea that methylation-induced nucleosome destabilization is connected to a worse fit of methylated DNA into the required nucleosome-bound conformation, we computed the elastic energy of the nucleosomal DNA using a harmonic deformation method [36,37,44]. This method provides a rough estimate of the energy required to deform a DNA fiber to adopt the super helical conformation in the nucleosome (full details in Suppl. Information Text S1). As shown in Figure 2, there is an evident correlation between the increase that methylation produces in the elastic deformation energy (DDE def.) and the free energy variation (DDG bind.) computed from MD/TI calculations. Clearly, methylation increases the stiffness of the CpG step [31], raising the energy cost required to wrap DNA around the histone octamers. This extra energy cost will be smaller in regions of high positive roll (naked DNA MeCpG steps have a higher roll than CpG steps [31]) than in regions of high negative roll. Thus, simple elastic considerations explain why methylation is better tolerated when the DNA faces the histones through the major groove (where positive roll is required) that when it faces histones through the minor groove (where negative roll is required). Nucleosome methylation can give rise to nucleosome repositioning We have established that methylation affects the wrapping of DNA in nucleosomes, but how does this translate into chromatin structure? As noted above, accumulation of minor groove methylations strongly destabilizes the nucleosome, and could trigger nucleosome unfolding, or notable changes in positioning or phasing of DNA around the histone core. While accumulation of methylations might be well tolerated if placed in favorable positions, accumulation in unfavorable positions would destabilize the nucleosome, which might trigger changes in chromatin structure. Chromatin could in fact react in two different ways in response to significant levels of methylation in unfavorable positions: i) the DNA could either detach from the histone core, leading to nucleosome eviction or nucleosome repositioning, or ii) the DNA could rotate around the histone core, changing its phase to place MeCpG steps in favorable positions. Both effects are anticipated to alter DNA accessibility and impact gene expression regulation. The sub-microsecond time scale of our MD trajectories of methylated DNAs bound to nucleosomes is not large enough to capture these effects, but clear trends are visible in cases of multiple mutations occurring in unfavorable positions, where unmethylated and methylated DNA sequences are out of phase by around 28 degrees (Figure S7 in Text S1). Due to this repositioning, large or small, DNA could move and the nucleosome structure could assume a more compact and distorted conformation, as detected by Lee and Lee [29], or a slightly open conformation as found in Jimenez-Useche et al. [30]. Using the harmonic deformation method, we additionally predicted the change in stability induced by cytosine methylation for millions of different nucleosomal DNA sequences. Consistently with our calculations, we used two extreme scenarios to prepare our DNA sequences (see Fig. 3): i) all positions where the minor grooves contact the histone core are occupied by CpG steps, and ii) all positions where the major grooves contact the histone core are occupied by CpG steps. We then computed the elastic energy required to wrap the DNA around the histone proteins in unmethylated and methylated states, and, as expected, observed that methylation disfavors DNA wrapping (Figure 3A). We have rescaled the elastic energy differences with a factor of 0.23 to match the DDG prediction in figure 2B. In agreement with the rest of our results, our analysis confirms that the effect of methylation is position-dependent. In fact, the overall difference between the two extreme methylation scenarios (all-in-minor vs all-in-major) is larger than 60 kJ/mol, the average difference being around 15 kJ/ mol. We have also computed the elastic energy differences for a million sequences with CpG/MeCpG steps positioned at all possible intermediate locations with respect to the position (figure 3B). The large differences between the extreme cases can induce rotations of DNA around the histone core, shifting its phase to allow the placement of the methylated CpG steps facing the histones through the major groove. It is illustrative to compare the magnitude of CpG methylation penalty with sequence dependent differences. Since there are roughly 1.5e88 possible 147 base pairs long sequence combinations (i.e., (4n+4(n/2))/2, n = 147), it is unfeasible to calculate all the possible sequence effects. However, using our elastic model we can provide a range of values based on a reasonably large number of samples. If we consider all possible nucleosomal sequences in the yeast genome (around 12 Mbp), the energy difference between the best and the worst sequence that could form a nucleosome is 0.7 kj/mol per base (a minimum of 1 kJ/mol and maximum of around 1.7 kJ/mol per base, the first best and the last worst sequences are displayed in Table S3 in Text S1). We repeated the same calculation for one million random sequences and we obtained equivalent results. Placing one CpG step every helical turn gives an average energetic difference between minor groove and major groove methylation of 15 kJ/ mol, which translates into ,0.5 kJ/mol per methyl group, 2 kJ/ mol per base for the largest effects. Considering that not all nucleosome base pair steps are likely to be CpG steps, we can conclude that the balance between the destabilization due to CpG methylation and sequence repositioning will depend on the PLOS Computational Biology | www.ploscompbiol.org 4 November 2013 | Volume 9 | Issue 11 | e1003354 DNA Methylation and Nucleosome Positioning Figure 3. Methylated and non-methylated DNA elastic deformation energies. (A) Distribution of deformation energies for 147 bplong random DNA sequences with CpG steps positioned every 10 base steps (one helical turn) in minor (red and dark red) and major (light and dark blue) grooves respectively. The energy values were rescaled by the slope of a best-fit straight line of figure 2, which is 0.23, to source of circulating FGF-21. The lack of association between circulating and muscle-expressed FGF-21 also suggests that muscle FGF-21 primarily works in a local manner regulating glucose metabolism in the muscle and/or signals to the adipose tissue in close contact to the muscle. Our study has some limitations. The number of subjects is small and some correlations could have been significant with greater statistical power. Another aspect is that protein levels of FGF-21 were not determined in the muscles extracts, consequently we cannot be sure the increase in FGF-21 mRNA is followed by increased protein expression. In conclusion, we show that FGF-21 mRNA is increased in skeletal muscle in HIV patients and that FGF-21 mRNA in muscle correlates to whole-body (primarily reflecting muscle) insulin resistance. These findings add to the evidence that FGF-21 is a myokine and that muscle FGF-21 might primarily work in an autocrine manner. Acknowledgments We thank the subjects for their participation in this study. 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