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Influence of low-level laser (LLL) on interleukin 6 (IL-6) levels in gingival crevicular fluid (GCF) during orthodontic tooth movement of periodontally affected rabbits
International Orthodontics 2019; 17: 227–234
Influence of low-level laser (LLL) on interleukin 6 (IL-6) levels in gingival crevicular fluid (GCF) during orthodontic tooth movement of periodontally affected rabbits
Original article
Websites: www.em-consulte.com www.sciencedirect.com
Essam Abdelalim Nassar 1,2, Ahmed Maher Fouda 2, Khalid Sadiaq Hassan 3
Available online: 30 April 2019
1. Imam Abdurahman Bin Faisal University, Preventive Dental Science Department, Saudi Arabia 2. Mansoura University, Orthodontic Department, Faculty of Dentistry, Egypt 3. Al-Azhar University, Assiut branch, Faculty of Dentistry, Egypt
Correspondence: Essam Abdelalim Nassar, Preventive Dental Sciences Department, College of Dentistry, Imam Abdulrahman Bin Faisal University, 1982 Dammam, Saudi Arabia. [email protected]
Summary Aim > To evaluate the effects of LLL on IL-6 levels in the GCF and the Probing Pocket Depth measurements (PPD) during orthodontic tooth movement in periodontally affected rabbits. Methods > Twenty-four rabbits were divided into 3 groups: Group 1(G1), healthy rabbits with orthodontic movement, Group 2(G2) periodontally affected rabbits and orthodontic movement, Group 3(G3) periodontally affected rabbits with orthodontic movement and LLL therapy. A 0.014 stainless steel spring was inserted in the upper central incisors to produce 60gm force. Laser CAT 500 was applied for 3 min/day for 2 weeks. PPD measurements were obtained at base line and after 14 days with electronic periodontal probe. Results > IL-6 levels increased gradually after application of orthodontic force, afterwards the 8th day, a significant difference in the Il-6 levels between G1 vs. G2 and G2 vs. G3 was observed. PPD measurements showed significant difference between the three groups at base line and after 14 days. Clinical Significance > LLL application can enhance periodontal ligament regeneration and decrease the periodontal tissue destruction through suppression of IL-6 levels.
tome 17 > n82 > June 2019 https://doi.org/10.1016/j.ortho.2019.03.004 © 2019 CEO. Published by Elsevier Masson SAS. All rights reserved.
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Keywords Tooth movement Cytokines Laser
Original article
E.A. Nassar, A.M. Fouda, K.S. Hassan
Mots clés Mouvement dentaire Cytokines Laser
Résumé Influence du laser de faible intensité (LLL) sur les taux d'interleukine 6 (IL-6) dans le fluide gingival sulculaire (GCF) pendant le mouvement orthodontique chez les lapins atteints de maladie parodontale Objectif > Évaluer les effets de la LLL sur les taux d'IL-6 dans le GCF et les mesures de la profondeur des poches au sondage (PPD) pendant le mouvement orthodontique dentaire chez les lapins atteints de maladie parodontale. Matériel et méthodes > Vingt-quatre lapins ont été divisés en 3 groupes : Groupe 1(G1) : lapins en bonne santé sous traitement orthodontique ; groupe 2(G2) : lapins avec atteinte parodontale sous traitement orthodontique ; groupe 3(G3) lapins avec atteinte parodontale, traitement orthodontique et thérapie LLL. Un ressort en acier inoxydable 0,014 a été inséré dans les incisives centrales supérieures pour produire une force de 60 g. Le LaserCat500 a été appliqué pendant 3 min/jour pendant 2 semaines. LaserCat500 Les mesures PPD ont été obtenues au départ et après 14 jours avec une sonde parodontale électronique. Résultats > Les taux d'IL-6 ont augmenté progressivement après l'application de la force orthodontique, après le 8e jour, une différence significative dans les taux d'IL-6 entre G1 et G2 et G2 et G3 a été observée. Les mesures de PPD ont montré une différence significative entre les trois groupes au départ et après 14 jours. Signification clinique > L'application de LLL peut améliorer la régénération du ligament parodontal et diminuer la destruction du tissu parodontal par la suppression des niveaux d'IL-6.
Introduction
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Orthodontic tooth movement is achieved by means of alveolar bone and periodontal ligament remodeling as a result to the applied forces [1]. Force application changes the equilibrium between collagen synthesis and degeneration [2] through a group of proteolytic enzymes called metalloproteinases (MMPs) such as MMP-1, MMP-8, and MMP-13, which control periodontal tissue remodelling [3,4]. The MMP-1 levels in the peridonuim of rats and humans were increased after application of orthodontic forces [5,6]. Cytokines such as Interleukins, prostaglandin and tumour necrosis factor-alpha (TNF-ɑ) were considered as the regulators of MMP-1 expression in humans [7,8]. Cytokines have an important role in intercellular signalling and have been involved in the pathology of periodontal diseases, bone resorption, and bone reaction to orthodontic treatment. The role of inflammatory mediators such as interleukins, prostaglandins and glycosaminoglycan has been investigated during orthodontic tooth movement [9,10]. Changes in the amount and concentration of Interleukin -6 (IL-6) in the periodontal tissues reflect the status of periodontal tissue inflammation. Higher levels of IL-6 in the crevicular fluid are shown after application of orthodontic forces [11,12]. Periodontal diseases are characterized by bone loss and decreased tissue support around the teeth due to inflammation of the periodontal supporting structures. Orthodontic appliances are considered as modifying factors for periodontal supporting tissues [13]. Artun and Urbye suggested that the periodontal
ligament might be destroyed during tooth tipping or intrusion in periodontally affected teeth [14]. LLL application was associated with healing of the damaged bone tissue following tooth extraction proved by radiological analysis [15]. In addition, LLL irradiation has been shown to increase the number of feasible osteocytes in the irradiated areas significantly by encouraging the production of bone matrix and creating an extremely reactive and vital bone tissue. Osteocytes have a principal role in coordinating osteoblast and osteoclast recruitment and activity [16]. Moreover, Nissan et al. reported that the LLL enhanced the bone-healing procedure in artificially formed osseous cavities through triggering calcium transfer for the period of new bone formation [17]. The aim of this study was to assess the effects of LLL on IL-6 levels in the gingival crevicular fluid and the probing pocket depth throughout orthodontic tooth movement in periodontally affected teeth in rabbit.
Materials and methods Sample preparation Sample size was calculated with EpiCalc 2000 version 1.02 (Brixton Books, Brixton, UK) software and indicated 8 rabbits for each group to be reliable at 80% power and 95% confidence interval. A flow chart for the experimental design is shown in (figure 1). A total of 24 New Zealand male rabbits, 3.0 to 3.5 Kg each (mean age was 16 weeks) were used in the study. The animals were randomly divided into 3 equal groups.
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Original article
Influence of low-level laser (LLL) on interleukin 6 (IL-6) levels in gingival crevicular fluid (GCF) during orthodontic tooth movement of periodontally affected rabbits
Figure 1 Flow chart of the experimental design
Production of experimental periodontal diseases Rabbits were anesthetized by a single intraperitoneal injection mixture of ketamine and xylazine (1:4). After the anesthesia, a 30 black silk ligature was applied around the maxillary incisors in a sub-marginal position. The ligature knot was placed on the buccal side of the teeth. Afterwards, a topical application of
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Porphyromonas gingivalis three times/week for 6-weeks to develop experimental periodontal diseases [18]. Porphyromonas gingivalis was prepared as described by Jain et al. Periodontal diseases was confirmed by the grade of inflammation in the gingival and alveolar bone loss quantification at the experimental sites [19].
Orthodontic tooth movement Two holes were drilled in the labial surface of the two central incisors of each rabbit with low speed round bur number 10 under irrigation with normal saline. A 0.014 stainless steel spring was adjusted to produce 60 gm. force according to Kilic et al. [20]. The forces produced by the spring were measured with force gauge (Correx Co, Bern, Switzerland). Each arm of the spring was inserted in a hole and the ends were bent distally. Any excess wire was trimmed to avoid any harm for the animal (figure 2).
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In group 1 (control group), healthy animals received orthodontic appliances. In group 2, periodontally affected animals with orthodontic appliance. Group 3 represented the periodontally affected animals with orthodontic appliance and LLL application. The weight of each animal was recorded at the beginning and checked throughout the experiment, there was no significant weight loss. All rabbits were left for one week before starting the experiment to accommodate to the new environments. Dietary pellets and water were given to the rabbits at standard times daily.
Original article
E.A. Nassar, A.M. Fouda, K.S. Hassan
Statistical analysis Data analysis was performed using SPSS 20.0 (IBM product Chicago, USA). The results were presented in terms of mean and standard deviation. Repeated measures-ANOVA was applied to compare intergroup and intragroup comparison of IL-6 levels among the three groups on various time intervals. Post-Hoc least significance test was applied for pairwise comparison of the studied groups. Unpaired t-test was applied to compare the mean PPD between baseline and after 14 days observations. Analysis of variance (ANOVA) compared the mean PPD and Posthoc Tukey test was performed to compare the difference of means between the groups. P-value 0.05 was considered a statistically significant result.
Figure 2 Collection of the GCF sample
The LLL application Laser CAT 500 with a contentious wavelength 904 nm was preadjusted to deliver a laser beam with an output power of 30 mW, and a frequency of 10000 Hz for 3 minutes according to the manufacturer's recommendation (MedSolution, Germany). The LLL was applied once a day for two weeks starting after the activation of the orthodontic appliance.
Probing pocket depth measurements PPD measurements were obtained from 4 sites at the upper incisors (mesial, mid-buccal, distal and mid-lingual). PPD were measured with an electronic, pressure-calibrated probe (PA-ON probe [Orange Dental, Biberach, Germany]. The tip of the probe was flexible and fitted with a ball 0.5 mm in diameter. The tip yields at a pressure of 20 Ncm according to the manufacturer guidelines. PPD measurements were shown on the graphic display of the probe and the average PPD measurements for each group at the base line and after 14 days were recorded.
Results Means and standard deviations of IL-6 levels in GCF of the investigated animals at different days were plotted in (figure 3, table I). In G1 and G2, the concentration of IL-6 increased gradually from the base line and reached its highest level on day 8 (20.2 pg/ml in G1, and 39.7 pg/ml in G2). On day 10 however, the Il-6 concentration started to decrease with the lowest level on day 14 (13.1 pg/ml in G1, and 29.1 pg/ ml in G2). On the other hand, in G3 the highest level was recorded in the second day (24.3 pg/ml) and it started to decrease toward the experiment end. A statistically significant difference in IL-6 at the base line among the 3 groups was found. Subsequently on the day 2, there was a significant difference in the IL-6 between G1 vs. G2 and G1 vs. G3. In contrast, no statistically significant difference was observed between G2 and G3. Additionally, at the 4th and 6th days a significant difference in IL-6 levels was recorded among the 3 groups (G1 vs. G2, G2 vs. G3 and G1 vs. G3). Afterward from the 8th day, there was a significant difference between G1 vs. G2 and G2 vs. G3 while there was no significant difference between G1 and G3. ANOVA showed a significant difference between PPD of the
IL-6 analysis
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Samples of GCF were taken from the upper incisors (figure 2) as described by Rudin et al. [21]. Paper strips (Periopaper, Pro Flow, Amityville, NY) were placed into the sulcus after the teeth were dried with the air. GCF volume was determined after by using Periotron 8000 (Ora Flow, Plainview, NY). The collected paper strips were stored in sterile tubes containing 200 mL of sterile sodium chloride solution at -20 8C until experimentation. The IL6 levels were assessed at the base line, 2nd, 4th, 6th, 8th, 10th, 12th and 14th days. IL-6 levels were measured using the immunoassay system (Immulite, Diagnostic Products, Los Angeles, Calif).
Figure 3 Comparing levels of interlukin-6 at different time points in the three groups
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TABLE I Comparison of mean, S.D and results of repeated ANOVA of IL-6 levels in the three groups at 8 various time intervals. Days T0 T2 T4 T6 T8 T10 T12 T14
Group-1 5.14 0.35
Group-2
Group-3
6.95 0.30
5.05 0.36
1,2
24.81 0.72
24.38 0.49
12.20 0.38
1,2,3
27.98 0.65
22.99 0.66
17.98 0.15
1,2,3
35.93 0.72
21.25 0.69
20.26 0.92
1,3
39.70 0.94
21.00 0.24
18.63 1.18
1,3
34.26 0.58
19.44 1.12
16.08 0.50
1,3
32.08 0.57
17.70 1.23
13.18 0.51
1,3
29.18 0.78
15.09 0.56
7.14 0.36
Original article
Influence of low-level laser (LLL) on interleukin 6 (IL-6) levels in gingival crevicular fluid (GCF) during orthodontic tooth movement of periodontally affected rabbits
T: Time T0: base line, T2: 2nd day, T4: 4th, T6: 6th, T8: 8th, T10: 10 th, T12: 12th, T14: 14th day. 1 Statistically significant difference group-1 vs. group-2 at P 0.05. 2 Statistically significant difference group-1 vs. group-3 at P 0.05. 3 Statistically significant difference group-2 vs. group-3 at P 0.05.
Discussion Orthodontic tooth movement can be damaging to the periodontal tissues if the orthodontic forces applied on periodontally affected teeth. Therefore search for a new method to enhance the periodontal regeneration during orthodontic tooth movement is mandatory. The current study was designed to evaluate the impact of LLL application on the IL-6 levels in gingival
Figure 4 PPD at the baseline and after 14 days in the experimental groups
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crevicular fluid and the PPD during orthodontic tooth movement in animal models having periodontally affected teeth. The LLL effect on orthodontic tooth movement and assessment of Il-6 levels in healthy animals were not included in our study design since they were evaluated earlier [22,23]. Animal experiment is an important tool to evaluate periodontal tissue remodelling resulted from orthodontic force and rabbits were chosen because they were recognized as a good small animal model to study the periodontal diseases [24]. In order to get a predictable and reproducible periodontitis, Porphyromonas gingivalis was topically applied one time each successive day for 6 weeks around teeth that were ligated before. Ligature wire alone was not capable of producing tissue damage in rabbits [16]. In this study, IL-6 expression was examined in the GCF in order to investigate the relation between IL-6 levels, the pathogenesis of the periodontal diseases and LLL therapy. It is generally accepted that the GCF reflects the immune and inflammatory reactions obtained from host–parasite interactions [25] and bio-mechanical stress [26]. Therefore, GCF constituents, including microbial products and inflammatory mediators, can be useful for the determination of the periodontal condition during periodontal inflammation [25] or orthodontic tooth movement [27]. Our findings showed a gradual increase in the IL-6 expression in the GCF after orthodontic force application. These findings were in accord with Uematsu et al. [11], who reported an increase in the concentration of IL-1ß, IL-6, tumour necrosis factor (TNF) and other inflammatory mediators after application of orthodontic forces in humans. In the current study, IL-6 levels were gradually increased and reached a maximum on day 8 in G1 and G3. A significantly higher concentration of IL-6 was noticed in G3
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three tested groups at base line as well as on the 14th day. Tukey test showed a non-significant difference between G2 and G3 at the base line. In contrast there was a significant difference between both groups and G1. Meanwhile, after 14 days there was no significant difference between G1 and G3 but there was a significant difference between the aforementioned groups and G2 (figure 4 and table II).
Original article
E.A. Nassar, A.M. Fouda, K.S. Hassan
TABLE II Periodontal depth measurements at base line and after 14 days in the three studied groups. Column1
PPD
Column 2
Column 3
Groups
Baseline
14 days
P value
Group-1
1.30 0.13
1.40 0.12
Group-2
1.60 0.11
Group-3
1.70 0.20
P value (1 vs. 2 vs. 3) P value 1 2
1.50 0.09
< 0.001
< 0.001
(2 vs. 3) P = 0.399
(1 vs. 3) P = 0.279
0.214 0.012 0.059
Significance at 5% level following the comparison into horizontal direction. Significance at 5% level following the comparison into vertical direction.
compared to G1. The periodontal condition augmented the expression of IL-6 in addition to the applied orthodontic force and then IL-6 expression declined in both groups. These findings are in accordance with other studies that reported a decrease in the levels of inflammatory cytokines on the 7th and 10th days following force activation [28,29]. On the other hand, IL-6 levels were more significantly increased in group 2 compared to G2 and G3. In group 3, IL-6 reached its highest level in the 2nd day and then decreased after LLL application. IL-6 is considered a major mediator of the host response for the tissue injury and infection. It plays a major role in B-cell differentiation in the immune system. It also has multiple biological activities, such as the enhancement of cell proliferation and bone resorption acceleration [30,31]. Therefore, IL-6 is involved in the pathogenesis of various inflammatory diseases and among them is the periodontal disease. Such findings indicated that the LLL could inhibit or reduce IL-6 production. Similarly, a significant inhibition of prostaglandin E2 and IL-1b production after application of LLL were reported earlier [32]. The current study showed a significant improvement in PPD measurements in G3 after application of the LLL. Improvement of the attachment level indicated periodontal tissue regeneration during orthodontic tooth movement. These finding are in agreement with Alazzawi et al. [33] and Gunji et al. [34], who concluded that laser irradiation can enhance the velocity of tooth movement and improve the quality of bone remodelling. They inferred that, laser irradiation increased NF-KB ligands (RANKL) gene expression and accelerate osteoclast differentiation facilitating bone resorption on the pressure side whereas on the tension side, irradiation led to enhance alkaline phosphatase (ALP) and proliferating cell nuclear antigen (PCNA) release that induced bone formation. According to the report of Kunimatsu et al. [35], laser irradiation increased cell division and migration of mouse calvarial cells (MT3T3-E1) through mitogen-activated protein kinase (MARK/ERK) signalling that enhance proliferation
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1.80 0.16
1,2
and migration of osteoblasts to improve regeneration of bone tissue. LLL was effective when used in healing areas of bone fracture, but on the other hand it has been unsuccessful when applied to normal tissue [36]. In addition, LLL therapy resulted in a better quality of bone, increased the production of differentiated osteoclasts, as well as accelerated tooth movement [37]. Furthermore LLL can enhance cellular production and differentiation of osteoblast lineage nodule-forming cells, especially in devoted precursors, resulting in a raise in the number of differentiated osteoblastic cells [38]. Gomes et al. [39], reported that laser irradiation led to continuous reorganization of the soft periodontal tissue, leading to the maintenance and integrity of the periodontal microstructure under the orthodontic force especially in uncontrolled diabetic rats. In G2 the impaired condition of periodontal tissue plus the orthodontic forces aggravated the inflammatory process and induced further destruction of periodontal tissue. Collagen degradation and deposition occurs normally in the absence of inflammation during normal physiological PDL and bone remodelling [40].
Conclusions and recommendations The application of low-level laser reduced PPD and decreased the inflammatory process through suppression of IL-6 levels and promoted healing during orthodontic tooth movement in periodontally affected animals. Future histopathological evaluation of the PDL to assess the changes after LLL therapy, additional examination of other clinical parameters such as gingival index and probing attachment level should be done. Further, comparative studies are recommended to compare the effects of LLL therapy on orthodontic tooth movement among treated and/or untreated periodontally compromised teeth.
Disclosure of interest The authors declare that they have no competing interest.
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Ethical approval This study was approved from Ethical approval committee at AlAzhar University, Assiut branch, Egypt.
Acknowledgement: We would like to thank Dr. Albannan for his assistance in anesthetizing the rabbits, Dr. Alsaied for his laboratory assistance in P. gingivalis production. Authors also thankful to Prof. Khalid Almas for critical review of the manuscript and Mr. Farooqi for his help.in data tabulation.
Original article
Influence of low-level laser (LLL) on interleukin 6 (IL-6) levels in gingival crevicular fluid (GCF) during orthodontic tooth movement of periodontally affected rabbits
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Influence of low-level laser (LLL) on interleukin 6 (IL-6) levels in gingival crevicular fluid (GCF) during orthodontic tooth movement of periodontally affected rabbits
Original article
Websites: www.em-consulte.com www.sciencedirect.com
Essam Abdelalim Nassar 1,2, Ahmed Maher Fouda 2, Khalid Sadiaq Hassan 3
Available online: 30 April 2019
1. Imam Abdurahman Bin Faisal University, Preventive Dental Science Department, Saudi Arabia 2. Mansoura University, Orthodontic Department, Faculty of Dentistry, Egypt 3. Al-Azhar University, Assiut branch, Faculty of Dentistry, Egypt
Correspondence: Essam Abdelalim Nassar, Preventive Dental Sciences Department, College of Dentistry, Imam Abdulrahman Bin Faisal University, 1982 Dammam, Saudi Arabia. [email protected]
Summary Aim > To evaluate the effects of LLL on IL-6 levels in the GCF and the Probing Pocket Depth measurements (PPD) during orthodontic tooth movement in periodontally affected rabbits. Methods > Twenty-four rabbits were divided into 3 groups: Group 1(G1), healthy rabbits with orthodontic movement, Group 2(G2) periodontally affected rabbits and orthodontic movement, Group 3(G3) periodontally affected rabbits with orthodontic movement and LLL therapy. A 0.014 stainless steel spring was inserted in the upper central incisors to produce 60gm force. Laser CAT 500 was applied for 3 min/day for 2 weeks. PPD measurements were obtained at base line and after 14 days with electronic periodontal probe. Results > IL-6 levels increased gradually after application of orthodontic force, afterwards the 8th day, a significant difference in the Il-6 levels between G1 vs. G2 and G2 vs. G3 was observed. PPD measurements showed significant difference between the three groups at base line and after 14 days. Clinical Significance > LLL application can enhance periodontal ligament regeneration and decrease the periodontal tissue destruction through suppression of IL-6 levels.
tome 17 > n82 > June 2019 https://doi.org/10.1016/j.ortho.2019.03.004 © 2019 CEO. Published by Elsevier Masson SAS. All rights reserved.
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Keywords Tooth movement Cytokines Laser
Original article
E.A. Nassar, A.M. Fouda, K.S. Hassan
Mots clés Mouvement dentaire Cytokines Laser
Résumé Influence du laser de faible intensité (LLL) sur les taux d'interleukine 6 (IL-6) dans le fluide gingival sulculaire (GCF) pendant le mouvement orthodontique chez les lapins atteints de maladie parodontale Objectif > Évaluer les effets de la LLL sur les taux d'IL-6 dans le GCF et les mesures de la profondeur des poches au sondage (PPD) pendant le mouvement orthodontique dentaire chez les lapins atteints de maladie parodontale. Matériel et méthodes > Vingt-quatre lapins ont été divisés en 3 groupes : Groupe 1(G1) : lapins en bonne santé sous traitement orthodontique ; groupe 2(G2) : lapins avec atteinte parodontale sous traitement orthodontique ; groupe 3(G3) lapins avec atteinte parodontale, traitement orthodontique et thérapie LLL. Un ressort en acier inoxydable 0,014 a été inséré dans les incisives centrales supérieures pour produire une force de 60 g. Le LaserCat500 a été appliqué pendant 3 min/jour pendant 2 semaines. LaserCat500 Les mesures PPD ont été obtenues au départ et après 14 jours avec une sonde parodontale électronique. Résultats > Les taux d'IL-6 ont augmenté progressivement après l'application de la force orthodontique, après le 8e jour, une différence significative dans les taux d'IL-6 entre G1 et G2 et G2 et G3 a été observée. Les mesures de PPD ont montré une différence significative entre les trois groupes au départ et après 14 jours. Signification clinique > L'application de LLL peut améliorer la régénération du ligament parodontal et diminuer la destruction du tissu parodontal par la suppression des niveaux d'IL-6.
Introduction
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Orthodontic tooth movement is achieved by means of alveolar bone and periodontal ligament remodeling as a result to the applied forces [1]. Force application changes the equilibrium between collagen synthesis and degeneration [2] through a group of proteolytic enzymes called metalloproteinases (MMPs) such as MMP-1, MMP-8, and MMP-13, which control periodontal tissue remodelling [3,4]. The MMP-1 levels in the peridonuim of rats and humans were increased after application of orthodontic forces [5,6]. Cytokines such as Interleukins, prostaglandin and tumour necrosis factor-alpha (TNF-ɑ) were considered as the regulators of MMP-1 expression in humans [7,8]. Cytokines have an important role in intercellular signalling and have been involved in the pathology of periodontal diseases, bone resorption, and bone reaction to orthodontic treatment. The role of inflammatory mediators such as interleukins, prostaglandins and glycosaminoglycan has been investigated during orthodontic tooth movement [9,10]. Changes in the amount and concentration of Interleukin -6 (IL-6) in the periodontal tissues reflect the status of periodontal tissue inflammation. Higher levels of IL-6 in the crevicular fluid are shown after application of orthodontic forces [11,12]. Periodontal diseases are characterized by bone loss and decreased tissue support around the teeth due to inflammation of the periodontal supporting structures. Orthodontic appliances are considered as modifying factors for periodontal supporting tissues [13]. Artun and Urbye suggested that the periodontal
ligament might be destroyed during tooth tipping or intrusion in periodontally affected teeth [14]. LLL application was associated with healing of the damaged bone tissue following tooth extraction proved by radiological analysis [15]. In addition, LLL irradiation has been shown to increase the number of feasible osteocytes in the irradiated areas significantly by encouraging the production of bone matrix and creating an extremely reactive and vital bone tissue. Osteocytes have a principal role in coordinating osteoblast and osteoclast recruitment and activity [16]. Moreover, Nissan et al. reported that the LLL enhanced the bone-healing procedure in artificially formed osseous cavities through triggering calcium transfer for the period of new bone formation [17]. The aim of this study was to assess the effects of LLL on IL-6 levels in the gingival crevicular fluid and the probing pocket depth throughout orthodontic tooth movement in periodontally affected teeth in rabbit.
Materials and methods Sample preparation Sample size was calculated with EpiCalc 2000 version 1.02 (Brixton Books, Brixton, UK) software and indicated 8 rabbits for each group to be reliable at 80% power and 95% confidence interval. A flow chart for the experimental design is shown in (figure 1). A total of 24 New Zealand male rabbits, 3.0 to 3.5 Kg each (mean age was 16 weeks) were used in the study. The animals were randomly divided into 3 equal groups.
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Original article
Influence of low-level laser (LLL) on interleukin 6 (IL-6) levels in gingival crevicular fluid (GCF) during orthodontic tooth movement of periodontally affected rabbits
Figure 1 Flow chart of the experimental design
Production of experimental periodontal diseases Rabbits were anesthetized by a single intraperitoneal injection mixture of ketamine and xylazine (1:4). After the anesthesia, a 30 black silk ligature was applied around the maxillary incisors in a sub-marginal position. The ligature knot was placed on the buccal side of the teeth. Afterwards, a topical application of
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Porphyromonas gingivalis three times/week for 6-weeks to develop experimental periodontal diseases [18]. Porphyromonas gingivalis was prepared as described by Jain et al. Periodontal diseases was confirmed by the grade of inflammation in the gingival and alveolar bone loss quantification at the experimental sites [19].
Orthodontic tooth movement Two holes were drilled in the labial surface of the two central incisors of each rabbit with low speed round bur number 10 under irrigation with normal saline. A 0.014 stainless steel spring was adjusted to produce 60 gm. force according to Kilic et al. [20]. The forces produced by the spring were measured with force gauge (Correx Co, Bern, Switzerland). Each arm of the spring was inserted in a hole and the ends were bent distally. Any excess wire was trimmed to avoid any harm for the animal (figure 2).
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In group 1 (control group), healthy animals received orthodontic appliances. In group 2, periodontally affected animals with orthodontic appliance. Group 3 represented the periodontally affected animals with orthodontic appliance and LLL application. The weight of each animal was recorded at the beginning and checked throughout the experiment, there was no significant weight loss. All rabbits were left for one week before starting the experiment to accommodate to the new environments. Dietary pellets and water were given to the rabbits at standard times daily.
Original article
E.A. Nassar, A.M. Fouda, K.S. Hassan
Statistical analysis Data analysis was performed using SPSS 20.0 (IBM product Chicago, USA). The results were presented in terms of mean and standard deviation. Repeated measures-ANOVA was applied to compare intergroup and intragroup comparison of IL-6 levels among the three groups on various time intervals. Post-Hoc least significance test was applied for pairwise comparison of the studied groups. Unpaired t-test was applied to compare the mean PPD between baseline and after 14 days observations. Analysis of variance (ANOVA) compared the mean PPD and Posthoc Tukey test was performed to compare the difference of means between the groups. P-value 0.05 was considered a statistically significant result.
Figure 2 Collection of the GCF sample
The LLL application Laser CAT 500 with a contentious wavelength 904 nm was preadjusted to deliver a laser beam with an output power of 30 mW, and a frequency of 10000 Hz for 3 minutes according to the manufacturer's recommendation (MedSolution, Germany). The LLL was applied once a day for two weeks starting after the activation of the orthodontic appliance.
Probing pocket depth measurements PPD measurements were obtained from 4 sites at the upper incisors (mesial, mid-buccal, distal and mid-lingual). PPD were measured with an electronic, pressure-calibrated probe (PA-ON probe [Orange Dental, Biberach, Germany]. The tip of the probe was flexible and fitted with a ball 0.5 mm in diameter. The tip yields at a pressure of 20 Ncm according to the manufacturer guidelines. PPD measurements were shown on the graphic display of the probe and the average PPD measurements for each group at the base line and after 14 days were recorded.
Results Means and standard deviations of IL-6 levels in GCF of the investigated animals at different days were plotted in (figure 3, table I). In G1 and G2, the concentration of IL-6 increased gradually from the base line and reached its highest level on day 8 (20.2 pg/ml in G1, and 39.7 pg/ml in G2). On day 10 however, the Il-6 concentration started to decrease with the lowest level on day 14 (13.1 pg/ml in G1, and 29.1 pg/ ml in G2). On the other hand, in G3 the highest level was recorded in the second day (24.3 pg/ml) and it started to decrease toward the experiment end. A statistically significant difference in IL-6 at the base line among the 3 groups was found. Subsequently on the day 2, there was a significant difference in the IL-6 between G1 vs. G2 and G1 vs. G3. In contrast, no statistically significant difference was observed between G2 and G3. Additionally, at the 4th and 6th days a significant difference in IL-6 levels was recorded among the 3 groups (G1 vs. G2, G2 vs. G3 and G1 vs. G3). Afterward from the 8th day, there was a significant difference between G1 vs. G2 and G2 vs. G3 while there was no significant difference between G1 and G3. ANOVA showed a significant difference between PPD of the
IL-6 analysis
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Samples of GCF were taken from the upper incisors (figure 2) as described by Rudin et al. [21]. Paper strips (Periopaper, Pro Flow, Amityville, NY) were placed into the sulcus after the teeth were dried with the air. GCF volume was determined after by using Periotron 8000 (Ora Flow, Plainview, NY). The collected paper strips were stored in sterile tubes containing 200 mL of sterile sodium chloride solution at -20 8C until experimentation. The IL6 levels were assessed at the base line, 2nd, 4th, 6th, 8th, 10th, 12th and 14th days. IL-6 levels were measured using the immunoassay system (Immulite, Diagnostic Products, Los Angeles, Calif).
Figure 3 Comparing levels of interlukin-6 at different time points in the three groups
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TABLE I Comparison of mean, S.D and results of repeated ANOVA of IL-6 levels in the three groups at 8 various time intervals. Days T0 T2 T4 T6 T8 T10 T12 T14
Group-1 5.14 0.35
Group-2
Group-3
6.95 0.30
5.05 0.36
1,2
24.81 0.72
24.38 0.49
12.20 0.38
1,2,3
27.98 0.65
22.99 0.66
17.98 0.15
1,2,3
35.93 0.72
21.25 0.69
20.26 0.92
1,3
39.70 0.94
21.00 0.24
18.63 1.18
1,3
34.26 0.58
19.44 1.12
16.08 0.50
1,3
32.08 0.57
17.70 1.23
13.18 0.51
1,3
29.18 0.78
15.09 0.56
7.14 0.36
Original article
Influence of low-level laser (LLL) on interleukin 6 (IL-6) levels in gingival crevicular fluid (GCF) during orthodontic tooth movement of periodontally affected rabbits
T: Time T0: base line, T2: 2nd day, T4: 4th, T6: 6th, T8: 8th, T10: 10 th, T12: 12th, T14: 14th day. 1 Statistically significant difference group-1 vs. group-2 at P 0.05. 2 Statistically significant difference group-1 vs. group-3 at P 0.05. 3 Statistically significant difference group-2 vs. group-3 at P 0.05.
Discussion Orthodontic tooth movement can be damaging to the periodontal tissues if the orthodontic forces applied on periodontally affected teeth. Therefore search for a new method to enhance the periodontal regeneration during orthodontic tooth movement is mandatory. The current study was designed to evaluate the impact of LLL application on the IL-6 levels in gingival
Figure 4 PPD at the baseline and after 14 days in the experimental groups
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crevicular fluid and the PPD during orthodontic tooth movement in animal models having periodontally affected teeth. The LLL effect on orthodontic tooth movement and assessment of Il-6 levels in healthy animals were not included in our study design since they were evaluated earlier [22,23]. Animal experiment is an important tool to evaluate periodontal tissue remodelling resulted from orthodontic force and rabbits were chosen because they were recognized as a good small animal model to study the periodontal diseases [24]. In order to get a predictable and reproducible periodontitis, Porphyromonas gingivalis was topically applied one time each successive day for 6 weeks around teeth that were ligated before. Ligature wire alone was not capable of producing tissue damage in rabbits [16]. In this study, IL-6 expression was examined in the GCF in order to investigate the relation between IL-6 levels, the pathogenesis of the periodontal diseases and LLL therapy. It is generally accepted that the GCF reflects the immune and inflammatory reactions obtained from host–parasite interactions [25] and bio-mechanical stress [26]. Therefore, GCF constituents, including microbial products and inflammatory mediators, can be useful for the determination of the periodontal condition during periodontal inflammation [25] or orthodontic tooth movement [27]. Our findings showed a gradual increase in the IL-6 expression in the GCF after orthodontic force application. These findings were in accord with Uematsu et al. [11], who reported an increase in the concentration of IL-1ß, IL-6, tumour necrosis factor (TNF) and other inflammatory mediators after application of orthodontic forces in humans. In the current study, IL-6 levels were gradually increased and reached a maximum on day 8 in G1 and G3. A significantly higher concentration of IL-6 was noticed in G3
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three tested groups at base line as well as on the 14th day. Tukey test showed a non-significant difference between G2 and G3 at the base line. In contrast there was a significant difference between both groups and G1. Meanwhile, after 14 days there was no significant difference between G1 and G3 but there was a significant difference between the aforementioned groups and G2 (figure 4 and table II).
Original article
E.A. Nassar, A.M. Fouda, K.S. Hassan
TABLE II Periodontal depth measurements at base line and after 14 days in the three studied groups. Column1
PPD
Column 2
Column 3
Groups
Baseline
14 days
P value
Group-1
1.30 0.13
1.40 0.12
Group-2
1.60 0.11
Group-3
1.70 0.20
P value (1 vs. 2 vs. 3) P value 1 2
1.50 0.09
< 0.001
< 0.001
(2 vs. 3) P = 0.399
(1 vs. 3) P = 0.279
0.214 0.012 0.059
Significance at 5% level following the comparison into horizontal direction. Significance at 5% level following the comparison into vertical direction.
compared to G1. The periodontal condition augmented the expression of IL-6 in addition to the applied orthodontic force and then IL-6 expression declined in both groups. These findings are in accordance with other studies that reported a decrease in the levels of inflammatory cytokines on the 7th and 10th days following force activation [28,29]. On the other hand, IL-6 levels were more significantly increased in group 2 compared to G2 and G3. In group 3, IL-6 reached its highest level in the 2nd day and then decreased after LLL application. IL-6 is considered a major mediator of the host response for the tissue injury and infection. It plays a major role in B-cell differentiation in the immune system. It also has multiple biological activities, such as the enhancement of cell proliferation and bone resorption acceleration [30,31]. Therefore, IL-6 is involved in the pathogenesis of various inflammatory diseases and among them is the periodontal disease. Such findings indicated that the LLL could inhibit or reduce IL-6 production. Similarly, a significant inhibition of prostaglandin E2 and IL-1b production after application of LLL were reported earlier [32]. The current study showed a significant improvement in PPD measurements in G3 after application of the LLL. Improvement of the attachment level indicated periodontal tissue regeneration during orthodontic tooth movement. These finding are in agreement with Alazzawi et al. [33] and Gunji et al. [34], who concluded that laser irradiation can enhance the velocity of tooth movement and improve the quality of bone remodelling. They inferred that, laser irradiation increased NF-KB ligands (RANKL) gene expression and accelerate osteoclast differentiation facilitating bone resorption on the pressure side whereas on the tension side, irradiation led to enhance alkaline phosphatase (ALP) and proliferating cell nuclear antigen (PCNA) release that induced bone formation. According to the report of Kunimatsu et al. [35], laser irradiation increased cell division and migration of mouse calvarial cells (MT3T3-E1) through mitogen-activated protein kinase (MARK/ERK) signalling that enhance proliferation
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1.80 0.16
1,2
and migration of osteoblasts to improve regeneration of bone tissue. LLL was effective when used in healing areas of bone fracture, but on the other hand it has been unsuccessful when applied to normal tissue [36]. In addition, LLL therapy resulted in a better quality of bone, increased the production of differentiated osteoclasts, as well as accelerated tooth movement [37]. Furthermore LLL can enhance cellular production and differentiation of osteoblast lineage nodule-forming cells, especially in devoted precursors, resulting in a raise in the number of differentiated osteoblastic cells [38]. Gomes et al. [39], reported that laser irradiation led to continuous reorganization of the soft periodontal tissue, leading to the maintenance and integrity of the periodontal microstructure under the orthodontic force especially in uncontrolled diabetic rats. In G2 the impaired condition of periodontal tissue plus the orthodontic forces aggravated the inflammatory process and induced further destruction of periodontal tissue. Collagen degradation and deposition occurs normally in the absence of inflammation during normal physiological PDL and bone remodelling [40].
Conclusions and recommendations The application of low-level laser reduced PPD and decreased the inflammatory process through suppression of IL-6 levels and promoted healing during orthodontic tooth movement in periodontally affected animals. Future histopathological evaluation of the PDL to assess the changes after LLL therapy, additional examination of other clinical parameters such as gingival index and probing attachment level should be done. Further, comparative studies are recommended to compare the effects of LLL therapy on orthodontic tooth movement among treated and/or untreated periodontally compromised teeth.
Disclosure of interest The authors declare that they have no competing interest.
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Ethical approval This study was approved from Ethical approval committee at AlAzhar University, Assiut branch, Egypt.
Acknowledgement: We would like to thank Dr. Albannan for his assistance in anesthetizing the rabbits, Dr. Alsaied for his laboratory assistance in P. gingivalis production. Authors also thankful to Prof. Khalid Almas for critical review of the manuscript and Mr. Farooqi for his help.in data tabulation.
Original article
Influence of low-level laser (LLL) on interleukin 6 (IL-6) levels in gingival crevicular fluid (GCF) during orthodontic tooth movement of periodontally affected rabbits
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