Short-Term Neurotoxic Effects of a Bioceramic Root Canal Sealer and the Modulatory Role of Stemregen®: A Rat Model Study

Short-Term Neurotoxic Effects of a Bioceramic Root Canal Sealer and the Modulatory Role of Stemregen®: A Rat Model Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Short-Term Neurotoxic Effects of a Bioceramic Root Canal Sealer and the Modulatory Role of Stemregen ® : A Rat Model Study Haydar İrfan YÜCEL, Mevlüt Sinan OCAK, Ebru GÖKDERE, Serkan DUNDAR, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7004747/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Extrusion of root canal sealers into neurovascular tissues can result in rare but serious neurological complications, including paresthesia and neuropathic pain. This study aimed to evaluate the neurotoxic effects of AH Plus® Bioceramic Sealer when extruded near peripheral nerve tissue and to assess the potential protective role of Stemregen®, a stem cell–mobilizing nutritional supplement. Methods Forty-eight male Sprague-Dawley rats were randomly assigned to four groups (n = 12): Control, Supplement only, Bioceramic only, and Bioceramic + Supplement. Sterile polyethylene tubes containing AH Plus® Bioceramic Sealer were applied in contact with the sciatic nerve in the relevant groups. Stemregen® was administered orally at 300 mg/kg/day for 15 days. At the end of the experiment, nerve tissues were harvested and examined histologically. Results Severe axonal degeneration, inflammation, and fibrosis were observed in the Bioceramic group compared to controls (p < 0.05). The Bioceramic + Supplement group showed reduced histological damage scores, though the differences were not statistically significant. Conclusions These findings suggest that the bioceramic sealer may induce peripheral neurotoxicity under direct exposure, while Stemregen® may offer limited histological improvement. Further long-term and functional studies are required to evaluate the clinical relevance of these results and to assess the therapeutic potential of nutritional stem cell modulators in endodontic practice. Dietary Supplements Nerve damage Premixed bioceramic Sealer extrusion Stem cells Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 INTRODUCTION Although most endodontic sealers are successfully used in routine practice, apical extrusion of root canal sealers into periapical anatomical structures—particularly the mandibular canal and mental foramen—may result in neurological complications such as paresthesia, hypoesthesia, or persistent pain [ 1 – 5 ]. These adverse outcomes are more frequently observed in the posterior mandibular region, where the porous trabecular bone permits easier diffusion of endodontic materials into surrounding neurovascular tissues [ 6 ]. The clinical severity depends on the duration of nerve contact, the volume extruded, and the inherent cytotoxicity of the material [ 7 – 9 ]. Management strategies vary according to the clinical picture and may include pharmacological intervention or surgical removal in progressive cases [ 10 – 13 ]. Bioceramic-based sealers have been increasingly adopted in endodontic therapy due to their favorable biological and physicochemical profiles. Formulated mainly with tricalcium silicate, these sealers offer excellent sealing properties, antimicrobial alkalinity, and high biocompatibility [ 14 , 15 ]. AH Plus® Bioceramic Sealer (Dentsply Sirona, Ballaigues, Switzerland) is a recently introduced injectable sealer composed of tricalcium silicate and zirconium dioxide, with a setting time of approximately 2–4 hours [ 16 – 18 ]. In vitro studies have demonstrated its positive bioactivity and cell viability [ 16 , 17 ]; however, in vivo data on its neurotoxicity are currently lacking. Although bioceramic sealers are generally biocompatible, their high alkalinity and formulation additives—such as dimethyl sulfoxide and lithium carbonate—warrant further investigation regarding their effects on nerve tissue in case of extrusion [ 19 – 25 ]. Recent regenerative strategies have focused on stem cell–based modulation for peripheral nerve repair. Nutritional interventions that mobilize endogenous stem cells may support neural regeneration by modulating inflammation, promoting trophic factor release, and enhancing repair processes [ 26 – 28 ]. Stemregen® (Biomics™, Incline Village, NV, USA) is a dietary supplement formulated to stimulate stem cell mobilization. Its active components—such as sea buckthorn, Notoginseng, Aloe vera, and fucoidan-containing bladderwrack—exhibit antioxidant and anti-inflammatory properties, as reported in previous studies [ 29 – 37 ], and its components are presented in Table 1 . However, its neuroprotective potential in peripheral nerve injury has not yet been explored in vivo. Table 1 Active ingredients contained in each capsule of Stemregen® Active Ingredient Amount Sea Buckthorn Extract (30% Proanthocyanidins) 250 mg Blue-Green Algae (Aphanizomenon flos-aquae) Extract 150 mg Bladderwrack (Fucus vesiculosus) Extract (20% Phlorotannins) 125 mg Notoginseng (Panax notoginseng) Extract (10% Notoginsenosides) 62,5 mg Aloe Vera Gel Powder (Stemaloe®) 50 mg 1→3 Beta-Glucan (85%) 50 mg Colostrum Powder (Transfer Factor) 25 mg Black Pepper (Piper nigrum) Extract 2,5 mg This study addresses a critical gap in the literature by evaluating the neurotoxic effects of AH Plus® Bioceramic Sealer in a rat sciatic nerve model and assessing whether systemic administration of Stemregen® can mitigate such effects. Therefore, this study aimed to evaluate the neurotoxic effects of AH Plus® Bioceramic Sealer on peripheral nerve tissue and to assess whether nutritional supplementation with Stemregen® could reduce inflammation and degeneration associated with such exposure. We hypothesized that AH Plus ® Bioceramic Sealer would induce neurotoxic effects in the rat sciatic nerve, and that Stemregen ® supplementation would reduce these adverse effects. MATERIAL AND METHODS This study was prepared in accordance with the PRILE 2021 guidelines for the reporting of animal experiments in the field of Endodontics; the flow diagram summarizing the experimental process is presented in Fig. 1 . The study was conducted with the permissions numbered 2023/16 − 04 dated 20.09.2023 from the Fırat University Local Ethics Committee for Animal Experiments and was carried out in accordance with the ARRIVE guideline principles regarding the protection of laboratory animals. All rats used in the experiment were provided by the Firat University Experimental Research Center (FUERC), and the experimental stages were carried out at the same center and at the Firat University Faculty of Medicine Pathology Laboratory. Determination of Sample Size and Formation of Experimental Groups Using the G*Power 3.1 (Version 3.1.9.2) program, the sample size was determined to be 12 rats per group and a total of 48 rats (n = 12, 4 groups) with an α error value of 0.05, a 95% confidence interval, 0.5 effect size, and 80% power (1-β = 0.80). Male Sprague-Dawley rats aged between 24–36 weeks and weighing approximately 300–350 grams, provided by FUERC, were used. Rats were preferred in the study due to their genetic similarity to humans and their common use in experimental studies. Additionally, male rats were used to minimize potential confounding effects of hormonal fluctuations associated with female reproductive cycles. All subjects were kept during the experiment in polyethylene cages with unrestricted access to food and water, in rooms with special ventilation systems at 70% humidity and 22–24°C temperature. The rats were randomly divided into four groups as summarized in Table 2 . Table 2 Experimental Groups and Interventions Group Number of Animals (n) Intervention Control (C) 12 Empty polyethylene tube placed on sciatic nerve Supplement (NS) 12 Empty polyethylene tube + Stemregen® (300 mg/kg/day, oral gavage) Bioceramic (BC) 12 Polyethylene tube filled with AH Plus® Bioceramic Sealer placed on sciatic nerve Bioceramic + Supplement (BC + NS) 12 Bioceramic Sealer + Stemregen® (300 mg/kg/day, oral gavage) Surgical Procedure To determine the anesthesia dosage, the weights of all 48 rats in the groups were measured. On day 0, anesthesia was applied intramuscularly with 5 mg/kg, Ketasol 10% (ketamine) (Richter Pharma AG, Wels, Austria) and 45 mg/kg, Rompun 2% (xylazine) (Bayer Animal Health GmbH, Leverkusen, Germany). The depth of anesthesia was checked using the toe pinch test. After shaving the gluteal and thigh regions of the rats, they were fixed face-down onto the procedure board with plaster tape. The surgical field was disinfected with a povidone iodine solution (Adeka İlaç, Samsun, Turkey). In the BC and BC + NS groups, to standardize the contact area between the canal filling paste and the sciatic nerve tissue and to minimize the contact of the paste with surrounding tissues, a sterile and non-toxic polyethylene tube (Galena Sağlık, Istanbul, Turkey) with a 4 mm diameter and 0.5 cm length was used (Fig. 2 ). To allow the root canal paste placed inside the tube to contact the sciatic nerve, the tube was longitudinally cut with a sterile scalpel to make it flexible and the AH Plus® Bioceramic Sealer paste was applied into the polyethylene tube using its special tip. A posterolateral longitudinal straight incision was made extending from the right greater trochanter to the lateral condyle of the femur to access the rats’ right sciatic nerve. Then, the sciatic nerve was exposed between the gluteus superficialis and the biceps femoris by blunt dissection and made visible. The membranous structures over the nerve were removed and the nerve was isolated from the surrounding tissues. After the plastic polyethylene tubes cut longitudinally were filled with paste, they were placed on the sciatic nerve isolated from the environment with a thin paraffin strip (Fig. 3 ). In the C and NS groups, sterile and non-toxic polyethylene tubes of 4 mm diameter and 0.5 cm length were placed around the sciatic nerve. Then these tubes were fixed with a thin paraffin strip, but no root canal paste was applied into the tube (Fig. 3 ). After all the procedures performed on the subjects, the sciatic nerve was placed back into its anatomical position and the incision area was closed with 3/0 silk sutures (Boz Tıbbi Malzeme A.Ş., Ankara, Turkey) (Fig. 3 ). Application of Nutritional Supplement and Histopthological Analysis Stemregen®, in powder mixture form inside capsules, was weighed precisely at 300 mg/kg and transferred into an experimental tube, then diluted with distilled water and mixed with a vortex device until dissolved. The prepared mixture was administered only to the subjects in the NS and BC + NS groups once a day by oral gavage for 15 days. At the end of the 15th day of the experiment, all rats were euthanized by gradual exposure to 80% carbon dioxide gas at a gas flow rate of 20% volume/minute. The sciatic nerve was excised, including healthy tissue from the proximal and distal ends of the area where the tube was placed, and then the polyethylene tube applied over the nerve was removed from the nerve tissue (Fig. 4 ). The sciatic nerve tissue samples were fixed in 10% buffered formalin solution for 24 hours. The fixed tissues were first washed under running water for 4–8 hours and then passed through a series of alcohol (50%-100%) and xylene with increasing concentrations for tissue processing. Subsequently, the tissues were embedded into blocks and sections 4–5 µm thick were taken using an automatic rotary RM2255 microtome (Leica Biosystems, Wetzlar, Germany). The obtained sections were deparaffinized by being kept in an oven at 60°C for two hours. Then the sections were stained with Hematoxylin-Eosin (H&E) and Luxol Fast Blue and mounted with Entellan® (Merck, Darmstadt, Germany). The stained sections were made ready for histological examination. All samples were examined and photographed with a BX53 trinocular microscope (Olympus Corporation, Tokyo, Japan). The evaluation of the experimental groups was carried out in three stages. In the first stage, the nerve tissue was evaluated for myelin, axon, and epineurium degeneration. In the second stage, the nerve tissue was evaluated for fibrosis, epineurium, and perineurium thickening. In the third stage, the tissue was semiquantitatively evaluated for lymphocyte infiltration, fibrocyte density, vacuolization, and edema. Each parameter was scored semiquantitatively and the evaluation was performed by an expert pathologist blinded to the experimental groups to minimize bias [ 20 ]. Semiquantitative histopathological evaluations were performed using predefined scoring criteria detailed in Table 3 . Table 3 Histological Scoring Parameters (Semiquantitative Evaluation) Parameter Description Scoring Myelin degeneration Loss or disruption of myelin sheath G0 (None) to G5 (Very Severe) Axonal degeneration Structural damage or disintegration of axons G0 to G5 Epineurium degeneration Degenerative changes in outer nerve sheath G0 to G5 Perineurial thickening Structural thickening of perineurium G0 to G5 Epineurial thickening Structural thickening of epineurium G0 to G5 Fibrosis Presence of fibrotic tissue around or within nerve bundles G0 to G5 Lymphocytic infiltration Degree of immune cell infiltration G0 to G5 Fibrocyte density Presence of fibrocytes within nerve tissue G0 to G5 Vacuolization Intracellular or extracellular vacuole formation G0 to G5 Edema Presence of interstitial fluid accumulation G0 to G5 Statistical Analysis IBM SPSS Statistics 22 (Armonk, NY: IBM Corp.) program was used for statistical analysis. The conformity of parameters to normal distribution was evaluated with Kolmogorov-Smirnov and Shapiro Wilks tests, and it was determined that the parameters did not show a normal distribution. While evaluating the study data, descriptive statistical methods (minimum, maximum, mean, standard deviation, median) were used, and for comparisons between groups, Kruskal Wallis test and Dunn’s test to determine the group causing the difference were used. Significance was considered at the p < 0.05 level. RESULTS Histological analysis revealed that the Bioceramic (BC) group exhibited significantly higher degeneration and inflammation scores compared to the Control (C) and Supplement (NS) groups across all evaluated parameters (p < 0.05; Table 4 , Table 5). Specifically, the BC group showed severe myelin and axonal degeneration, prominent thickening of the epineurium and perineurium, and increased fibrocyte density, vacuolization, and interstitial edema. The median scores for myelin degeneration and edema reached grade 3, demonstrating significantly greater neural injury than in the other groups (p < 0.001). Table 4 Histological Scoring Results Control Group Supplement Group Bioceramic Group Bioceramic + Supplement Group G0 G1 G2 G3 G4 G5 G0 G1 G2 G3 G4 G5 G0 G1 G2 G3 G4 G5 G0 G1 G2 G3 G4 G5 P Myelin Degeneration 7 5 — — — — 8 4 — — — — — — 3 7 2 — — 4 5 3 — — 0,001* Axonal Degeneration 8 4 — — — — 9 3 — — — — — 3 4 5 — — — 6 3 3 — — 0,001* Epineurium Degeneration 8 4 — — — — 8 4 — — — — 3 6 3 — — — 4 6 2 — — — 0,032* Fibrosis 9 3 — — — — 9 3 — — — — — 5 5 2 — — — 6 4 2 — — 0,001* Epineurial Thickening 10 2 — — — — 10 2 — — — — — 4 8 — — — — 9 3 — — — 0,001* Perineurial Thickening 9 3 — — — — 9 3 — — — — — 7 5 — — — — 8 4 — — — 0,001* Lymphocyte Infiltration 7 5 — — — — 8 4 — — — — — — 7 4 1 — — 4 5 3 — — 0,001* Fibrocyte Density 8 4 — — — — 8 4 — — — — — 6 4 2 — — — 7 3 2 — — 0,001* Vacuolization 8 4 — — — — 9 3 — — — — — 5 4 3 — — — 7 5 — — — 0,001* Edema 7 5 — — — — 10 2 — — — — — — 3 6 3 — — 5 6 1 — — 0,001* P: Significance level, G: Grade, G0 (None), G1 (Mild), G2 (Moderate), G3 (Significant), G4 (Severe), G5 (Very Severe) *Kruskal–Wallis Test, P < 0.05 Table 5. Comparison of the Groups Based on the Evaluated Parameters. Histopathological scores (0-5 scale) for myelin degeneration, axon degeneration, epineurium/perineurium thickening, fibrosis, lymphocyte infiltration, fibrocyte density, vacuolization, and edema. Minimum, median, and maximum values represent the range of scores across 12 rats per group. Control Group (a) Supplement Group (b) Bioceramic Group (c) Bioceramic + Supplement Group (d) Evaluated Parameters Min Med Max Min Med Max Min Med Max Min Med Max P Myelin Degeneration 0 0.42±0.51 (0) 1 0 0.33±0.49 (0) (b-c*)(b-d*) 1 2 2.92±0.67 (3) (a-c*)(b-c*) 4 1 1.92±0.79 (2) (a-d*)(b-d*) 3 0,001* Axonal Degeneration 0 0.33±0.49 (0) 1 0 0.25±0.45 (0) (b-c*)(b-d*) 1 1 2.17±0.83 (2) (a-c*)(b-c*) 3 1 1.75±0.87 (1.5) (a-d*)(b-d*) 3 0,001* Epineurium Degeneration 0 0.33±0.49 (0) 1 0 0.33±0.49 (0) (b-c*) 1 0 1.0±0.74 (1) (a-c*)(b-c*) 2 0 0.83±0.72 (1) 2 0,032* Fibrosis 0 0.25±0.45 (0) 1 0 0.25±0.45 (0) (b-c*)(b-d*) 1 1 1.75±0.75 (2) (a-c*)(b-c*) 3 1 1.67±0.78 (1.5) (a-d*)(b-d*) 3 0,001* Epineurial Thickening 0 0.17±0.39 (0) 1 0 0.17±0.39 (0) (b-c*)(b-d*) 1 1 1.67±0.49 (2) (a-c*)(b-c*) 2 1 1.25±0.45 (1) (a-d*)(b-d*) 2 0,001* Perineurial Thickening 0 0.25±0.45 (0) 1 0 0.25±0.45 (0) (b-c*)(b-d*) 1 1 1.42±0.51 (1) (a-c*)(b-c*) 2 1 1.33±0.49 (1) (a-d*)(b-d*) 2 0,001* Lymphocyte Infiltration 0 0.42±0.51 (0) 1 0 0.33±0.49 (0) (b-c*)(b-d*) 1 2 2.5±0.67 (2) (a-c*)(b-c*) 4 1 1.92±0.79 (2) (a-d*)(b-d*) 3 0,001* Fibrocyte Density 0 0.33±0.49 (0) 1 0 0.33±0.49 (0) (b-c*)(b-d*) 1 1 1.67±0.78 (1.5) (a-c*)(b-c*) 3 1 1.58±0.79 (1) (a-d*)(b-d*) 3 0,001* Vacuolization 0 0.33±0.49 (0) 1 0 0.25±0.45 (0) (b-c*)(b-d*) 1 1 1.83±0.83 (2) (a-c*)(b-c*) 3 1 1.42±0.51 (1) (a-d*)(b-d*) 2 0,001* Edema 0 0.42±0.51 (0) 1 0 0.17±0.39 (0) (b-c*)(b-d*) 1 2 3.0±0.74 (3) (a-c*)(b-c*) 4 1 1.67±0.65 (1) (a-d*)(b-d*) 3 0,001* P: Significance level, Min: Minimum, Med: Median, Max: Maximum, a: Control group, b: Supplement group, c: Bioceramic group, d: Bioceramic + Supplement group. (x–y*): There is a statistically significant difference between groups x and y Kruskal–Wallis Test / Dunn’s Post Hoc Test, P < 0.05 In contrast, the Bioceramic + Supplement (BC + NS) group demonstrated lower median scores for all histological markers when compared to the BC group. Notable reductions were observed in axonal degeneration (median: 1.75 vs. 2.17), fibrosis (1.67 vs. 1.75), and lymphocyte infiltration (1.92 vs. 2.50). However, none of these differences reached statistical significance (p > 0.05). The NS and C groups exhibited minimal or no pathological changes, with grade 0 or 1 scores observed in all parameters. The structural integrity of the nerve was well preserved in these groups. Semiquantitative scoring results for all evaluated parameters, including myelin degeneration, axonal degeneration, fibrosis, perineurial and epineurial thickening, edema, and inflammatory cell infiltration, are presented in Tables 4 and 5. Representative histological images are shown in Figs. 5 and 6 . DISCUSSION We hypothesized that the bioceramic root canal sealer AH Plus® Bioceramic Sealer would induce neurotoxic effects in the rat sciatic nerve, and that the nutritional supplement Stemregen® would reduce these neurotoxic effects. The null hypothesis stated that the sealer would not cause neural damage and that Stemregen® would have no mitigating effect. Based on the semiquantitative histopathological findings, the null hypothesis was partially rejected. Significant neural degeneration and inflammation were observed in the Bioceramic group (p 0.05). Neurotoxic Effects of Bioceramic Sealer Application of the bioceramic sealer resulted in marked histopathological alterations, including disruption of myelin architecture, axonal injury, thickening of the perineurium, and notable inflammatory cell infiltration. These outcomes align with previous reports indicating that endodontic sealers, particularly when extruded near neural structures, can provoke adverse neural responses [ 5 , 6 ]. Although bioceramic sealers are generally considered biocompatible in in vitro settings [ 18 ], such environments fail to capture the complex interactions that occur upon direct nerve contact in vivo. The BC group demonstrated prominent histological alterations, including axonal and myelin degeneration, perineurial thickening, lymphocyte infiltration, and interstitial edema—all of which align with prior case-based evidence suggesting adverse effects when sealers are extruded into neurovascular spaces. These changes were most notable in parameters such as myelin degeneration (median score = 3) and edema (median score = 3), indicating acute neural tissue response to chemical exposure. Although in vitro studies have suggested the biocompatibility of calcium silicate–based sealers [ 16 – 18 ], in vivo reports indicate that direct contact with nerve tissue can provoke adverse effects [ 19 , 20 ]. Therefore, the present findings underscore the need for caution in clinical cases involving close proximity to neural structures such as the inferior alveolar nerve. One likely mechanism underlying this neurotoxicity is the high alkalinity generated during the setting reaction of tricalcium silicate, which may destabilize nerve membranes, disturb calcium homeostasis, and initiate apoptotic cascades [ 18 – 20 ]. Moreover, the presence of formulation additives such as dimethyl sulfoxide (DMSO) and lithium carbonate may amplify neural toxicity. DMSO has been shown to increase cell membrane permeability, facilitating the penetration of reactive compounds into nerve tissue and potentially exacerbating cytotoxic effects [ 38 , 39 ]. While lithium carbonate is used therapeutically for mood stabilization, its potential neurotoxic effects—including those on myelin integrity—have primarily been documented in central nervous system models. To date, evidence regarding its impact on peripheral nerve tissue remains limited and inconclusive [ 23 – 25 ]. The root canal paste may have caused ischemia and hypoxia in nerve tissue by exerting mechanical pressure through the polyethylene tube, impairing blood flow and triggering inflammation [ 40 ]. Additionally, the surgical procedure itself may have contributed to the mild inflammation in the C and NS groups and further increased tissue damage in the BC and BC + NS groups [ 41 ]. Clinically, these observations are particularly relevant for posterior mandibular regions, where the proximity of root apices to the mandibular canal increases the risk of sealer extrusion affecting the inferior alveolar nerve [ 3 , 4 , 10 ]. As this model demonstrates, even a single, localized exposure to the material may lead to measurable neural tissue damage within a short period. A sciatic nerve model was selected due to its large caliber, well-defined anatomy, and ease of surgical access, which allow for reproducible placement of test materials and standardized histological assessment. Although anatomically distinct, its mixed motor-sensory composition shares functional similarities with the inferior alveolar nerve, making it a suitable surrogate for peripheral neurotoxicity evaluation [ 42 ]. Furthermore, the direct-contact application used in this study represents a worst-case scenario rather than typical clinical conditions of apical extrusion, where surrounding periapical tissues may buffer or dilute material exposure. Therefore, while the model provides valuable insight into potential biological effects, caution is warranted when extrapolating these findings directly to clinical settings. Potential Neuroprotective Role of Stemregen® The BC + NS group showed a downward trend in all inflammation and degeneration parameters compared to the BC-only group, especially in axonal damage, fibrocyte density, and vacuolization. However, these reductions did not reach statistical significance, possibly due to the acute timeline of the model or the modest effect size of the supplement [ 26 , 28 ]. While the downward trend observed in axonal degeneration, fibrosis, and lymphocytic infiltration suggests a potential protective effect of Stemregen®, none of these reductions were statistically significant (p > 0.05). In animals treated with Stemregen® in conjunction with the bioceramic sealer, histopathological damage scores—including axonal degeneration, myelin disorganization, and inflammatory infiltration—were consistently lower than those observed in the BC-only group. Despite consistently lower semiquantitative scores in the BC + NS group, the differences failed to achieve statistical significance when compared to the Bioceramic-only group (p > 0.05 for all parameters). According to the manufacturer, Stemregen® is a commercially available multi-ingredient dietary supplement promoted to stimulate endogenous stem cell release from the bone marrow and to modulate systemic inflammation by acting on the immune environment. Its botanical components include sea buckthorn, Notoginseng, fucoidan, and Aloe vera, several of which have demonstrated anti-inflammatory, antioxidant, and neuroprotective properties in various experimental models [ 29 – 37 ]. For instance, Notoginseng saponins, such as ginsenosides and notoginsenosides, may enhance stem cell mobilization and protect nerve tissue by reducing inflammation, oxidative stress, and promoting regeneration [ 36 , 37 ]. Similarly, Stemaloe® (Aloe vera gel powder) and 1→3 beta-glucans have been reported to enhance circulating stem cell levels and support immune function, potentially aiding tissue repair in nerve injury models [ 43 , 44 ]. Bladderwrack algae, rich in phenolic compounds, also contribute to the reduction of inflammation in nerve tissue by regulating oxidative stress and supporting stem cell mobilization [ 35 ]. Also, blue-green algae help stem cells mobilize from the bone marrow by blocking L-selectin [ 32 ]. These features are thought to help reduce inflammation in nerve tissue. While these compounds have been studied independently, Stemregen® as a combined formulation has not yet been evaluated in any peer-reviewed in vivo models involving peripheral nerve injury. This limits direct attribution of any observed effect to stem cell mobilization or anti-inflammatory synergy. While the active ingredients of Stemregen® have documented immunomodulatory and antioxidant properties in isolation, the effects of the full formulation in peripheral nerve injury remain to be validated in long-term or functional outcome models. Study Limitations and Future Directions Several limitations should be considered when interpreting these results. Firstly, reliance solely on histopathological evaluation restricts the ability to assess molecular and functional aspects of nerve damage. Future studies should incorporate complementary methods such as nerve conduction testing, immunohistochemistry, and gene expression analysis to provide a more comprehensive understanding of injury and repair mechanisms. Secondly, only AH Plus® Bioceramic Sealer was tested. It is important to clarify that although AH Plus® Bioceramic Sealer is no longer available on the market, there is no evidence linking its withdrawal to safety concerns arising from adverse biological effects. Available information suggests that the product was discontinued due to commercial and marketing considerations, rather than due to observed neurotoxicity or clinical complications. Consequently, the findings of this study should not be interpreted as a factor in the decision to withdraw this sealer. Although this specific product has been withdrawn from the market, its chemical characteristics—including tricalcium silicate content and alkaline-setting reaction—are representative of other bioceramic sealers still in clinical use, rendering the findings relevant beyond the tested brand [ 18 ]. Thirdly, although polyethylene tubes were employed to standardize sealer placement, the degree of mechanical pressure exerted on the sciatic nerve was not quantified. Therefore, the contribution of compression-induced ischemia to the observed histopathological changes cannot be ruled out [ 40 ]. To further expand on these findings, future investigations should employ longer follow-up periods to evaluate late-stage healing, including potential regenerative effects. Functional testing, such as nerve conduction studies, would provide valuable information on the clinical relevance of structural changes. Additionally, molecular-level assessments could clarify the roles of inflammatory and reparative signaling pathways. Comparative analyses of alternative bioceramic sealers and stem cell–activating formulations may help differentiate material- or agent-specific effects. Ultimately, such studies would improve the risk assessment and clinical selection of root canal sealers in complex anatomical contexts. From a clinical perspective, these findings should be interpreted with caution. While direct contact between root canal sealers and nerve tissue is rare in daily practice, accidental extrusion into adjacent neurovascular structures—particularly in anatomically vulnerable areas like the mandibular canal—can occur. This study highlights the potential biological risks associated with such events and underscores the importance of precise working length control and careful obturation, especially when using sealers with high alkalinity or reactive excipients. CONCLUSIONS In this in vivo rat model, AH Plus® Bioceramic Sealer induced significant neurotoxic effects in peripheral nerve tissue, as evidenced by increased degeneration, inflammation, and structural damage (p < 0.05). Systemic administration of Stemregen® led to mild reductions in histopathological injury scores when combined with the sealer; however, these differences did not reach statistical significance (p > 0.05). While a downward trend was observed, the clinical relevance of this potential protective effect remains inconclusive. These results underscore the importance of minimizing sealer extrusion, particularly in anatomically sensitive regions, and highlight the need for further preclinical and translational studies evaluating both the biocompatibility of calcium silicate–based sealers and the therapeutic value of regenerative adjuncts such as stem cell–mobilizing supplements. Abbreviations FUERC Fırat University Experimental Research Center C Control Group NS Nutritional Supplement Group BC Bioceramic Group BC + NS Bioceramic plus Nutritional Supplement Group H&E Hematoxylin and Eosin DMSO Dimethyl Sulfoxide SPSS Statistical Package for the Social Sciences FUBAP Fırat University Scientific Research Projects Declarations ETHICS APPROVAL AND CONSENT TO PARTICIPATE All experiments in this study were conducted in accordance with the ARRIVE guidelines and approved by the Fırat University Local Ethics Committee for Animal Experiments (protocol number 2023/16-04, dated September 20, 2023). CONSENT FOR PUBLICATION Not applicable AVAILABILITY OF DATA AND MATERIALS All data generated or analyzed during this study are included in this published article. COMPETING INTERESTS The authors declare no competing interests FUNDING This study was supported by Firat University Scientific Research Project Coordination (Grant number: DHF.23.07). AUTHOR CONTRIBUTIONS Haydar İrfan YÜCEL: Conceptualization, Methodology, Resources, Investigation, Data curation, Writing – Original Draft Preparation, Writing - review and editing Mevlüt Sinan OCAK: Supervision, Conceptualization, Methodology, Investigation, Funding acquisition, Resources, Writing - review and editing Serkan DÜNDAR: Methodology, Writing - review and editing İbrahim Hanifi ÖZERCAN: Methodology, Investigation, Writing - review and editing Ebru GÖKDERE: Methodology, Writing - review and editing ACKNOWLEDGEMENTS This manuscript derived from Haydar İrfan YÜCEL’s thesis. CLINICAL TRIAL NUMBER Not applicable References Poveda R, Bagán JV, Fernández JM, Sanchis JM. Mental nerve paresthesia associated with endodontic paste within the mandibular canal: report of a case. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006;102(5):e46–9. 10.1016/j.tripleo.2006.03.022 . Tamse A, Kaffe I, Littner MM, Kozlovsky A. Paresthesia following overextension of AH-26: report of two cases and review of the literature. J Endod. 1982;8(2):88–90. 10.1016/S0099-2399(82)80265-3 . Morse DR. Infection-related mental and inferior alveolar nerve paresthesia: literature review and presentation of two cases. J Endod. 1997;23(7):457–60. 10.1016/S0099-2399(97)80303-2 . Köseoğlu BG, Tanrikulu S, Sübay RK, Sencer S. Anesthesia following overfilling of a root canal sealer into the mandibular canal: a case report. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006;101(6):803–6. 10.1016/j.tripleo.2005.07.015 . Gallas-Torreira MM, Reboiras-López MD, García-García A, Gándara-Rey J. Mandibular nerve paresthesia caused by endodontic treatment. Med Oral 2003 Aug-Oct;8(4):299–303. PMID: 12937392. Tilotta-Yasukawa F, Millot S, El Haddioui A, Bravetti P, Gaudy JF. Labiomandibular paresthesia caused by endodontic treatment: an anatomic and clinical study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006;102(4):e47–59. 10.1016/j.tripleo.2006.02.017 . Pogrel MA. Damage to the inferior alveolar nerve as the result of root canal therapy. J Am Dent Assoc. 2007;138(1):65–9. 10.14219/jada.archive.2007.0022 . Boiesen J, Brodin P. Neurotoxic effect of two root canal sealers with calcium hydroxide on rat phrenic nerve in vitro. Endod Dent Traumatol. 1991;7(6):242–5. 10.1111/j.1600-9657.1991.tb00210.x . Ahlgren FK, Johannessen AC, Hellem S. Displaced calcium hydroxide paste causing inferior alveolar nerve paraesthesia: report of a case. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2003;96(6):734–7. 10.1016/j.tripleo.2003.08.018 . Plotino G, Venturi M, Grande NM. Complications due to root canal filling procedures. In: Jain PR, editor. Common Complications in Endodontics: Prevention and Management. Cham: Springer; 2018. pp. 101–46. Orstavik D, Brodin P, Aas E. Paraesthesia following endodontic treatment: survey of the literature and report of a case. Int Endod J. 1983;16(4):167–72. 10.1111/j.1365-2591.1983.tb01320.x . Yaltirik M, Ozbas H, Erisen R. Surgical management of overfilling of the root canal: a case report. Quintessence Int. 2002;33(9):670–2. PMID: 12666891. Grötz KA, Al-Nawas B, de Aguiar EG, Schulz A, Wagner W. Treatment of injuries to the inferior alveolar nerve after endodontic procedures. Clin Oral Investig. 1998;2(2):73–6. 10.1007/s007840050048 . Awawdeh L, Al-Qudah A, Hamouri H, Chakra RJ. Outcomes of Vital Pulp Therapy Using Mineral Trioxide Aggregate or Biodentine: A Prospective Randomized Clinical Trial. J Endod. 2018;44(11):1603–9. 10.1016/j.joen.2018.08.004 . Parirokh M, Torabinejad M, Dummer PMH. Mineral trioxide aggregate and other bioactive endodontic cements: an updated overview - part I: vital pulp therapy. Int Endod J. 2018;51(2):177–205. 10.1111/iej.12841 . Souza LC, Neves GST, Kirkpatrick T, Letra A, Silva R. Physicochemical and Biological Properties of AH Plus Bioceramic. J Endod. 2023;49(1):69–76. 10.1016/j.joen.2022.10.009 . Sanz JL, López-García S, Rodríguez-Lozano FJ, et al. Cytocompatibility and bioactive potential of AH Plus Bioceramic Sealer: An in vitro study. Int Endod J. 2022;55(10):1066–80. 10.1111/iej.13805 . Chopra V. Bioceramics in Endodontics. 1st ed. New Jersey: Wiley Blackwell; 2024. Fonseca DA, Paula AB, Marto CM et al. Biocompatibility of Root Canal Sealers: A Systematic Review of In Vitro and In Vivo Studies. Materials (Basel). 2019;12(24):4113. 10.3390/ma12244113 Tuğ Kılkış B, Er K, Taşdemir T, et al. Neurotoxicity of various root canal sealers on rat sciatic nerve: an electrophysiologic and histopathologic study. Clin Oral Investig. 2015;19(8):2091–100. 10.1007/s00784-015-1447-y . Theparambil SM, Hosford PS, Ruminot I, et al. Astrocytes regulate brain extracellular pH via a neuronal activity-dependent bicarbonate shuttle. Nat Commun. 2020;11(1):5073. 10.1038/s41467-020-18756-3 . Theparambil SM, Hosford PS, Ruminot I, et al. Astrocytes regulate brain extracellular pH via a neuronal activity-dependent bicarbonate shuttle. Nat Commun. 2020;11(1):5073. 10.1038/s41467-020-18756-3 . Published 2020 Oct 8. Ataoğlu A. Lithium-induced neurotoxicity. Turkiye Klinikleri J Int Med Sci. 2006;2(29):52–9. Prettyman R. Lithium neurotoxicity at subtherapeutic serum levels. Br J Psychiatry. 1994;164(1):123. 10.1192/bjp.164.1.123a . Giuliani E, Iseppi D, Orlandi MC, Alfonso A, Barbieri A. Prolonged neurological burden in severe lithium intoxication. Minerva Anestesiol. 2010;76(6):463–5. Li X, Guan Y, Li C, et al. Immunomodulatory effects of mesenchymal stem cells in peripheral nerve injury. Stem Cell Res Ther. 2022;13(1):18. 10.1186/s13287-021-02690-2 . Sullivan R, Dailey T, Duncan K, Abel N, Borlongan CV. Peripheral Nerve Injury: Stem Cell Therapy and Peripheral Nerve Transfer. Int J Mol Sci. 2016;17(12):2101. 10.3390/ijms17122101 . Hussain G, Wang J, Rasul A, et al. Current Status of Therapeutic Approaches against Peripheral Nerve Injuries: A Detailed Story from Injury to Recovery. Int J Biol Sci. 2020;16(1):116–34. 10.7150/ijbs.35653 . Usubalieva A, Eyiz V, Totubaeva N, Tontul İ. Chemical Composition and Antioxidant Activity of Sea-Buckthorn (Hippophae rhamnoides L.) Grown in Issyk-Kul Region, Kyrgyz Republic. Akademik Gıda Dec. 2022;20(4):321–8. 10.24323/akademik-gida.1224265 . Drapeau C, Benson KF, Jensen GS. Rapid and selective mobilization of specific stem cell types after consumption of a polyphenol-rich extract from sea buckthorn berries (Hippophae) in healthy human subjects. Clin Interv Aging. 2019;14:253–63. 10.2147/CIA.S186893 . Fatima T, Snyder CL, Schroeder WR, et al. Fatty acid composition of developing sea buckthorn (Hippophae rhamnoides L.) berry and the transcriptome of the mature seed. PLoS ONE. 2012;7(4):e34099. 10.1371/journal.pone.0034099 . Jensen GS, Hart AN, Zaske LA, et al. Mobilization of human CD34 + CD133 + and CD34 + CD133(-) stem cells in vivo by consumption of an extract from Aphanizomenon flos-aquae–related to modulation of CXCR4 expression by an L-selectin ligand? Cardiovasc Revasc Med. 2007;8(3):189–202. 10.1016/j.carrev.2007.03.004 . Ale MT, Mikkelsen JD, Meyer AS. Important determinants for fucoidan bioactivity: a critical review of structure-function relations and extraction methods for fucose-containing sulfated polysaccharides from brown seaweeds. Mar Drugs. 2011;9(10):2106–30. 10.3390/md9102106 . Cabral EM, Mondala JRM, Oliveira M, et al. Influence of molecular weight fractionation on the antimicrobial and anticancer properties of a fucoidan rich-extract from the macroalgae Fucus vesiculosus. Int J Biol Macromol. 2021;186:994–1002. 10.1016/j.ijbiomac.2021.06.182 . Obluchinskaya ED, Pozharitskaya ON, Zakharova LV, Daurtseva AV, Flisyuk EV, Shikov AN. Efficacy of Natural Deep Eutectic Solvents for Extraction of Hydrophilic and Lipophilic Compounds from Fucus vesiculosus. Molecules. 2021;26(14):4198. 10.3390/molecules26144198 . Li Y, Suo L, Liu Y, Li H, Xue W. Protective effects of ginsenoside Rg1 against oxygen-glucose-deprivation-induced apoptosis in neural stem cells. J Neurol Sci. 2017;373:107–12. 10.1016/j.jns.2016.12.036 . Zheng M, Xin Y, Li Y, et al. Ginsenosides: A Potential Neuroprotective Agent. Biomed Res Int. 2018;2018:8174345. 10.1155/2018/8174345 . Jacob SW, Herschler R. Pharmacology of DMSO. Cryobiology. 1986;23(1):14–27. 10.1016/0011-2240(86)90014-3 . Gironi B, Kahveci Z, McGill B, et al. Effect of DMSO on the Mechanical and Structural Properties of Model and Biological Membranes. Biophys J. 2020;119(2):274–86. 10.1016/j.bpj.2020.05.037 . Lundborg G, Dahlin LB. The pathophysiology of nerve compression. Hand Clin. 1992;8(2):215–27. Hildenborg M. Systemic inflammation and neuroimmunity in surgical trauma. Karolinska Institutet. 2024. https://openarchive.ki.se/articles/thesis/Systemic_inflammation_and_neuroimmunity_in_surgical_trauma/26018335?file=49081306 . Accessed 25 Dec 2024. Dowdall T, Robinson I, Meert TF. Comparison of five different rat models of peripheral nerve injury. Pharmacol Biochem Behav. 2005;80(1):93–108. 10.1016/j.pbb.2004.10.016 . Drapeau C, Benson KF, James J, Jensen GS. Aloe macroclada from Madagascar triggers transient bone marrow stem cell mobilization. J Stem Cell Res Ther. 2015;5(6):287. Cramer DE, Wagner S, Li B, et al. Mobilization of hematopoietic progenitor cells by yeast-derived beta-glucan requires activation of matrix metalloproteinase-9. Stem Cells. 2008;26(5):1231–40. 10.1634/stemcells.2007-0712 . Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7004747","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":496818901,"identity":"cf4c5c87-c6d4-4735-82dc-b352bc1f4f54","order_by":0,"name":"Haydar İrfan YÜCEL","email":"","orcid":"","institution":"Firat University","correspondingAuthor":false,"prefix":"","firstName":"Haydar","middleName":"İrfan","lastName":"YÜCEL","suffix":""},{"id":496818902,"identity":"f9a487ca-7464-41ea-a268-8741005f5757","order_by":1,"name":"Mevlüt Sinan OCAK","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAzklEQVRIiWNgGAWjYNCCAzb8bBAWM9Fa0iTbGBgYG8Ba2IjTcliygWgtuv2HD374cea8BJ/04ecPGCqsExvkex/g1WJ2Iy1ZsufGbQk2vjTDBoYz6YkNbOwGBLTwmDHwfLhdx8bDYNjA2HYYqIWAy8zOnzFj/PPhnAQbD/vHBsZ/xGg5kGPGzHPjAFALD9CWBmK0AP0iLXMmGaSlcEbCsXTjNrY0Qg47fPDjm2N2EvI97Bs+fKixlu1nPoZfCypIYCA2JkfBKBgFo2AU4AUAGZpCCG8sySMAAAAASUVORK5CYII=","orcid":"","institution":"Firat University","correspondingAuthor":true,"prefix":"","firstName":"Mevlüt","middleName":"Sinan","lastName":"OCAK","suffix":""},{"id":496818904,"identity":"69a99190-71d1-4832-9cce-eb6da7283bce","order_by":2,"name":"Ebru GÖKDERE","email":"","orcid":"","institution":"Firat University","correspondingAuthor":false,"prefix":"","firstName":"Ebru","middleName":"","lastName":"GÖKDERE","suffix":""},{"id":496818906,"identity":"4361ba9b-a58e-4986-addf-a4e49fb79f4e","order_by":3,"name":"Serkan DUNDAR","email":"","orcid":"","institution":"Firat University","correspondingAuthor":false,"prefix":"","firstName":"Serkan","middleName":"","lastName":"DUNDAR","suffix":""},{"id":496818907,"identity":"0d5d3d21-c85a-4b1a-b4a8-b4298e3f06c1","order_by":4,"name":"İbrahim Hanifi ÖZERCAN","email":"","orcid":"","institution":"Firat University","correspondingAuthor":false,"prefix":"","firstName":"İbrahim","middleName":"Hanifi","lastName":"ÖZERCAN","suffix":""}],"badges":[],"createdAt":"2025-06-29 20:38:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7004747/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7004747/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":88669728,"identity":"81ae18e9-a37c-4d74-82d5-ca50a18c5fb0","added_by":"auto","created_at":"2025-08-09 03:30:52","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":278116,"visible":true,"origin":"","legend":"\u003cp\u003eFlow diagram of the study (PRILE 2021).\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7004747/v1/ed5ffcb24693da7948450ab7.jpg"},{"id":88670011,"identity":"76b22aed-b4ab-4e2f-82ab-9dc714de5d02","added_by":"auto","created_at":"2025-08-09 03:38:52","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":89761,"visible":true,"origin":"","legend":"\u003cp\u003ePreparation of the polyethylene tube.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7004747/v1/396ad42020f49f40ea22e4c2.jpg"},{"id":88670063,"identity":"a3046202-369a-4b76-8a1a-4ecc8ae5d2e0","added_by":"auto","created_at":"2025-08-09 03:46:52","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":178078,"visible":true,"origin":"","legend":"\u003cp\u003eSurgical Procedures. A (Sciatic nerve), B (Aplication of an empty polyethylene tube to the sciatic nerve), C (Applicaton of a polyethylene tube containing root canal paste to the sciatic nerve), D (Suturing of the tissues after the surgical procedure).\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7004747/v1/286ce2ff643e868326e04d50.jpg"},{"id":88670016,"identity":"534276b6-cf65-4939-b2b8-222c6e5b480a","added_by":"auto","created_at":"2025-08-09 03:38:52","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":162670,"visible":true,"origin":"","legend":"\u003cp\u003eHarvesting of tissue samples.\u003c/p\u003e","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7004747/v1/06a1f92edf0b01f33a1d6891.jpg"},{"id":88669747,"identity":"e2031cd8-2772-4fdd-823c-7319c27b967d","added_by":"auto","created_at":"2025-08-09 03:30:52","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":695019,"visible":true,"origin":"","legend":"\u003cp\u003eH\u0026amp;E staining images of the samples; \u003cstrong\u003eControl Group\u003c/strong\u003e A) 10X Magnification B) 20X Magnification, \u003cstrong\u003eNutritional Supplement Group\u003c/strong\u003e C) 10X Magnification D) 20X Magnification, \u003cstrong\u003eBioceramic Group\u003c/strong\u003e E) 10X Magnification (red arrow; thickening in the perineurium, green arrow: thickening and degeneration in the epineurium, black arrow: paste residue) F) 20X Magnification (orange arrow: lymphocyte infiltration, white arrow: fibrocyte density, yellow arrow: vacuolization, dark green arrow: fibrosis, blue arrow: edema) \u003cstrong\u003eBioceramic + Nutritional Supplement Group\u003c/strong\u003e G) 10X Magnification (red arrow: thickening in the perineurium, green arrow: thickening and degeneration in the epineurium) H) 20X Magnification (orange arrow: lymphocyte infiltration, white arrow: fibrocyte density, yellow arrow: vacuolization, dark green arrow: fibrosis, blue arrow: edema).\u003c/p\u003e","description":"","filename":"Figure5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7004747/v1/6cae2381a754356604ec8de0.jpg"},{"id":88669734,"identity":"8328ea33-ab02-4e92-b62f-78aa8fba0f65","added_by":"auto","created_at":"2025-08-09 03:30:52","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":741137,"visible":true,"origin":"","legend":"\u003cp\u003eLuxol Fast Blue staining images of the samples; \u003cstrong\u003eControl Group\u003c/strong\u003e A) 10X Magnification B) 20X Magnification, \u003cstrong\u003eNutritional Supplement Group\u003c/strong\u003e C) 10X Magnification D) 20x Magnification, \u003cstrong\u003eBioceramic Group\u003c/strong\u003e E) 10X Magnification (black arrow: paste residue) F) 20X Magnification (green notched arrow: myelin degeneration, gray notched arrow: axon degeneration), \u003cstrong\u003eBioceramic + Nutritional Supplement Group \u003c/strong\u003eG) 10X Magnification H) 20X Magnification (green notched arrow: myelin degeneration, gray notched arrow: axon degeneration).\u003c/p\u003e","description":"","filename":"Figure6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7004747/v1/fbadeba3295714706cbe9c77.jpg"},{"id":100949890,"identity":"29d93153-9369-447e-8f81-187121a5ce81","added_by":"auto","created_at":"2026-01-23 07:06:12","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3629365,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7004747/v1/dadacd00-30c7-4734-b334-544666617483.pdf"},{"id":88670014,"identity":"733dbb77-84c4-4ef2-a271-21e52d74bfac","added_by":"auto","created_at":"2025-08-09 03:38:52","extension":"jpeg","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":737056,"visible":true,"origin":"","legend":"","description":"","filename":"GraphicalAbstract.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7004747/v1/0731fbe494d60f1d7a116dcc.jpeg"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eShort-Term Neurotoxic Effects of a Bioceramic Root Canal Sealer and the Modulatory Role of Stemregen\u003csup\u003e®\u003c/sup\u003e: A Rat Model Study\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eAlthough most endodontic sealers are successfully used in routine practice, apical extrusion of root canal sealers into periapical anatomical structures\u0026mdash;particularly the mandibular canal and mental foramen\u0026mdash;may result in neurological complications such as paresthesia, hypoesthesia, or persistent pain [\u003cspan additionalcitationids=\"CR2 CR3 CR4\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. These adverse outcomes are more frequently observed in the posterior mandibular region, where the porous trabecular bone permits easier diffusion of endodontic materials into surrounding neurovascular tissues [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The clinical severity depends on the duration of nerve contact, the volume extruded, and the inherent cytotoxicity of the material [\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Management strategies vary according to the clinical picture and may include pharmacological intervention or surgical removal in progressive cases [\u003cspan additionalcitationids=\"CR11 CR12\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eBioceramic-based sealers have been increasingly adopted in endodontic therapy due to their favorable biological and physicochemical profiles. Formulated mainly with tricalcium silicate, these sealers offer excellent sealing properties, antimicrobial alkalinity, and high biocompatibility [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. AH Plus\u0026reg; Bioceramic Sealer (Dentsply Sirona, Ballaigues, Switzerland) is a recently introduced injectable sealer composed of tricalcium silicate and zirconium dioxide, with a setting time of approximately 2\u0026ndash;4 hours [\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In vitro studies have demonstrated its positive bioactivity and cell viability [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]; however, in vivo data on its neurotoxicity are currently lacking. Although bioceramic sealers are generally biocompatible, their high alkalinity and formulation additives\u0026mdash;such as dimethyl sulfoxide and lithium carbonate\u0026mdash;warrant further investigation regarding their effects on nerve tissue in case of extrusion [\u003cspan additionalcitationids=\"CR20 CR21 CR22 CR23 CR24\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eRecent regenerative strategies have focused on stem cell\u0026ndash;based modulation for peripheral nerve repair. Nutritional interventions that mobilize endogenous stem cells may support neural regeneration by modulating inflammation, promoting trophic factor release, and enhancing repair processes [\u003cspan additionalcitationids=\"CR27\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Stemregen\u0026reg; (Biomics\u0026trade;, Incline Village, NV, USA) is a dietary supplement formulated to stimulate stem cell mobilization. Its active components\u0026mdash;such as sea buckthorn, Notoginseng, Aloe vera, and fucoidan-containing bladderwrack\u0026mdash;exhibit antioxidant and anti-inflammatory properties, as reported in previous studies [\u003cspan additionalcitationids=\"CR30 CR31 CR32 CR33 CR34 CR35 CR36\" citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e], and its components are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. However, its neuroprotective potential in peripheral nerve injury has not yet been explored in vivo.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eActive ingredients contained in each capsule of Stemregen\u0026reg;\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eActive Ingredient\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAmount\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSea Buckthorn Extract (30% Proanthocyanidins)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e250 mg\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBlue-Green Algae (Aphanizomenon flos-aquae) Extract\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e150 mg\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBladderwrack (Fucus vesiculosus) Extract (20% Phlorotannins)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e125 mg\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNotoginseng (Panax notoginseng) Extract (10% Notoginsenosides)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e62,5 mg\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAloe Vera Gel Powder (Stemaloe\u0026reg;)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e50 mg\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1\u0026rarr;3 Beta-Glucan (85%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e50 mg\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eColostrum Powder (Transfer Factor)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e25 mg\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBlack Pepper (Piper nigrum) Extract\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2,5 mg\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eThis study addresses a critical gap in the literature by evaluating the neurotoxic effects of AH Plus\u0026reg; Bioceramic Sealer in a rat sciatic nerve model and assessing whether systemic administration of Stemregen\u0026reg; can mitigate such effects. Therefore, this study aimed to evaluate the neurotoxic effects of AH Plus\u0026reg; Bioceramic Sealer on peripheral nerve tissue and to assess whether nutritional supplementation with Stemregen\u0026reg; could reduce inflammation and degeneration associated with such exposure.\u003c/p\u003e\u003cp\u003eWe hypothesized that AH Plus\u003csup\u003e\u0026reg;\u003c/sup\u003e Bioceramic Sealer would induce neurotoxic effects in the rat sciatic nerve, and that Stemregen\u003csup\u003e\u0026reg;\u003c/sup\u003e supplementation would reduce these adverse effects.\u003c/p\u003e"},{"header":"MATERIAL AND METHODS","content":"\u003cp\u003e This study was prepared in accordance with the PRILE 2021 guidelines for the reporting of animal experiments in the field of Endodontics; the flow diagram summarizing the experimental process is presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The study was conducted with the permissions numbered 2023/16\u0026thinsp;\u0026minus;\u0026thinsp;04 dated 20.09.2023 from the Fırat University Local Ethics Committee for Animal Experiments and was carried out in accordance with the ARRIVE guideline principles regarding the protection of laboratory animals. All rats used in the experiment were provided by the Firat University Experimental Research Center (FUERC), and the experimental stages were carried out at the same center and at the Firat University Faculty of Medicine Pathology Laboratory.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eDetermination of Sample Size and Formation of Experimental Groups\u003c/b\u003e\u003c/p\u003e\u003cp\u003eUsing the G*Power 3.1 (Version 3.1.9.2) program, the sample size was determined to be 12 rats per group and a total of 48 rats (n\u0026thinsp;=\u0026thinsp;12, 4 groups) with an α error value of 0.05, a 95% confidence interval, 0.5 effect size, and 80% power (1-β\u0026thinsp;=\u0026thinsp;0.80). Male Sprague-Dawley rats aged between 24\u0026ndash;36 weeks and weighing approximately 300\u0026ndash;350 grams, provided by FUERC, were used. Rats were preferred in the study due to their genetic similarity to humans and their common use in experimental studies. Additionally, male rats were used to minimize potential confounding effects of hormonal fluctuations associated with female reproductive cycles. All subjects were kept during the experiment in polyethylene cages with unrestricted access to food and water, in rooms with special ventilation systems at 70% humidity and 22\u0026ndash;24\u0026deg;C temperature. The rats were randomly divided into four groups as summarized in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eExperimental Groups and Interventions\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGroup\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNumber of Animals (n)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eIntervention\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eControl (C)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eEmpty polyethylene tube placed on sciatic nerve\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSupplement (NS)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eEmpty polyethylene tube\u0026thinsp;+\u0026thinsp;Stemregen\u0026reg; (300 mg/kg/day, oral gavage)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBioceramic (BC)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePolyethylene tube filled with AH Plus\u0026reg; Bioceramic Sealer placed on sciatic nerve\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBioceramic\u0026thinsp;+\u0026thinsp;Supplement (BC\u0026thinsp;+\u0026thinsp;NS)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBioceramic Sealer\u0026thinsp;+\u0026thinsp;Stemregen\u0026reg; (300 mg/kg/day, oral gavage)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eSurgical Procedure\u003c/b\u003e\u003c/p\u003e\u003cp\u003eTo determine the anesthesia dosage, the weights of all 48 rats in the groups were measured. On day 0, anesthesia was applied intramuscularly with 5 mg/kg, Ketasol 10% (ketamine) (Richter Pharma AG, Wels, Austria) and 45 mg/kg, Rompun 2% (xylazine) (Bayer Animal Health GmbH, Leverkusen, Germany). The depth of anesthesia was checked using the toe pinch test. After shaving the gluteal and thigh regions of the rats, they were fixed face-down onto the procedure board with plaster tape. The surgical field was disinfected with a povidone iodine solution (Adeka İla\u0026ccedil;, Samsun, Turkey).\u003c/p\u003e\u003cp\u003eIn the BC and BC\u0026thinsp;+\u0026thinsp;NS groups, to standardize the contact area between the canal filling paste and the sciatic nerve tissue and to minimize the contact of the paste with surrounding tissues, a sterile and non-toxic polyethylene tube (Galena Sağlık, Istanbul, Turkey) with a 4 mm diameter and 0.5 cm length was used (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eTo allow the root canal paste placed inside the tube to contact the sciatic nerve, the tube was longitudinally cut with a sterile scalpel to make it flexible and the AH Plus\u0026reg; Bioceramic Sealer paste was applied into the polyethylene tube using its special tip. A posterolateral longitudinal straight incision was made extending from the right greater trochanter to the lateral condyle of the femur to access the rats\u0026rsquo; right sciatic nerve. Then, the sciatic nerve was exposed between the gluteus superficialis and the biceps femoris by blunt dissection and made visible. The membranous structures over the nerve were removed and the nerve was isolated from the surrounding tissues. After the plastic polyethylene tubes cut longitudinally were filled with paste, they were placed on the sciatic nerve isolated from the environment with a thin paraffin strip (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eIn the C and NS groups, sterile and non-toxic polyethylene tubes of 4 mm diameter and 0.5 cm length were placed around the sciatic nerve. Then these tubes were fixed with a thin paraffin strip, but no root canal paste was applied into the tube (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). After all the procedures performed on the subjects, the sciatic nerve was placed back into its anatomical position and the incision area was closed with 3/0 silk sutures (Boz Tıbbi Malzeme A.Ş., Ankara, Turkey) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cb\u003eApplication of Nutritional Supplement and Histopthological Analysis\u003c/b\u003e\u003c/p\u003e\u003cp\u003eStemregen\u0026reg;, in powder mixture form inside capsules, was weighed precisely at 300 mg/kg and transferred into an experimental tube, then diluted with distilled water and mixed with a vortex device until dissolved. The prepared mixture was administered only to the subjects in the NS and BC\u0026thinsp;+\u0026thinsp;NS groups once a day by oral gavage for 15 days.\u003c/p\u003e\u003cp\u003eAt the end of the 15th day of the experiment, all rats were euthanized by gradual exposure to 80% carbon dioxide gas at a gas flow rate of 20% volume/minute. The sciatic nerve was excised, including healthy tissue from the proximal and distal ends of the area where the tube was placed, and then the polyethylene tube applied over the nerve was removed from the nerve tissue (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe sciatic nerve tissue samples were fixed in 10% buffered formalin solution for 24 hours. The fixed tissues were first washed under running water for 4\u0026ndash;8 hours and then passed through a series of alcohol (50%-100%) and xylene with increasing concentrations for tissue processing. Subsequently, the tissues were embedded into blocks and sections 4\u0026ndash;5 \u0026micro;m thick were taken using an automatic rotary RM2255 microtome (Leica Biosystems, Wetzlar, Germany). The obtained sections were deparaffinized by being kept in an oven at 60\u0026deg;C for two hours. Then the sections were stained with Hematoxylin-Eosin (H\u0026amp;E) and Luxol Fast Blue and mounted with Entellan\u0026reg; (Merck, Darmstadt, Germany). The stained sections were made ready for histological examination.\u003c/p\u003e\u003cp\u003eAll samples were examined and photographed with a BX53 trinocular microscope (Olympus Corporation, Tokyo, Japan).\u003c/p\u003e\u003cp\u003eThe evaluation of the experimental groups was carried out in three stages. In the first stage, the nerve tissue was evaluated for myelin, axon, and epineurium degeneration. In the second stage, the nerve tissue was evaluated for fibrosis, epineurium, and perineurium thickening. In the third stage, the tissue was semiquantitatively evaluated for lymphocyte infiltration, fibrocyte density, vacuolization, and edema.\u003c/p\u003e\u003cp\u003eEach parameter was scored semiquantitatively and the evaluation was performed by an expert pathologist blinded to the experimental groups to minimize bias [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Semiquantitative histopathological evaluations were performed using predefined scoring criteria detailed in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eHistological Scoring Parameters (Semiquantitative Evaluation)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eParameter\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDescription\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eScoring\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMyelin degeneration\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLoss or disruption of myelin sheath\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eG0 (None) to G5 (Very Severe)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAxonal degeneration\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eStructural damage or disintegration of axons\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eG0 to G5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEpineurium degeneration\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDegenerative changes in outer nerve sheath\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eG0 to G5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePerineurial thickening\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eStructural thickening of perineurium\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eG0 to G5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEpineurial thickening\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eStructural thickening of epineurium\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eG0 to G5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFibrosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePresence of fibrotic tissue around or within nerve bundles\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eG0 to G5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLymphocytic infiltration\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDegree of immune cell infiltration\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eG0 to G5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFibrocyte density\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePresence of fibrocytes within nerve tissue\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eG0 to G5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVacuolization\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIntracellular or extracellular vacuole formation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eG0 to G5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEdema\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePresence of interstitial fluid accumulation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eG0 to G5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eIBM SPSS Statistics 22 (Armonk, NY: IBM Corp.) program was used for statistical analysis. The conformity of parameters to normal distribution was evaluated with Kolmogorov-Smirnov and Shapiro Wilks tests, and it was determined that the parameters did not show a normal distribution. While evaluating the study data, descriptive statistical methods (minimum, maximum, mean, standard deviation, median) were used, and for comparisons between groups, Kruskal Wallis test and Dunn\u0026rsquo;s test to determine the group causing the difference were used. Significance was considered at the p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 level.\u003c/p\u003e\u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003eHistological analysis revealed that the Bioceramic (BC) group exhibited significantly higher degeneration and inflammation scores compared to the Control (C) and Supplement (NS) groups across all evaluated parameters (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05; Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, Table\u0026nbsp;5). Specifically, the BC group showed severe myelin and axonal degeneration, prominent thickening of the epineurium and perineurium, and increased fibrocyte density, vacuolization, and interstitial edema. The median scores for myelin degeneration and edema reached grade 3, demonstrating significantly greater neural injury than in the other groups (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eHistological Scoring Results\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"26\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c14\" colnum=\"14\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c15\" colnum=\"15\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c16\" colnum=\"16\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c17\" colnum=\"17\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c18\" colnum=\"18\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c19\" colnum=\"19\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c20\" colnum=\"20\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c21\" colnum=\"21\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c22\" colnum=\"22\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c23\" colnum=\"23\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c24\" colnum=\"24\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c25\" colnum=\"25\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c26\" colnum=\"26\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e\u003cp\u003eControl Group\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"6\" nameend=\"c13\" namest=\"c8\"\u003e\u003cp\u003eSupplement Group\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"6\" nameend=\"c19\" namest=\"c14\"\u003e\u003cp\u003eBioceramic Group\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"6\" nameend=\"c25\" namest=\"c20\"\u003e\u003cp\u003eBioceramic\u0026thinsp;+\u0026thinsp;Supplement Group\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c26\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eG0\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eG1\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eG2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eG3\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eG4\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eG5\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eG0\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eG1\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u003cp\u003eG2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c11\"\u003e\u003cp\u003eG3\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c12\"\u003e\u003cp\u003eG4\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c13\"\u003e\u003cp\u003eG5\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c14\"\u003e\u003cp\u003eG0\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c15\"\u003e\u003cp\u003eG1\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c16\"\u003e\u003cp\u003eG2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c17\"\u003e\u003cp\u003eG3\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c18\"\u003e\u003cp\u003eG4\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c19\"\u003e\u003cp\u003eG5\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c20\"\u003e\u003cp\u003eG0\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c21\"\u003e\u003cp\u003eG1\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c22\"\u003e\u003cp\u003eG2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c23\"\u003e\u003cp\u003eG3\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c24\"\u003e\u003cp\u003eG4\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c25\"\u003e\u003cp\u003eG5\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c26\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMyelin Degeneration\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c11\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c12\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c13\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c14\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c15\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c16\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c17\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c18\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c19\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c20\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c21\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c22\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c23\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c24\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c25\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c26\"\u003e\u003cp\u003e0,001*\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAxonal Degeneration\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e8\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e4\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e\u003cb\u003e9\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e\u003cb\u003e3\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c15\"\u003e\u003cp\u003e\u003cb\u003e3\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c16\"\u003e\u003cp\u003e\u003cb\u003e4\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u003cp\u003e\u003cb\u003e5\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c18\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c19\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c20\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c21\"\u003e\u003cp\u003e\u003cb\u003e6\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c22\"\u003e\u003cp\u003e\u003cb\u003e3\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c23\"\u003e\u003cp\u003e\u003cb\u003e3\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c24\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c25\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c26\"\u003e\u003cp\u003e\u003cb\u003e0,001*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eEpineurium Degeneration\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e8\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e4\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e\u003cb\u003e8\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e\u003cb\u003e4\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003e\u003cb\u003e3\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c15\"\u003e\u003cp\u003e\u003cb\u003e6\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c16\"\u003e\u003cp\u003e\u003cb\u003e3\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c18\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c19\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c20\"\u003e\u003cp\u003e\u003cb\u003e4\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c21\"\u003e\u003cp\u003e\u003cb\u003e6\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c22\"\u003e\u003cp\u003e\u003cb\u003e2\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c23\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c24\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c25\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c26\"\u003e\u003cp\u003e\u003cb\u003e0,032*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eFibrosis\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e9\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e3\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e\u003cb\u003e9\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e\u003cb\u003e3\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c15\"\u003e\u003cp\u003e\u003cb\u003e5\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c16\"\u003e\u003cp\u003e\u003cb\u003e5\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u003cp\u003e\u003cb\u003e2\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c18\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c19\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c20\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c21\"\u003e\u003cp\u003e\u003cb\u003e6\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c22\"\u003e\u003cp\u003e\u003cb\u003e4\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c23\"\u003e\u003cp\u003e\u003cb\u003e2\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c24\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c25\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c26\"\u003e\u003cp\u003e\u003cb\u003e0,001*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eEpineurial Thickening\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e10\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e2\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e\u003cb\u003e10\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e\u003cb\u003e2\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c15\"\u003e\u003cp\u003e\u003cb\u003e4\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c16\"\u003e\u003cp\u003e\u003cb\u003e8\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c18\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c19\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c20\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c21\"\u003e\u003cp\u003e\u003cb\u003e9\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c22\"\u003e\u003cp\u003e\u003cb\u003e3\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c23\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c24\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c25\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c26\"\u003e\u003cp\u003e\u003cb\u003e0,001*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePerineurial Thickening\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e9\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e3\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e\u003cb\u003e9\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e\u003cb\u003e3\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c15\"\u003e\u003cp\u003e\u003cb\u003e7\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c16\"\u003e\u003cp\u003e\u003cb\u003e5\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c18\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c19\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c20\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c21\"\u003e\u003cp\u003e\u003cb\u003e8\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c22\"\u003e\u003cp\u003e\u003cb\u003e4\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c23\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c24\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c25\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c26\"\u003e\u003cp\u003e\u003cb\u003e0,001*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eLymphocyte Infiltration\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e7\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e5\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e\u003cb\u003e8\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e\u003cb\u003e4\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c15\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c16\"\u003e\u003cp\u003e\u003cb\u003e7\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u003cp\u003e\u003cb\u003e4\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c18\"\u003e\u003cp\u003e\u003cb\u003e1\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c19\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c20\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c21\"\u003e\u003cp\u003e\u003cb\u003e4\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c22\"\u003e\u003cp\u003e\u003cb\u003e5\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c23\"\u003e\u003cp\u003e\u003cb\u003e3\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c24\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c25\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c26\"\u003e\u003cp\u003e\u003cb\u003e0,001*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eFibrocyte Density\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e8\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e4\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e\u003cb\u003e8\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e\u003cb\u003e4\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c15\"\u003e\u003cp\u003e\u003cb\u003e6\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c16\"\u003e\u003cp\u003e\u003cb\u003e4\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u003cp\u003e\u003cb\u003e2\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c18\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c19\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c20\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c21\"\u003e\u003cp\u003e\u003cb\u003e7\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c22\"\u003e\u003cp\u003e\u003cb\u003e3\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c23\"\u003e\u003cp\u003e\u003cb\u003e2\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c24\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c25\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c26\"\u003e\u003cp\u003e\u003cb\u003e0,001*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eVacuolization\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e8\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e4\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e\u003cb\u003e9\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e\u003cb\u003e3\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c15\"\u003e\u003cp\u003e\u003cb\u003e5\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c16\"\u003e\u003cp\u003e\u003cb\u003e4\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u003cp\u003e\u003cb\u003e3\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c18\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c19\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c20\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c21\"\u003e\u003cp\u003e\u003cb\u003e7\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c22\"\u003e\u003cp\u003e\u003cb\u003e5\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c23\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c24\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c25\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c26\"\u003e\u003cp\u003e\u003cb\u003e0,001*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eEdema\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e7\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e5\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e\u003cb\u003e10\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e\u003cb\u003e2\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c15\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c16\"\u003e\u003cp\u003e\u003cb\u003e3\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u003cp\u003e\u003cb\u003e6\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c18\"\u003e\u003cp\u003e\u003cb\u003e3\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c19\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c20\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c21\"\u003e\u003cp\u003e\u003cb\u003e5\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c22\"\u003e\u003cp\u003e\u003cb\u003e6\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c23\"\u003e\u003cp\u003e\u003cb\u003e1\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c24\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c25\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c26\"\u003e\u003cp\u003e\u003cb\u003e0,001*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"26\"\u003e\u003cem\u003eP: Significance level, G: Grade, G0 (None), G1 (Mild), G2 (Moderate), G3 (Significant), G4 (Severe), G5 (Very Severe)\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"26\"\u003e*Kruskal\u0026ndash;Wallis Test, \u003cem\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eTable 5.\u003c/strong\u003e Comparison of the Groups Based on the Evaluated Parameters. Histopathological scores (0-5 scale) for myelin degeneration, axon degeneration, epineurium/perineurium thickening, fibrosis, lymphocyte infiltration, fibrocyte density, vacuolization, and edema. Minimum, median, and maximum values represent the range of scores across 12 rats per group.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"1055\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 11.3852%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 20.6831%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eControl Group\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;(a)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 20.9677%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSupplement Group\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;(b)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 19.7343%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBioceramic Group (c)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 20.9677%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBioceramic + Supplement Group (d)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.26186%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 11.3852%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEvaluated Parameters\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.88235%;\"\u003e\n \u003cp\u003eMin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.86717%;\"\u003e\n \u003cp\u003eMed\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.93359%;\"\u003e\n \u003cp\u003eMax\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.12334%;\"\u003e\n \u003cp\u003eMin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5313%;\"\u003e\n \u003cp\u003eMed\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.31309%;\"\u003e\n \u003cp\u003eMax\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.31309%;\"\u003e\n \u003cp\u003eMin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.96205%;\"\u003e\n \u003cp\u003eMed\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.4592%;\"\u003e\n \u003cp\u003eMax\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.4592%;\"\u003e\n \u003cp\u003eMin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.7211%;\"\u003e\n \u003cp\u003eMed\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.78748%;\"\u003e\n \u003cp\u003eMax\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.26186%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 11.3852%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMyelin Degeneration\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.88235%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.86717%;\"\u003e\n \u003cp\u003e0.42\u0026plusmn;0.51 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.93359%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.12334%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5313%;\"\u003e\n \u003cp\u003e0.33\u0026plusmn;0.49 (0)\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(b-c*)(b-d*)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.31309%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.31309%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.96205%;\"\u003e\n \u003cp\u003e2.92\u0026plusmn;0.67 (3)\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(a-c*)(b-c*)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.4592%;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.4592%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.7211%;\"\u003e\n \u003cp\u003e1.92\u0026plusmn;0.79 (2)\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(a-d*)(b-d*)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.78748%;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.26186%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0,001*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 11.3852%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAxonal Degeneration\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.88235%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.86717%;\"\u003e\n \u003cp\u003e0.33\u0026plusmn;0.49 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.93359%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.12334%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5313%;\"\u003e\n \u003cp\u003e0.25\u0026plusmn;0.45 (0)\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(b-c*)(b-d*)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.31309%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.31309%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.96205%;\"\u003e\n \u003cp\u003e2.17\u0026plusmn;0.83 (2)\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(a-c*)(b-c*)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.4592%;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.4592%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.7211%;\"\u003e\n \u003cp\u003e1.75\u0026plusmn;0.87 (1.5)\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(a-d*)(b-d*)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.78748%;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.26186%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0,001*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 11.3852%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEpineurium Degeneration\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.88235%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.86717%;\"\u003e\n \u003cp\u003e0.33\u0026plusmn;0.49 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.93359%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.12334%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5313%;\"\u003e\n \u003cp\u003e0.33\u0026plusmn;0.49 (0)\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(b-c*)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.31309%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.31309%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.96205%;\"\u003e\n \u003cp\u003e1.0\u0026plusmn;0.74 (1)\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(a-c*)(b-c*)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.4592%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.4592%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.7211%;\"\u003e\n \u003cp\u003e0.83\u0026plusmn;0.72 (1)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.78748%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.26186%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0,032*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 11.3852%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFibrosis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.88235%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.86717%;\"\u003e\n \u003cp\u003e0.25\u0026plusmn;0.45 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.93359%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.12334%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5313%;\"\u003e\n \u003cp\u003e0.25\u0026plusmn;0.45 (0)\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(b-c*)(b-d*)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.31309%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.31309%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.96205%;\"\u003e\n \u003cp\u003e1.75\u0026plusmn;0.75 (2)\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(a-c*)(b-c*)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.4592%;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.4592%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.7211%;\"\u003e\n \u003cp\u003e1.67\u0026plusmn;0.78 (1.5)\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(a-d*)(b-d*)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.78748%;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.26186%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0,001*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 11.3852%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEpineurial Thickening\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.88235%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.86717%;\"\u003e\n \u003cp\u003e0.17\u0026plusmn;0.39 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.93359%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.12334%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5313%;\"\u003e\n \u003cp\u003e0.17\u0026plusmn;0.39 (0)\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(b-c*)(b-d*)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.31309%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.31309%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.96205%;\"\u003e\n \u003cp\u003e1.67\u0026plusmn;0.49 (2)\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(a-c*)(b-c*)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.4592%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.4592%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.7211%;\"\u003e\n \u003cp\u003e1.25\u0026plusmn;0.45 (1)\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(a-d*)(b-d*)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.78748%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.26186%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0,001*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 11.3852%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePerineurial Thickening\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.88235%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.86717%;\"\u003e\n \u003cp\u003e0.25\u0026plusmn;0.45 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.93359%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.12334%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5313%;\"\u003e\n \u003cp\u003e0.25\u0026plusmn;0.45 (0)\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(b-c*)(b-d*)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.31309%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.31309%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.96205%;\"\u003e\n \u003cp\u003e1.42\u0026plusmn;0.51 (1)\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(a-c*)(b-c*)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.4592%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.4592%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.7211%;\"\u003e\n \u003cp\u003e1.33\u0026plusmn;0.49 (1)\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(a-d*)(b-d*)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.78748%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.26186%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0,001*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 11.3852%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLymphocyte Infiltration\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.88235%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.86717%;\"\u003e\n \u003cp\u003e0.42\u0026plusmn;0.51 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.93359%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.12334%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5313%;\"\u003e\n \u003cp\u003e0.33\u0026plusmn;0.49 (0)\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(b-c*)(b-d*)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.31309%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.31309%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.96205%;\"\u003e\n \u003cp\u003e2.5\u0026plusmn;0.67 (2)\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(a-c*)(b-c*)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.4592%;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.4592%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.7211%;\"\u003e\n \u003cp\u003e1.92\u0026plusmn;0.79 (2)\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(a-d*)(b-d*)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.78748%;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.26186%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0,001*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 11.3852%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFibrocyte Density\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.88235%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.86717%;\"\u003e\n \u003cp\u003e0.33\u0026plusmn;0.49 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.93359%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.12334%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5313%;\"\u003e\n \u003cp\u003e0.33\u0026plusmn;0.49 (0)\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(b-c*)(b-d*)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.31309%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.31309%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.96205%;\"\u003e\n \u003cp\u003e1.67\u0026plusmn;0.78 (1.5)\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(a-c*)(b-c*)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.4592%;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.4592%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.7211%;\"\u003e\n \u003cp\u003e1.58\u0026plusmn;0.79 (1)\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(a-d*)(b-d*)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.78748%;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.26186%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0,001*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 11.3852%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVacuolization\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.88235%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.86717%;\"\u003e\n \u003cp\u003e0.33\u0026plusmn;0.49 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.93359%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.12334%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5313%;\"\u003e\n \u003cp\u003e0.25\u0026plusmn;0.45 (0)\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(b-c*)(b-d*)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.31309%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.31309%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.96205%;\"\u003e\n \u003cp\u003e1.83\u0026plusmn;0.83 (2)\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(a-c*)(b-c*)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.4592%;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.4592%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.7211%;\"\u003e\n \u003cp\u003e1.42\u0026plusmn;0.51 (1)\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(a-d*)(b-d*)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.78748%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.26186%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0,001*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 11.3852%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEdema\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.88235%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.86717%;\"\u003e\n \u003cp\u003e0.42\u0026plusmn;0.51 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.93359%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.12334%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5313%;\"\u003e\n \u003cp\u003e0.17\u0026plusmn;0.39 (0)\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(b-c*)(b-d*)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.31309%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.31309%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.96205%;\"\u003e\n \u003cp\u003e3.0\u0026plusmn;0.74 (3)\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(a-c*)(b-c*)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.4592%;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.4592%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.7211%;\"\u003e\n \u003cp\u003e1.67\u0026plusmn;0.65 (1)\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(a-d*)(b-d*)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.78748%;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.26186%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0,001*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eP: Significance level, Min: Minimum, Med: Median, Max: Maximum, a: Control group, b: Supplement group, c: Bioceramic group, d: Bioceramic + Supplement group. (x\u0026ndash;y*):\u0026nbsp;There is a statistically significant difference between groups x and y\u003cbr\u003e\u0026nbsp;Kruskal\u0026ndash;Wallis Test / Dunn\u0026rsquo;s Post Hoc Test, P \u0026lt; 0.05\u003c/p\u003e\u003cp\u003eIn contrast, the Bioceramic\u0026thinsp;+\u0026thinsp;Supplement (BC\u0026thinsp;+\u0026thinsp;NS) group demonstrated lower median scores for all histological markers when compared to the BC group. Notable reductions were observed in axonal degeneration (median: 1.75 vs. 2.17), fibrosis (1.67 vs. 1.75), and lymphocyte infiltration (1.92 vs. 2.50). However, none of these differences reached statistical significance (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e\u003cp\u003eThe NS and C groups exhibited minimal or no pathological changes, with grade 0 or 1 scores observed in all parameters. The structural integrity of the nerve was well preserved in these groups.\u003c/p\u003e\u003cp\u003eSemiquantitative scoring results for all evaluated parameters, including myelin degeneration, axonal degeneration, fibrosis, perineurial and epineurial thickening, edema, and inflammatory cell infiltration, are presented in Tables\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e and 5. Representative histological images are shown in Figs.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e and \u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eWe hypothesized that the bioceramic root canal sealer AH Plus\u0026reg; Bioceramic Sealer would induce neurotoxic effects in the rat sciatic nerve, and that the nutritional supplement Stemregen\u0026reg; would reduce these neurotoxic effects. The null hypothesis stated that the sealer would not cause neural damage and that Stemregen\u0026reg; would have no mitigating effect. Based on the semiquantitative histopathological findings, the null hypothesis was partially rejected. Significant neural degeneration and inflammation were observed in the Bioceramic group (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), while the Bioceramic\u0026thinsp;+\u0026thinsp;Supplement group exhibited lower scores across all parameters. However, these reductions did not reach statistical significance (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e\u003cp\u003e\u003cb\u003eNeurotoxic Effects of Bioceramic Sealer\u003c/b\u003e\u003c/p\u003e\u003cp\u003eApplication of the bioceramic sealer resulted in marked histopathological alterations, including disruption of myelin architecture, axonal injury, thickening of the perineurium, and notable inflammatory cell infiltration. These outcomes align with previous reports indicating that endodontic sealers, particularly when extruded near neural structures, can provoke adverse neural responses [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Although bioceramic sealers are generally considered biocompatible in in vitro settings [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], such environments fail to capture the complex interactions that occur upon direct nerve contact in vivo. The BC group demonstrated prominent histological alterations, including axonal and myelin degeneration, perineurial thickening, lymphocyte infiltration, and interstitial edema\u0026mdash;all of which align with prior case-based evidence suggesting adverse effects when sealers are extruded into neurovascular spaces. These changes were most notable in parameters such as myelin degeneration (median score\u0026thinsp;=\u0026thinsp;3) and edema (median score\u0026thinsp;=\u0026thinsp;3), indicating acute neural tissue response to chemical exposure. Although in vitro studies have suggested the biocompatibility of calcium silicate\u0026ndash;based sealers [\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], in vivo reports indicate that direct contact with nerve tissue can provoke adverse effects [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Therefore, the present findings underscore the need for caution in clinical cases involving close proximity to neural structures such as the inferior alveolar nerve.\u003c/p\u003e\u003cp\u003eOne likely mechanism underlying this neurotoxicity is the high alkalinity generated during the setting reaction of tricalcium silicate, which may destabilize nerve membranes, disturb calcium homeostasis, and initiate apoptotic cascades [\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Moreover, the presence of formulation additives such as dimethyl sulfoxide (DMSO) and lithium carbonate may amplify neural toxicity. DMSO has been shown to increase cell membrane permeability, facilitating the penetration of reactive compounds into nerve tissue and potentially exacerbating cytotoxic effects [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. While lithium carbonate is used therapeutically for mood stabilization, its potential neurotoxic effects\u0026mdash;including those on myelin integrity\u0026mdash;have primarily been documented in central nervous system models. To date, evidence regarding its impact on peripheral nerve tissue remains limited and inconclusive [\u003cspan additionalcitationids=\"CR24\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe root canal paste may have caused ischemia and hypoxia in nerve tissue by exerting mechanical pressure through the polyethylene tube, impairing blood flow and triggering inflammation [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. Additionally, the surgical procedure itself may have contributed to the mild inflammation in the C and NS groups and further increased tissue damage in the BC and BC\u0026thinsp;+\u0026thinsp;NS groups [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eClinically, these observations are particularly relevant for posterior mandibular regions, where the proximity of root apices to the mandibular canal increases the risk of sealer extrusion affecting the inferior alveolar nerve [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. As this model demonstrates, even a single, localized exposure to the material may lead to measurable neural tissue damage within a short period.\u003c/p\u003e\u003cp\u003eA sciatic nerve model was selected due to its large caliber, well-defined anatomy, and ease of surgical access, which allow for reproducible placement of test materials and standardized histological assessment. Although anatomically distinct, its mixed motor-sensory composition shares functional similarities with the inferior alveolar nerve, making it a suitable surrogate for peripheral neurotoxicity evaluation [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. Furthermore, the direct-contact application used in this study represents a worst-case scenario rather than typical clinical conditions of apical extrusion, where surrounding periapical tissues may buffer or dilute material exposure. Therefore, while the model provides valuable insight into potential biological effects, caution is warranted when extrapolating these findings directly to clinical settings.\u003c/p\u003e\u003cp\u003e\u003cb\u003ePotential Neuroprotective Role of Stemregen\u0026reg;\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe BC\u0026thinsp;+\u0026thinsp;NS group showed a downward trend in all inflammation and degeneration parameters compared to the BC-only group, especially in axonal damage, fibrocyte density, and vacuolization. However, these reductions did not reach statistical significance, possibly due to the acute timeline of the model or the modest effect size of the supplement [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. While the downward trend observed in axonal degeneration, fibrosis, and lymphocytic infiltration suggests a potential protective effect of Stemregen\u0026reg;, none of these reductions were statistically significant (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05). In animals treated with Stemregen\u0026reg; in conjunction with the bioceramic sealer, histopathological damage scores\u0026mdash;including axonal degeneration, myelin disorganization, and inflammatory infiltration\u0026mdash;were consistently lower than those observed in the BC-only group. Despite consistently lower semiquantitative scores in the BC\u0026thinsp;+\u0026thinsp;NS group, the differences failed to achieve statistical significance when compared to the Bioceramic-only group (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05 for all parameters).\u003c/p\u003e\u003cp\u003eAccording to the manufacturer, Stemregen\u0026reg; is a commercially available multi-ingredient dietary supplement promoted to stimulate endogenous stem cell release from the bone marrow and to modulate systemic inflammation by acting on the immune environment. Its botanical components include sea buckthorn, Notoginseng, fucoidan, and Aloe vera, several of which have demonstrated anti-inflammatory, antioxidant, and neuroprotective properties in various experimental models [\u003cspan additionalcitationids=\"CR30 CR31 CR32 CR33 CR34 CR35 CR36\" citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. For instance, Notoginseng saponins, such as ginsenosides and notoginsenosides, may enhance stem cell mobilization and protect nerve tissue by reducing inflammation, oxidative stress, and promoting regeneration [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Similarly, Stemaloe\u0026reg; (Aloe vera gel powder) and 1\u0026rarr;3 beta-glucans have been reported to enhance circulating stem cell levels and support immune function, potentially aiding tissue repair in nerve injury models [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. Bladderwrack algae, rich in phenolic compounds, also contribute to the reduction of inflammation in nerve tissue by regulating oxidative stress and supporting stem cell mobilization [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Also, blue-green algae help stem cells mobilize from the bone marrow by blocking L-selectin [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. These features are thought to help reduce inflammation in nerve tissue.\u003c/p\u003e\u003cp\u003eWhile these compounds have been studied independently, Stemregen\u0026reg; as a combined formulation has not yet been evaluated in any peer-reviewed in vivo models involving peripheral nerve injury. This limits direct attribution of any observed effect to stem cell mobilization or anti-inflammatory synergy. While the active ingredients of Stemregen\u0026reg; have documented immunomodulatory and antioxidant properties in isolation, the effects of the full formulation in peripheral nerve injury remain to be validated in long-term or functional outcome models.\u003c/p\u003e\u003cp\u003e\u003cb\u003eStudy Limitations and Future Directions\u003c/b\u003e\u003c/p\u003e\u003cp\u003eSeveral limitations should be considered when interpreting these results. Firstly, reliance solely on histopathological evaluation restricts the ability to assess molecular and functional aspects of nerve damage. Future studies should incorporate complementary methods such as nerve conduction testing, immunohistochemistry, and gene expression analysis to provide a more comprehensive understanding of injury and repair mechanisms. Secondly, only AH Plus\u0026reg; Bioceramic Sealer was tested. It is important to clarify that although AH Plus\u0026reg; Bioceramic Sealer is no longer available on the market, there is no evidence linking its withdrawal to safety concerns arising from adverse biological effects. Available information suggests that the product was discontinued due to commercial and marketing considerations, rather than due to observed neurotoxicity or clinical complications. Consequently, the findings of this study should not be interpreted as a factor in the decision to withdraw this sealer. Although this specific product has been withdrawn from the market, its chemical characteristics\u0026mdash;including tricalcium silicate content and alkaline-setting reaction\u0026mdash;are representative of other bioceramic sealers still in clinical use, rendering the findings relevant beyond the tested brand [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThirdly, although polyethylene tubes were employed to standardize sealer placement, the degree of mechanical pressure exerted on the sciatic nerve was not quantified. Therefore, the contribution of compression-induced ischemia to the observed histopathological changes cannot be ruled out [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eTo further expand on these findings, future investigations should employ longer follow-up periods to evaluate late-stage healing, including potential regenerative effects. Functional testing, such as nerve conduction studies, would provide valuable information on the clinical relevance of structural changes. Additionally, molecular-level assessments could clarify the roles of inflammatory and reparative signaling pathways. Comparative analyses of alternative bioceramic sealers and stem cell\u0026ndash;activating formulations may help differentiate material- or agent-specific effects. Ultimately, such studies would improve the risk assessment and clinical selection of root canal sealers in complex anatomical contexts.\u003c/p\u003e\u003cp\u003eFrom a clinical perspective, these findings should be interpreted with caution. While direct contact between root canal sealers and nerve tissue is rare in daily practice, accidental extrusion into adjacent neurovascular structures\u0026mdash;particularly in anatomically vulnerable areas like the mandibular canal\u0026mdash;can occur. This study highlights the potential biological risks associated with such events and underscores the importance of precise working length control and careful obturation, especially when using sealers with high alkalinity or reactive excipients.\u003c/p\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003eIn this in vivo rat model, AH Plus\u0026reg; Bioceramic Sealer induced significant neurotoxic effects in peripheral nerve tissue, as evidenced by increased degeneration, inflammation, and structural damage (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Systemic administration of Stemregen\u0026reg; led to mild reductions in histopathological injury scores when combined with the sealer; however, these differences did not reach statistical significance (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05). While a downward trend was observed, the clinical relevance of this potential protective effect remains inconclusive. These results underscore the importance of minimizing sealer extrusion, particularly in anatomically sensitive regions, and highlight the need for further preclinical and translational studies evaluating both the biocompatibility of calcium silicate\u0026ndash;based sealers and the therapeutic value of regenerative adjuncts such as stem cell\u0026ndash;mobilizing supplements.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eFUERC Fırat University Experimental Research Center\u003c/p\u003e\n\u003cp\u003eC Control Group\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNS Nutritional Supplement Group\u003c/p\u003e\n\u003cp\u003eBC Bioceramic Group\u003c/p\u003e\n\u003cp\u003eBC + NS Bioceramic plus Nutritional Supplement Group\u003c/p\u003e\n\u003cp\u003eH\u0026amp;E Hematoxylin and Eosin\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDMSO Dimethyl Sulfoxide\u003c/p\u003e\n\u003cp\u003eSPSS Statistical Package for the Social Sciences\u003c/p\u003e\n\u003cp\u003eFUBAP Fırat University Scientific Research Projects\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eETHICS APPROVAL AND CONSENT TO PARTICIPATE\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll experiments in this study were conducted in accordance with the ARRIVE guidelines and approved by the Fırat University Local Ethics Committee for Animal Experiments (protocol number 2023/16-04, dated September 20, 2023).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCONSENT FOR PUBLICATION\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAVAILABILITY OF DATA AND MATERIALS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed during this study are included in this published article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCOMPETING INTERESTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFUNDING\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis study was supported by Firat University Scientific Research Project Coordination (Grant number: DHF.23.07).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAUTHOR CONTRIBUTIONS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHaydar İrfan Y\u0026Uuml;CEL: Conceptualization, Methodology, Resources, Investigation, Data curation, Writing \u0026ndash; Original Draft Preparation, Writing - review and editing\u003c/p\u003e\n\u003cp\u003eMevl\u0026uuml;t Sinan OCAK: Supervision, Conceptualization, Methodology, Investigation, Funding acquisition, Resources, Writing - review and editing\u003c/p\u003e\n\u003cp\u003eSerkan D\u0026Uuml;NDAR: Methodology, Writing - review and editing\u003c/p\u003e\n\u003cp\u003eİbrahim Hanifi \u0026Ouml;ZERCAN: Methodology, Investigation, Writing - review and editing\u003c/p\u003e\n\u003cp\u003eEbru G\u0026Ouml;KDERE: Methodology, Writing - review and editing\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eACKNOWLEDGEMENTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis manuscript derived from Haydar İrfan Y\u0026Uuml;CEL\u0026rsquo;s thesis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCLINICAL TRIAL NUMBER\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003ePoveda R, Bag\u0026aacute;n JV, Fern\u0026aacute;ndez JM, Sanchis JM. 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Stem Cells. 2008;26(5):1231\u0026ndash;40. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1634/stemcells.2007-0712\u003c/span\u003e\u003cspan address=\"10.1634/stemcells.2007-0712\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Dietary Supplements, Nerve damage, Premixed bioceramic, Sealer extrusion, Stem cells","lastPublishedDoi":"10.21203/rs.3.rs-7004747/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7004747/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eExtrusion of root canal sealers into neurovascular tissues can result in rare but serious neurological complications, including paresthesia and neuropathic pain. This study aimed to evaluate the neurotoxic effects of AH Plus\u0026reg; Bioceramic Sealer when extruded near peripheral nerve tissue and to assess the potential protective role of Stemregen\u0026reg;, a stem cell\u0026ndash;mobilizing nutritional supplement.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eForty-eight male Sprague-Dawley rats were randomly assigned to four groups (n\u0026thinsp;=\u0026thinsp;12): Control, Supplement only, Bioceramic only, and Bioceramic\u0026thinsp;+\u0026thinsp;Supplement. Sterile polyethylene tubes containing AH Plus\u0026reg; Bioceramic Sealer were applied in contact with the sciatic nerve in the relevant groups. Stemregen\u0026reg; was administered orally at 300 mg/kg/day for 15 days. At the end of the experiment, nerve tissues were harvested and examined histologically.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eSevere axonal degeneration, inflammation, and fibrosis were observed in the Bioceramic group compared to controls (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). The Bioceramic\u0026thinsp;+\u0026thinsp;Supplement group showed reduced histological damage scores, though the differences were not statistically significant.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eThese findings suggest that the bioceramic sealer may induce peripheral neurotoxicity under direct exposure, while Stemregen\u0026reg; may offer limited histological improvement. Further long-term and functional studies are required to evaluate the clinical relevance of these results and to assess the therapeutic potential of nutritional stem cell modulators in endodontic practice.\u003c/p\u003e","manuscriptTitle":"Short-Term Neurotoxic Effects of a Bioceramic Root Canal Sealer and the Modulatory Role of Stemregen®: A Rat Model Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-09 03:30:47","doi":"10.21203/rs.3.rs-7004747/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5424fa7e-e876-4853-b471-040571a077a2","owner":[],"postedDate":"August 9th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-22T12:11:59+00:00","versionOfRecord":[],"versionCreatedAt":"2025-08-09 03:30:47","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7004747","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7004747","identity":"rs-7004747","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}