A Randomized Controlled Trial Evaluating the Effect of Local Application of Sodium Alendronate Gel and Low-Level Laser Therapy (LLLT) On Peri-Implant Tissue Healing in Wistar Rats

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Methods Twenty-four male Wistar rats were randomly divided into 4 groups: Group 1 (the control group), Group 2 (the Sodium Alendronate group), Group 3 (the Sodium Alendronate and LLLT group), and Group 4 (the LLLT group). Mini implants were placed in right and left femur bones in all the four groups. Implants of groups 2 and 3 were coated in 1mg Carbapol gel incorporated with 1 mg Sodium alendronate. Groups 3 and 4 were exposed to LLLT (CO2 laser, wavelength 830nm; 2.1J/cm2) on 1st, 7th, 14th and 21st day. Animals were sacrificed on the 28th day, following which the femurs were dissected out and stored in 10% buffered formaldehyde for histopathological analysis. Results Groups 3 and 4 showed bony union and formation of reorganized spongiosa whereas Groups 1 and 2 showed fibrous union. The bone marrow from Group 3 had an adult-type fatty marrow, while that from Group 2 and 4 was occupied by red blood cells. Group 1 showed initial stages of bone healing in which the defect occupied more than half of the bone marrow. Conclusion LLLT given using CO2 laser therapy, together with a one-time application of Sodium Alendronate in Carbapol gel at the time of implant placement optimally enhances healing of peri-implant tissues. " } { "@context": "http://schema.org", "@type": "BreadcrumbList", "itemListElement": [ { "@type": "ListItem", "position": "1", "item": { "@id": "https://f1000research.com/", "name": "Home" } }, { "@type": "ListItem", "position": "2", "item": { "@id": "https://f1000research.com/browse/articles", "name": "Browse" } }, { "@type": "ListItem", "position": "3", "item": { "@id": "https://f1000research.com/articles/14-147", "name": "A Randomized Controlled Trial Evaluating the Effect of Local Application..." } } ] } Home Browse A Randomized Controlled Trial Evaluating the Effect of Local Application... ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article Mishra D, Urala AS, Nayak AS et al. A Randomized Controlled Trial Evaluating the Effect of Local Application of Sodium Alendronate Gel and Low-Level Laser Therapy (LLLT) On Peri-Implant Tissue Healing in Wistar Rats [version 1; peer review: 2 approved] . F1000Research 2025, 14 :147 ( https://doi.org/10.12688/f1000research.160479.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Research Article A Randomized Controlled Trial Evaluating the Effect of Local Application of Sodium Alendronate Gel and Low-Level Laser Therapy (LLLT) On Peri-Implant Tissue Healing in Wistar Rats [version 1; peer review: 2 approved] Divya Mishra 1 * , Arun S Urala 1 , Ashwath S Nayak https://orcid.org/0000-0002-8029-6002 2 , [...] Divya S https://orcid.org/0000-0001-8957-8914 1 * , Rajay Kamath 3 , Lakshmi Narayan Bairy https://orcid.org/0000-0002-1828-6946 4 , Gargi S 1 Divya Mishra 1 * , Arun S Urala 1 , [...] Ashwath S Nayak https://orcid.org/0000-0002-8029-6002 2 , Divya S https://orcid.org/0000-0001-8957-8914 1 * , Rajay Kamath 3 , Lakshmi Narayan Bairy https://orcid.org/0000-0002-1828-6946 4 , Gargi S 1 * Equal contributors PUBLISHED 30 Jan 2025 Author details Author details 1 Department of Orthodontics and Dentofacial Orthopaedics, Manipal College of Dental Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India 2 Department of Orthodontics and Dentofacial Orthopaedics, Bapuji Dental College and Hospital, Davanagere, Karanataka, 577004, India 3 Department of Clinical Genomics, Mayo Clinic Minnesota, Rochester, Minnesota, USA 4 Department of Pharmacology, RAK College of Medical Sciences, RAK Medical and Health Sciences University, Ra’s Al Khaimah, United Arab Emirates Divya Mishra Roles: Conceptualization, Data Curation, Formal Analysis, Methodology, Writing – Review & Editing Arun S Urala Roles: Conceptualization, Project Administration, Writing – Review & Editing Ashwath S Nayak Roles: Writing – Review & Editing Divya S Roles: Resources, Supervision, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Rajay Kamath Roles: Writing – Review & Editing Lakshmi Narayan Bairy Roles: Supervision Gargi S Roles: Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS This article is included in the Manipal Academy of Higher Education gateway. Abstract Objective To evaluate the effect of local application of Sodium Alendronate incorporated in Carbapol gel together with LLLT on peri-implant tissue healing in Wistar rat femurs. Methods Twenty-four male Wistar rats were randomly divided into 4 groups: Group 1 (the control group), Group 2 (the Sodium Alendronate group), Group 3 (the Sodium Alendronate and LLLT group), and Group 4 (the LLLT group). Mini implants were placed in right and left femur bones in all the four groups. Implants of groups 2 and 3 were coated in 1mg Carbapol gel incorporated with 1 mg Sodium alendronate. Groups 3 and 4 were exposed to LLLT (CO2 laser, wavelength 830nm; 2.1J/cm 2 ) on 1 st, 7 th , 14 th and 21 st day. Animals were sacrificed on the 28th day, following which the femurs were dissected out and stored in 10% buffered formaldehyde for histopathological analysis. Results Groups 3 and 4 showed bony union and formation of reorganized spongiosa whereas Groups 1 and 2 showed fibrous union. The bone marrow from Group 3 had an adult-type fatty marrow, while that from Group 2 and 4 was occupied by red blood cells. Group 1 showed initial stages of bone healing in which the defect occupied more than half of the bone marrow. Conclusion LLLT given using CO2 laser therapy, together with a one-time application of Sodium Alendronate in Carbapol gel at the time of implant placement optimally enhances healing of peri-implant tissues. READ ALL READ LESS Keywords Micro-implants, anchorage, animal study, Low level laser therapy, photo-biomodulation, bisphosphonates Corresponding Author(s) Arun S Urala ( [email protected] ) Divya S ( [email protected] ) Close Corresponding authors: Arun S Urala, Divya S Competing interests: No competing interests were disclosed. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2025 Mishra D et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Mishra D, Urala AS, Nayak AS et al. A Randomized Controlled Trial Evaluating the Effect of Local Application of Sodium Alendronate Gel and Low-Level Laser Therapy (LLLT) On Peri-Implant Tissue Healing in Wistar Rats [version 1; peer review: 2 approved] . F1000Research 2025, 14 :147 ( https://doi.org/10.12688/f1000research.160479.1 ) First published: 30 Jan 2025, 14 :147 ( https://doi.org/10.12688/f1000research.160479.1 ) Latest published: 30 Jan 2025, 14 :147 ( https://doi.org/10.12688/f1000research.160479.1 ) Clinical significance Mini-implant used as stationary anchorage tends to fail due to peri-implantitis or poor bone quality and many other reasons. As these mini-implants derive support from cortical bone and not via osseointegration, achieving their stability for a long run has become a prime concern. In this study, we have come up with an alternate way which can be followed for improving the stability of the implants. The practice of using mini-implants is now getting into the mainstream and hence we have done many studies pertaining to the same. The novel method was evaluated by conducting study on Wistar rats. Background Skeletal anchorage has gained popularity in orthodontic practice, particularly in situations where 75% or more space is needed for retraction of anterior teeth - termed critical anchorage - especially when a successful treatment outcome is expected or desired. 1 Miniscrew placement is one of the easiest ways to achieve skeletal anchorage for anterior tooth retraction, however, stability and patient safety following orthodontic loading of miniscrews determine overall success of orthodontic treatment. 2 Following implant placement, healthy tissues around the implant pose as biological barriers to many intraoral microorganisms that have the propensity to cause inflammation. 3 Inflammation of peri-implant tissues, known as peri-implantitis, has the potential to increase implant failure by 30%. 4 Peri-implantitis features inflammation of bone around the implant, bleeding on probing, epithelial infiltration and, in some cases, suppuration, which inadvertently leads to failure. 5 Furthermore, bone around the neck of screw implants can be lost due to inflammation. 6 , 7 These are serious problems that need to be addressed at the cellular level to facilitate bone repair in order for implant placement to be successful. To that end, adjunctive treatments like Low-Level Laser Therapy (LLLT) and the local application of bisphosphonates have been considerably employed to optimally enhance peri implant healing. The biostimulatory effect of LLLT can be considered ‘photostimulatory’ or ‘photomodulatory’ when both nucleic acid formation and cell division increase. 8 , 9 LLLT also has shown to markedly increase production of osteocytes because of its positive effect on the bone matrix. 10 It is also observed that damaged bone can be actively repaired with LLLT irradiation. 11 On the other hand, Bisphosphonates are pyrophosphate analogs which are stable and can affect bone matrix formation. They can stimulate proliferation and differentiation of osteoblasts, which in turn enhances bone formation, while inhibiting catabolic osteoclast activity. 12 These advantages make bisphosphonates the therapy of choice in settings of osteolytic disease and osteoporosis. 13 Notably, Sodium Alendronate, which positively affects osteoblast maturation, has become the most commonly used bisphosphonate, 14 , 15 however, its systemic administration is precluded when healing of bone around the implant is specifically needed, though it has shown to increase bone formation. Side effects to its use include gastrointestinal disorders and nephrocalcinosis. 16 Furthermore, previous studies have reported severe pain and tissue necrosis at the site of injection. 17 Hence, local drug delivery of Sodium alendronate at the injury site is considered safe. 18 Various studies have reported both LLLT and Bisphosphonates have beneficial effect on bone repair, 19 but none of the studies have evaluated the combined effects of LLLT and local Bisphosphonate therapy on the healing of peri-implant tissues. Hence, our study aims at filling in the knowledge gap. Here, we evaluate the combined effect of local application of Sodium Alendronate incorporated in Carbapol gel and Low Level Laser Therapy on peri-implant tissue healing in Wistar rats. Methods Twenty-four male Wistar rats, 6-7 months of age, and weighing about 250-300 g each, were used in this study. Approval was obtained from the Institutional Animal Ethics Committee (IAEC/KMC/11/2016) before the commencement of the study. The sample size (n) is calculated according to the formula 20 : n = z 2 ∗ p ∗ ( 1 − p ) / e 2 where, z = 1.96 for a confidence level (α) of 95%, p = proportion (expressed as a decimal), e = margin of error. z = 1.96 , p = 0.015 , e = 0.05 On substitution with the values n = 1.96 2 ∗ 0.015 ∗ ( 1 − 0.015 ) / 0.05 2 n = 0.0568 / 0.0025 = 22.704 n ≈ 23 The calculated sample size was 23 rounded to 24; 6 in each group were considered N = 6 Animals were randomly divided into 4 groups ( Flowchart 1 ). Flowchart 1. Animals divided randomly into 4 groups. This is a double-blind study. Placement of implants was carried out in all the four groups, after the animals were anaesthetized with thiopentone sodium (45 mg/kg, i.p., Thiosol sodium® Neon Laboratories Limited). 21 – 23 After the animal was placed in the lateral decubitus position, 24 the lateral portion of the posterior limb was shaved ( Figure 1 ). Figure 1. Animals positioned on their lateral decubitus position and lateral part of posterior limb was shaved. Under sterile aseptic conditions, a surgical incision was made, extending from the femoro-tibio-patellar joint (the distal reference point) to the major trochanter (the proximal reference point). Following the exposure of the deeper subcutaneous layers, the intermuscular septum - a thin white line which separates the biceps femoral and superficial gluteus muscles - was identified. 24 The intermuscular septum was incised and the two muscle groups were carefully separated using a pair of dissecting scissors, to expose the femur ( Figure 2 ). The widest portion of the femur was then chosen for implant placement 24 ( Figure 3 ). Figure 2. Femur bone exposed and two muscle groups were separated. Figure 3. Implant placed on widest portion of femur bone. Self-Drilling, titanium miniscrews (obtained from M/S S.K. Surgicals) of 1.5 × 6 mm in dimension ( Figure 4 ) were used in this study; one screw was placed on the right femur and one on the left. A manual driver was used to place all the screws monocortically, leaving 2 to 3 threads visible above the surface of the bone. The implants placed in groups 2 and 3 were coated with Carbapol gel containing Sodium Alendronate at a concentration of 1 mg Sodium Alendronate per mg Carbapol gel. Gel phase was preferred to liquid medium, due to increased sustainability in the local area. Figure 4. Self-Drilling, titanium miniscrew (M/S S.K. Surgicals) 1.5 × 6 mm. Following implant placement, closure was done in layers, with the muscular and skin layers being approximated using catgut (3-O) and silk (3-O) sutures respectively. LLLT was carried out in groups 3 and 4 after implant placement (1st day) and was repeated on the 7 th , 14 th and 21 st days with the help of a CO 2 laser administered at a wavelength of 830 nm. The dose received was about 2.1 J/cm 2 (39.2 × 10 −3 W × 55 sec). To obtain maximum exposure of the peri-implant area to the laser beam, the implant head was identified on palpation and marked using an IR (Infrared) card prior to LLLT during the exposure period ( Figure 5 ). The animals were sacrificed on the 28 th day with an overdose of anesthesia (Thiopental sodium 50 mg/kg). The right and left femurs were dissected out and fixed in 10% neutral buffered formaldehyde. Figure 5. Infra-red card. For histology, femur decalcification was carried out using 10% EDTA for a period of 6-8 weeks; 5 μ sections were generated after the specimens were embedded in paraffin. Hematoxylin and Eosin staining was done and the sections were examined in a bright field microscope using a 10× objective lens. The amount of healing was evaluated microscopically using a histological scoring system proposed by Heiple et al. 25 ( Table 1 ). Table 1. Histological Scoring System Developed by Heiple et al. Category Point Union Highest score is 4 No sign of union 0 Fibrous union 1 Osteochondral union 2 Bone union 3 Complete Reorganization 4 Spongiosa The highest score is 4 No sign of cellular activity 0 Early bone formation 1 Active new bone formation 2 Reorganized spongiosa formation 3 Complete reorganized spongiosa 4 Cortex The highest score is 4 Absence of cortex 0 Early detection 1 Initiation of formation 2 Reorganization in majority 3 Complete organization 4 Bone Marrow The highest score is 4 Not available 0 Detection of fibrinous material 1 Defect occupying more than half 2 Fully occupying the red bone marrow 3 Adult type fatty marrow 4 Sum of histologic scores 16 Results Data analysis was done using SPSS software version 20.0 for windows. Intergroup comparison was carried out using one-way ANOVA and further evaluated by Post-hoc Tukey test. Histological results on day 28 revealed that specimens of groups 3 and 4 showed bony union whereas groups 1 and 2 showed fibrous union. There was formation of reorganized spongiosa in groups 3 and 4, while groups 1 and 2 had signs of early bone formation. Cortical reorganization was present in all the groups. Bone marrow examination of group 3 revealed adult type of fatty bone marrow, while that from groups 2 and 4 was occupied by red blood cells. Specimens of group 1 showed initial stages of bone healing in which the defect occupied more than half of the bone marrow cavity. Statistically, when Post hoc test was applied between the groups on both right and left sides, groups 3 and 4 showed significantly higher scores in terms of union when compared to groups 1 (p = 0.0014, 0.0025) and 2 (p = 0.007, 0.0012) ( Tables 2 , 3 ). Statistically significant differences were found when groups 3 and 4 were compared with group 1 for spongiosa, bone marrow formation and overall histological score ( Tables 2 , 3 ). Compared to the control group, groups 3 and 4 showed reorganized spongiosa with an adult-type fatty bone marrow which is indicative of good healing ( Tables 2 , 3 ). There was a significant difference between groups 3 and 1 (p = 0.015), and group 2 (p = 0.046) in terms of cortical bone organization and formation. No statistically significant differences were seen between groups 3 and 4 with respect to the histological score ( Tables 2 , 3 ). Comparing the scores between the right and left sides, no statistically significant differences were observed ( Table 4 ). Table 2. statistical analysis between the groups on 28 th day-left side. Group 1 Group 2 Group 3 Group 4 P value (ANOVA test) Post hoc (between the groups) p value Union 2.2±0.447 2.16±0.752 3.76±0.516 3.6±0.547 0.0001 * 1 vs 2 0.999 1 vs 3 0.0014 * 1 vs 4 0.0025 * 2 vs 3 0.0007 * 2 vs 4 0.0012 * 3 vs 4 0.9614 Spongiosa 2.2±0.447 3±0.0 3.66±0.516 3.4±0.547 0.0001 * 1 vs 2 0.0191 1 vs 3 0.0002 * 1 vs 4 0.0006 * 2 vs 3 0.0987 2 vs 4 0.3383 3 vs 4 0.8422 Cortex 3±0.0 3.16±0.408 3.83±0.408 3.6±0.547 0.0096 * 1 vs 2 0.9020 1 vs 3 0.0155 * 1 vs 4 0.0833 2 vs 3 0.0465 * 2 vs 4 0.2351 3 vs 4 0.7610 Bone marrow 2.8±0.447 3.62±0.408 4±0.0 3.8±0.447 0.0002 * 1 vs 2 0.0060 * 1 vs 3 0.0002 * 1 vs 4 0.0010 * 2 vs 3 0.3150 2 vs 4 0.8132 3 vs 4 0.7860 Total score 10.2±1.095 12.16±0.752 15.16±1.329 14.4±1.516 0.0000 * 1 vs 2 0.0645 1 vs 3 0.0000 * 1 vs 4 0.0001 * 2 vs 3 0.0032 * 2 vs 4 0.0219 * 3 vs 4 0.7256 * P<0.05 is significant. Table 3. Statistical analysis between the groups on 28 th day-right side. Control group Group 2 Group 3 Group 4 P value (ANOVA test) Post hoc (between the groups) p value Union 2.2±0.447 2.33±0.816 3.6±0.816 3.3±0.547 0.0043 * 1 vs 2 0.9941 1vs 3 0.0155 * 1vs 4 0.0541 2 vs 3 0.0192 * 2 vs 4 0.0697 3 vs 4 0.8712 Spongiosa 2.4±0.547 2.83±0.408 3.83±0.408 3.4±0.547 0.0004 * 1 vs 2 0.4202 1vs 3 0.0005 * 1vs 4 0.0091 * 2 vs 3 0.0091 * 2 vs 4 0.1665 3 vs 4 0.4202 Cortex 3±0.0 3.23±0.632 4±0.0 3.4±0.547 0.0076 * 1 vs 2 0.7932 1vs 3 0.0060 * 1vs 4 0.4008 2 vs 3 0.0294 * 2 vs 4 0.8897 3 vs 4 0.9994 Bone marrow 2.2±0.447 3.66±0.516 4±0.0 3.8±0.447 0.0000 * 1 vs 2 0.0000 * 1vs 3 0.0000 * 1vs 4 0.0000 * 2 vs 3 0.4078 2 vs 4 0.9006 3 vs 4 0.7860 Total score 9.8±0.836 11.83±1.941 15.16±0.983 14.2±1.095 0.0000 * 1 vs 2 0.0768 1vs 3 0.0000 * 1vs 4 0.0001 * 2 vs 3 0.0023 * 2 vs 4 0.0238 * 3 vs 4 0.6152 * P<0.05 is significant. Table 4. Comparison between scores of left and right side. Control group Group 2 Group 3 Group 4 Union LEFT 2.2±0.447 2.16±0.752 3.76±0.516 3.6±0.547 RIGHT 2.2±0.447 2.33±0.816 3.6±0.816 3.3±0.547 P value (t- test) 1(t=0.0) 0.715(t=0.375) 0.693(t=0.405) 0.364(t=0.949) Spongiosa LEFT 2.2±0.447 3±0.0 3.66±0.516 3.4±0.547 RIGHT 2.4±0.547 2.83±0.408 3.83±0.408 3.43±0.547 P value (t- test) 0.503(t=0.693) 0.344(t=0.991) 0.540(t=0.633) 0.962(t=0.095) Cortex LEFT 3±0.0 3.16±0.408 3.83±0.408 3.6±0.547 RIGHT 3±0.0 3.23±0.632 4±0.0 3.4±0.547 P value (t- test) 1(t=0.0) 0.824(t=0.227) 0.335(t=1.020) 0.541(t=0.633) Bone marrow LEFT 2.8±0.447 3.62±0.408 4±0.0 3.8±0.447 RIGHT 2.2±0.547 3.66±0.516 4±0.447 3.8±0.447 P value (t- test) 0.064(t=2.08) 0.884(t=0.148) 0.914(t=0.08) 1(t=0.0) Total LEFT 10.2±1.095 12.16±0.752 15.16±1.329 14.4±1.516 RIGHT 9.8±0.836 11.83±1.941 15.16±0.983 14.2±1.095 P value (t- test) 0.493(t=0.711) 0.751(t=0.388) 0.892(t=0.101) 0.811(t=0.175) Discussion Placement of mini-implants is one of the easiest ways to achieve skeletal anchorage in situations of critical anchorage, because patient compliance is not needed, though it has many shortcomings of its own. Peri-implantitis is one of the important factors that contribute to dental implant failure. 6 Park et al demonstrated in their study that bone around mini screws in the neck can be damaged due to inflammation. Prevention of inflammation around screw implants is important for success of the mini implant. 26 Therefore, many adjunctive treatments have been applied to facilitate faster healing by reducing inflammation. Fujimura et al reported in their study that orthodontic movement of tooth as well as root resorption was inhibited by bisphosphonates. Similarly, Ortega et al concluded that small doses of zolendronate, when applied locally, provided good anchorage and prevented bone loss. Additionally, Akoyl et al reported that local irrigation with Sodium Alendronate trihydrate (at 1mg/ml) proved to be beneficial for healing. They also reported that Sodium Alendronate and LLLT when employed simultaneously on bone defects in Wistar rats enhanced healing. 19 In the present study, 1 mg of Sodium Alendronate was incorporated in 1 mg of Carbapol gel (as the latter increases sustainability of drug) and placed around the thread portion of the implant in groups 2 and 3. It was reported by Guimaraes et al that the beneficial effect of bisphosphonates is dose-dependent and, when applied at higher concentration to the bone surface, sodium alendronate (at 10mg/g) resulted in unfavourable bone remodeling around the implants. 27 Though stimulation of bone healing with the help of LLLT is not exactly understood, it is said to be multifactorial and may include stimulation of angiogenesis, production of collagen, 28 – 30 proliferation and differentiation of osteogenic cells 31 mitochondrial respiration and ATP synthesis. 32 , 33 In an in vitro study, Khadra et al reported that LLLT (830nm, 1.5 or 3J/cm 2 ) increases attachment, multiplication, differentiation of cells, and formation of TGFβ-1; thus LLLT can regulate cellular activity of human osteoblast-like cells cultured on titanium implants. 34 Pretel et al showed that the application of a GaAlAs (Gallium, Aluminum, and Arsenide) diode laser directly on bone defects in rats leads to modulation of initial inflammatory response and enhanced healing. 35 Korany et al in their study reported that LLLT increases new bone maturation, on seventh and tenth day after irradiation. 36 On the other hand, Khadra et al in their study reported that LLLT (GaAlAs diode laser, 830nm, 75mW) showed noticeable increase of calcium, phosphorous and proteins at 14 th as well as 28 th day, which may increase bone formation in calvaria of rats. 37 Therefore, in our study by adhering to same wavelength and almost equal power density (830 nm, 39.2 mw) CO 2 laser was employed at 7-day intervals (for 55 seconds each) at day 1 following implant placement, and was repeated at the 7 th , 14 th and 21 st day. All animals were sacrificed at the end of 28 th day from implant placement. Pinheiro et al evaluated effects of laser (830 nm, 4 J/cm 2 ) on defects of bone grafted with inorganic bovine bone on femur of Wistar rats; it was reported that LLLT was beneficial for the repair of bone defects when a graft was placed. 38 They reported that on the 30 th day there was presence of high collagen fiber formation which signified mature bone formation. 38 Many studies suggested that a dose of 1-5 J/cm 2 of LLLT is successful in producing beneficial effects in soft tissues as well as in bone. 38 – 44 A lower wavelength is prone to dispersion and does not penetrate deep into skin compared to a higher wavelength. 45 In one study, it was reported that a laser wavelength of 632 nm penetrates 0.5-1 mm before 37% intensity was lost. 46 Pinherio et al reported that only some percentile of energy is lost before infra-red wavelength penetrates 2 mm deep into the skin. 34 Therefore, infra-red (IR) laser light at a wavelength of 630 nm was used in the present study for better bone penetration. Thus, the effect of sodium alendronate alone (Group 2), the combined effect of LLLT and sodium alendronate (Group 3), and the effect of LLLT alone (Group 4) was evaluated and compared with that of controls (Group 1) on 28 th day, as can be seen in Figure 6 , where the implant surface (with bone formation) in Group 3 was treated with sodium alendronate and LLLT, while Figure 7 depicts the implant surface (with bone formation) in Group 4 treated with LLLT alone. Figure 6. Day 28 of group 3 implant surface with bone formation (photomicrograph of H&E stained slides, original magnification ×10). Figure 7. Day 28 of group 4 implant surface with bone formation (photomicrograph of H&E stained slides, original magnification ×10). Histological scores of Groups 3 and 4 were statistically significant when compared with Groups 1 and 2 ( Table 2 ). Presence of bony union with reorganized spongiosa, which is considered one of the important features of favorable healing, was seen in Groups 3 ( Figure 8 ) and 4, whereas Groups 1 and 2 showed osteochondral union with formation of new bone. Presence of osteo-chondral union after 28 days is considered a sign of unfavorable healing. Reorganization of the cortex was appreciated in all the 4 groups but was significantly higher in Groups 3 ( Figure 9 ) and 4 ( Figure 10 ), compared to Group 1 (control); thus healing in Groups 3 and 4 was faster and more favorable in these groups. Adult-type fatty marrow, the presence of which is highly desirable and considered the most important feature of healing, was appreciated in Groups 3 ( Figure 11 ) and 4 ( Figure 12 ), whereas it was not appreciated in the control as well as in the Sodium alendronate groups. Thus, a faster healing was present in Groups 3 and 4, compared to Groups 2 and 1. Rats of Groups 3 and 4 were irradiated with LLLT at 7-day intervals and sacrificed on the 28 th day so that the effect of sodium alendronate combined with LLLT could be evaluated for mature bone formation. It can be seen in both these groups ( Figures 13 , 14 respectively) that there is formation of mature bone as well as reorganization of cortex. Thus, LLLT alone or when combined with Sodium alendronate increases formation of new bone. Figure 8. Day 28 of group 3 presence of bony union with reorganized spongiosa formation (photomicrograph of H&E stained slides, original magnification ×10). Figure 9. Day 28 of group 3 reorganized spongiosa and bone marrow formation (photomicrograph of H&E stained slides, original magnification ×10). Figure 10. Day 28 of group 4 reorganized spongiosa and bone marrow formation (photomicrograph of H&E stained slides, original magnification ×10). Figure 11. Day 28 of group 3 areas of bone with adult type of fatty marrow (photomicrograph of H&E stained slides, original magnification ×10). Figure 12. Day 28 group 4 areas of bone with adult type of fatty marrow (photomicrograph of H&E stained slides, original magnification ×10). Figure 13. Day 28 of group 3 mature bone formation and reorganization of cortex (photomicrograph of H&E stained slides, original magnification ×10). Figure 14. Day 28 of group 4 mature bone formation, marrow spaces and reorganization of cortex (photomicrograph of H&E stained slides, original magnification ×10). The sum of histological scores was statistically significant for Groups 3 and 4, compared to Groups 1 and 2; thus we can interpret that Groups 3 and 4 showed better healing than in Groups 1 and 2 after 28 days of implant placement. The Sodium Alendronate group (Group 2) in our study did not yield any statistically significant results but had higher histological scores when compared to Group 1 (control) except for bone marrow formation. Hence, Group 2 showed better healing, compared to the control group. When the histological scores of Groups 3 and 4 were compared, no statistically significant differences were observed between them, but Group 3 had more histological scores; therefore, Group 3 had better healing compared to Group 4. Also, no statistically significant differences could be attributed, when scores between the right and the left side were compared. Conclusions Peri-implant healing of Orthodontic Mini screws placed in Wistar rat femurs could be enhanced by the use of CO 2 laser therapy, when harnessed at a wavelength of 830 nm, the dose received was about 2.1 J/cm 2 (39.2 mW × 10 −3 W × 55 sec) and when combined with 1mg Sodium Alendronate mixed with 1mg Carbapol gel. At the histological level, there is increased formation of reorganized spongiosa and cortical bone as well as enhanced production of adult-type fatty bone marrow. Ethical approval Before commencing the study, clearance was obtained from the Institutional Animal Ethics Committee, Kasturba Medical College Manipal, Karnataka – IAEC/KMC/11/2016. Animal ethics All animal experiments were conducted in compliance with the Institutional Animal Ethics Committee, and the protocol was approved by the same. Efforts were made to minimize animal suffering throughout the study, including the use of appropriate anesthesia. At the conclusion of the experiments, animals were humanely euthanized per ethical guidelines to ensure minimal distress. Consent for publication Not applicable. Authors’ contributions DM and DS realized the research. DM, ASU, ASN, DS was the major contributor in writing the manuscript. DS, LNB, GS helped with the research. ASU, ASN, DS corrected the manuscript. All the authors read and approved the final manuscript. Data availability statement Underlying data Figshare: A Randomized Controlled Trial Evaluating the Effect of Local Application of Sodium Alendronate Gel and Low-Level Laser Therapy (LLLT) On Peri-Implant Tissue Healing in Wistar Rats. Doi: https://doi.org/ 10.6084/m9.figshare.28093763 . 47 This project contains following underlying data: • Excel.xlsx Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0). Extended data Reporting guidelines ARRIVE guidelines: Doi: https://doi.org/10.6084/m9.figshare.28093763 . 47 Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0). Acknowledgements Not applicable. Bibliography 1. Biomechanics in Clinical Orthodontics by Ravindra Nanda. 3rd ed.WB Saunders Company. 2. Kravitz ND, Kusnoto B: Risks and complications of orthodontic miniscrews. Am. J. Orthod. Dentofacial Orthop. 2007 Apr; 131 (4 Suppl): S43–S51. Publisher Full Text 3. Sanchez-Garces MA, Gay-Escoda C: Peri-implantitis. Med. Oral Patol. Oral Cir. Bucal. 2004; 9 (suppl): 63–69. 4. Costa A, Pasta G, Bergamaschi G: Intraoral hard and soft tissue depths for temporary anchorage devices. Semin. Orthod. 2005; 11 : 10–15. Publisher Full Text 5. Othman S, Haugen E, Gjermo P: The effect of chlorhexidine supplementation in a periodontal dressing. Acta Odontol. Scand. 1989 Dec; 47 (6): 361–366. PubMed Abstract | Publisher Full Text 6. Zitzmann NU, Berglundh T, Ericsson I, et al. : Spontaneous progression of experimentally induced periimplantitis. J. Clin. Periodontol. 2004 Oct; 31 (10): 845–849. PubMed Abstract | Publisher Full Text 7. Ericsson I, Berglundh T, Marinello C, et al. : Long-standing plaque and gingivitis at implants and teeth in the dog. Clin. Oral Implants Res. 1992 Sep; 3 (3): 99–103. PubMed Abstract | Publisher Full Text 8. Gupta A, Dai T, Hamblin MR: Effect of red and near-infrared wavelengths on low-level laser (light) therapy-induced healing of partial-thickness dermal abrasion in mice. Lasers Med. Sci. 2014 Jan; 29 (1): 257–265. PubMed Abstract | Publisher Full Text | Free Full Text 9. Ueda Y, Shimizu N: Effects of pulse frequency of low-level laser therapy (LLLT) on bone nodule formation in rat calvarial cells. J. Clin. Laser Med. Surg. 2003 Oct; 21 (5): 271–277. PubMed Abstract | Publisher Full Text 10. Dörtbudak O, Haas R, Mailath-Pokorny G: Effect of low-power laser irradiation on bony implant sites. Clin. Oral Implants Res. 2002 Jun; 13 (3): 288–292. PubMed Abstract | Publisher Full Text 11. Akyol UK, Güngörmüş M: Effect of biostimulation on healing of bone defects in diabetic rats. Photomed. Laser Surg. 2010 Jun; 28 (3): 411–416. PubMed Abstract | Publisher Full Text 12. Kashii M, Hashimoto J, Nakano T, et al. : Alendronate treatment promotes bone formation with a less anisotropic microstructure during intramembranous ossification in rats. J. Bone Miner. Metab. 2008; 26 (1): 24–33. PubMed Abstract | Publisher Full Text 13. von Knoch F , Jaquiery C, Kowalsky M, et al. : Effects of bisphosphonates on proliferation and osteoblast differentiation of human bone marrow stromal cells. Biomaterials. 2005 Dec; 26 (34): 6941–6949. PubMed Abstract | Publisher Full Text 14. Russell RG, Watts NB, Ebetino FH, et al. : Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporos Int. 2008 Jun; 19 (6): 733–759. PubMed Abstract | Publisher Full Text 15. Lindsay R, Watts NB, Lange JL, et al. : Effectiveness of risedronate and alendronate on nonvertebral fractures: an observational study through 2 years of therapy. Osteoporos Int. 2013 Aug; 24 (8): 2345–2352. PubMed Abstract | Publisher Full Text 16. Tekin U, Tüz HH, Onder E, et al. : Effects of alendronate on rate of distraction in rabbit mandibles. J. Oral Maxillofac. Surg. 2008 Oct; 66 (10): 2042–2049. PubMed Abstract | Publisher Full Text 17. Lin JH: Bisphosphonates: a review of their pharmacokinetic properties. Bone. 1996 Feb; 18 (2): 75–85. Publisher Full Text 18. Omi H, Kusumi T, Kijima H, et al. : Locally administered low-dose alendronate increases bone mineral density during distraction osteogenesis in a rabbit model. J. Bone Joint Surg. Br. 2007 Jul; 89-B (7): 984–988. Publisher Full Text 19. Akyol UK, Sipal S, Demirci E, et al. : The influence of low-level laser therapy with alendronate irrigation on healing of bone defects in rats. Lasers Med. Sci. 2015 Apr; 30 (3): 1141–1146. PubMed Abstract | Publisher Full Text 20. Chow S, Shao J, Wang H: Sample Size Calculations in Clinical Research. 2nd ed.Philadelphia, PA: Chapman & Hall/CRC Biostatistics Series; 2008; 71. Publisher Full Text 21. Nakhate KT, Bharne AP, Verma VS, et al. : Plumbagin ameliorates memory dysfunction in streptozotocin induced Alzheimer’s disease via activation of Nrf2/ARE pathway and inhibition of β-secretase. Biomed. Pharmacother. 2018 May; 101 : 379–390. PubMed Abstract | Publisher Full Text 22. Bhorkar AA, Dandekar MP, Nakhate KT, et al. : Involvement of the central melanocortin system in the effects of caffeine on anxiety-like behavior in mice. Life Sci. 2014 Jan 30; 95 (2): 72–80. PubMed Abstract | Publisher Full Text 23. Kokare DM, Shelkar GP, Borkar CD, et al. : A simple and inexpensive method to fabricate a cannula system for intracranial injections in rats and mice. J. Pharmacol. Toxicol. Methods. 2011 Nov-Dec; 64 (3): 246–250. PubMed Abstract | Publisher Full Text 24. Costa CM, Bernardes G, Ely JB, et al. : Proposal for access to the femur in rats. Int. J. Biotechnol. Mol. Biol. Res. 2011; 2 (4): 73–79. 25. Heiple KG, Goldberg VM, Powell AE, et al. : Biology of cancellous bone grafts. Orthop. Clin. North Am. 1987 Apr; 18 (2): 179–185. Publisher Full Text 26. Park HS, Jeong SH, Kwon OW: Factors affecting the clinical success of screw implants used as orthodontic anchorage. Am. J. Orthod. Dentofacial Orthop. 2006 Jul; 130 (1): 18–25. Publisher Full Text 27. Guimarães MB, Bueno RS, Blaya MB, et al. : Influence of the local application of sodium alendronate gel on osseointegration of titanium implants. Int. J. Oral Maxillofac. Surg. 2015 Nov; 44 (11): 1423–1429. PubMed Abstract | Publisher Full Text 28. Oron U, Yaakobi T, Oron A, et al. : Attenuation of infarct size in rats and dogs after myocardial infarction by low-energy laser irradiation. Lasers Surg. Med. 2001; 28 (3): 204–211. PubMed Abstract | Publisher Full Text 29. Lam TS, Abergel RP, Ca M, et al. : Laser stimulation of collagen synthesis in human skin fibroblast cultures. Laser Life Sci. 1989; 1 : 61–77. 30. Bosatra M, Jucci A, Olliaro P, et al. : In vitro fibroblast and dermis fibroblast activation by laser irradiation at low energy. An electron microscopic study. Dermatologica. 1984; 168 (4): 157–162. PubMed Abstract | Publisher Full Text 31. Yaakobi T, Maltz L, Oron U: Promotion of bone repair in the cortical bone of the tibia in rats by low energy laser (He-Ne) irradiation. Calcif. Tissue Int. 1996 Oct; 59 (4): 297–300. PubMed Abstract | Publisher Full Text 32. Morimoto Y, Arai T, Kikuchi M, et al. : Effect of low-intensity argon laser irradiation on mitochondrial respiration. Lasers Surg. Med. 1994; 15 (2): 191–199. PubMed Abstract | Publisher Full Text 33. Yu W, Naim JO, McGowan M, et al. : Photomodulation of oxidative metabolism and electron chain enzymes in rat liver mitochondria. Photochem. Photobiol. 1997 Dec; 66 (6): 866–871. PubMed Abstract | Publisher Full Text 34. Khadra M, Lyngstadaas SP, Haanaes HR, et al. : Effect of laser therapy on attachment, proliferation and differentiation of human osteoblast-like cells cultured on titanium implant material. Biomaterials. 2005 Jun; 26 (17): 3503–3509. PubMed Abstract | Publisher Full Text 35. Pretel H, Lizarelli RF, Ramalho LT: Effect of low-level laser therapy on bone repair: histological study in rats. Lasers Surg. Med. 2007 Dec; 39 (10): 788–796. PubMed Abstract | Publisher Full Text 36. Korany NS, Mehanni SS, Hakam HM, et al. : Evaluation of socket healing in irradiated rats after diode laser exposure (histological and morphometric studies). Arch. Oral Biol. 2012 Jul; 57 (7): 884–891. PubMed Abstract | Publisher Full Text 37. Khadra M, Kasem N, Haanaes HR, et al. : Enhancement of bone formation in rat calvarial bone defects using low-level laser therapy. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 2004 Jun; 97 (6): 693–700. PubMed Abstract | Publisher Full Text 38. Pinheiro AL, Limeira Júnior Fde A, Gerbi ME, et al. : Effect of 830-nm laser light on the repair of bone defects grafted with inorganic bovine bone and decalcified cortical osseous membrane. J. Clin. Laser Med. Surg. 2003 Oct; 21 (5): 301–306. PubMed Abstract | Publisher Full Text 39. Pinheiro AL, Cavalcanti ET, Pinheiro TI, et al. : Low-level laser therapy in the management of disorders of the maxillofacial region. J. Clin. Laser Med. Surg. 1997; 15 (4): 181–183. PubMed Abstract | Publisher Full Text 40. Mester E, Spiry T, Szende B, et al. : Effect of laser rays on wound healing. Am. J. Surg. 1971 Oct; 122 (4): 532–535. Publisher Full Text 41. Mester E, Korényi-Both A, Spiry T, et al. : Stimulation of wound healing by means of laser rays. (Clinical and electron microscopical study). Acta Chir. Acad. Sci. Hung. 1973; 14 (4): 347–356. PubMed Abstract 42. Braverman B, McCarthy RJ, Ivankovich AD, et al. : Effect of helium-neon and infrared laser irradiation on wound healing in rabbits. Lasers Surg. Med. 1989; 9 (1): 50–58. PubMed Abstract | Publisher Full Text 43. Reddy GK, Stehno-Bittel L, Enwemeka CS: Laser photostimulation of collagen production in healing rabbit Achilles tendons. Lasers Surg. Med. 1998; 22 (5): 281–287. PubMed Abstract | Publisher Full Text 44. Yu W, Naim JO, Lanzafame RJ: Effects of photostimulation on wound healing in diabetic mice. Lasers Surg. Med. 1997; 20 (1): 56–63. PubMed Abstract | Publisher Full Text 45. Kolárová H, Ditrichová D, Wagner J: Penetration of the laser light into the skin in vitro. Lasers Surg. Med. 1999; 24 (3): 231–235. Publisher Full Text 46. Basford JR: Low intensity laser therapy: still not an established clinical tool. Lasers Surg. Med. 1995; 16 (4): 331–342. Publisher Full Text 47. Divya S: A Randomized Controlled Trial Evaluating the Effect of Local Application of Sodium Alendronate Gel and Low-Level Laser Therapy (LLLT) On Peri-Implant Tissue Healing in Wistar Rats. figshare. [Dataset]. 2024. Publisher Full Text Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 30 Jan 2025 ADD YOUR COMMENT Comment Author details Author details 1 Department of Orthodontics and Dentofacial Orthopaedics, Manipal College of Dental Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India 2 Department of Orthodontics and Dentofacial Orthopaedics, Bapuji Dental College and Hospital, Davanagere, Karanataka, 577004, India 3 Department of Clinical Genomics, Mayo Clinic Minnesota, Rochester, Minnesota, USA 4 Department of Pharmacology, RAK College of Medical Sciences, RAK Medical and Health Sciences University, Ra’s Al Khaimah, United Arab Emirates Divya Mishra Roles: Conceptualization, Data Curation, Formal Analysis, Methodology, Writing – Review & Editing Arun S Urala Roles: Conceptualization, Project Administration, Writing – Review & Editing Ashwath S Nayak Roles: Writing – Review & Editing Divya S Roles: Resources, Supervision, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Rajay Kamath Roles: Writing – Review & Editing Lakshmi Narayan Bairy Roles: Supervision Gargi S Roles: Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information The author(s) declared that no grants were involved in supporting this work. Article Versions (1) version 1 Published: 30 Jan 2025, 14:147 https://doi.org/10.12688/f1000research.160479.1 Copyright © 2025 Mishra D et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Mishra D, Urala AS, Nayak AS et al. A Randomized Controlled Trial Evaluating the Effect of Local Application of Sodium Alendronate Gel and Low-Level Laser Therapy (LLLT) On Peri-Implant Tissue Healing in Wistar Rats [version 1; peer review: 2 approved] . F1000Research 2025, 14 :147 ( https://doi.org/10.12688/f1000research.160479.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 1 VERSION 1 PUBLISHED 30 Jan 2025 Views 0 Cite How to cite this report: Allareddy V. Reviewer Report For: A Randomized Controlled Trial Evaluating the Effect of Local Application of Sodium Alendronate Gel and Low-Level Laser Therapy (LLLT) On Peri-Implant Tissue Healing in Wistar Rats [version 1; peer review: 2 approved] . F1000Research 2025, 14 :147 ( https://doi.org/10.5256/f1000research.176384.r364233 ) The direct URL for this report is: https://f1000research.com/articles/14-147/v1#referee-response-364233 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 27 Feb 2025 Veerasathpurush Allareddy , Department of Orthodontics, University of Illinois Chicago, Chicago, Illinois, USA Approved VIEWS 0 https://doi.org/10.5256/f1000research.176384.r364233 Mishra and colleagues evaluate the combined effect of local application of Sodium Alendronate incorporated in Carbapol gel and Low Level Laser Therapy on peri-implant tissue healing in Wistar rats. 24 Wistar rats aged 6 to 7 months were used in ... Continue reading READ ALL Mishra and colleagues evaluate the combined effect of local application of Sodium Alendronate incorporated in Carbapol gel and Low Level Laser Therapy on peri-implant tissue healing in Wistar rats. 24 Wistar rats aged 6 to 7 months were used in this study. The authors showed that Peri-implant healing of Orthodontic Mini Implants can be enhanced by use of CO2 laser therapy combined with Sodium Alendronate incorporated in Carbapol gel. This study has much clinical significance and translational potential. The authors did an excellent job setting up the context of study and quoting pertinent literature. The methods section clearly explained the experiments conducted and the statistical analyses were appropriate. Overall, a very interesting and informative study. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: Cleft and Craniofacial Orthodontics, Practice-Based Research, and Big Data Analytics. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Allareddy V. Reviewer Report For: A Randomized Controlled Trial Evaluating the Effect of Local Application of Sodium Alendronate Gel and Low-Level Laser Therapy (LLLT) On Peri-Implant Tissue Healing in Wistar Rats [version 1; peer review: 2 approved] . F1000Research 2025, 14 :147 ( https://doi.org/10.5256/f1000research.176384.r364233 ) The direct URL for this report is: https://f1000research.com/articles/14-147/v1#referee-response-364233 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Views 0 Cite How to cite this report: B G. Reviewer Report For: A Randomized Controlled Trial Evaluating the Effect of Local Application of Sodium Alendronate Gel and Low-Level Laser Therapy (LLLT) On Peri-Implant Tissue Healing in Wistar Rats [version 1; peer review: 2 approved] . F1000Research 2025, 14 :147 ( https://doi.org/10.5256/f1000research.176384.r364236 ) The direct URL for this report is: https://f1000research.com/articles/14-147/v1#referee-response-364236 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 12 Feb 2025 Goutham B , Department of Orthodontics and Dentofacial Orthopaedics, Coorg Institute of Dental Sciences, Virajpet, Karnataka, India Approved VIEWS 0 https://doi.org/10.5256/f1000research.176384.r364236 The study precisely evaluated the impact of Sodium Alendronate (SA) in Carbapol gel and Low-Level Laser Therapy (LLLT) on peri-implant tissue healing in Wistar rats, showing that the combined approach enhanced bone formation compared to individual treatments or controls. ... Continue reading READ ALL The study precisely evaluated the impact of Sodium Alendronate (SA) in Carbapol gel and Low-Level Laser Therapy (LLLT) on peri-implant tissue healing in Wistar rats, showing that the combined approach enhanced bone formation compared to individual treatments or controls. This study has a well-structured methodology and clear parameters providing potential clinical relevance for orthodontics. The study highlights the potential of combining SA and LLLT to optimize peri-implant healing, warranting further investigation for clinical application. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? I cannot comment. A qualified statistician is required. Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: Accelerated orthodontics, Implant dentistry, smile designing I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT B G. Reviewer Report For: A Randomized Controlled Trial Evaluating the Effect of Local Application of Sodium Alendronate Gel and Low-Level Laser Therapy (LLLT) On Peri-Implant Tissue Healing in Wistar Rats [version 1; peer review: 2 approved] . F1000Research 2025, 14 :147 ( https://doi.org/10.5256/f1000research.176384.r364236 ) The direct URL for this report is: https://f1000research.com/articles/14-147/v1#referee-response-364236 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 30 Jan 2025 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 Version 1 30 Jan 25 read read Goutham B , Coorg Institute of Dental Sciences, Virajpet, India Veerasathpurush Allareddy , University of Illinois Chicago, Chicago, USA Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Allareddy V. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 27 Feb 2025 | for Version 1 Veerasathpurush Allareddy , Department of Orthodontics, University of Illinois Chicago, Chicago, Illinois, USA 0 Views copyright © 2025 Allareddy V. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Mishra and colleagues evaluate the combined effect of local application of Sodium Alendronate incorporated in Carbapol gel and Low Level Laser Therapy on peri-implant tissue healing in Wistar rats. 24 Wistar rats aged 6 to 7 months were used in this study. The authors showed that Peri-implant healing of Orthodontic Mini Implants can be enhanced by use of CO2 laser therapy combined with Sodium Alendronate incorporated in Carbapol gel. This study has much clinical significance and translational potential. The authors did an excellent job setting up the context of study and quoting pertinent literature. The methods section clearly explained the experiments conducted and the statistical analyses were appropriate. Overall, a very interesting and informative study. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes Competing Interests No competing interests were disclosed. Reviewer Expertise Cleft and Craniofacial Orthodontics, Practice-Based Research, and Big Data Analytics. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) Allareddy V. Peer Review Report For: A Randomized Controlled Trial Evaluating the Effect of Local Application of Sodium Alendronate Gel and Low-Level Laser Therapy (LLLT) On Peri-Implant Tissue Healing in Wistar Rats [version 1; peer review: 2 approved] . F1000Research 2025, 14 :147 ( https://doi.org/10.5256/f1000research.176384.r364233) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-147/v1#referee-response-364233 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 B G. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 12 Feb 2025 | for Version 1 Goutham B , Department of Orthodontics and Dentofacial Orthopaedics, Coorg Institute of Dental Sciences, Virajpet, Karnataka, India 0 Views copyright © 2025 B G. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The study precisely evaluated the impact of Sodium Alendronate (SA) in Carbapol gel and Low-Level Laser Therapy (LLLT) on peri-implant tissue healing in Wistar rats, showing that the combined approach enhanced bone formation compared to individual treatments or controls. This study has a well-structured methodology and clear parameters providing potential clinical relevance for orthodontics. The study highlights the potential of combining SA and LLLT to optimize peri-implant healing, warranting further investigation for clinical application. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? I cannot comment. A qualified statistician is required. Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes Competing Interests No competing interests were disclosed. Reviewer Expertise Accelerated orthodontics, Implant dentistry, smile designing I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) B G. Peer Review Report For: A Randomized Controlled Trial Evaluating the Effect of Local Application of Sodium Alendronate Gel and Low-Level Laser Therapy (LLLT) On Peri-Implant Tissue Healing in Wistar Rats [version 1; peer review: 2 approved] . F1000Research 2025, 14 :147 ( https://doi.org/10.5256/f1000research.176384.r364236) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-147/v1#referee-response-364236 Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions Adjust parameters to alter display View on desktop for interactive features Includes Interactive Elements View on desktop for interactive features Competing Interests Policy Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. 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