Critical-sized marginal defects around implants treated with xenografts in rabbits

Critical-sized marginal defects around implants treated with xenografts in rabbits | 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 Critical-sized marginal defects around implants treated with xenografts in rabbits Akihisa Asano, Samuel Porfirio Xavier, Erick Ricardo Silva, Kenzo Morinaga, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3635546/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 29 Jan, 2024 Read the published version in Oral and Maxillofacial Surgery → Version 1 posted 7 You are reading this latest preprint version Abstract Background: Healing of critical-size defects is a well-known problem that has been challenged in several studies. The aim of the experiment was to evaluate bone formation and osseointegration of implants installed in critical defects of the mandibular body simultaneously grafted with Bio-Oss® or Cerabone®. Material and methods: Defects, 10 mm wide and 3 mm deep, were prepared at both lateral aspects of the mandible in 12 rabbits. One implant was installed in the center of the defect, and bovine xenografts produced either at low (Bio-Oss®; Low-T) or high (Cerabone®; High-T) temperatures were used to fill the defects. A collagen membrane was placed to cover the sites. Healing was evaluated 10 weeks after surgery. Results: In both groups, most sites showed optimal healing with closure of the coronal entrance of the defects. However, residual defects occupied by soft tissues and biomaterial particles were observed, even though generally limited to some regions of the defect. Osseointegration of the implant surface in the region of the defect was poor in both groups. Conclusions: Circumferential marginal critical-size defects around implants filled with bovine xenografts presented regions with a complete healing in both groups. However, the healing was not complete at all regions in most defects; therefore, a complete optimal healing of critical-size marginal defects cannot be predicted. animal study bone healing histology morphometry biomaterial bone defect Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 1. Introduction Reconstruction of alveolar bone defects, resulting from ageing, trauma, ablative procedures, or oral pathologies, remains a surgical problem [ 1 ]. Critical defects are those in which the extension compromises spontaneous bone repair [ 2 ]. Autologous bone is still considered the “gold standard” for maxillofacial bone augmentation [ 3 , 4 ]. However, extensive defects may require volumes of bone that are only available in extra-oral donor sites. Consequently, the morbidity associated with bone harvesting has become a major concern [ 5 ]. To overcome these disadvantages, bone substitutes have been developed to assist bone formation by both maintaining the three-dimensional framework and developing an osteoconductive environment in the region to be repaired [ 6 ]. These events lead to migration of osteoblasts and deposition of bone matrix [ 7 ]. Bio-Oss® is an osteoconductive bone substitute obtained from bovine bone, which supports proliferation of blood vessels and cell migration. It has been demonstrated that it can achieve adequate bone formation in both animal [ 8 – 11 ] and clinical studies [ 12 – 13 ]. This xenogeneic biomaterial is composed of deproteinized bovine bone mineral processed at 300º C, consisting of porous inorganic hydroxyapatite [ 14 – 16 ]. Due to its porosity and the high release of calcium ions, vascular and bone formation is favored [ 17 – 20 ]. In addition, it promotes osteoblastic activity in the early stages of bone regeneration [ 21 ]. Cerabone® is a xenogenous biomaterial composed of bovine bone mineral and acts in a way to enable osteoconduction. It is processed at 1,200ºC and presents a less intense gradual release of calcium ions [ 16 , 22 ]. The use of this biomaterial has been reported by a few animal [ 23 – 25 ] and clinical studies [ 26 , 27 ]. Recently, it has been demonstrated that this xenograft supports the formation of new and stable bone volume in circumferential defects around implants in minipigs [ 28 ]. However, the histological outcomes of deproteinized bovine bone (i.e., Bio-Oss® vs Cerabone®) in critical defects around implants in the mandible of rabbits have not been evaluated yet. Hence, the present study aimed to evaluate bone formation and osseointegration of implants installed in critical defects of the mandibular body simultaneously grafted with Bio-Oss® or Cerabone®. 2. Materials and Methods 2.1 Ethical statements This research project was approved by the Committee on Ethics in the Use of Animals of the Faculty of Dentistry of Ribeirão Preto, University of São Paulo, Brazil, on May 20, 2022, protocol #2022.1.287.58.3. The proposed experimental procedures were carried out in accordance with legislation for animal experimentation in Brazil. The ARRIVE Checklist was used in this study. 2.2 Study design The present study had a prospective, randomized, split-mouth study (test and control sides in the same animal) design. Defects, 10 mm wide and 3 mm deep, were prepared at both the lateral aspects of the mandible and an implant was placed in the center of each defect. The defects were randomly filled with either Bio-Oss® (low temperature; Low-T sites) or Cerabone® (high temperature; High-T sites) and a collagen membrane was placed to cover the region. Histological analyses were performed after 10 weeks of healing. 2.3 Experimental animals and sample size The sample size was evaluated using data from a previous experiment performed by the same group in which the healing of two biomaterials was studied after 10 weeks from sinus floor elevation in rabbit. In a two-tails evaluation, applying an α=0.05, a power of 0.8 and a calculated effect size of 0.9785, a sample size of 11 pairs of animals was obtained to reject the null hypothesis that the difference is zero reaching an actual power of 0.83 (G*Power 3.1.9.4) [29,30]. The sample was increased to 12 for possible complications. Hence, 12 adult male New Zealand White rabbits, weighing ~4.0 kg and aged ~5 months, were included in the study. 2.4 Randomization and allocation concealment An author (S.P.X.) who was not involved in the selection of animals, or any surgical procedure carried out the randomization electronically. The allocation treatment was kept concealed in a sealed opaque envelope, opened after implant installation. All histological slides were codes and the histological examinator was not informed about treatment al-location. Nevertheless, the two biomaterials could be identified for different aspects in histology. 2.5 Biomaterials Bio-Oss® (Geistlich Biomaterial, Wolhusen, LU, Switzerland) is deproteinized bovine mineral bone with sinterization at 300º, porosity of 75 to 80%, with pores of 20 to 200µm and average particulate size of 0.5 - 1mm [16]. Cerabone® (Botiss Biomaterials GmbH, Zossen, Germany) is completely formed by hydroxyapatite from bovine cancellous bone, with sinterization at 1200°c, porosity of 65 to 80%, with pores of 600 to 900µm and average particle size of 0.5 - 1mm [16]. Bio-Gide (Geistlich) is a porcine-derived resorbable membrane composed of types I and III collagen. It is composed of a bilayer structure with a smooth outer layer aimed at avoiding the progression of soft tissues within the region to be regenerated, and a porous inner layer that aims to favor bone cells and vessel growth [31]. 2.6 Anesthetic procedures The anesthetic procedures started with the use of acepromazine I.M. (1.0 mg/kg; Acepran, Vetnil, Louveira, São Paulo), and xylazine I.M. (3.0 mg/Kg; Laboratórios Calier S/A, Barcelona, Spain) and ketamine I.M. (50.0 mg/Kg; União Química Farmacêutica Nacional S/A, Embuguaçú, São Paulo, Brazil). Antibiotic therapy was initiated with oxy-tetracycline. (0.2 ml/Kg; Biovet; Vargem Grande Paulista, São Paulo, Brazil). After shaving, the area to be operated disinfected with 1% polyvinylpyrrolidone iodine solution (Ri-odeíne Tintura, Rioquímica, São José do Rio Preto, São Paulo, Brazil). Local anesthesia was added with 2% mepivacaine and 1:100,000 noradrenaline (Mepinor, Nova DFL, Rio de Janeiro, Brazil). 2.7 Surgical procedure The clinical surgical procedures were performed by an experienced and qualified operator (V.F.B.; see acknowledgments). A linear incision of about 2.5-3 cm was made on the skin at the lower border of the mandible. Muscles and periosteum were reflected to expose the buccal bone of the mandibular angle. Defects, 10 mm wide and 3 mm deep, were pre-pared bilaterally using a trephine and finalized with burs. One implant, 8.5mm long and 3.25mm in diameter (Leader Medica, Padua, Italy) was installed in the center of each defect with the rough margin flush to the periphery of the defect (Figures 1A and 2A). The defects were filled with either Bio-Oss® (Low-T sites; figure 1B) or Cerabone® (High-T sites; Figure 2B). A collagen membrane (Bio-Gide) was used to cover the experimental region (Figure 1C and 2C). Vicryl 4-0 was used on the periosteum and muscular planes, and Nylon 4-0 to suture the skin. 2.8 Animal maintenance The animals were kept in individual cages at the Animal Facility of the Faculty of Dentistry of Ribeirão Preto, University of São Paulo and were fed with specifically tailored food and had access to water ad libitum. The room was acclimatized with split air conditioning and exhaust fan (27 to 34 air changes/h), and automatic lighting control (12-hour light-dark cycle)..In the postoperative period and in the following three days, all animals received ketoprofen (3.0 mg/kg, 12/12h, I.M., 10% Ketofen, Merial, Campinas, São Paulo, Brazil) and 2% tramadol hydrochloride (1.0 mg/kg, 12 /12h, subcutaneous, Cronidor, Agener União Saúde Animal, Apucarana, Paraná, Brazil) in the postoperative period and in the following three days. A rigorous protocol for monitoring the animals was carried out throughout the experimental period, paying daily attention to the basic biological functions, feeding and excretion, behavioral signs in relation to postoperative pain, and monitoring of post-surgical infections and surgical wounds for suture care, bleeding, and/or signs of infection. 2.9 Euthanasia The animals were euthanized by administering an overdose (2.0 mL) of intravenous thiopental 1.0 g (Thiopentax; Cristália, Itapira, São Paulo, Brazil) 10 weeks, The experimental regions were dissected and reduced to individual blocks and maintained in 10% paraformaldehyde for fixation. 2.10 Histological processing After fixation, all blocks were washed and then include in the process of dehydration, resin inclusion (LR WhiteTM HardGrid, London Resin Co Ltd, Berkshire, United Kingdom) and polymerization. Subsequently, the specimens were cut following a transaxial plane in the center of the block guided by the implant positioned at the center of the graft. Two sections of approximately 100 – 150 µm thickness were obtained that were then ground to a thickness of approximately 60–80 µm using a cutting/grinding equipment (Exakt, Apparatebau, Norderstedt, Germany). Histological sections were stained with either Toluidine Blue or with Stevenel’s Blue and Alizarin Red. 2.11 Histomorphometric evaluation The histological assessments were performed by an experienced assessor (E.F.D.R., see acknowledgements) after a calibration with another expert (D.B). For the linear measurements, the following references were used: B, the most coronal bone to implant contact level; M, the implant margin; F, the floor of the original defect, positioned 3 mm apically to M. The following classification was applied based the distance between B and F (B-F), that is the bone gain from the base of the original defect: M-F ≤1 mm, 1> M-F ≤2mm, M-F >2mm. Bone-to-implant contact percentage (BIC%) was evaluated within 3 mm of the defect. The morphometric measurements were performed in six locations (Figure 3), three of which close to the implant (I-S, internal superior; I-C, internal central; I-I, internal inferior), two central (C-S, central superior; C, central) and one external (E-S, external superior). New bone, xenograft, mix structure (composed of a mixture of xenograft and newly formed bone) and soft tissues were assessed. For the evaluation, one grid containing squares of 75 µm in dimension was superimposed onto the photomicrographs of each region using NIS-Elements software (Nikon, Tokyo, Japan). Each region was examined with a dimension of about 1 mm2. 2.12 Experimental outcomes and statistical methods. The values obtained are expressed as the mean ± standard deviation. The primary variable was the mineralized new bone. The secondary variables were other tissues evaluated in the morphometric analysis. The Shapiro-Wilk test was used to determine the normality of data and, according to the results, the differences between the test and control sides were evaluated by a paired t-test or a Wilcoxon matched-pairs signed rank test. GraphPad Prism (version 10.0.2 for Windows, GraphPad Software, Boston, Massachusetts, USA, www.graphpad.com) was used for statistical analyses. The significance level was 5%. 3. Results 3.1 Clinical outcomes Two animals died after surgery. Ten animals healed uneventfully and were available for histological processing. At the histological analysis, one implant was lost, and the animal was excluded from histological analysis, resulting in n=9. 3.2 Descriptive histological evaluation After 10 weeks of healing, several sites presented optimal healing with closure of the coronal entrance of the defects in both the Low-T (Figures 4A,B), and High-T (Figures 5A,B) sites. In these defects, the bone had grown among the granules gaining integration on them and occupied all regions examined. Several particles of biomaterial were noted be-yond the base of the defect, possibly due to a migration into the marrow spaces enclosed between the two cortical layers of the mandible. Not all defects were found to be healed perfectly. Some sites presented residual defects occupied by soft tissue and particles of biomaterials, that were sometimes surround-ed by new bone (Figure 6A,B). In several biopsies of both groups, it was noted a better healing at one site laterally to the implant compared to the opposite side. In some biopsies, the worst sites presented root residues laterally to the defect, occurrences that might have compromised the healing. This event was noted in both the Low-T (Figure 7A) and the High-T (Figure 7B) sites. 3.3 Histomorphometric assessments After ten weeks of healing, a higher amount of new bone was found in the Low-T (21.0%) compared to the Hight-T (14.2%) sites (Table 1). Considering the total amount of new bone, the difference was not statistically significant (0.074). New bone was higher at the Low-T compared the High-T in all regions evaluated, being the difference statistically significant in two of them (ii and c; Table 2). Considering only the best sides, that excluded possible interference by the root residues, new bone was 26.7% at the Low-T and 20.5% at the High-T (p=0.132). The xenograft was present at similar percentages in both groups (20.1% and 18.0% at the Low-T and High-T, respectively). The lowest concentration of xenograft was found in the ii and is regions for both groups. Most sites presented a coronal level of osseointegration positioned at a distance ≥ 2 mm from the implant margin. Bone gain was similar in both groups, presenting mean values of 0.87 ±0.97 mm in the Low-T group, and 0.89 ±1.2 mm in the High-T group (p= 0.973). The BIC% was 15.3% (24.8%) and 20.5% (23.4%) for the Low-T and High-T sites, respectively (p=0.688). 4. Discussion The present study showed that critical defects 10 mm wide and 3 mm deep might heal when filled with xenografts. However, healing was not complete on either side lateral to the implant. Higher amounts of bone and xenografts were found in the Low-T group (21.0% and 19.7 %, respectively) than in the High-T group (14.2% and 14.2 %, respective-ly). However, the differences were not statistically significant (p=0.074 and p=0.063 for new bone and xenografts, respectively). The loss of two animals after surgery and one im-plant in another animal compromised the results. However, in two regions, I-I and C, a statistically significant difference in favor of the Low-T group compared to the High-T group was found, confirming a tendency for better results in the former than in the latter group. The region with the lowest new bone percentage was the I-C in both groups. Most sites presented a low rate of bone gain. The BIC% evaluated between B and F was 15.3% and 20.5% in the Low-T and High-T groups, respectively (p=0.688). The healing of critical-size defects is a well-known problem that has been challenged in several studies. In one experiment in rabbits, through-and-through circumferential critical-size bone defects were prepared both in the calvaria (10 mm in diameter) and in the mandible (11 mm in diameter) [32]. The defects were left healed spontaneously or filled with either biphasic calcium phosphate granules or autogenous bone. After 10 weeks, the defects in the mandible at the autogenous sites appeared filled in the microCT analysis by a bone tissue volume ratio (BV/TV) of 37.8%. The empty defects were unable to heal spontaneously, showing a BV/TV of 23.5% and the histological analysis disclosed the presence of connective tissue occupying a vast central region of the defect. The defects with the bi-phasic biomaterial healed partially, presenting a BV/TV of 17.1%. The defects prepared in the present study were slightly smaller but were not through-and-through defects. This, in turn, means that the absence of a full-thickness bone defect left the bone at the base to contribute to bone formation. This resulted in optimal healing of several defects with closure of the coronal entrance, although this result was of-ten limited to one site lateral to the implant. In another experiment in the mandible of rabbits, box-shaped defects of 3 mm in width and 2 mm in depth were made [33]. The boxes were prepared by applying different diameters, that is 4, 5, 6, 8, and 10-mm. Healing was analyzed after 4, 8, and 12 weeks. It was shown that healing was faster in the smallest defects. After 12 weeks, at the microCT analysis, these defects were filled with newly formed bone with a BV/TV >90%. The 8- and 10-mm long defects were underfilled, with a BV/TV of ~25-27%. Similarly, at the histological analysis, the new bone area ratio compared to the total defect area was 12-14% in the larger defects, while at those smaller was >60%. In the present study, the defect was 10 mm in diameter. Moreover, it was deeper (3 mm instead of 2 mm) and circumferential, so the defect had similar dimensions all around the center, in contrast to a box-shaped defect. However, an implant 3.25 mm in diameter was placed in the center of the defect. This might be interpreted as a factor that switched the 10 mm wide defect to a circumferential gap of ~3.4 mm around the implant. Circumferential self-contained marginal defects around implants with gaps of 1.25 mm [34-37] or 2.25 mm [38] showed optimal healing after four months from surgery. All defects were filled with newly formed bone and the coronal level of osseointegration at the implant was very close to the implant margin. However, osseointegration within the defect region was limited in the present study. The difference in the outcome might be related to the dimensions of the gap, which was wider in the present study, and to the model and location used, being dogs and alveolar bone, respectively, in the studies mentioned above. It should be moreover considered that the placement of an implant within a marginal defect increases the healing time and changes the healing pattern of the defect. In fact, a defect [39] or an extraction socket [40,41] might be almost filled by woven bone after 1 month. Instead, the placement of an implant in defects [34,35,42] or extraction sockets [43,44] will increase the healing time by at least one month compared to sites without im-plants. In the presence of an implant, the defect will be filled with newly formed bone within a month as well. However, a defect ~0.4 mm wide around the implant remains, separating the implant surface from the newly formed bone, effectively preventing osseointegration within the defect. This residual defect will be filled by new bone in contact with the implant within 3-4 months after surgery owing to the osteoconductivity of the implant surface [34-38]. The osteoconductivity of the implant surface is of crucial im-portance in these cases. Turned surfaces, for instance, were unable to allow a complete healing of this defect around the implants [45,46]. However, in the present study, poor osseointegration within the defect could be associated with insufficient closure of the defect by new bone, preventing support for bone formation on the implant surface. As limitations of the present study should be mentioned the model used, being the cortical lateral wall of the mandible instead of alveolar bone, and the faster healing of rabbits compared humans [47]. Moreover, the inclusion within some defect or roots residues seems to have compromised the healing in some sites. 5. Conclusion Circumferential marginal critical-size defects around implants filled with bovine xenografts presented sites with a complete healing in both groups. However, the healing was not complete all around the defect in most defects; therefore, a complete optimal healing of critical-size marginal defects cannot be predicted. Declarations Data Availability Statement: The data is available following a reasonable request. Acknowledgments: We thank Dr. Vitor Ferreira Balan for the surgical procedures and Mr. Sebastiao Blanco (University of São Paulo, Faculty of Dentistry of Ribeirão Preto) for processing the histological slides. The scientific contribution in the histological assessment by Dr. Ermenegildo Federico De Rossi (ARDEC Academy, Rimini, Italy) was greatly appreciated. The implants were donated by Leader Medica, Padua, Italy. Conflicts of Interest: The authors declare no conflict of interest. Funding Declaration: The study was economically supported by ARDEC Academy, Rimini, Italy References Götz C, Warnke PH, Kolk A. Current and future options of regeneration methods and reconstructive surgery of the facial skeleton. Oral Surg Oral Med Oral Pathol Oral Radiol. 2015 Sep;120(3):315-23. doi: 10.1016/j.oooo.2015.05.022. Epub 2015 Jun 15. PMID: 26297391. Schmitz JP, Hollinger JO. The critical size defect as an experimental model for craniomandibulofacial nonunions. Clin Orthop Relat Res. 1986 Apr;(205):299-308. PMID: 3084153. Corbella S, Taschieri S, Weinstein R, Del Fabbro M. Histomorphometric outcomes after lateral sinus floor elevation procedure: a systematic review of the literature and meta-analysis. Clin Oral Implants Res. 2016 Sep;27(9):1106-22. doi: 10.1111/clr.12702. Epub 2015 Oct 10. PMID: 26452326. Fretwurst T, Gad LM, Nelson K, Schmelzeisen R. Dentoalveolar reconstruction: modern approaches. Curr Opin Otolaryngol Head Neck Surg. 2015 Aug;23(4):316-22. doi: 10.1097/MOO.0000000000000167. PMID: 26101873. Nkenke E, Neukam FW. Autogenous bone harvesting and grafting in advanced jaw resorption: morbidity, resorption and implant survival. Eur J Oral Implantol. 2014 Summer;7 Suppl 2:S203-17. PMID: 24977256. Blank BS, Levy AR. Combined treatment of a large periodontal defect using GTR and DFDBA. Int J Periodontics Restorative Dent. 1999 Oct;19(5):481-7. PMID: 10709514. Borie E, Fuentes R, Del Sol M, Oporto G, Engelke W. The influence of FDBA and autogenous bone particles on regeneration of calvaria defects in the rabbit: a pilot study. Ann Anat. 2011 Oct 20;193(5):412-7. doi: 10.1016/j.aanat.2011.06.003. Epub 2011 Jul 8. PMID: 21802915. Jensen T, Schou S, Stavropoulos A, Terheyden H, Holmstrup P. Maxillary sinus floor augmentation with Bio-Oss or Bio-Oss mixed with autogenous bone as graft in animals: a systematic review. Int J Oral Maxillofac Surg. 2012 Jan;41(1):114-20. doi: 10.1016/j.ijom.2011.08.010. Epub 2011 Oct 13. PMID: 22000958. Caneva M, Lang NP, Garcia Rangel IJ, Ferreira S, Caneva M, De Santis E, Botticelli D. Sinus mucosa elevation using Bio-Oss® or Gingistat® collagen sponge: an experimental study in rabbits. Clin Oral Implants Res. 2017 Jul;28(7):e21-e30. doi: 10.1111/clr.12850. Epub 2016 Apr 15. PMID: 27080163. Masuda K, Silva ER, Apaza Alccayhuaman KA, Botticelli D, Xavier SP. Histologic and Micro-CT Analyses at Implants Placed Immediately After Maxillary Sinus Elevation Using Large or Small Xenograft Granules: An Experimental Study in Rabbits. Int J Oral Maxillofac Implants. 2020 Jul/Aug;35(4):739-748. doi: 10.11607/jomi.8067. PMID: 32724925. Godoy EP, Alccayhuaman KAA, Botticelli D, Amaroli A, Balan VF, Silva ER, Xavier SP. Osteoconductivity of Bovine Xenograft Granules of Different Sizes in Sinus Lift: A Histomorphometric Study in Rabbits. Dent J (Basel). 2021 May 31;9(6):61. doi: 10.3390/dj9060061. PMID: 34072644; PMCID: PMC8227860. Jensen T, Schou S, Stavropoulos A, Terheyden H, Holmstrup P. Maxillary sinus floor augmentation with Bio-Oss or Bio-Oss mixed with autogenous bone as graft: a systematic review. Clin Oral Implants Res. 2012 Mar;23(3):263-73. doi: 10.1111/j.1600-0501.2011.02168.x. Epub 2011 Mar 28. PMID: 21443592. Mordenfeld A, Lindgren C, Hallman M. Sinus Floor Augmentation Using Straumann® BoneCeramic™ and Bio-Oss® in a Split Mouth Design and Later Placement of Implants: A 5-Year Report from a Longitudinal Study. Clin Implant Dent Relat Res. 2016 Oct;18(5):926-936. doi: 10.1111/cid.12374. Epub 2015 Sep 10. PMID: 26358740. Accorsi-Mendonça T, Conz MB, Barros TC, de Sena LA, Soares Gde A, Granjeiro JM. Physicochemical characterization of two deproteinized bovine xenografts. Braz Oral Res. 2008 Jan-Mar;22(1):5-10. doi: 10.1590/s1806-83242008000100002. PMID: 18425238. Berberi A, Samarani A, Nader N, Noujeim Z, Dagher M, Kanj W, Mearawi R, Salemeh Z, Badran B. Physicochemical characteristics of bone substitutes used in oral surgery in comparison to autogenous bone. Biomed Res Int. 2014;2014:320790. doi: 10.1155/2014/320790. Epub 2014 Jul 8. Lee JH, Yi GS, Lee JW, Kim DJ. Physicochemical characterization of porcine bone-derived grafting material and com-parison with bovine xenografts for dental applications. J Periodontal Implant Sci. 2017 Dec;47(6):388-401. doi: 10.5051/jpis.2017.47.6.388) Hoexter DL. Bone regeneration graft materials. J Oral Implantol. 2002;28(6):290-4. doi: 10.1563/1548-1336(2002)0282.3.CO;2. Iezzi G, Degidi M, Piattelli A, Mangano C, Scarano A, Shibli JA, Perrotti V. Comparative histological results of different biomaterials used in sinus augmentation procedures: a human study at 6 months. Clin Oral Implants Res. 2012 Dec;23(12):1369-76. doi: 10.1111/j.1600-0501.2011.02308.x. Epub 2011 Nov 2. Lee DZ, Chen ST, Darby IB. Maxillary sinus floor elevation and grafting with deproteinized bovine bone mineral: a clinical and histomorphometric study. Clin Oral Implants Res. 2012 Aug;23(8):918-24. doi: 10.1111/j.1600-0501.2011.02239.x. Epub 2011 Jun 24. PMID: 21707754. do Desterro Fde P, Sader MS, Soares GD, Vidigal GM Jr. Can inorganic bovine bone grafts present distinct properties? Braz Dent J. 2014;25(4):282-8. doi: 10.1590/0103-6440201300067. PMID: 25250490. Tapety FI, Amizuka N, Uoshima K, Nomura S, Maeda T. A histological evaluation of the involvement of Bio-Oss in osteoblastic differentiation and matrix synthesis. Clin Oral Implants Res. 2004 Jun;15(3):315-24. doi: 10.1111/j.1600-0501.2004.01012.x. PMID: 15142094. Riachi F, Naaman N, Tabarani C, Aboelsaad N, Aboushelib MN, Berberi A, Salameh Z. Influence of material properties on rate of resorption of two bone graft materials after sinus lift using radiographic assessment. Int J Dent. 2012;2012:737262. doi: 10.1155/2012/737262. Epub 2012 Jul 31. PMID: 22899930; PMCID: PMC3415107. Gomez J, Bergamo ET, Tovar N, Talib HS, Pippenger BE, Herdia V, Cox M, Coelho PG, Witek L. Microtomographic re-construction of mandibular defects treated with xenografts and collagen-based membranes: A pre-clinical minipig model. Med Oral Patol Oral Cir Bucal. 2021 Nov 1;26(6):e825-e833. doi: 10.4317/medoral.24811. PMID: 34564687; PMCID: PMC8601645. Sargolzaie N, Kadkhodazadeh M, Ebadian AR, Shafieian R, Pourkaveh S, Naghibi N, Ramandie MF. Histological Evaluation of Bone Regeneration Using Hydroxyapatite Based Bone Substitute Derived from Antler: An Animal Study. J Long Term Eff Med Implants. 2022;32(1):77-84. doi: 10.1615/JLongTermEffMedImplants.2021039830. PMID: 35377997. Ferreira Balan V, Botticelli D, Peñarrocha-Oltra D, Masuda K, Pires Godoy E, Xavier SP. Maxillary Sinus Floor Aug-mentation with Two Different Inorganic Bovine Bone Grafts: an Experimental Study in Rabbits. Chin J Dent Res. 2022 Jun 10;25(2):93-105. doi: 10.3290/j.cjdr.b3086337. PMID: 35686589. Tawil G, Barbeck M, Unger R, Tawil P, Witte F. Sinus Floor Elevation Using the Lateral Approach and Window Repositioning and a Xenogeneic Bone Substitute as a Grafting Material: A Histologic, Histomorphometric, and Radiographic Analysis. Int J Oral Maxillofac Implants. 2018 September/October;33(5):1089–1096. doi: 10.11607/jomi.6226. Epub 2018 Jun 12. PMID: 29894551. Čandrlić M, Tomas M, Karl M, Malešić L, Včev A, Perić Kačarević Ž, Matijević M. Comparison of Injectable Biphasic Calcium Phosphate and a Bovine Xenograft in Socket Preservation: Qualitative and Quantitative Histologic Study in Humans. Int J Mol Sci. 2022 Feb 25;23(5):2539. doi: 10.3390/ijms23052539. PMID: 35269686; PMCID: PMC8910217. Catros S, Sandgren R, Pippenger BE, Fricain JC, Herber V, El Chaar E. A Novel Xenograft Bone Substitute Supports Stable Bone Formation in Circumferential Defects Around Dental Implants in Minipigs. Int J Oral Maxillofac Implants. 2020 Nov/Dec;35(6):1122-1131. doi: 10.11607/jomi.8265. PMID: 33270052.4. Faul F, Erdfelder E, Buchner A, Lang AG. Statistical power analyses using G*Power 3.1: tests for correlation and regression analyses. Behav Res Methods. 2009 Nov;41(4):1149-60. doi: 10.3758/BRM.41.4.1149. PMID: 19897823. Faul F, Erdfelder E, Lang AG, Buchner A. G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods. 2007 May;39(2):175-91. doi: 10.3758/bf03193146. PMID: 17695343. Schwarz F, Sager M, Ferrari D, Mihatovic I, Becker J. Influence of recombinant human platelet-derived growth factor on lateral ridge augmentation using biphasic calcium phosphate and guided bone regeneration: a histomorphometric study in dogs. J Periodontol. 2009 Aug;80(8):1315-23. doi: 10.1902/jop.2009.090034]. Kotagudda Ranganath S, Schlund M, Delattre J, Ferri J, Chai F. Bilateral double site (calvarial and mandibular) critical-size bone defect model in rabbits for evaluation of a craniofacial tissue engineering constructs. Mater Today Bio. 2022 Apr 20;14:100267. doi: 10.1016/j.mtbio.2022.100267. Wang Y, Zhang X, Mei S, Li Y, Khan AA, Guan S, Li X. Determination of critical-sized defect of mandible in a rabbit model: Micro-computed tomography, and histological evaluation. Heliyon. 2023 Jul 17;9(7):e18047. doi: 10.1016/j.heliyon.2023.e18047. Botticelli D, Berglundh T, Buser D, Lindhe J. Appositional bone formation in marginal defects at implants. Clin Oral Implants Res. 2003 Feb;14(1):1-9. doi: 10.1034/j.1600-0501.2003.140101.x. PMID: 12562359. Botticelli D, Berglundh T, Buser D, Lindhe J. The jumping distance revisited: An experimental study in the dog. Clin Oral Implants Res. 2003 Feb;14(1):35-42. doi: 10.1034/j.1600-0501.2003.140105.x. PMID: 12562363. Botticelli D, Berglundh T, Lindhe J. The influence of a biomaterial on the closure of a marginal hard tissue defect adjacent to implants. An experimental study in the dog. Clin Oral Implants Res. 2004 Jun;15(3):285-92. doi: 10.1046/j.1600-0501.2003.01008.x. PMID: 15142090. Botticelli D, Persson LG, Lindhe J, Berglundh T. Bone tissue formation adjacent to implants placed in fresh extraction sockets: an experimental study in dogs. Clin Oral Implants Res. 2006 Aug;17(4):351-8. doi: 10.1111/j.1600-0501.2006.01270.x. PMID: 16907764. Botticelli D, Berglundh T, Lindhe J. Resolution of bone defects of varying dimension and configuration in the marginal portion of the peri-implant bone. An experimental study in the dog. J Clin Periodontol. 2004 Apr;31(4):309-17. doi: 10.1111/j.1600-051X.2004.00502.x. PMID: 15016260. Carmagnola D, Berglundh T, Lindhe J. The effect of a fibrin glue on the integration of Bio-Oss with bone tissue. A experimental study in labrador dogs. J Clin Periodontol. 2002 May;29(5):377-83. doi: 10.1034/j.1600-051x.2002.290501.x. PMID: 12060419. Araújo MG, Lindhe J. Dimensional ridge alterations following tooth extraction. An experimental study in the dog. J Clin Periodontol. 2005 Feb;32(2):212-8. doi: 10.1111/j.1600-051X.2005.00642.x. PMID: 15691354. Scala A, Lang NP, Schweikert MT, de Oliveira JA, Rangel-Garcia I Jr, Botticelli D. Sequential healing of open extraction sockets. An experimental study in monkeys. Clin Oral Implants Res. 2014 Mar;25(3):288-295. doi: 10.1111/clr.12148. Epub 2013 Apr 1. PMID: 23551527. Rossi F, Botticelli D, Pantani F, Pereira FP, Salata LA, Lang NP. Bone healing pattern in surgically created circumferential defects around submerged implants: an experimental study in dog. Clin Oral Implants Res. 2012 Jan;23(1):41-8. doi: 10.1111/j.1600-0501.2011.02170.x. Epub 2011 Mar 28. PMID: 21443594. Araújo MG, Wennström JL, Lindhe J. Modeling of the buccal and lingual bone walls of fresh extraction sites following implant installation. Clin Oral Implants Res. 2006 Dec;17(6):606-14. doi: 10.1111/j.1600-0501.2006.01315.x. PMID: 17092217. Mainetti T, Lang NP, Bengazi F, Favero V, Soto Cantero L, Botticelli D. Sequential healing at implants installed immediately into extraction sockets. An experimental study in dogs. Clin Oral Implants Res. 2016 Jan;27(1):130-8. doi: 10.1111/clr.12533. Epub 2014 Dec 18. PMID: 25521008. Akimoto K, Becker W, Persson R, Baker DA, Rohrer MD, O'Neal RB. Evaluation of titanium implants placed into simulated extraction sockets: a study in dogs. Int J Oral Maxillofac Implants. 1999 May-Jun;14(3):351-60. PMID: 10379108. Botticelli D, Berglundh T, Persson LG, Lindhe J. Bone regeneration at implants with turned or rough surfaces in self-contained defects. An experimental study in the dog. J Clin Periodontol. 2005 May;32(5):448-55. doi: 10.1111/j.1600-051X.2005.00693.x. PMID: 15842258. Botticelli D, Lang NP. Dynamics of osseointegration in various human and animal models - a comparative analysis. Clin Oral Implants Res. 2017 Jun;28(6):742-748. doi: 10.1111/clr.12872. Epub 2016 May 23. Tables Table 1. Histomorphometric evaluation of soft and hard tissues within the whole defects. Means values and standard deviations in percentage. P-values between Low-T and High-T sites are reported. N=9. Low-T High-T New bone Xenograft Soft tissues New bone Xenograft Soft tissues Mean (SD) 21.0 (8.5) 19.7 (6.4) 58.9 (12.1) 14.2 (5.4) 14.2 (8.6) 67.8 (12.4) p-value 0.074 0.063 0.101 Table 2. Histomorphometric evaluation of soft and hard tissues in the various regions within the defects. Means values and standard deviations in percentage. Regions evaluated: I-S, internal superior; I-C, internal central; I-I, internal inferior; C-S, central superior; C, central; E-S, external superior. * = p<0.05. N=9. Low-T High-T New bone Xenograft Soft tissues New bone Xenograft Soft tissues I-S 18.4 (14.4) 13.1 (8.8) 68.5 (18.2) 12.7 (12.0) 13.9 (7.5) 73.4 (17.4) I-C 13.4 (11.9) 23.1 (7.1) 63.5 (18.1) 9.4 (10.7) 18.7 (17.0) 71.9 (18.8) I-I 23.8 (6.4)* 15.7 (7.4) 60.5 (9.6)* 16.5 (8.1)* 11.7 (11.2) 71.8 (12.7)* C-S 22.8 (16.0) 20.4 (9.0) 56.7 (17.0) 12.8 (8.2) 23.3 (10.2) 64.0 (15.9) C 23.7 (12.8)* 23.6 (11.9) 52.7 (10.0) 15.0 (7.0)* 21.9 (13.4) 63.1 (14.4) E-S 24.1 (8.9) 24.6 (13.7) 51.3 (17.5) 18.7 (11.7) 18.5 (8.2) 62.8 (12.0) Additional Declarations No competing interests reported. Supplementary Files 02ASANOTABLESBIOOSSvsCERABONEwithIMPLANT.docx Cite Share Download PDF Status: Published Journal Publication published 29 Jan, 2024 Read the published version in Oral and Maxillofacial Surgery → Version 1 posted Editorial decision: Revision requested 14 Jan, 2024 Reviews received at journal 09 Jan, 2024 Reviewers agreed at journal 26 Dec, 2023 Reviewers invited by journal 26 Nov, 2023 Submission checks completed at journal 20 Nov, 2023 Editor assigned by journal 20 Nov, 2023 First submitted to journal 19 Nov, 2023 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-3635546","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":251498045,"identity":"3d809ff0-1f34-48a9-afc7-ad31e0989915","order_by":0,"name":"Akihisa Asano","email":"","orcid":"","institution":"Osaka Dental University","correspondingAuthor":false,"prefix":"","firstName":"Akihisa","middleName":"","lastName":"Asano","suffix":""},{"id":251498046,"identity":"81bcbdc4-2de6-429d-99a5-cb5ecb6dcef1","order_by":1,"name":"Samuel Porfirio Xavier","email":"","orcid":"","institution":"University of São Paulo","correspondingAuthor":false,"prefix":"","firstName":"Samuel","middleName":"Porfirio","lastName":"Xavier","suffix":""},{"id":251498047,"identity":"5236198b-56e0-4082-aa14-cb39f6b4a0b8","order_by":2,"name":"Erick Ricardo Silva","email":"","orcid":"","institution":"University of São Paulo","correspondingAuthor":false,"prefix":"","firstName":"Erick","middleName":"Ricardo","lastName":"Silva","suffix":""},{"id":251498048,"identity":"fa14b75b-5a1d-435f-a1c5-ad97b3022ea2","order_by":3,"name":"Kenzo Morinaga","email":"","orcid":"","institution":"Osaka Dental University","correspondingAuthor":false,"prefix":"","firstName":"Kenzo","middleName":"","lastName":"Morinaga","suffix":""},{"id":251498049,"identity":"3b083b4b-23e7-4ee8-84cf-7ffb0101a120","order_by":4,"name":"Daniele Botticelli","email":"data:image/png;base64,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","orcid":"","institution":"Osaka Dental University","correspondingAuthor":true,"prefix":"","firstName":"Daniele","middleName":"","lastName":"Botticelli","suffix":""},{"id":251498050,"identity":"197f65ea-52c8-4b22-8138-e7cb294d7d6f","order_by":5,"name":"Yasushi Nakajima","email":"","orcid":"","institution":"Osaka Dental University","correspondingAuthor":false,"prefix":"","firstName":"Yasushi","middleName":"","lastName":"Nakajima","suffix":""},{"id":251498051,"identity":"28590a91-7f18-4fb4-a803-1f9cbd300ae2","order_by":6,"name":"Shunsuke Baba","email":"","orcid":"","institution":"Osaka Dental University","correspondingAuthor":false,"prefix":"","firstName":"Shunsuke","middleName":"","lastName":"Baba","suffix":""}],"badges":[],"createdAt":"2023-11-19 16:59:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3635546/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3635546/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10006-024-01216-3","type":"published","date":"2024-01-29T15:00:29+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":46997761,"identity":"8f6eb4f8-b79e-44dc-b2ba-283ee7bb8857","added_by":"auto","created_at":"2023-11-23 22:50:53","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1772854,"visible":true,"origin":"","legend":"\u003cp\u003eClinical photographs of a Low-T site. A, a defect, ~10mm wide and ~3mm deep defect was prepared and implant was installed about in the center. B, defect filled with biomaterial. C, collagen membrane on the top of the defect.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3635546/v1/22ed1d15f554a4a9064a6df7.jpg"},{"id":46996565,"identity":"caac146c-2829-4be4-a4e0-77b99081cf85","added_by":"auto","created_at":"2023-11-23 22:42:53","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1959723,"visible":true,"origin":"","legend":"\u003cp\u003eClinical photographs of a Low-T site. A, a defect, ~10mm wide and ~3mm deep defect was prepared and implant was installed about in the center. B, defect filled with biomaterial. C, collagen membrane on the top of the defect.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3635546/v1/c32934b1fa7033207c417fbc.jpg"},{"id":46996568,"identity":"0d8c84e6-6132-4382-a5b1-18167fad4ee2","added_by":"auto","created_at":"2023-11-23 22:42:53","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":4402493,"visible":true,"origin":"","legend":"\u003cp\u003eSix locations were evaluated within the grafted region both sides to the implant: I-S, internal superior; I-C, internal central; I-I, internal inferior), two central (C-S, central superior; C, central) and one external (E-S, external superior).\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3635546/v1/acff3f809bffed7fced29593.jpg"},{"id":46996570,"identity":"6b0cc59e-b961-4f8c-a0f8-d0862bc39048","added_by":"auto","created_at":"2023-11-23 22:42:53","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":4565625,"visible":true,"origin":"","legend":"\u003cp\u003ePhotomicrographs of ground sections showing healing aspects at the Low-T sites after ten weeks of healing. New bone was found in all regions of the defect and on the implant and bio-material surfaces. New bone accomplished to close the entrance of the defects. Stevenel’s blue and alizarin red stain.\u003c/p\u003e","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3635546/v1/a9a7595fdcd3c64a88946979.jpg"},{"id":46996567,"identity":"3c7fc4b2-adf5-4874-82c9-93e5ec7d4b55","added_by":"auto","created_at":"2023-11-23 22:42:53","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":4001967,"visible":true,"origin":"","legend":"\u003cp\u003ePhotomicrographs of ground sections showing healing aspects at the High-T sites after ten weeks of healing. New bone was found in all regions of the defect and on the implant and biomaterial surfaces. New bone accomplished to close the entrance of the defects. Stevenel’s blue and alizarin red stain.\u003c/p\u003e","description":"","filename":"Figure5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3635546/v1/4042e9394c9e717664343691.jpg"},{"id":46996572,"identity":"e1ca99cd-8d43-43c7-9225-7657d7ce600e","added_by":"auto","created_at":"2023-11-23 22:42:53","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":3570988,"visible":true,"origin":"","legend":"\u003cp\u003ePhotomicrographs of ground sections showing healing aspects at the Low-T (A) and High-T (B) sites after ten weeks of healing. Not all sites healed perfectly, and residual defects were detected. Stevenel’s blue and alizarin red stain.\u003c/p\u003e","description":"","filename":"Figure6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3635546/v1/f11baedf7fb405f46009d453.jpg"},{"id":46996569,"identity":"1d1fe17d-3dd9-4e43-8433-34fc57172d0e","added_by":"auto","created_at":"2023-11-23 22:42:53","extension":"jpg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":3457249,"visible":true,"origin":"","legend":"\u003cp\u003ePhotomicrographs of ground sections showing healing aspects at inlay graft sites after 10 weeks. The presence of a root residue might have influenced the healing. Stevenel’s blue and alizarin red stain. Stevenel’s blue and alizarin red stain.\u003c/p\u003e","description":"","filename":"Figure7.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3635546/v1/b8470614b25eebb7854948ea.jpg"},{"id":50673711,"identity":"aa0a3c9a-02b7-43ec-ac31-538bc705bbf4","added_by":"auto","created_at":"2024-02-05 15:02:15","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1413159,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3635546/v1/4eb00a81-3a90-4eb4-ab1e-98c204f26e59.pdf"},{"id":46996564,"identity":"ff4b8c95-d632-412d-884e-e170aac26c55","added_by":"auto","created_at":"2023-11-23 22:42:53","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":15350,"visible":true,"origin":"","legend":"","description":"","filename":"02ASANOTABLESBIOOSSvsCERABONEwithIMPLANT.docx","url":"https://assets-eu.researchsquare.com/files/rs-3635546/v1/d262bb209e184183f139eac3.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Critical-sized marginal defects around implants treated with xenografts in rabbits","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eReconstruction of alveolar bone defects, resulting from ageing, trauma, ablative procedures, or oral pathologies, remains a surgical problem [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Critical defects are those in which the extension compromises spontaneous bone repair [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAutologous bone is still considered the \u0026ldquo;gold standard\u0026rdquo; for maxillofacial bone augmentation [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. However, extensive defects may require volumes of bone that are only available in extra-oral donor sites. Consequently, the morbidity associated with bone harvesting has become a major concern [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTo overcome these disadvantages, bone substitutes have been developed to assist bone formation by both maintaining the three-dimensional framework and developing an osteoconductive environment in the region to be repaired [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. These events lead to migration of osteoblasts and deposition of bone matrix [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eBio-Oss\u0026reg; is an osteoconductive bone substitute obtained from bovine bone, which supports proliferation of blood vessels and cell migration. It has been demonstrated that it can achieve adequate bone formation in both animal [\u003cspan additionalcitationids=\"CR9 CR10\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] and clinical studies [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis xenogeneic biomaterial is composed of deproteinized bovine bone mineral processed at 300\u0026ordm; C, consisting of porous inorganic hydroxyapatite [\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Due to its porosity and the high release of calcium ions, vascular and bone formation is favored [\u003cspan additionalcitationids=\"CR18 CR19\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. In addition, it promotes osteoblastic activity in the early stages of bone regeneration [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCerabone\u0026reg; is a xenogenous biomaterial composed of bovine bone mineral and acts in a way to enable osteoconduction. It is processed at 1,200\u0026ordm;C and presents a less intense gradual release of calcium ions [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. The use of this biomaterial has been reported by a few animal [\u003cspan additionalcitationids=\"CR24\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] and clinical studies [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Recently, it has been demonstrated that this xenograft supports the formation of new and stable bone volume in circumferential defects around implants in minipigs [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. However, the histological outcomes of deproteinized bovine bone (i.e., Bio-Oss\u0026reg; vs Cerabone\u0026reg;) in critical defects around implants in the mandible of rabbits have not been evaluated yet.\u003c/p\u003e \u003cp\u003eHence, the present study aimed to evaluate bone formation and osseointegration of implants installed in critical defects of the mandibular body simultaneously grafted with Bio-Oss\u0026reg; or Cerabone\u0026reg;.\u003c/p\u003e"},{"header":"2. Materials and Methods","content":"\u003cp\u003e\u003cem\u003e2.1 Ethical statements\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis research project was approved by the Committee on Ethics in the Use of Animals of the Faculty of Dentistry of Ribeir\u0026atilde;o Preto, University of S\u0026atilde;o Paulo, Brazil, on May 20, 2022, protocol #2022.1.287.58.3. The proposed experimental procedures were carried out in accordance with legislation for animal experimentation in Brazil. The ARRIVE Checklist was used in this study.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e2.2 Study design\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe present study had a prospective, randomized, split-mouth study (test and control sides in the same animal) design. Defects, 10 mm wide and 3 mm deep, were prepared at both the lateral aspects of the mandible and an implant was placed in the center of each defect. The defects were randomly filled with either Bio-Oss\u0026reg; (low temperature; Low-T sites) or Cerabone\u0026reg; (high temperature; High-T sites) and a collagen membrane was placed to cover the region. Histological analyses were performed after 10 weeks of healing.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e2.3 Experimental animals and sample size\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe sample size was evaluated using data from a previous experiment performed by the same group in which the healing of two biomaterials was studied after 10 weeks from sinus floor elevation in rabbit. In a two-tails evaluation, applying an \u0026alpha;=0.05, a power of 0.8 and a calculated effect size of 0.9785, a sample size of 11 pairs of animals was obtained to reject the null hypothesis that the difference is zero reaching an actual power of 0.83 (G*Power 3.1.9.4) [29,30]. The sample was increased to 12 for possible complications. Hence, 12 adult male New Zealand White rabbits, weighing ~4.0 kg and aged ~5 months, were included in the study.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e2.4 Randomization and allocation concealment\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAn author (S.P.X.) who was not involved in the selection of animals, or any surgical procedure carried out the randomization electronically. The allocation treatment was kept concealed in a sealed opaque envelope, opened after implant installation. All histological slides were codes and the histological examinator was not informed about treatment al-location. Nevertheless, the two biomaterials could be identified for different aspects in histology.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e2.5 Biomaterials\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eBio-Oss\u0026reg; (Geistlich Biomaterial, Wolhusen, LU, Switzerland) is deproteinized bovine mineral bone with sinterization at 300\u0026ordm;, porosity of 75 to 80%, with pores of 20 to 200\u0026micro;m and average particulate size of 0.5 - 1mm [16].\u003c/p\u003e\n\u003cp\u003eCerabone\u0026reg; (Botiss Biomaterials GmbH, Zossen, Germany) is completely formed by hydroxyapatite from bovine cancellous bone, with sinterization at 1200\u0026deg;c, porosity of 65 to 80%, with pores of 600 to 900\u0026micro;m and average particle size of 0.5 - 1mm [16].\u003c/p\u003e\n\u003cp\u003eBio-Gide (Geistlich) is a porcine-derived resorbable membrane composed of types I and III collagen. It is composed of a bilayer structure with a smooth outer layer aimed at avoiding the progression of soft tissues within the region to be regenerated, and a porous inner layer that aims to favor bone cells and vessel growth [31].\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e2.6 Anesthetic procedures\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe anesthetic procedures started with the use of acepromazine I.M. (1.0 mg/kg; Acepran, Vetnil, Louveira, S\u0026atilde;o Paulo), and xylazine I.M. (3.0 mg/Kg; Laborat\u0026oacute;rios Calier S/A, Barcelona, Spain) and ketamine I.M. (50.0 mg/Kg; Uni\u0026atilde;o Qu\u0026iacute;mica Farmac\u0026ecirc;utica Nacional S/A, Embugua\u0026ccedil;\u0026uacute;, S\u0026atilde;o Paulo, Brazil). Antibiotic therapy was initiated with oxy-tetracycline. (0.2 ml/Kg; Biovet; Vargem Grande Paulista, S\u0026atilde;o Paulo, Brazil). After shaving, the area to be operated disinfected with 1% polyvinylpyrrolidone iodine solution (Ri-ode\u0026iacute;ne Tintura, Rioqu\u0026iacute;mica, S\u0026atilde;o Jos\u0026eacute; do Rio Preto, S\u0026atilde;o Paulo, Brazil). Local anesthesia was added with 2% mepivacaine and 1:100,000 noradrenaline (Mepinor, Nova DFL, Rio de Janeiro, Brazil).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e2.7 Surgical procedure\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe clinical surgical procedures were performed by an experienced and qualified operator (V.F.B.; see acknowledgments). A linear incision of about 2.5-3 cm was made on the skin at the lower border of the mandible. Muscles and periosteum were reflected to expose the buccal bone of the mandibular angle. Defects, 10 mm wide and 3 mm deep, were pre-pared bilaterally using a trephine and finalized with burs. One implant, 8.5mm long and 3.25mm in diameter (Leader Medica, Padua, Italy) was installed in the center of each defect with the rough margin flush to the periphery of the defect (Figures 1A and 2A).\u003c/p\u003e\n\u003cp\u003eThe defects were filled with either Bio-Oss\u0026reg; (Low-T sites; figure 1B) or Cerabone\u0026reg; (High-T sites; Figure 2B). A collagen membrane (Bio-Gide) was used to cover the experimental region (Figure 1C and 2C). Vicryl 4-0 was used on the periosteum and muscular planes, and Nylon 4-0 to suture the skin.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e2.8 Animal maintenance\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe animals were kept in individual cages at the Animal Facility of the Faculty of Dentistry of Ribeir\u0026atilde;o Preto, University of S\u0026atilde;o Paulo and were fed with specifically tailored food and had access to water ad libitum. The room was acclimatized with split air conditioning and exhaust fan (27 to 34 air changes/h), and automatic lighting control (12-hour light-dark cycle)..In the postoperative period and in the following three days, all animals received ketoprofen (3.0 mg/kg, 12/12h, I.M., 10% Ketofen, Merial, Campinas, S\u0026atilde;o Paulo, Brazil) and 2% tramadol hydrochloride (1.0 mg/kg, 12 /12h, subcutaneous, Cronidor, Agener Uni\u0026atilde;o Sa\u0026uacute;de Animal, Apucarana, Paran\u0026aacute;, Brazil) in the postoperative period and in the following three days. A rigorous protocol for monitoring the animals was carried out throughout the experimental period, paying daily attention to the basic biological functions, feeding and excretion, behavioral signs in relation to postoperative pain, and monitoring of post-surgical infections and surgical wounds for suture care, bleeding, and/or signs of infection.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e2.9 Euthanasia\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe animals were euthanized by administering an overdose (2.0 mL) of intravenous thiopental 1.0 g (Thiopentax; Crist\u0026aacute;lia, Itapira, S\u0026atilde;o Paulo, Brazil) 10 weeks, The experimental regions were dissected and reduced to individual blocks and maintained in 10% paraformaldehyde for fixation.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e2.10 Histological processing\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAfter fixation, all blocks were washed and then include in the process of dehydration, resin inclusion (LR WhiteTM HardGrid, London Resin Co Ltd, Berkshire, United Kingdom) and polymerization. Subsequently, the specimens were cut following a transaxial plane in the center of the block guided by the implant positioned at the center of the graft.\u003c/p\u003e\n\u003cp\u003eTwo sections of approximately 100 \u0026ndash; 150 \u0026micro;m thickness were obtained that were then ground to a thickness of approximately 60\u0026ndash;80 \u0026micro;m using a cutting/grinding equipment (Exakt, Apparatebau, Norderstedt, Germany). Histological sections were stained with either Toluidine Blue or with Stevenel\u0026rsquo;s Blue and Alizarin Red.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e2.11 Histomorphometric evaluation\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe histological assessments were performed by an experienced assessor (E.F.D.R., see acknowledgements) after a calibration with another expert (D.B).\u003c/p\u003e\n\u003cp\u003eFor the linear measurements, the following references were used: B, the most coronal bone to implant contact level; M, the implant margin; F, the floor of the original defect, positioned 3 mm apically to M. The following classification was applied based the distance between B and F (B-F), that is the bone gain from the base of the original defect: M-F \u0026le;1 mm, 1\u0026gt; M-F \u0026le;2mm, M-F \u0026gt;2mm. Bone-to-implant contact percentage (BIC%) was evaluated within 3 mm of the defect.\u003c/p\u003e\n\u003cp\u003eThe morphometric measurements were performed in six locations (Figure 3), three of which close to the implant (I-S, internal superior; I-C, internal central; I-I, internal inferior), two central (C-S, central superior; C, central) and one external (E-S, external superior). New bone, xenograft, mix structure (composed of a mixture of xenograft and newly formed bone) and soft tissues were assessed. For the evaluation, one grid containing squares of 75 \u0026micro;m in dimension was superimposed onto the photomicrographs of each region using NIS-Elements software (Nikon, Tokyo, Japan). Each region was examined with a dimension of about 1 mm2.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e2.12 Experimental outcomes and statistical methods.\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe values obtained are expressed as the mean \u0026plusmn; standard deviation. The primary variable was the mineralized new bone. The secondary variables were other tissues evaluated in the morphometric analysis. The Shapiro-Wilk test was used to determine the normality of data and, according to the results, the differences between the test and control sides were evaluated by a paired t-test or a Wilcoxon matched-pairs signed rank test. GraphPad Prism (version 10.0.2 for Windows, GraphPad Software, Boston, Massachusetts, USA, www.graphpad.com) was used for statistical analyses. The significance level was 5%.\u0026nbsp;\u003c/p\u003e"},{"header":"3. Results","content":"\u003cp\u003e\u003cem\u003e3.1 Clinical outcomes\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eTwo animals died after surgery. Ten animals healed uneventfully and were available for histological processing. At the histological analysis, one implant was lost, and the animal was excluded from histological analysis, resulting in n=9.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e3.2 Descriptive histological evaluation\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAfter 10 weeks of healing, several sites presented optimal healing with closure of the coronal entrance of the defects in both the Low-T (Figures 4A,B), and High-T (Figures 5A,B) sites. In these defects, the bone had grown among the granules gaining integration on them and occupied all regions examined. Several particles of biomaterial were noted be-yond the base of the defect, possibly due to a migration into the marrow spaces enclosed between the two cortical layers of the mandible.\u003c/p\u003e\n\u003cp\u003eNot all defects were found to be healed perfectly. Some sites presented residual defects occupied by soft tissue and particles of biomaterials, that were sometimes surround-ed by new bone (Figure 6A,B).\u003c/p\u003e\n\u003cp\u003eIn several biopsies of both groups, it was noted a better healing at one site laterally to the implant compared to the opposite side. In some biopsies, the worst sites presented root residues laterally to the defect, occurrences that might have compromised the healing. This event was noted in both the Low-T (Figure 7A) and the High-T (Figure 7B) sites.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e3.3 Histomorphometric assessments\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAfter ten weeks of healing, a higher amount of new bone was found in the Low-T (21.0%) compared to the Hight-T (14.2%) sites (Table 1).\u003c/p\u003e\n\u003cp\u003eConsidering the total amount of new bone, the difference was not statistically significant (0.074). New bone was higher at the Low-T compared the High-T in all regions evaluated, being the difference statistically significant in two of them (ii and c; Table 2). Considering only the best sides, that excluded possible interference by the root residues, new bone was 26.7% at the Low-T and 20.5% at the High-T (p=0.132). The xenograft was present at similar percentages in both groups (20.1% and 18.0% at the Low-T and High-T, respectively). The lowest concentration of xenograft was found in the ii and is regions for both groups.\u003c/p\u003e\n\u003cp\u003eMost sites presented a coronal level of osseointegration positioned at a distance \u0026ge; 2 mm from the implant margin. Bone gain was similar in both groups, presenting mean values of 0.87 \u0026plusmn;0.97 mm in the Low-T group, and 0.89 \u0026plusmn;1.2 mm in the High-T group (p= 0.973). The BIC% was 15.3% (24.8%) and 20.5% (23.4%) for the Low-T and High-T sites, respectively (p=0.688).\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThe present study showed that critical defects 10 mm wide and 3 mm deep might heal when filled with xenografts. However, healing was not complete on either side lateral to the implant. Higher amounts of bone and xenografts were found in the Low-T group (21.0% and 19.7 %, respectively) than in the High-T group (14.2% and 14.2 %, respective-ly). However, the differences were not statistically significant (p=0.074 and p=0.063 for new bone and xenografts, respectively). The loss of two animals after surgery and one im-plant in another animal compromised the results. However, in two regions, I-I and C, a statistically significant difference in favor of the Low-T group compared to the High-T group was found, confirming a tendency for better results in the former than in the latter group. The region with the lowest new bone percentage was the I-C in both groups. Most sites presented a low rate of bone gain. The BIC% evaluated between B and F was 15.3% and 20.5% in the Low-T and High-T groups, respectively (p=0.688).\u003c/p\u003e\n\u003cp\u003eThe healing of critical-size defects is a well-known problem that has been challenged in several studies. In one experiment in rabbits, through-and-through circumferential critical-size bone defects were prepared both in the calvaria (10 mm in diameter) and in the mandible (11 mm in diameter) [32]. The defects were left healed spontaneously or filled with either biphasic calcium phosphate granules or autogenous bone. After 10 weeks, the defects in the mandible at the autogenous sites appeared filled in the microCT analysis by a bone tissue volume ratio (BV/TV) of 37.8%. The empty defects were unable to heal spontaneously, showing a BV/TV of 23.5% and the histological analysis disclosed the presence of connective tissue occupying a vast central region of the defect. The defects with the bi-phasic biomaterial healed partially, presenting a BV/TV of 17.1%.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe defects prepared in the present study were slightly smaller but were not through-and-through defects. This, in turn, means that the absence of a full-thickness bone defect left the bone at the base to contribute to bone formation. This resulted in optimal healing of several defects with closure of the coronal entrance, although this result was of-ten limited to one site lateral to the implant.\u003c/p\u003e\n\u003cp\u003eIn another experiment in the mandible of rabbits, box-shaped defects of 3 mm in width and 2 mm in depth were made [33]. The boxes were prepared by applying different diameters, that is 4, 5, 6, 8, and 10-mm. Healing was analyzed after 4, 8, and 12 weeks. It was shown that healing was faster in the smallest defects. After 12 weeks, at the microCT analysis, these defects were filled with newly formed bone with a BV/TV \u0026gt;90%. The 8- and 10-mm long defects were underfilled, with a BV/TV of ~25-27%. Similarly, at the histological analysis, the new bone area ratio compared to the total defect area was 12-14% in the larger defects, while at those smaller was \u0026gt;60%.\u003c/p\u003e\n\u003cp\u003eIn the present study, the defect was 10 mm in diameter. Moreover, it was deeper (3 mm instead of 2 mm) and circumferential, so the defect had similar dimensions all around the center, in contrast to a box-shaped defect. However, an implant 3.25 mm in diameter was placed in the center of the defect. This might be interpreted as a factor that switched the 10 mm wide defect to a circumferential gap of ~3.4 mm around the implant. Circumferential self-contained marginal defects around implants with gaps of 1.25 mm [34-37] or 2.25 mm [38] showed optimal healing after four months from surgery. All defects were filled with newly formed bone and the coronal level of osseointegration at the implant was very close to the implant margin. However, osseointegration within the defect region was limited in the present study. The difference in the outcome might be related to the dimensions of the gap, which was wider in the present study, and to the model and location used, being dogs and alveolar bone, respectively, in the studies mentioned above.\u003c/p\u003e\n\u003cp\u003eIt should be moreover considered that the placement of an implant within a marginal defect increases the healing time and changes the healing pattern of the defect. In fact, a defect [39] or an extraction socket [40,41] might be almost filled by woven bone after 1 month. Instead, the placement of an implant in defects [34,35,42] or extraction sockets [43,44] will increase the healing time by at least one month compared to sites without im-plants. In the presence of an implant, the defect will be filled with newly formed bone within a month as well. However, a defect ~0.4 mm wide around the implant remains, separating the implant surface from the newly formed bone, effectively preventing osseointegration within the defect. This residual defect will be filled by new bone in contact with the implant within 3-4 months after surgery owing to the osteoconductivity of the implant surface [34-38]. The osteoconductivity of the implant surface is of crucial im-portance in these cases. Turned surfaces, for instance, were unable to allow a complete healing of this defect around the implants [45,46]. However, in the present study, poor osseointegration within the defect could be associated with insufficient closure of the defect by new bone, preventing support for bone formation on the implant surface.\u003c/p\u003e\n\u003cp\u003eAs limitations of the present study should be mentioned the model used, being the cortical lateral wall of the mandible instead of alveolar bone, and the faster healing of rabbits compared humans [47]. Moreover, the inclusion within some defect or roots residues seems to have compromised the healing in some sites.\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eCircumferential marginal critical-size defects around implants filled with bovine xenografts presented sites with a complete healing in both groups. However, the healing was not complete all around the defect in most defects; therefore, a complete optimal healing of critical-size marginal defects cannot be predicted.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData Availability Statement:\u003c/strong\u003e The data is available following a reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u003c/strong\u003e We thank Dr. Vitor Ferreira Balan for the surgical procedures and Mr. Sebastiao Blanco (University of S\u0026atilde;o Paulo, Faculty of Dentistry of Ribeir\u0026atilde;o Preto) for processing the histological slides. The scientific contribution in the histological assessment by Dr. Ermenegildo Federico De Rossi (ARDEC Academy, Rimini, Italy) was greatly appreciated. The implants were donated by Leader Medica, Padua, Italy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest:\u0026nbsp;\u003c/strong\u003eThe authors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding Declaration:\u003c/strong\u003e The study was economically supported by ARDEC Academy, Rimini, Italy\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eG\u0026ouml;tz C, Warnke PH, Kolk A. Current and future options of regeneration methods and reconstructive surgery of the facial skeleton. Oral Surg Oral Med Oral Pathol Oral Radiol. 2015 Sep;120(3):315-23. doi: 10.1016/j.oooo.2015.05.022. Epub 2015 Jun 15. PMID: 26297391.\u003c/li\u003e\n\u003cli\u003eSchmitz JP, Hollinger JO. The critical size defect as an experimental model for craniomandibulofacial nonunions. Clin Orthop Relat Res. 1986 Apr;(205):299-308. PMID: 3084153.\u003c/li\u003e\n\u003cli\u003eCorbella S, Taschieri S, Weinstein R, Del Fabbro M. Histomorphometric outcomes after lateral sinus floor elevation procedure: a systematic review of the literature and meta-analysis. Clin Oral Implants Res. 2016 Sep;27(9):1106-22. doi: 10.1111/clr.12702. Epub 2015 Oct 10. PMID: 26452326.\u003c/li\u003e\n\u003cli\u003eFretwurst T, Gad LM, Nelson K, Schmelzeisen R. Dentoalveolar reconstruction: modern approaches. Curr Opin Otolaryngol Head Neck Surg. 2015 Aug;23(4):316-22. doi: 10.1097/MOO.0000000000000167. PMID: 26101873.\u003c/li\u003e\n\u003cli\u003eNkenke E, Neukam FW. Autogenous bone harvesting and grafting in advanced jaw resorption: morbidity, resorption and implant survival. Eur J Oral Implantol. 2014 Summer;7 Suppl 2:S203-17. PMID: 24977256.\u003c/li\u003e\n\u003cli\u003eBlank BS, Levy AR. Combined treatment of a large periodontal defect using GTR and DFDBA. Int J Periodontics Restorative Dent. 1999 Oct;19(5):481-7. PMID: 10709514.\u003c/li\u003e\n\u003cli\u003eBorie E, Fuentes R, Del Sol M, Oporto G, Engelke W. The influence of FDBA and autogenous bone particles on regeneration of calvaria defects in the rabbit: a pilot study. Ann Anat. 2011 Oct 20;193(5):412-7. doi: 10.1016/j.aanat.2011.06.003. Epub 2011 Jul 8. PMID: 21802915.\u003c/li\u003e\n\u003cli\u003eJensen T, Schou S, Stavropoulos A, Terheyden H, Holmstrup P. Maxillary sinus floor augmentation with Bio-Oss or Bio-Oss mixed with autogenous bone as graft in animals: a systematic review. Int J Oral Maxillofac Surg. 2012 Jan;41(1):114-20. doi: 10.1016/j.ijom.2011.08.010. Epub 2011 Oct 13. PMID: 22000958.\u003c/li\u003e\n\u003cli\u003eCaneva M, Lang NP, Garcia Rangel IJ, Ferreira S, Caneva M, De Santis E, Botticelli D. Sinus mucosa elevation using Bio-Oss\u0026reg; or Gingistat\u0026reg; collagen sponge: an experimental study in rabbits. Clin Oral Implants Res. 2017 Jul;28(7):e21-e30. doi: 10.1111/clr.12850. Epub 2016 Apr 15. PMID: 27080163.\u003c/li\u003e\n\u003cli\u003eMasuda K, Silva ER, Apaza Alccayhuaman KA, Botticelli D, Xavier SP. Histologic and Micro-CT Analyses at Implants Placed Immediately After Maxillary Sinus Elevation Using Large or Small Xenograft Granules: An Experimental Study in Rabbits. Int J Oral Maxillofac Implants. 2020 Jul/Aug;35(4):739-748. doi: 10.11607/jomi.8067. PMID: 32724925.\u003c/li\u003e\n\u003cli\u003eGodoy EP, Alccayhuaman KAA, Botticelli D, Amaroli A, Balan VF, Silva ER, Xavier SP. Osteoconductivity of Bovine Xenograft Granules of Different Sizes in Sinus Lift: A Histomorphometric Study in Rabbits. Dent J (Basel). 2021 May 31;9(6):61. doi: 10.3390/dj9060061. PMID: 34072644; PMCID: PMC8227860.\u003c/li\u003e\n\u003cli\u003eJensen T, Schou S, Stavropoulos A, Terheyden H, Holmstrup P. Maxillary sinus floor augmentation with Bio-Oss or Bio-Oss mixed with autogenous bone as graft: a systematic review. Clin Oral Implants Res. 2012 Mar;23(3):263-73. doi: 10.1111/j.1600-0501.2011.02168.x. Epub 2011 Mar 28. PMID: 21443592.\u003c/li\u003e\n\u003cli\u003eMordenfeld A, Lindgren C, Hallman M. Sinus Floor Augmentation Using Straumann\u0026reg; BoneCeramic\u0026trade; and Bio-Oss\u0026reg; in a Split Mouth Design and Later Placement of Implants: A 5-Year Report from a Longitudinal Study. Clin Implant Dent Relat Res. 2016 Oct;18(5):926-936. doi: 10.1111/cid.12374. Epub 2015 Sep 10. PMID: 26358740.\u003c/li\u003e\n\u003cli\u003eAccorsi-Mendon\u0026ccedil;a T, Conz MB, Barros TC, de Sena LA, Soares Gde A, Granjeiro JM. Physicochemical characterization of two deproteinized bovine xenografts. Braz Oral Res. 2008 Jan-Mar;22(1):5-10. doi: 10.1590/s1806-83242008000100002. PMID: 18425238.\u003c/li\u003e\n\u003cli\u003eBerberi A, Samarani A, Nader N, Noujeim Z, Dagher M, Kanj W, Mearawi R, Salemeh Z, Badran B. Physicochemical characteristics of bone substitutes used in oral surgery in comparison to autogenous bone. Biomed Res Int. 2014;2014:320790. doi: 10.1155/2014/320790. Epub 2014 Jul 8.\u003c/li\u003e\n\u003cli\u003eLee JH, Yi GS, Lee JW, Kim DJ. Physicochemical characterization of porcine bone-derived grafting material and com-parison with bovine xenografts for dental applications. J Periodontal Implant Sci. 2017 Dec;47(6):388-401. doi: 10.5051/jpis.2017.47.6.388)\u003c/li\u003e\n\u003cli\u003eHoexter DL. Bone regeneration graft materials. J Oral Implantol. 2002;28(6):290-4. doi: 10.1563/1548-1336(2002)028\u0026lt;0290:BRGM\u0026gt;2.3.CO;2.\u003c/li\u003e\n\u003cli\u003eIezzi G, Degidi M, Piattelli A, Mangano C, Scarano A, Shibli JA, Perrotti V. Comparative histological results of different biomaterials used in sinus augmentation procedures: a human study at 6 months. Clin Oral Implants Res. 2012 Dec;23(12):1369-76. doi: 10.1111/j.1600-0501.2011.02308.x. Epub 2011 Nov 2.\u003c/li\u003e\n\u003cli\u003eLee DZ, Chen ST, Darby IB. Maxillary sinus floor elevation and grafting with deproteinized bovine bone mineral: a clinical and histomorphometric study. Clin Oral Implants Res. 2012 Aug;23(8):918-24. doi: 10.1111/j.1600-0501.2011.02239.x. Epub 2011 Jun 24. PMID: 21707754.\u003c/li\u003e\n\u003cli\u003edo Desterro Fde P, Sader MS, Soares GD, Vidigal GM Jr. Can inorganic bovine bone grafts present distinct properties? Braz Dent J. 2014;25(4):282-8. doi: 10.1590/0103-6440201300067. PMID: 25250490.\u003c/li\u003e\n\u003cli\u003eTapety FI, Amizuka N, Uoshima K, Nomura S, Maeda T. A histological evaluation of the involvement of Bio-Oss in osteoblastic differentiation and matrix synthesis. Clin Oral Implants Res. 2004 Jun;15(3):315-24. doi: 10.1111/j.1600-0501.2004.01012.x. PMID: 15142094.\u003c/li\u003e\n\u003cli\u003eRiachi F, Naaman N, Tabarani C, Aboelsaad N, Aboushelib MN, Berberi A, Salameh Z. Influence of material properties on rate of resorption of two bone graft materials after sinus lift using radiographic assessment. Int J Dent. 2012;2012:737262. doi: 10.1155/2012/737262. Epub 2012 Jul 31. PMID: 22899930; PMCID: PMC3415107.\u003c/li\u003e\n\u003cli\u003eGomez J, Bergamo ET, Tovar N, Talib HS, Pippenger BE, Herdia V, Cox M, Coelho PG, Witek L. Microtomographic re-construction of mandibular defects treated with xenografts and collagen-based membranes: A pre-clinical minipig model. Med Oral Patol Oral Cir Bucal. 2021 Nov 1;26(6):e825-e833. doi: 10.4317/medoral.24811. PMID: 34564687; PMCID: PMC8601645.\u003c/li\u003e\n\u003cli\u003eSargolzaie N, Kadkhodazadeh M, Ebadian AR, Shafieian R, Pourkaveh S, Naghibi N, Ramandie MF. Histological Evaluation of Bone Regeneration Using Hydroxyapatite Based Bone Substitute Derived from Antler: An Animal Study. J Long Term Eff Med Implants. 2022;32(1):77-84. doi: 10.1615/JLongTermEffMedImplants.2021039830. PMID: 35377997.\u003c/li\u003e\n\u003cli\u003eFerreira Balan V, Botticelli D, Pe\u0026ntilde;arrocha-Oltra D, Masuda K, Pires Godoy E, Xavier SP. Maxillary Sinus Floor Aug-mentation with Two Different Inorganic Bovine Bone Grafts: an Experimental Study in Rabbits. Chin J Dent Res. 2022 Jun 10;25(2):93-105. doi: 10.3290/j.cjdr.b3086337. PMID: 35686589.\u003c/li\u003e\n\u003cli\u003eTawil G, Barbeck M, Unger R, Tawil P, Witte F. Sinus Floor Elevation Using the Lateral Approach and Window Repositioning and a Xenogeneic Bone Substitute as a Grafting Material: A Histologic, Histomorphometric, and Radiographic Analysis. Int J Oral Maxillofac Implants. 2018 September/October;33(5):1089\u0026ndash;1096. doi: 10.11607/jomi.6226. Epub 2018 Jun 12. PMID: 29894551.\u003c/li\u003e\n\u003cli\u003eČandrlić M, Tomas M, Karl M, Male\u0026scaron;ić L, Včev A, Perić Kačarević Ž, Matijević M. Comparison of Injectable Biphasic Calcium Phosphate and a Bovine Xenograft in Socket Preservation: Qualitative and Quantitative Histologic Study in Humans. Int J Mol Sci. 2022 Feb 25;23(5):2539. doi: 10.3390/ijms23052539. PMID: 35269686; PMCID: PMC8910217.\u003c/li\u003e\n\u003cli\u003eCatros S, Sandgren R, Pippenger BE, Fricain JC, Herber V, El Chaar E. A Novel Xenograft Bone Substitute Supports Stable Bone Formation in Circumferential Defects Around Dental Implants in Minipigs. Int J Oral Maxillofac Implants. 2020 Nov/Dec;35(6):1122-1131. doi: 10.11607/jomi.8265. PMID: 33270052.4.\u003c/li\u003e\n\u003cli\u003eFaul F, Erdfelder E, Buchner A, Lang AG. Statistical power analyses using G*Power 3.1: tests for correlation and regression analyses. Behav Res Methods. 2009 Nov;41(4):1149-60. doi: 10.3758/BRM.41.4.1149. PMID: 19897823.\u003c/li\u003e\n\u003cli\u003eFaul F, Erdfelder E, Lang AG, Buchner A. G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods. 2007 May;39(2):175-91. doi: 10.3758/bf03193146. PMID: 17695343.\u003c/li\u003e\n\u003cli\u003eSchwarz F, Sager M, Ferrari D, Mihatovic I, Becker J. Influence of recombinant human platelet-derived growth factor on lateral ridge augmentation using biphasic calcium phosphate and guided bone regeneration: a histomorphometric study in dogs. J Periodontol. 2009 Aug;80(8):1315-23. doi: 10.1902/jop.2009.090034].\u003c/li\u003e\n\u003cli\u003eKotagudda Ranganath S, Schlund M, Delattre J, Ferri J, Chai F. Bilateral double site (calvarial and mandibular) critical-size bone defect model in rabbits for evaluation of a craniofacial tissue engineering constructs. Mater Today Bio. 2022 Apr 20;14:100267. doi: 10.1016/j.mtbio.2022.100267.\u003c/li\u003e\n\u003cli\u003eWang Y, Zhang X, Mei S, Li Y, Khan AA, Guan S, Li X. Determination of critical-sized defect of mandible in a rabbit model: Micro-computed tomography, and histological evaluation. Heliyon. 2023 Jul 17;9(7):e18047. doi: 10.1016/j.heliyon.2023.e18047.\u003c/li\u003e\n\u003cli\u003eBotticelli D, Berglundh T, Buser D, Lindhe J. Appositional bone formation in marginal defects at implants. Clin Oral Implants Res. 2003 Feb;14(1):1-9. doi: 10.1034/j.1600-0501.2003.140101.x. PMID: 12562359.\u003c/li\u003e\n\u003cli\u003eBotticelli D, Berglundh T, Buser D, Lindhe J. The jumping distance revisited: An experimental study in the dog. Clin Oral Implants Res. 2003 Feb;14(1):35-42. doi: 10.1034/j.1600-0501.2003.140105.x. PMID: 12562363. \u003c/li\u003e\n\u003cli\u003eBotticelli D, Berglundh T, Lindhe J. The influence of a biomaterial on the closure of a marginal hard tissue defect adjacent to implants. An experimental study in the dog. Clin Oral Implants Res. 2004 Jun;15(3):285-92. doi: 10.1046/j.1600-0501.2003.01008.x. PMID: 15142090.\u003c/li\u003e\n\u003cli\u003eBotticelli D, Persson LG, Lindhe J, Berglundh T. Bone tissue formation adjacent to implants placed in fresh extraction sockets: an experimental study in dogs. Clin Oral Implants Res. 2006 Aug;17(4):351-8. doi: 10.1111/j.1600-0501.2006.01270.x. PMID: 16907764.\u003c/li\u003e\n\u003cli\u003eBotticelli D, Berglundh T, Lindhe J. Resolution of bone defects of varying dimension and configuration in the marginal portion of the peri-implant bone. An experimental study in the dog. J Clin Periodontol. 2004 Apr;31(4):309-17. doi: 10.1111/j.1600-051X.2004.00502.x. PMID: 15016260.\u003c/li\u003e\n\u003cli\u003eCarmagnola D, Berglundh T, Lindhe J. The effect of a fibrin glue on the integration of Bio-Oss with bone tissue. A experimental study in labrador dogs. J Clin Periodontol. 2002 May;29(5):377-83. doi: 10.1034/j.1600-051x.2002.290501.x. PMID: 12060419.\u003c/li\u003e\n\u003cli\u003eAra\u0026uacute;jo MG, Lindhe J. Dimensional ridge alterations following tooth extraction. An experimental study in the dog. J Clin Periodontol. 2005 Feb;32(2):212-8. doi: 10.1111/j.1600-051X.2005.00642.x. PMID: 15691354.\u003c/li\u003e\n\u003cli\u003eScala A, Lang NP, Schweikert MT, de Oliveira JA, Rangel-Garcia I Jr, Botticelli D. Sequential healing of open extraction sockets. An experimental study in monkeys. Clin Oral Implants Res. 2014 Mar;25(3):288-295. doi: 10.1111/clr.12148. Epub 2013 Apr 1. PMID: 23551527.\u003c/li\u003e\n\u003cli\u003eRossi F, Botticelli D, Pantani F, Pereira FP, Salata LA, Lang NP. Bone healing pattern in surgically created circumferential defects around submerged implants: an experimental study in dog. Clin Oral Implants Res. 2012 Jan;23(1):41-8. doi: 10.1111/j.1600-0501.2011.02170.x. Epub 2011 Mar 28. PMID: 21443594.\u003c/li\u003e\n\u003cli\u003eAra\u0026uacute;jo MG, Wennstr\u0026ouml;m JL, Lindhe J. Modeling of the buccal and lingual bone walls of fresh extraction sites following implant installation. Clin Oral Implants Res. 2006 Dec;17(6):606-14. doi: 10.1111/j.1600-0501.2006.01315.x. PMID: 17092217.\u003c/li\u003e\n\u003cli\u003eMainetti T, Lang NP, Bengazi F, Favero V, Soto Cantero L, Botticelli D. Sequential healing at implants installed immediately into extraction sockets. An experimental study in dogs. Clin Oral Implants Res. 2016 Jan;27(1):130-8. doi: 10.1111/clr.12533. Epub 2014 Dec 18. PMID: 25521008.\u003c/li\u003e\n\u003cli\u003eAkimoto K, Becker W, Persson R, Baker DA, Rohrer MD, O\u0026apos;Neal RB. Evaluation of titanium implants placed into simulated extraction sockets: a study in dogs. Int J Oral Maxillofac Implants. 1999 May-Jun;14(3):351-60. PMID: 10379108.\u003c/li\u003e\n\u003cli\u003eBotticelli D, Berglundh T, Persson LG, Lindhe J. Bone regeneration at implants with turned or rough surfaces in self-contained defects. An experimental study in the dog. J Clin Periodontol. 2005 May;32(5):448-55. doi: 10.1111/j.1600-051X.2005.00693.x. PMID: 15842258.\u003c/li\u003e\n\u003cli\u003eBotticelli D, Lang NP. Dynamics of osseointegration in various human and animal models - a comparative analysis. Clin Oral Implants Res. 2017 Jun;28(6):742-748. doi: 10.1111/clr.12872. Epub 2016 May 23.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"514\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\" valign=\"top\"\u003e\n \u003cp\u003eTable 1. Histomorphometric evaluation of soft and hard tissues within the whole defects. Means values and standard deviations in percentage. P-values between Low-T and High-T sites are reported. N=9.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eLow-T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eHigh-T\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNew bone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eXenograft\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSoft tissues\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNew bone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eXenograft\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSoft tissues\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e21.0 (8.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e19.7 (6.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e58.9 (12.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e14.2 (5.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e14.2 (8.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e67.8 (12.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ep-value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.074\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.063\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.101\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"7\" valign=\"top\"\u003e\n \u003cp\u003eTable 2.\u0026nbsp;Histomorphometric evaluation of soft and hard tissues in the various regions within the defects. Means values and standard deviations in percentage. Regions evaluated: I-S, internal superior; I-C, internal central; I-I, internal inferior; C-S, central superior; C, central; E-S, external superior. * = p\u0026lt;0.05. N=9.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.340344168260039%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"42.829827915869984%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eLow-T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"42.829827915869984%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eHigh-T\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003eNew bone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003eXenograft\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003eSoft tissues\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003eNew bone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003eXenograft\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003eSoft tissues\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003eI-S\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\"\u003e\n \u003cp\u003e18.4 (14.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\"\u003e\n \u003cp\u003e13.1 (8.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\"\u003e\n \u003cp\u003e68.5 (18.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\"\u003e\n \u003cp\u003e12.7 (12.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\"\u003e\n \u003cp\u003e13.9 (7.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\"\u003e\n \u003cp\u003e73.4 (17.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003eI-C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\"\u003e\n \u003cp\u003e13.4 (11.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\"\u003e\n \u003cp\u003e23.1 (7.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\"\u003e\n \u003cp\u003e63.5 (18.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\"\u003e\n \u003cp\u003e9.4 (10.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\"\u003e\n \u003cp\u003e18.7 (17.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\"\u003e\n \u003cp\u003e71.9 (18.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003eI-I\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\"\u003e\n \u003cp\u003e23.8 (6.4)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\"\u003e\n \u003cp\u003e15.7 (7.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\"\u003e\n \u003cp\u003e60.5 (9.6)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\"\u003e\n \u003cp\u003e16.5 (8.1)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\"\u003e\n \u003cp\u003e11.7 (11.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\"\u003e\n \u003cp\u003e71.8 (12.7)*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003eC-S\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\"\u003e\n \u003cp\u003e22.8 (16.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\"\u003e\n \u003cp\u003e20.4 (9.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\"\u003e\n \u003cp\u003e56.7 (17.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\"\u003e\n \u003cp\u003e12.8 (8.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\"\u003e\n \u003cp\u003e23.3 (10.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\"\u003e\n \u003cp\u003e64.0 (15.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003eC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\"\u003e\n \u003cp\u003e23.7 (12.8)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\"\u003e\n \u003cp\u003e23.6 (11.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\"\u003e\n \u003cp\u003e52.7 (10.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\"\u003e\n \u003cp\u003e15.0 (7.0)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\"\u003e\n \u003cp\u003e21.9 (13.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\"\u003e\n \u003cp\u003e63.1 (14.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003eE-S\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\"\u003e\n \u003cp\u003e24.1 (8.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\"\u003e\n \u003cp\u003e24.6 (13.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\"\u003e\n \u003cp\u003e51.3 (17.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\"\u003e\n \u003cp\u003e18.7 (11.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\"\u003e\n \u003cp\u003e18.5 (8.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\"\u003e\n \u003cp\u003e62.8 (12.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"oral-and-maxillofacial-surgery","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"omfs","sideBox":"Learn more about [Oral and Maxillofacial Surgery](http://link.springer.com/journal/10006)","snPcode":"10006","submissionUrl":"https://submission.nature.com/new-submission/10006/3","title":"Oral and Maxillofacial Surgery","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"animal study, bone healing, histology, morphometry, biomaterial, bone defect","lastPublishedDoi":"10.21203/rs.3.rs-3635546/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3635546/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Healing of critical-size defects is a well-known problem that has been challenged in several studies. The aim of the experiment was to evaluate bone formation and osseointegration of implants installed in critical defects of the mandibular body simultaneously grafted with Bio-Oss® or Cerabone®.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMaterial and methods: \u003c/strong\u003eDefects, 10 mm wide and 3 mm deep, were prepared at both lateral aspects of the mandible in 12 rabbits. One implant was installed in the center of the defect, and bovine xenografts produced either at low (Bio-Oss®; Low-T) or high (Cerabone®; High-T) temperatures were used to fill the defects. A collagen membrane was placed to cover the sites. Healing was evaluated 10 weeks after surgery.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e In both groups, most sites showed optimal healing with closure of the coronal entrance of the defects. However, residual defects occupied by soft tissues and biomaterial particles were observed, even though generally limited to some regions of the defect. Osseointegration of the implant surface in the region of the defect was poor in both groups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e Circumferential marginal critical-size defects around implants filled with bovine xenografts presented regions with a complete healing in both groups. However, the healing was not complete at all regions in most defects; therefore, a complete optimal healing of critical-size marginal defects cannot be predicted.\u003c/p\u003e","manuscriptTitle":"Critical-sized marginal defects around implants treated with xenografts in rabbits","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-11-23 22:42:48","doi":"10.21203/rs.3.rs-3635546/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-01-14T08:36:59+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-01-09T20:57:28+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"76c0a761-b1e9-450f-afa1-6d0c13625535","date":"2023-12-26T12:56:39+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-11-26T07:27:01+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2023-11-20T23:05:08+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-11-20T23:05:08+00:00","index":"","fulltext":""},{"type":"submitted","content":"Oral and Maxillofacial Surgery","date":"2023-11-19T16:45:02+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"oral-and-maxillofacial-surgery","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"omfs","sideBox":"Learn more about [Oral and Maxillofacial Surgery](http://link.springer.com/journal/10006)","snPcode":"10006","submissionUrl":"https://submission.nature.com/new-submission/10006/3","title":"Oral and Maxillofacial Surgery","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"3dad3ffb-2d6b-47b2-a957-81353565abb4","owner":[],"postedDate":"November 23rd, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-02-05T15:02:03+00:00","versionOfRecord":{"articleIdentity":"rs-3635546","link":"https://doi.org/10.1007/s10006-024-01216-3","journal":{"identity":"oral-and-maxillofacial-surgery","isVorOnly":false,"title":"Oral and Maxillofacial Surgery"},"publishedOn":"2024-01-29 15:00:29","publishedOnDateReadable":"January 29th, 2024"},"versionCreatedAt":"2023-11-23 22:42:48","video":"","vorDoi":"10.1007/s10006-024-01216-3","vorDoiUrl":"https://doi.org/10.1007/s10006-024-01216-3","workflowStages":[]},"version":"v1","identity":"rs-3635546","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3635546","identity":"rs-3635546","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}