Bone formation around implants in extraction sockets after immediate implantation in response to different treatments: a pre-clinical study in the canine posterior mandible

doi:10.21203/rs.3.rs-1819762/v1

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Bone formation around implants in extraction sockets after immediate implantation in response to different treatments: a pre-clinical study in the canine posterior mandible

https://doi.org/10.21203/rs.3.rs-1819762/v1

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Aim This study aimed to explore new bone formation around implants in extraction sockets after immediate implantation in the canine posterior mandible in response to different treatments.

Materials and methods The 4^th premolar and the 1^st molar of six Labrador dogs were extracted from the mandible, and then, 4 dental implants were implanted. The mesial and distal gaps between the implants and the sockets were treated with one of four methods and divided into the following groups: (1) the blank group (group BG), (2) the collagen membrane (CM) group (group C), (3) the deproteinized bovine bone mineral (DBBM) group (group D), and (4) the DBBM+CM group (group DC). Sequential fluorescent labeling was performed at 4, 8, and 10 weeks after the operation. After 12 weeks, the dogs were euthanized, and specimens were collected for micro-CT scanning and histological analysis.

Results The survival rate was 100%. Micro-CT showed significant differences in bone mineral density (BMD) and bone volume fraction (BVF) among the four groups (P = 0.040, P = 0.009); other indicators were not significantly different among the groups. Histological analysis showed that the proportion of new bone formation and bone-to-implant contact (BIC) were not significantly different among the groups.

Conclusion The current study demonstrated that although DBBM can significantly increase BMD and BVF, the use of DBBM and CM did not significantly improve bone formation in extraction sockets around the implants.

Clinical relevance According to the current animal experiment, DBBM and CM may not have a significant impact on bone formation in the extraction socket of IIP in the posterior mandible, suggesting that there was no sufficient reason to recommend the application of these two kinds of materials in mesiodistal extraction sockets around IIP in mandibular molar sites.

immediate implants

posterior mandible

extraction socket

bone formation

In recent decades, dental implants have been widely used to restore the function and appearance of missing teeth. Conventionally, teeth should be extracted in advance, and the sites should heal for 3–6 months before implantation[1]. With the development of technology and the accumulation of experience, clinicians have begun to carry out immediate implant placement (IIP) after extraction at both anterior and molar sites[2]. A comparative study (2012) of IIP in the molar region[3] showed that success rates and alveolar bone loss were not significantly different between IIP and delayed implant placement. According to a recent systematic review, the survival rate of IIP at molar sites is 98%[4]; this success, together with its advantages—fewer surgical procedures and preservation of the alveolar ridge[5]—explains why IIP is becoming the preferred approach.

However, there are several issues that remain controversial in the protocol for IIP at molar sites. One of these issues is how to treat the gap between dental implants and the walls of the extraction socket to achieve a better clinical outcome. Due to the complex anatomical structure of extraction sockets in the posterior area, there is always space between the surface of an implant and the walls of a fresh socket.

Due to concerns that the existence of this space may lead to bone resorption around the implant and changes in the contour of the alveolar ridge, clinicians in the last century proposed using bone graft materials and barrier membranes to treat the sockets to promote new bone formation[6]. The role of the barrier membrane is to prevent connective tissue and epithelial cells from migrating to the defect area and to ensure a stable environment for osteoblasts[7]. Bio-Gide® (Geistlich, Wolhusen, Switzerland) is a double-layer absorbable non-crosslinked collagen membrane (CM) made from natural collagen that has been widely used worldwide for various applications. It is often used in combination with bone graft materials for large defects[8], which can significantly reduce the resorption of the alveolar ridge[9]. Bio-Oss® (Geistlich, Wolhusen, Switzerland), which consists of deproteinized bovine bone mineral (DBBM) particles, is currently the most widely used xenograft material in the world. According to certain research reports, the use of CM and DBBM alone or in combination can increase the proportion of mineralized tissue in a defect[10]; reduce horizontal bone resorption[11]; and, particularly, preserve the contour of the alveolar ridge and the tissue thickness [12–14]. Thus, many clinicians have reached a consensus that it is recommended to use DBBM and CM in the anterior zone where the aesthetic outcome is important[5, 15].

However, for the molar area, especially the posterior mandible, the buccal bone plate is relatively thick, and the aesthetic outcome is less important. Moreover, the extraction sockets are mainly present in mesiodistal sites, differing from the condition of the anterior area. Whether the conclusion of the anterior area is applicable to the posterior sites remains unknown. It is currently common to place bone graft materials or (and) barrier membranes to ensure the formation of new bone around the implant. However, there are several shortcomings—a complex surgical process, increased healing time, a relatively high cost of materials and poor mechanical properties[11, 16]. On the other hand, when no graft is used, the operation time is shortened, and the surgical procedure is simplified; moreover, no additional cost is incurred. It is worth noting that a recent review[17] stated that the current evidence cannot determine whether the placement of bone graft materials or (and) barrier membranes should be recommended to improve the success rate and satisfaction of IIP. Another systematic review in 2020[18] concluded that for IIP at molar sites, there were no significant differences in survival rate, success rate or marginal bone loss according to the presence or absence of grafting material; this outcome suggests that grafting material fails to improve the clinical effect of IIP in the posterior area, but the use of grafting material is still recommended for this procedure. Several recent clinical studies[19, 20] have reported high survival and success rates in the posterior area when no graft was used. A retrospective cohort study[21] also found that grafting did not lead to differences in crestal bone width changes. Furthermore, a systematic review[22] proposed that the existing evidence did not provide solid support for the benefits of using DBBM and CM in IIP. Thus, there is currently no consensus on this issue in the molar area.

In addition, there is a lack of carefully designed controlled experiments conducted in the molar area to show the influence of the placement of bone graft materials or the use of barrier membranes on osteogenesis in the extraction socket. There are relatively few studies on IIP in the molar area, and these studies are mainly based on some case reports or retrospective studies, and the use of materials or membranes is often related to flapless surgery[23], wide implants[24, 25], special surface treatment implants[26], or buccal bone wall defects[27]. Therefore, this issue has always been clinically controversial and has not been resolved thus far.

Hence, in this study, a controlled animal experiment was conducted to explore the effects of different methods of dealing with the gaps and osteogenesis in the extraction socket after implantation in the posterior mandible to provide a potential solution to the aforementioned issue and a reference for clinical practice.

This study was designed according to the modified Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines for preclinical in vivo experiments [28]. The research was carried out in Shanghai after receiving approval from the Medical Animal Care & Welfare Committee of Shanghai Ninth People’s Hospital affiliated with Shanghai Jiao Tong University, School of Medicine (HKDL2018225).

Animals and facilities

Six female Labrador dogs aged between 1.5 and 2 years, weighing approximately 20 kg, were used. All dogs were healthy, housed in kennels and fed a soft diet by qualified staff onsite during the entire procedure.

Experimental materials

A total of 22 cylindrical dental implants (OsseoSpeed™, Astra Tech^®, Dentsply Sirona, USA; 4 mm in diameter and 10 mm long) were used. A bone substitute consisting of DBBM (Bio-Oss^®, Geistlich, Wolhusen, Switzerland) and a non-crosslinked porcine CM (Bio-Gide^®, Geistlich, Wolhusen, Switzerland) was used.

Experimental design

In each hemimandible, the fourth premolar (P4) and the first molar (M1) were extracted, and implants were immediately inserted into the fresh socket. After IIP, the extraction sockets were allocated to one of the following groups. Every two sites of one hemimandible were allocated to one group, which means that P4 and M1 were distributed among groups in a balanced way. One of the dogs lost its 1^st molars, and therefore, there were 5 implants in groups BG and C. Due to the lack of relevant experimental data, the sample size was determined by referring to existing similar studies [29, 30]. The groups were defined as follows:

1. group BG (n = 5), blank group

2. group C (n = 5), with CM (Bio-Gide^®) only

3. group D (n = 6), with DBBM (Bio-Oss^®) only

4. group DC (n = 6), with DBBM (Bio-Oss^®) and CM (Bio-Gide^®)

The order of treatments and measurements were determined randomly to minimize potential confounders.

Surgical procedures

The animals were anesthetized with tiletamine hydrochloride, zolazepam hydrochloride (Zoletil^®50, 0.1 mg/kg) and xylazine hydrochloride (Huamu^®, 1~2 mg/kg). The P4 and the M1 were extracted. Every tooth was extracted with minimally invasive technology, namely, separation with a cutting drill and removal with extracting forceps. A blinded examiner carefully measured the dimensions of the socket using a periodontal probe (Hu-Friedy^®, Chicago, IL, USA) and confirmed that the walls of the socket were intact. Sharp edges of alveolar bone were trimmed away so that the septal bone was suitable for implantation. The site was prepared according to the manufacturer’s instructions. A Ф4.0 × 10 mm cylindrical implant (OsseoSpeed™, Astra Tech^®, Dentsply Sirona, USA) was placed with a torque of more than 35 Ncm. The shoulder of the implant was placed at the level of the buccal bone crest, and a cover screw was installed. Each implant was placed at the septal bone.

In group BG, after the implants were installed, no materials or CMs were placed, and blood filled the gap naturally; that is, natural healing began. In group C, the gap was not filled with any material. The mucoperiosteal flap on the lingual side was separated, and one side of a 30 mm × 40 mm Bio-Gide^® membrane was inserted to cover the socket. Then, the other side of the membrane was covered with a buccal mucoperiosteal flap. In group D, an appropriate amount of Bio-Oss^® was selected according to the size of the gap. Large particles and the small particles were mixed at a ratio of 1:1 and moistened with saline in advance. The gap was filled with Bio-Oss^®, which was compacted to ensure that the gap was filled with particles. Then, the mucoperiosteal flap was reset and sutured. In group DC, the gap was filled with Bio-Oss^® particles, followed by Bio-Gide^®, and finally, the flaps were repositioned and sutured. Surgical photos of the different groups are shown in Figure 1, and a schematic diagram of the surgical procedure is shown in Figure 2.

Antibiotics and analgesics were injected into the animals for 7 days after the surgery, and over the next 14 days, the dogs were fed water-softened food.

Sequential fluorescence labeling

Triple fluorescence labeling of the alveolar bone was conducted according to previous research [30]. For the next four, eight and ten weeks, animals under anesthesia were injected with three kinds of fluorochromes: tetracycline hydrochloride (TE, 25 mg/kg), calcein (CA, 20 mg/kg), and alizarin red S (AL, 30 mg/kg).

Euthanasia

After 12 weeks, the dogs were euthanized with an overdose of anesthetics, and their bone blocks were harvested for histologic analysis. Undecalcified specimens were fixed in 10% buffered formalin.

Micro-CT analysis

The specimens were scanned by a micro-CT machine (Skyscan1076, Bruker, Belgium), and the settings were as follows: source voltage (kV)=70, source current (uA)= 141, image pixel size (µm)= 36.5200, filter=Al 1.0 mm, exposure (ms)=110, rotation step (deg)=0.700, and frame averaging=On (1). The data were processed with software (Microview, Scanco Medical AG). The 35-μm thick 2D slices were reconstructed into a 3D model. The volume of interest (VOI) of each implant was a cylinder 3 mm in diameter and 4 mm in height starting at the level of the thread in the mesial and distal area near the implant. The biopsies were approximately aligned with the implant axes. The main characteristics used to evaluate the newly formed bone were as follows: bone volume (BV), total volume (TV), bone surface (BS), bone mineral density (BMD, representing the density of bone mineral in the bone tissue), bone volume fraction (BV/TV, representing the ratio of bone tissue volume to tissue volume, which can directly reflect the changes of bone volume), bone surface volume ratio (BS/BV, representing the area of bone tissue per unit volume), trabecular thickness (Tb.Th, representing the average trabecular bone thickness), trabecular number (Tb.N, representing the mean number of bone and nonbone tissue intersections per millimeter), and trabecular separation (Tb.Sp, representing the mean width of the cavity between bone trabeculae). The micro-CT screenshots of each group are shown in Figure 3.

3D reconstruction and bone height measurement

The data obtained from the micro-CT scans were reconstructed using Mimics 21.0 (Materialise, USA) software. The height of the new bone in the mesiodistal sites of the implants was obtained, and the measurement method is shown in Figure 4.

Histological analysis

After fixation in formaldehyde solution, the specimen was dehydrated with a series of alcohol of increasing concentrations. Then, the specimens were placed into the embedding solution (methyl methacrylate: dibutyl phthalate = 4:1). When the resin was completely cured, the specimen was obtained. Each mesiodistal section representing the central area of the implant was prepared for biopsy. This cutting direction was determined to observe bone formation in the mesiodistal sockets around the implants. After the sections were reduced to a thickness of 20-25 μm by grinding and polishing, they were subjected to fluorescence microscopy analysis (confocal laser scanning microscopy, TCS SP8 STED 3X, Leica, Wetzlar, Germany). The number of pixels labeled with different colors in each image was used to calculate the percentage of mineralized bone in ImageJ software (National Institutes of Health, USA). After that, when Stevenel's blue and van Gieson’s picrofuchsin staining was complete, the sections were observed under a microscope (Olympus, Tokyo, Japan). The region of interest (ROI) was a rectangle with a length of 40 mm and a width of 10 mm located at the edge of the implant, below the shoulder. Bone-to-implant contact (BIC) was defined as the ratio of the length of contact between the implant and bone in the area to the full length of the implant thread. The percentage of the new bone area around the implants was determined by the ratio of the new bone area to the total ROI area.

Data analysis

Groups C and BG each contained 5 sites due to the lack of M1s in one dog. Group DC and D each contained 6 sites. The data are shown as the mean value ± standard deviation. The normality of the distribution was tested by the Shapiro–Wilk test, and then, the homogeneity of variance was analyzed. For the normally distributed data that met homogeneity of variance, one-way ANOVA was further performed to assess the differences among groups. If P < 0.05, then further post hoc Tukey tests were performed to evaluate the significance. For data that did not meet the normal distribution or homogeneity of variance, the Kruskal-Wallis test was used to assess the difference among groups, and Bonferroni correction was used to correct p-values. The above statistics were calculated with SPSS 25.0 software (Chicago, IL, USA).

All the sites healed uneventfully after surgery. No adverse events occurred during recovery.

Micro-CT measurements

It could be observed from the sagittal slides that in the two groups using DBBM, group D and DC, the density of DBBM around the implant was relatively higher than that in the two groups without DBBM. In terms of quantitative analysis, there was a significant difference in BMD (mg/cm3) among these groups (P = 0.040 < 0.05). Further pairwise comparisons showed that there was a significant difference between groups C and DC, C and D, BG and DC. Although there was no significant difference between groups D and BG, the average BMD value of group D was comparable to that of group DC and higher than those of groups BG and C. The BMD value of group BG was equivalent to the average value of group C.

Regarding the BV fraction (BV/TV), group BG was significantly different from groups D (P = 0.043 < 0.05) and DC (P = 0.029 < 0.05). At the same time, group C was significantly different from groups D (P = 0.043 < 0.05) and DC (P = 0.029 < 0.05). Similar to BMD, the BVF values of BG and C were equivalent, and the values of D and DC were equivalent.

For the BS area to BV ratio (BS/BV), Tb.Th, Tb.N and Tb.Sp, there was no significant difference among the four groups (P > 0.05). Micro-CT measurement results are shown in Figure 3.

3D reconstruction and bone height

The mesiodistal bone height values are shown in Figure 4. The bone height observed here was actually the distance from the top of the implant to the most coronal point of the alveolar ridge near the implant. This index is often measured by X-ray in clinical practice and is usually defined as marginal bone loss (MBL). The shortest mesial distance was in group C, -1.26 ± 0.51 mm, and the greatest distance was in group BG, at -1.88 ± 1.16 mm. The mesial average value was -1.62 ± 0.95 mm. The distal bone heights of groups C and D were almost equal. The distal average value was -1.41 ± 0.96 mm. The mesiodistal average value was -1.52 ± 0.95 mm, with no significant difference among these groups (P > 0.05).

Fluorescence labeling

Sequential fluorescence staining indicated bone formation during different periods (Figure 5). The ratio of areas with sequential fluorescent labels can represent the speed of bone formation in different periods. The fluorochrome-stained area proportion was calculated at 2, 6 and 10 weeks after surgery, and yellow, green and red represented weeks 2, 6 and 10, respectively. There was no statistically significant difference in the ratio of fluorescent staining area among the four groups at different periods, which means that during the observation period (12 weeks), different treatments had no significant effect on the rate of new bone formation.

Histological observations and histomorphometry

Newly formed bone was observed around all implants in the four groups (Figure 6). In group BG, new bone accumulated around the coronal level of the implant, and the proportion of new bone was relatively low. The implant was supported mainly by woven bone. The outcome was similar in group C; woven bone accounted for a large proportion of the bone present, and the amount of lamellar bone was small. The patterns in groups D and DC were slightly different from those in the other two groups. The DBBM was mostly surrounded by a large amount of woven bone and accumulated apically, resulting in a dramatic increase in the stained area. It is worth noting that despite the abundance of new bone near the DBBM, the BV in the ROI seemed similar to that in the other two groups. Another noteworthy phenomenon was that a large number of DBBM particles occupied some of the space around the implants, which affected the combination of new bone and implants.

The proportion of new bone was the lowest in group BG, 22 ± 9%, followed by 24 ± 12% in group C. The area of new bone in groups D and DC increased compared with that in the other two groups, as the proportion of new bone was 27 ± 6% (group D) and 25 ± 7% (group DC). However, there was no significant difference in the proportion of new bone area among the four groups (P = 0.588). For the BIC area, group C had the highest value at 43 ± 13%, followed by 35 ± 16% in group D; group BG had the lowest value at 27 ± 16%. There was no significant difference in BIC area. The residual rates of DBBM in groups D and DC were similar, with no significant difference.

This experiment compared the effect of using DBBM or CM or the combination of both in the extraction sockets around immediately placed implants. The current study demonstrated that although DBBM can significantly increase BMD and BVF, DBBM and CM did not significantly improve bone formation in the gap around the implant.

Although the proportion of new bone was not significantly different among the groups, the groups using bone graft materials had slightly better results than groups BG and C, indicating that DBBM particles have a certain ability to maintain space and promote osteogenesis. This trend was consistent with the results of Sanz M et al[10]. The authors believed that, whether combined with CM or not, DBBM particles showed a significant ability to promote bone formation but only in a large defect area. In this study, the width of the sockets was between 4–10 mm, and the depth was 8–15 mm; this socket could thus be defined as a large defect. Therefore, DBBM can show a tendency to promote osteogenesis. It is worth noting that the proportion of new bone in group D was higher than that in group DC. Notably, the proportion of DBBM in group D was lower than that in group DC. It can be inferred that this difference was due to the presence of the barrier membrane, which increased the proportion of DBBM and correspondingly decreased the proportion of new bone. This finding was confirmed in the studies of Sanz M et al.[10] and Carmagnola D et al.[31], in which the DBBM was found to occupy a large amount of space, filling the area of potential new bone growth. This may be one of the reasons why the proportion of new bone in this study did not differ significantly among the groups. No significant difference was found between groups C and BG, indicating that CM alone failed to promote the formation of new bone. In the study of Sanz M et al.[10], the group with CM alone had the largest proportion of new bone. This difference may be due to the different research models used. This study was carried out in a complete extraction socket with a complete three-sided bone wall, while the study of Sanz M et al. was aimed at a non-contained defect with a single wall. This may indicate that CM played a crucial role in single-wall defects, whereas in fresh extraction sockets with intact bone walls, CM showed little benefit. In terms of the BIC ratio, group C had a relatively higher value than the others despite no significant difference. This suggested that CM alone may be able to promote osseointegration. When the results of bone height were taken together, group C showed the best results. The phenomenon that BIC was related to marginal bone height was also found in the study of Catros S et al.[32], who found that as BIC increased, MBL decreased accordingly. This finding further indicates that CM alone may play a positive role in implant osseointegration. A number of studies [30, 33, 34] have shown that CM can protect tooth extraction sockets and facilitate bone formation. Sanz M et al.[10] believed that CM prevented the migration of the materials, which could provide a relatively stable environment for osteogenesis. Hence, CM played an irreplaceable role in the reconstruction of the extraction sockets.

However, we also found that CM combined with DBBM failed to further improve the outcome, which may be the result of two possible reasons. One possible reason was that DBBM particles moved coronally, which may undermine the barrier effect of CM. This observation was also reported in the study of Mariano Sanz et al[14]. Due to the inherent drawbacks of CM—easy to deform and easy to absorb—it was very likely that the movement of the DBBM would deform CM and destroy the ability of CM to maintain space. This speculation was also confirmed in the study of Jung UW et al.[13], where a crosslinked CM was compared with a non-crosslinked CM. The results showed that the crosslinked CM maintained its structure after 16 weeks, when the non-crosslinked CM almost lost its integrity. Additionally, the crosslinked CM significantly promoted the formation of periosteum-like tissue. The second reason may be that a large number of DBBM particles occupied the space in the socket, negatively affecting the blood supply around the implant and the natural healing process of the extraction socket[35], thus obstructing osseointegration around the implants. This hypothesis was based on the results of histological observation. The light pink DBBM particles accumulated around the implant, taking up space and hindering the new bone from integrating with the implant. In the three-dimensional reconstruction of the specimens, it was found that there was an annular gap around the shoulder of some implants in the groups where DBBM was used, which was confirmed in the study of Sanz M et al.[11]. The authors filled the gap with 90% DBBM and found that the bone graft failed to further promote the healing of the gap. It was found that the implant was surrounded by a soft tissue band, with a large number of DBBM particles wrapped in it. This finding was also consistent with that of Araújo M et al.[36], who found that DBBM outside the area of new bone was wrapped by connective tissue, thus preventing the gap from healing. This outcome further illustrated that the presence of DBBM may hinder the combination of new bone and implants and indicated the protective role of CM. This finding may explain why the survival rate of the implant was unrelated to the grafting material and suggest that a stable space and sufficient blood supply may play a vital role in implant osseointegration.

The mesial and distal new bone height (MBL) can intuitively show the influence of different methods. Group C showed a subtle positive trend in accordance with the BIC results, but the difference still did not reach statistical significance, suggesting that DBBM and CM failed to improve MBL. This result was similar to that of a randomized clinical trial (RCT) study[15] and the same as that of the aforementioned systematic review[18]. According to the research of Mastrangelo F et al., inclusion of DBBM and CM did not improve MBL or probing depth but only improved the clinical aesthetic outcome and patient satisfaction. The difference between that research and this study was that the former focused on the maxillary anterior area. In the review by Ragucci et al., bone graft materials were widely used (of 20 studies, 16 studies used bong grafts). The results showed that bone graft materials did not significantly affect the survival rate, success rate or MBL of implants, which was consistent with this study. Nevertheless, when the aesthetic outcome was not the main concern, if the inclusion of DBBM and CM did not significantly improve bone formation in the sockets, there was no sufficient reason to recommend the use of these materials in the molar area.

This study found that in the two groups using DBBM, the BMD and BVF were significantly increased. In addition, other indexes were not significantly different among the four groups. The presence of DBBM significantly increased BMD because the DBBM contained a large amount of hydroxyapatite, and a certain pressure was applied to fill the gap tightly, which led to a significant increase in the BMD. Since it was impossible to distinguish DBBM from new bone in micro-CT, the result needed to be considered together with the results of histology. This increase in density did not lead to a substantial increase in the amount and quality of new bone through histomorphometry. Similarly, there was a significant increase in BVF in the two groups in which bone graft was used, and this increase was presumably due to the existence of a large number of dense DBBM particles. However, the significant increase in BMD and BVF may be the result of the characteristics of the material itself, and this increase failed to improve osteogenesis. Tb.N (1/mm), Tb.Th (mm) and Tb.Sp (mm) were the main indicators for evaluating the morphological structure of trabecular bone, which can reflect the quality of trabecular bone in the ROI. These three values were not significantly different among the four groups. It can be concluded that DBBM and CM do not significantly improve the process and quality of trabecular bone reconstruction.

The proportion of the fluorescence labeling area can reflect the mineralization of new bone, so it has been widely used to evaluate the process of bone formation and reconstruction in animals[37]. The results showed no difference among the groups, indicating that the grafting material failed to speed up bone formation around the implant in the current study.

In the extraction sockets of IIP in the posterior mandible, except that DBBM could significantly increase the BMD and BVF around the implant, DBBM and CM had a minimal effect on new bone formation, osseointegration and bone quality. This conclusion supported the latest systematic review[18] and suggested that the use of bone grafts had no significant effect on the survival rate and MBL in the IIP of the molar area. The research conducted by Urban T et al.[38] was similar to this study. For indicators such as MBL and probing depth, there was no significant difference among the three treatment methods, which was consistent with some parts of this study. Therefore, Urban T et al. believed that it was impossible to determine which treatment method was worth recommending.

According to the current animal experiment, DBBM and CM may not have a significant impact on bone formation in the extraction socket of IIP in the posterior mandible, suggesting that there was no sufficient reason to recommend the application of these two kinds of materials in mesiodistal extraction sockets around IIP in mandibular molar sites. This conclusion can provide reliable controlled experimental research data for resolving the aforementioned controversial problems, laying a solid foundation for further research.

Due to the limitations of this study, it remains unknown whether loading and restoration can influence the stability of the implants. Furthermore, long-term follow-up and RCTs are still required to confirm this conclusion.

The current study demonstrated that although DBBM can significantly increase BMD and BVF, the use of DBBM and CM has not been observed to significantly improve bone formation in the extraction sockets around the implant.

Author contributions Yiwen Zhang, Qin Zhou, Jing Wu and Duohong Zou were responsible for data collection and analysis; Yiwen Zhang, Qin Zhou and Maolin Zhang guided the writing of the manuscript; Yong Zhou and Mohan Wang were responsible for the surgical approach; Zhiyuan Zhang and Duohong Zou were responsible for the critical revisions of the paper and conceived the concept for the study. All the authors agree with the submission.

Acknowledgments This study was supported by the National Natural Science Foundation of China (31870969, 32171347), CAMS Innovation Fund for Medical Sciences (CIFMS) (2019-I2M-5-037), and Shanghai Municipal Education Commission Two-hundred Talent (20191816).

Ethics approval The study protocol was approved by the ethics committee of Shanghai Ninth People’s Hospital (2018225) prior to study start and was performed in compliance with the 1964 World Medical Association Declaration of Helsinki and its later amendments.

Conflict of interest The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article

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No competing interests reported.

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Bone formation around implants in extraction sockets after immediate implantation in response to different treatments: a pre-clinical study in the canine posterior mandible

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