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

doi:10.21203/rs.3.rs-3635546/v1

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

https://doi.org/10.21203/rs.3.rs-3635546/v1

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published 29 Jan, 2024

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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

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®.

2.1 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%.

3.1 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).

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.

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.

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

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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)

No competing interests reported.

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

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