UNIVERSIDADE ESTADUAL PAULISTA

“JÚLIO DE MESQUITA FILHO”

Instituto de Ciência e Tecnologia

Campus de São José dos Campos

ORIGINAL ARTICLE DOI: https://doi.org/10.4322/bds.2024.e4511

Braz Dent Sci 2024 Oct/Dec;27 (4): e4511

This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in

any medium, provided the original work is properly cited.

Biocompatibility and bioactive potential of new bioceramic sealers

in rat bone tissue: histological analysis

Biocompatibilidade e potencial bioativo de novos selantes biocerâmicos em tecido ósseo de rato: análise histológica

Marcus Victor Vaz Soares CASTRO1 , Wanderson Carvalho de ALMEIDA1 , Humbelina Alves da SILVA1 ,

Brunna da Silva FIRMINO1 , Daniel Fernandes FALCÃO2 , Lucas Fernandes FALCÃO2 , Moara e Silva Conceição PINTO1 ,

Antonione Santos Bezerra PINTO1 , Maria Ângela Arêa Leão FERRAZ1 , Carlos Alberto Monteiro FALCÃO1 

1 - Universidade Estadual do Piauí, Faculdade de Odontologia. Parnaíba, PI, Brazil.

2 - Focus Grupo Educacional. Teresina, PI, Brazil.

How to cite: Castro MVVS, Almeida WC, Silva HA, Firmino BS, Falcão DF, Falcão LF et al. Biocompatibility and bioactive potential of

new bioceramic sealers in rat bone tissue: histological analysis. Braz Dent Sci. 2024;27:e4511. https://doi.org/10.4322/bds.2024.e4511

ABSTRACT

Objective: Sealer Plus BC and Bio-C Sealer are new silicate-based sealers. We aimed to evaluate the biocompatibility

and bioactivity of these silicate-based endodontic sealers compared to that of AH Plus epoxy resin sealer. Material

and Methods: Fifteen rats underwent a surgical procedure to create a cavity in the tibial bone, where the sealer was

inserted according to the group. The animals were euthanized after postoperative period of 15 days. Histological

analysis was made, and the results were scored according to the signs of repair, quality of the bone tissue, and presence

of inammation. ANOVA Kruskal-Wallis and Mann-Whitney tests (p <0.05) were performed. Results: Sealer Plus

BC showed neoformation or presence of bone tissue in 73.33% of samples. Bio-C Sealer showed connective tissue

in differentiation or presence of bone in 66.66%. AH Plus showed 80% (p = 0.01) of the samples with granulated

tissue in the bone defect. Sealer Plus BC presented 46.66% of samples with absence of inammatory cells and Bio-C

Sealer showed moderate inammatory process in 66.66% (p = 0.02). Conclusion: The two silicate-based sealers

presented better biocompatibility and bioactivity compared to AH Plus epoxy resin sealer.

KEYWORDS

Animal Model; Calcium Silicate; Endontics; Endodontic obturation; Material testing.

RESUMO

Objetivo: Sealer Plus BC e Bio-C Sealer são novos selantes à base de silicato. Nosso objetivo foi avaliar a

biocompatibilidade e bioatividade desses cimentos endodônticos à base de silicato em comparação com o cimento

de resina epóxi AH Plus. Material e Métodos: Quinze ratos foram submetidos a procedimento cirúrgico para

confecção de cavidade no osso tibial, onde foi inserido o cimento de acordo com o grupo. Os animais foram

eutanasiados após 15 dias de pós-operatório. Foi feita análise histológica e os resultados foram pontuados de

acordo com sinais de reparo, qualidade do tecido ósseo e presença de inamação. Foram realizados testes ANOVA

Kruskal-Wallis e Mann-Whitney (p<0,05). Resultados: O Sealer Plus BC apresentou neoformação ou presença

de tecido ósseo em 73,33% das amostras. O Bio-C Sealer apresentou tecido conjuntivo em diferenciação ou

presença de osso em 66,66%. O AH Plus apresentou 80% (p = 0,01) das amostras com tecido granulado no

defeito ósseo. O Sealer Plus BC apresentou 46,66% de amostras com ausência de células inamatórias e o Bio-C

Sealer apresentou processo inamatório moderado em 66,66% (p = 0,02). Conclusão: Os dois cimentos à base

de silicatos apresentaram melhor biocompatibilidade e bioatividade em relação ao cimento resina epóxi AH Plus.

PALAVRAS-CHAVE

Modelo Animal; Silicato de cálcio; Endodontia; Obturação endodôntica; Teste de materiais.

Braz Dent Sci 2024 Oct/Dec;27 (4): e4511

Castro MVVS et al.

Biocompatibility and bioactive potential of new bioceramic sealers in rat bone tissue: histological analysis

Castro MVVS et al. Biocompatibility and bioactive potential of new bioceramic

sealers in rat bone tissue: histological analysis

INTRODUCTION

To understand the material–tissue interaction

is critical to improving the biomaterial-assisted

healing process; therefore; studies have focused

on assessing biocompatibility [1], considering

that root canal sealers can be extruded into the

periapical medullary bone producing harmful

effects like additional inammation, and foreign

body reactions [2]. Bone tissue has a complex

structure, and researchers have sought to study

materials capable of repairing structural defects.

In recent years, attention has been paid to

the potential of bioactive materials, including

bioceramics, given the possibility of favorable

interaction for tissue repair [3].

Bioceramic sealers have advantages as

biocompatibility, presence of calcium phosphate

in their composition, they are non-toxic and non-

absorbable, generally recognized as inducers of

bone formation [4-6]. It has been reported the

importance of hydraulic calcium silicate cements as

advantageous root sealers like lling bone defects

[2,4]. Given their physicochemical and biological

characteristics, calcium silicate sealers have obtained

similar or superior results to conventional cements

both in vitro and in vivo [7]. Animal models

are indispensable for testing bone-substitute

biomaterials. The small animal models, including

rats, are benecial because they have easy handling

and a life span suitable for observation [8-12].

Sealer Plus BC is a calcium silicate-based

material with excellent biochemical properties

known to promote an increase in pH [6], which is

thought to be associated with calcium release and

thus accelerated healing [13,14]. Bio-C Sealer is

another premixed sealer containing calcium silicates

in this composition [15]. This material can induce

mineralization according to the release of calcium

ions [16] and present alkalinity ability [17].

This primary goal of this work was to

compare the biocompatibility and bioactivity

of these two silicate-based endodontic sealers

with that of AH Plus resin cement, which has

a long history of use due to its faster setting

time, lower solubility, lower lm thickness and

higher radiopacity compared to other materials

. We focused on the mineralized-tissue-inducing

capacity according to tissue scores of formation

and quality, maturation score, and degree of

inammation. The null hypothesis is that have

no difference between the bone healing provide

by bioceramics or epoxy resin sealers.

MATERIAL AND METHODS

Animals

The research protocol was approved by

the Animal Use Ethics Committee of Piaui State

University (protocol no.: 0175/2018). We used

15 male rats (Rattus norvegicus albinus, Wistar;

250–300 g; 8–12-weeks old). The animals were

kept in clean cages (n = 5/cage) with litter

bedding and a 12-hour light/dark cycle. Animals

were provided a normal diet and water ad libitum.

The animals were used to assess

biocompatibility and bioactivity according to the

bone regeneration-inducing capacities of Sealer

Plus BC (lot no.: WR770100; MK Life, Porto

Alegre, Rio Grande do Sul, Brazil; composition:

zirconium oxide, tricalcium silicate, dicalcium

silicate, calcium hydroxide, and propylene glycol)

and Bio-C Sealer (lot no.: 45225; Angelus,

Londrina, Paraná, Brazil; composition: calcium

silicates, calcium aluminate, calcium oxide,

zirconium oxide, iron oxide, silicon dioxide, and

dispersing agent) relative to AH Plus (lot no.:

337957J; Dentsply DeTrey, Konstanz, Baden-

Württemberg, Germany).

To understand the bone-healing process

associated with these materials, we created a

bone defect. For this purpose, animals were

randomly assigned to three groups: group 1,

Sealer Plus BC cement test; group 2, Bio-C Sealer;

and group 3, AH Plus. We used ve animals per

group based on previous studies [18-20].

Surgical procedure

At 1 h before the procedure, dipyrone was

applied subcutaneously (160 mg/kg). The rats

were weighed and then intraperitoneally injected

with 100 mg/kg of ketamine combined with

10 mg/kg of xylazine for general anesthesia.

Trichotomy was performed in the right hind leg,

followed by disinfection with polyvinylpyrridoline-

iodine and incision with a No. 15 scalpel blade.

When visualizing the tibial bone tissue, a cavity

was prepared using a low-speed dental drill (Kerr,

Sollentuna, Sweden) with isotonic saline irrigation.

The size of the defect was 2.3 mm in diameter. The

cements were prepared according to manufacturer

guidelines and applied immediately after handling,

lling the entire cavity. Subsequently, the wound

was sutured with 3-0 nylon thread and washed

with polyvinylpyrrolidone-iodine.

Braz Dent Sci 2024 Oct/Dec;27 (4): e4511

Castro MVVS et al.

Biocompatibility and bioactive potential of new bioceramic sealers in rat bone tissue: histological analysis

Castro MVVS et al. Biocompatibility and bioactive potential of new bioceramic

sealers in rat bone tissue: histological analysis

Tetracycline antibiotic was administered

in a single dose (20 mg/kg) immediately after

surgery. At 12-h post-surgery, subcutaneous

dipyrone (160 mg/kg) was used. Given that

this was a preliminary study, we adopted a

short timeline for evaluation (i.e., a single time

point was chosen according to previous studies

to analyze initial healing progressing) [14,15].

At 15-days post-surgery, the animals were

euthanized by tiopental overdose (100 mg/kg)

according to the recommendations of the Panel

on Euthanasia of the American Association of

Veterinary Medicine, and tibial samples were

collected for histologic analysis.

Histology

The right tibia was harvested and immediately

xed in 10% formaldehyde in buffer. After 24 h,

the tissue was immersed in decalcifying solution

(4% nitric acid) until softened, followed by

washing and parafnization. Each sample was

sliced into three pieces, resulting in 15 per

group. Hematoxylin and eosin staining was

performed for histologic analysis to evaluate

the formation and quality of bone tissue, degree

of collagen maturation, tissue mineral density,

and degree of inammation. The denition of

the histological scores (Table I) was based on

previously established standardized scores [14]

adapted from literature [21-24]. The analysis was

performed by a blind professional.

Statistical analysis

SPSS statistical software (v.21.0; IBM Corp.,

Armonk, NY, USA) was used to perform statistical

analyses. Nonparametric comparative analyses

were performed between groups. According to

the sample characteristics and the 15 units per

group, a one-factor Kruskal–Wallis analysis of

variance test was performed in three groups for

each of the three parameters analyzed, which

allowed verication of the average of the ranks

for each of the groups. The results were supported

by Mann–Whitney U tests for comparison of two

groups. The level of signicance considered was

p< 0.05.

RESULTS

In the formation and quality of the newly

formed tissue (Tables II(A) and III(A)) Sealer Plus

BC show bone neoformation or presence of bone

Table I. Histological scores

Score (A) Bone tissue formation and quality

score

Tissue neoformation (defect ﬁlled with

connective tissue containing blood

capillaries, ﬁbroblasts, macrophages, and

collagen ﬁber neoformation)

Dense connective tissue suggesting

diﬀerentiation into bone tissue with the

presence of many cells and ﬁbers in the

process of organization

Bone neoformation, in which connective

tissue is in the process of diﬀerentiation,

forming bone matrix, or osteon

4 Presence of bone tissue

Score (B) Degree of collagen maturation and

tissue mineral density scores

1No sign of bone union, bed ﬁlling with

connective tissue

Osteon (formation of connective tissue in

bone with osteoprogenitor and osteogenic

cells)

3 Isolated spicules of immature bone

4 Compact bone formation

Score (C) Degree of inﬂammation score

1 Absence of inﬂammatory cells

2 Moderate presence of inﬂammatory cells

3 Intense presence of inﬂammatory cells

Table II. Distribution of groups according to sum and average

of posts

(A) Bone quality scores

Group Average of posts

1 - Sealer Plus BC 28.00

2 - Bio-C Sealer 27.10

3 - AH Plus 13.90

Note: χ2 = 12,06; gl = 2; p = 0,01.

(B) Tissue maturation scores

Group Average of posts

1 - Sealer Plus BC 27.77

2 - Bio-C Sealer 27.10

3 - AH Plus 14.13

Note: χ2 = 11,07; gl = 2; p = 0,01

Group Average of posts

1 - Sealer Plus BC 16.67

2 - Bio-C Sealer 29.03

3 - AH Plus 23.30

Note: χ2 = 7,37; gl = 2; p = 0,02.

Braz Dent Sci 2024 Oct/Dec;27 (4): e4511

Castro MVVS et al.

Biocompatibility and bioactive potential of new bioceramic sealers in rat bone tissue: histological analysis

Castro MVVS et al. Biocompatibility and bioactive potential of new bioceramic

sealers in rat bone tissue: histological analysis

tissue in 73.33% of samples, dense connective

tissue in 20% and defect lled with connective

tissue in 6.66%. Bio-C Sealer have 66.66% in

which connective tissue is in the process of

differentiation or presence of bone tissue and

33.33% presented tissue neoformation. These

two groups differed (p = 0.01) from AH Plus

(Table II(A) and III(A)) which have 80% of the

samples in the initial tissue-repair phase with a

predominance of granulated tissue in the bone

defect (Figure 1e and f), 13.33% have bone

neoformation and 6.66% presented bone tissue.

Degree of collagen maturation parameter

(Tables II(B) and III(B)) in Sealer Plus BC

presented 66.66% of samples with isolated

spicules of immature bone, in 26.66% have

connective tissue and no bone union in 6.66%.

Bio-C Sealer have isolated spicules in 53.33%

of samples, show compact bone in 13.33%

(Figure 1b and d), osteon was present in 6.66%

and 26.66% bed lling with connective tissue. AH

Plus differed (p = 0.01) from the other groups,

with no sign of bone union in 73.33%, isolated

spicules in 20% and connective tissue with

osteoprogenitor and osteogenic cells in 6.66%.

According to the inflammation parameter

(Tables II(C) and III(C)), the Sealer Plus BC

displayed 46.66% of slides with an absence

of inflammatory cells, 46.66% of moderate

inammation and 6.66% with intense presence of

inammatory cells. Bio-C Sealer show 66.66% with

moderate inammatory process, in 20% intense

presence of inammatory cells and 13.33% with

absent of inammatory. AH Plus showed 26.66%

of samples with an absence of inammatory cells,

40% with moderate inammatory inltrate and

33.33% with intense inammation. The difference

(p = 0.02) in this parameter was between Sealer

Plus BC and Bio-C Sealer.

DISCUSSION

According to the degree of collagen

maturation, the bioceramic cements presented no

difference results between them, with presence

of bone tissue or connective tissue differentiation

forming bone matrix in most samples and allowing

good maturation of the bone tissue along with the

presence of compact bone in some laminae. This

was similar to a study in which all bioceramic

sealers promoted repair in mineral tissue and

supports the concept that if a material provides

tissue deposition, it also promotes the healing

process [25,26]. The results associated with AH

Plus were different from those of the bioceramic

cements, with majority of the tissue samples

showing initial tissue formation and presenting

the bone defect lled only by connective tissue.

Tissue neoformation might be associated

with properties of calcium ion release, which

provides mineral deposition [27]. Si-containing

ionic products are as important as calcium

because their release can promote osteogenic

differentiation of stem cells [28]. The amount

of calcium released by bioceramic cements is

superior to that by AH Plus [29], which is in line

with the higher mineralization observed by Sealer

Plus BC and Bio-C Sealer in the present study. A

previous study reported that the presence of AH

Plus does not signicantly interfere with the repair

process, because neoformation of bone tissue in

contact with this cement progressed like that

of an empty control cavity [30]. Another study

suggested that AH Plus does not induce calcium

release or alkalizing activity [31]. Collectively,

these results suggest that the biocompatibility of

AH Plus is due to its lack of interference in the

physiological repair process.

The availability of calcium ions is associated

with a process that favors an alkaline pH essential

for the establishment of a formative matrix,

which in turn accelerates the tissue-healing

Table III. Comparisons between groups

(A) Bone quality scores

Compared

samples

Diﬀerence

between averages

Statistical

signiﬁcance

Group 1 × Group 2 0.46 0.87

Group 1 × Group 3 10.46 0.01*

Group 2 × Group 3 7.74 0.01*

(B) Tissue maturation scores

Compared

samples

Diﬀerence

between averages

Statistical

signiﬁcance

Group 1 × Group 2 0.34 0.94

Group 1 × Group 3 8.90 0.01*

Group 2 × Group 3 7.96 0.01*

Compared

samples

Diﬀerence

between averages

Statistical

signiﬁcance

Group 1 × Group 2 7.74 0.02*

Group 1 × Group 3 4.94 0.09

Group 2 × Group 3 4.34 0.15

Note: *p < 0,05 (signiﬁcant).

Braz Dent Sci 2024 Oct/Dec;27 (4): e4511

Castro MVVS et al.

Biocompatibility and bioactive potential of new bioceramic sealers in rat bone tissue: histological analysis

Castro MVVS et al. Biocompatibility and bioactive potential of new bioceramic

sealers in rat bone tissue: histological analysis

process [6,32,33]. Release of calcium ions and

high pH values were observed in a previous study

evaluating the physical and chemical properties

of Sealer Plus BC [6] and Bio-C Sealer [12].

During the setting process of calcium silicate-

based cements, calcium ions can be released,

thereby providing alkalinity to the wound

microenvironment [25].

Considering the preliminary characterization

of this study, the limitations include the

absence of additional times points and tests

like sophisticated evaluation of inammatory

cells as myeloperoxidase expression and

computed tomography measurements to bone

histomorphometry. However, the results obtained

provide a preliminary understanding of the bone

tissue behavior in contact of these two new

products. Despite the short timeline evaluation

their potential in promoting rapid recovery

present signicant results.

The degree of inflammation indicated

a higher number of Sealer Plus BC-treated

Figure 1 - H&E histological images demonstrating the bone tissue response after contact with obturator materials. Sealer Plus BC group

10 (a) and 40 (b) magniﬁcation showing bone neoformation with bone matrix suggesting diﬀerentiation for bone tissue, and presence of

osteoprogenitor and osteogenic cells. Bio-C Sealer Group 10 (c) and 40 (d) magniﬁcation exhibiting connective tissue diﬀerentiating forming

bone matrix, and moderate presence of inﬂammatory cells. Group AH Plus 10 (e) and 40 (f) magniﬁcation showing tissue neoformation with

connective tissue ﬁlling the defect, with no sign of bone union, and moderate to intense presence of inﬂammatory cells.

Braz Dent Sci 2024 Oct/Dec;27 (4): e4511

Castro MVVS et al.

Biocompatibility and bioactive potential of new bioceramic sealers in rat bone tissue: histological analysis

Castro MVVS et al. Biocompatibility and bioactive potential of new bioceramic

sealers in rat bone tissue: histological analysis

samples without inammatory cells relative to

other treatment groups, which agrees with a

previous study reporting little or no inammatory

response from the use of a bioceramic material

[34]. Over half of the tissue slides from the Bio-C

Sealer treatment group presented moderate

inammation scores. In general, the inammatory

process in tissues treated with bioceramic cements

is expected during the initial repair period [21],

which was included in the 15 postoperative days

applied in the present study. The difference

between the two bioceramic-based cements

might suggest that the inammatory process was

more evident in specimens treated with the Bio-C

Sealer product; however, as previously described,

this factor did not interfere with tissue repair.

AH Plus sealer resulted in high inammation

values, which was in line with another study

confirming the presence of an inflammatory

reaction [35]. Recent reports indicated marked

cytotoxic effects from freshly prepared AH Plus

in vitro, with enlarged osteoblasts suggesting

degeneration attributable to the resinous cement

composition [36] likely causative of DNA-strand

breakage and possible formaldehyde release [37].

However, acute characteristics were not present

2 weeks after sealer preparation [32], and the

biocompatibility of AH Plus promoted reduced

inammation over time [38].

Sealer Plus BC and Bio-C Sealer demonstrate

biocompatibility and bioactive potential in the

initial repair process. Sealer Plus BC produced

little or no inammation. Bio-C Sealer caused

an initial higher degree of inammation without

prejudice in bone healing process. In addition

to biocompatibility and bioactivity these sealers

are ready-to-use, meaning less technique steps.

A follow up in longer timeline is important to a

better establishment of these materials ability

with accelerate tissue repair.

CONCLUSION

Sealer Plus BC and Bio-C Sealer have

biocompatibility and bioactive potential superior

to AH Plus in the initial bone repair process.

Acknowledgements

All the authors are grateful for all those

involved in the preparation and development of

this work.

Author’s Contributions

MVVSC, WCA, HAS, BSF, DFF, LFF, MSCP,

ASBP, MÂALF, CAMF: Conceptualization,

Methodology, Software, Validation, Formal

Analysis, Investigation, Resources, Data Curation,

Writing – Original Draft Preparation, Writing –

Review & Editing, Visualization and Supervision.

Conict of Interest

The authors have no conicts of interest to

declare.

Funding

This research did not receive any specic

grant from funding agencies in the public,

commercial, or not-for-prot sectors.

Regulatory Statement

This study was conducted in accordance

with all the provisions of the local animal subjects

oversight committee guidelines and policies of:

the ethics committee on the use of Animals of

State University of Piauí. This study protocol was

reviewed and approved by the ethics committee

on the use of Animals of State University of Piauí

under the approval number 0175/2018.

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Castro MVVS et al. Biocompatibility and bioactive potential of new bioceramic

sealers in rat bone tissue: histological analysis

Date submitted: 2024 Sept 07

Accept submission: 2024 Dec 05

Wanderson Carvalho de Almeida

(Corresponding address)

Universidade Estadual do Piauí, Faculdade de Odontologia. Parnaíba, PI, Brazil.

Email: wangstron@gmail.com

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