Monica Calasans-MaiaRodrigo ResendeGustavo FernandesJose Calasans-MaiaAdriana Terezinha AlvesJos�e Mauro Granjeiro

A randomized controlled clinical trialto evaluate a new xenograft foralveolar socket preservation

Authors’ affiliations:Monica Calasans-Maia, Rodrigo Resende,Department of Oral Surgery, Fluminense FederalUniversity, Niteroi, BrazilGustavo Fernandes, Cell and Molecular BiologyDepartment, Fluminense Federal University,Niteroi, BrazilJose Calasans-Maia, Department of Orthodontics,Fluminense Federal University, Nova Friburgo,BrazilAdriana Terezinha Alves, Department of OralPathology, Gama Filho University, Rio de Janeiro,BrazilJos�e Mauro Granjeiro, Fluminense FederalUniversity, Niteroi, BrazilBioengineering Program, National Institute ofMetrology Standardization and Industrial Quality,Duque de Caxias, Brazil

Corresponding author:Monica Calasans-MaiaDepartment of Oral SurgeryFluminense Federal UniversityRua Mario Santos Braga30. CentroNiteroiRio de janeiroCEP: 24020-140Brazile-mail: monicacalasansmaia@gmail.com

Key words: bone implant interactions, bone substitutes, clinical research, clinical trials

Abstract

Objective: The aim of this clinical trial was to compare the effect of Bio-Oss� and a new bovine

xenograft (Osseus�) in alveolar sockets after a 24-week healing period.

Materials and methods: A total of 20 adult volunteers ages 30–60 were subjected to single tooth

extraction. A tooth extraction was performed at the baseline. All sites were randomly allocated to

two test groups (TG1: grafted using a new bovine xenograft, Osseus�, and TG2: grafted using

commercially available bovine xenograft-Bio-Oss�). Six months later, a sample of the grafted area

was obtained and implants were inserted in the same site. Histological sections were examined

focusing on the presence of fibrous connective tissue (CT), and newly formed bone in direct

contact with the graft. The HE-stained sections were subjected to histomorphometrical evaluation

using Image Pro-Plus� software (Release 7.0). The definitive crown was placed 3 months later.

Results: Upon completion of the study, no patients were removed from the study and all inserted

implants (10 in each group) were eventually integrated. After 6 months, in the TG1, the mean

value of new bone formation was 33.7 (�7.1), for CT was 32.3 (�8.9) and for the remaining

biomaterial was 10.7 (�16.2). In the TG2, the mean value of new bone formation was 19.3 (�22.6),

of the CT was 49.9 (�14.1) and of the remaining biomaterial was 22.6 (�7.9).

Conclusions: No statistically significant difference was observed between TG1 and TG2 after

6 months (P > 0.05), and both biomaterials afforded a more favorable implant position.

The aim of implant dentistry is to restore

missing or extracted teeth by placing implants

in anatomical, esthetical, and long-term

functional restorative positions (Kutkut et al.

2012). The amount of hard tissue resorption

following tooth extraction occasionally

involves prosthetically driven implant place-

ment; therefore, the development of ridge

preservation techniques that result in less

alveolar bone loss is of great interest (Sisti

et al. 2012). Extraction socket wound healing

is characterized by resorption of the alveolar

bone at the extraction site, which reduces

the bone volume available for implant place-

ment. Major changes in the extraction socket

occur during the first year after tooth extrac-

tion, with two-thirds of the bone loss occur-

ring within the first 3 months (Schropp et al.

2003; Ara�ujo et al. 2008; Van der Weijden

et al. 2009), although dimensional changes

are observed up to 1 year after tooth extrac-

tion, resulting in a 50% reduction in the buc-

colingual dimension of the alveolar ridge

(Schropp et al. 2003), primarily due to the

resorption of the buccal bone plate (Ara�ujo &

Lindhe 2011). The ridge preservation proce-

dures facilitate the preservation of the alveo-

lar architecture to prevent hard and soft

tissue collapse and minimize or eliminate

the necessity for future augmentation proce-

dures (Tan et al. 2012). Many graft materials,

such as autogenous bone grafts (Pelegrine

et al. 2010), allografts (Wood et al. 2012;

xenografts (Calasans-Maia et al. 2009; Fernan-

des et al. 2011; Spinato et al. 2012; Festa

et al. 2011), and alloplasts (Gonshor et al.

2011; Ruga et al. 2011; Brkovic et al. 2012),

have been used to maintain the dimensions

of the alveolar ridge after extraction in

humans. Although some of these graft mate-

rials preserved the post-extraction alveolar

ridge dimensions to some extent, the quan-

tity and the quality of the bone tissue forma-

tion in the socket varied and the presence

of these materials has often affected the

usual healing process (Heberer et al. 2011).

Date:Accepted 3 July 2013

To cite this article:Calasans-Maia M, Resende R, Fernandes G, Calasans-Maia J,Alves AT, Granjeiro JM. A randomized controlled clinicaltrial to evaluate a new xenograft for alveolar socketpreservation.Clin. Oral Impl. Res. 00, 2013, 1–6doi: 10.1111/clr.12237

© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 1

Xenografts are obtained from a species that is

different from that of the recipients, and as

osteoconductors, these grafts are predomi-

nantly made from the inorganic portion of

animal bone tissue (Granjeiro et al. 2005;

Munhoz et al. 2006; Calasans-Maia et al.

2009; Accorsi-Mendonc�a et al. 2011; Zam-

buzzi et al. 2012). The processing of bovine

bone results in two distinct types of materi-

als: inorganic and organic (predominantly col-

lagen type I). Inorganic material is free of

proteins and cells because it only consists of

hydroxyapatite. The proteins are removed

through heat treatment at temperatures

above 300°C or alkali treatment, followed by

neutralization, thus eliminating the risk of

disease transmission. However, the bioab-

sorption of these materials is reduced with

increasing temperature (Wenz et al. 2001).

Indeed, bovine materials obtained from Brazil

are regarded favorably, as Brazilian cattle are

free of spongiform encephalopathy (BSE or

mad cow disease). A new Brazilian bone sub-

stitute (Osseous�; SIN, S~ao Paulo, SP, Brazil),

comprising an inorganic bovine bone matrix,

has been used as an alternative graft material

for ridge preservation after tooth extraction

prior to implant placement. In previous in

vivo studies, we confirmed that this bovine

xenograft is a biocompatible, bioabsorbable

osteoconductor (Calasans-Maia et al. 2009;

Jardelino-Lima et al. 2008). The aim of this

study was to compare the effects of two

deproteinized bovine bone minerals in the

healing of fresh extraction sockets using

clinical, histological, and histomorphometric

analyses.

Material and methods

This study was performed in compliance

with the principles outlined in the Declara-

tion of Helsinki concerning experimentation

involving human subjects. Quality assess-

ment was carried out based on the RCT-

checklist of the CONSORT-statements

(Schulz et al. 2010). All procedures and mate-

rials in the present study were approved

through the relevant independent committee

on the Ethics of Human Research of Flumin-

ense Federal University (CEP/HUAP nº 118),

and the volunteer subjects were informed

about the study protocol and required to sign

a consent form. Twenty patients (ten women

and 10 men) participated in this randomized,

controlled clinical trial, which took place in

the Dental Clinical Research Center at Flu-

minense Federal University, Rio de Janeiro,

Brazil (Table 1, Data S1). A minimum sample

size (10 subjects per group) was established

in an attempt to minimize the publication

bias (Vignoletti et al. 2012, Sisti et al. 2012).

Patient selection

All the patients were in general good health.

Any patient requiring one tooth extraction

(hopeless tooth for periodontal, traumatic, or

caries reasons) and showing a bone defect

between 3 and 5 mm at the buccal wall and

no soft tissue recession was eligible for this

study according to specific exclusion and

inclusion criteria (Table 2). The recruitment

of the volunteers was carried out during

6 months, and all volunteers were followed

up for a period of 12 months after prosthetic

rehabilitation. The volunteer subjects were

randomly assigned to the tests groups using

an envelope system distribution provided by

the principal investigator.

Presurgical procedures

The medical and dental histories of the

patients were reviewed, and each patient

was evaluated using periapical radiographs,

clinical photographs, study casts, and clinical

examinations of the extraction sites. Sub-

sequently, the volunteers were provided

with detailed oral hygiene instructions, and

customized surgical splints were fabricated

on the study casts for use in reentry proce-

dures to accurately obtain bone biopsies from

the center of the grafted sockets.

Surgical procedures

The following implant procedure was used at

all extraction sites. The extraction was

performed under local anesthesia, without the

elevation of a mucoperiosteal flap (Fig. 1a,b,

Data S1). A periotome and the appropriate

dental forceps were used to minimize surgical

trauma of the surrounding tissue. The thor-

ough curettage of all soft tissue debris in the

alveolus was performed during the extraction

at all extraction sites to ensure the removal of

all granulation tissue and stimulate bleeding

from the osseous base to promote healing. A

caliper (Dentaurum�; Dentaurum Dental

Technology, Ispringen, Germany) was subse-

quently used to measure the horizontal ridge

width (buccolingually) at the midpoint of the

alveolar crest using the mid-buccal and mid-

palatal marks on the cervical bone surface as

published before (Mardas et al. 2011, Vigno-

letti et al. 2012). After completion of the mea-

surements, the randomization envelope was

opened and the assigned treatment test Osse-

ous� (SIN) or control (Geistlich Biomaterials,

Wollhusen, Switzerland) was revealed to the

surgeon. The implant did not exceed the

height of the alveolar crest, and the site was

visually inspected to ensure that the biomate-

rial was saturated with blood (Fig. 1c). Pri-

mary wound closure was performed following

the elevation and rotation of the mucoperio-

steal flap (Fig. 1d,e). Postoperative antibiotic

therapy (500-mg Azithromycin) was adminis-

tered once a day for the first postoperative

week, and a disinfectant mouth rinse (0.12%

Chlorhexidine) was prescribed two times per

day, for the first two postoperative weeks.

Postoperative clinical evaluations of the

patients were performed at 1, 7, 30, and

Table 1. List of volunteer subjects investigated

Patient Gender Age ToothExperimentalgroups

1 Female 30 46* 12 Female 52 37* 23 Female 53 37* 24 Male 44 21‡ 15 Female 34 46* 26 Male 58 46‡ 17 Male 50 47‡ 28 Female 51 46* 29 Female 34 36* 110 Female 34 16* 111 Female 53 22† 112 Male 50 27‡ 213 Male 60 15† 214 Male 52 36‡ 215 Male 23 47* 216 Female 56 36† 117 Female 48 26* 118 Female 45 24† 119 Female 33 34† 220 Female 31 36† 1

*Extraction due to periodontal reason.†caries.‡tooth/root fracture.

Table 2. Inclusion and exclusion criteria

Inclusion criteria Exclusion criteria

Age between 30 and 60 yearsGood general healthPresence of a hopeless tooth requiringextraction

The extraction site would be suitable forreplacement by a dental implant

Volunteer subjects had voluntarily signedthe informed consent

Pregnancy or lactating periodSmokingChronic treatment with any medication knownto affect oral status and bone turnover

Contraindicate surgical treatmentSuffering from a known psychological disorder

2 | Clin. Oral Impl. Res. 0, 2013 / 1–6 © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Calasans-Maia et al �Alveolar socket preservation with xenograft

90 days to determine the presence of compli-

cations, such as infection with inflammation,

wound dehiscence, or loss of graft material.

After 6 months, all sockets were evaluated

through clinical and radiographic examination

(Fig. 1f,g).

Surgical reentry

At 24 weeks after extraction, the implants

were placed. A mucoperiosteal flap was

raised, and the site of extraction was identi-

fied using a customized surgical splint. A

caliper was used to measure the horizontal

ridge width buccolingually. A core biopsy

with a depth of 6 mm was obtained from the

center of the extraction site. A trephine bur

(2 mm in diameter, SIN) was used to collect

the biopsy specimen (Fig. 2a), followed by

dental implant placement according to the

manufacturer’s surgical protocol. Try-On or

Strong implants (SIN) were used (Fig. 2b,c).

The mucoperiosteal flaps were closed with

interrupted sutures (Silk suture 4-0, Ethi-

con�). After 6 months, the implants were

successfully placed at all sites in the control

and test groups (Fig. 2d).

Histological evaluation

Bone biopsy specimens (6 9 2 mm) obtained

from the grafted and ungrafted sockets were

fixed in 10% formalin for 2 days and subse-

quently decalcified in bone decalcification

solution (Alkimia�; Allkimia, Campinas, Bra-

zil) for 48 h. After routine processing, the tis-

sues were embedded in paraffin, sectioned

longitudinally into multiple 4lm-thick sec-

tions and stained with Hematoxylin and

Eosin (H&E) and Masson’s trichrome stain.

The two most central sections were obtained

from each specimen. For the qualitative and

morphologic analysis of the remodeling pro-

cess, the stained preparations were examined

under a light microscope (Zeiss Axioplan) at a

minimum 209 magnification and the entire

section was evaluated. Ten digital images of

each section were acquired and used to trace

the areas identified as vital bone, biomaterial

particles, and connective tissue (CT)/other

non-bone components. Image analysis soft-

ware (Image ProPlus�, Release 7.0; MediaCy-

bernetics, Silver Spring, MD, USA) was used

to create individual layers of newly formed

bone, biomaterial particles, and CT/other non-

bone components, which were assessed by a

single observer blinded to the clinical data.

Statistical analysis

The results were expressed as the means �95%CI. The Mann–Whitney unpaired test were

performed, considering significant differences if

P < 0.05.

Results

Clinical findings

Clinical healing was uneventful and free of

infection or symptoms in all volunteers from

both groups. Age and gender did not signifi-

cantly affect the clinical outcomes of this

study.

Almost complete soft tissue closure was

observed at 10 days after extraction in both

test groups. After 6 months of healing, when

the bone specimen sample was obtained, both

groups exhibited the same bone density and

showed the same resistance on trephine appli-

cation. Bone core samples were retrieved, and

implants were placed in all sockets. The hori-

zontal ridge width (buccolingually) was mea-

sured at the midpoint of the alveolar crest

using the mid-buccal and mid-palatal marks

on the cervical bone crest before the tooth

extraction and after 6 months of socket heal-

ing, and the results are showed in Table 3.

Statically significant differences were not

observed between the groups.

(a) (b)

(c)

(d)

(e)

(f)

(g)

Fig. 1. (a, b) Clinical and radiographic aspects of the hopeless tooth; (c) socket filled with the osseus xenograft; (d)

The flap was advanced coronally for primary closure; (e) radiographic aspect of the immediate area post grafting; (f,

g) clinical and radiographic aspects at 6 months after grafting.

© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 3 | Clin. Oral Impl. Res. 0, 2013 / 1–6

Calasans-Maia et al �Alveolar socket preservation with xenograft

Histological observations

Test sites

One experienced blinded pathologist performed

the histological evaluation. Histological slides

were prepared, and the cores were examined at

209 and 409 magnification, revealing new

bone formation in all grafted sockets. The for-

mation of new well-mineralized vital trabecu-

lar bone was observed in all examined sections.

The new bone showed trabecular organization,

with collagen fibers arranged in a meshwork

pattern and osteocytes randomly distributed

(a)

(b)

(c)

(d)

Fig. 2. (a) Before implant installation a 2-mm specimen was removed using a trephine; (b, c) Clinical and

radiographic images of the installed implant; (d) Prosthetic rehabilitation.

Table 3. Clinical outcomes with respect towidth in millimeters (standard deviation inparentheses)

Tooth Group Baseline EndChange inwidth (mm)

46 1 11 10.6 0.437 2 10 9.5 0.537 2 9.5 9.1 0.421 1 8.0 7.8 0.246 2 11.2 10.9 0.346 1 12.1 11.6 0.547 2 12.3 12 0.346 2 11 10.4 0.636 1 11.5 11.1 0.416 1 11 10.8 0.222 1 7.0 6.8 0.227 2 12.0 11.7 0.315 2 6.5 6.3 0.236 2 11.5 11.2 0.347 2 12.4 12 0.436 1 11.8 11.6 0.226 1 12.1 12 0.124 1 9.0 8.8 0.234 2 7.0 6.4 0.636 1 11.9 11.4 0.5

(a) (b)

Fig. 3. (a, b) Photomicrographs of the interface between xenograft and the new formed bone, Stain HE, 109 and

409 augmentation.

(a)

(b)

(c)

Fig. 4. Histomorphometric evaluation of the alveolar

sockets grafted with Bio-Oss� and Osseus�, consider-

ing the volume density of (a) newly-formed bone; (b)

connective tissue and (c) residual biomaterial particles.

Points in the plot represent all data, mean 95% of confi-

dence interval (bars).

4 | Clin. Oral Impl. Res. 0, 2013 / 1–6 © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Calasans-Maia et al �Alveolar socket preservation with xenograft

within the trabeculae in large spindle-shaped

lacunae (Fig. 3a,b). Loose fibrous tissue with

thin vessels filled the trabecular spaces. Dense,

trabecular bone patterns were observed in both

test groups. The overall mean value of the

newly formed vital bone area fraction for TG1

was 33.6% (�7.1) and 19.3% (�22.5) for TG2.

For TG1, the mean value of the newly formed

CT was 32.3% (�8.8), and the mean value

of the remaining biomaterial was 10.6%

(�16.2). For TG2, the mean value of the CT

was 49.9% (�14.0), and the mean value of the

remaining biomaterial was 22.5% (�7.9)

(Fig. 4).

Discussion

The present randomized clinical trial com-

pared two bovine xenografts (Bio-Oss� and

Osseus�) for the preservation of the alveolar

ridge dimensions following tooth extraction.

The clinical, histological, and histomorpho-

metrical evaluations did not show significant

differences between the two materials. In the

present study, biopsy specimens were

obtained and dental implants were placed

after a 6-month healing period. A healing

period of 6 months was selected because this

time point was used in two previously

reported systematic reviews. The first sys-

tematic review showed 29–63% horizontal

bone loss and 11–22% vertical bone loss

after 6 months following tooth extraction

and demonstrated rapid reductions in the

first 3–6 months, followed by gradual reduc-

tions in the dimensions (Tan et al. 2012).

The second systematic review showed a

3.8 mm horizontal reduction in width and a

1.24 mm vertical reduction in height of the

alveolar ridge within 6 months after tooth

extraction (H€ammerle et al. 2012). These

studies demonstrated rapid reductions in the

first 3–6 months, followed by gradual reduc-

tions in the dimensions. A previous study

discussed so-called ridge preservation tech-

niques, which are categorized into two differ-

ent groups: techniques for maintaining the

ridge profile (ridge preservation) and tech-

niques for enlarging the ridge profile (ridge

augmentation). The reasons for ridge preser-

vation include the maintenance of the exist-

ing soft and hard tissue envelope,

maintenance of a stable ridge volume for

optimizing the functional and esthetic out-

comes, and the simplification of treatment

procedures subsequent to ridge preservation

(Vignoletti et al. 2012). Contraindications for

ridge preservation were considered in patients

irradiated in the area planned for ridge preser-

vation, patients taking biphosphonates and

when general contraindications against oral

surgical interventions and infections at the

site planned for ridge preservation were

observed, which could not be treated during

ridge preservation surgery (H€ammerle et al.

2012). The volunteer subjects included in the

present clinical trial did not present contrain-

dications for ridge preservation. In the pres-

ent study, mucoperiosteal flaps were raised

to preserve the ridge profile and facilitate

primary wound closure. The primary closure

of the wound is beneficial with respect to

the volume gained as a result of this

approach (H€ammerle et al. 2012). Cellular

differentiation, augmentation material break-

down, and bone replacement were evidenced

at the grafted sites, largely preserving the

dimensions of the alveolar ridge after

6 months of healing. In the present study, a

very small horizontal resorption of the bone

crest after the two types of treatments was

observed in both groups, confirming previous

clinical and preclinical reports that post-

extraction healing is always characterized by

osseous resorption and significant contour

changes especially in the horizontal plane of

the residual alveolar ridge (Schropp et al.

2003; Ara�ujo & Lindhe 2011). These changes

may be limited because our sample is mainly

composed by molars. A shorter 3-month

healing period should be evaluated in future

studies. A recent systematic review evalu-

ated bone healing after tooth extraction,

with or without an intervention, and the

histological evaluation revealed a large pro-

portion of residual graft material that might

account for some of the differences in the

alveolar ridge dimensions observed during

the follow-up exam (Morjaria et al. 2012).

Another recent systematic review evaluated

the effectiveness of bone preservation using

graft materials in non-molar alveolar regions

and suggested that the graft materials might

not prevent physiological resorptive bone

processes after tooth extraction, although

these materials might reduce changes in the

resulting bone dimensions (Ten Heggeler

et al. 2011).

Conclusions

The alterations in the dimension of the alve-

olar ridge following tooth extraction were

similar between the groups, affording a more

favorable implant position.

Acknowledgements: The authors

thank Sistema de Implantes Nacional, S~ao

Paulo, Brazil (SIN) for providing financial

support for this study. We also want to

express our thanks to Dr. Alfredo Schnetzler

Neto and Frederico, Prosthodontists, Rio de

Janeiro, Brazil for his significant

contributions to developing the

prosthodontic rehabilitation.

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Supporting Information

Additional Supporting Information may be

found in the online version of this article:

Data S1. CONSORT statement 2001 check-

list.

6 | Clin. Oral Impl. Res. 0, 2013 / 1–6 © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Calasans-Maia et al �Alveolar socket preservation with xenograft