[email protected]

M. Araújo
E. Linder
J. Lindhe
Effect of a xenograft on early bone
formation in extraction sockets:
an experimental study in dog
Authors’ affiliations:
Mauricio Araújo, Department of Dentistry,
State University of Maringá, Paraná, Brazil
Elena Linder, Jan Lindhe, Institute of Odontology,
The Sahlgrenska Academy at Göteborg University,
Gothenburg, Sweden
Key words: biomaterial, bone formation, extraction socket, grafting
Correspondence to:
M. Araújo
Rua Silva Jardim
15/sala 03
87013-010 Maringá
Paraná
Brazil
Tel.: þ 55 44 3224 6444
Fax: þ 55 44 3224 6444
e-mail: [email protected]
Material and methods: Five beagle dogs were used. The distal roots of the third and fourth
Abstract
Aim: The aim of this study was to study the effect on early bone formation resulting from
the placement of a xenograft in the fresh extraction socket in dogs.
s
mandibular premolars were removed. In one quadrant, a graft consisting of Bio-Oss
Collagen was placed in the fresh extraction wound, while the corresponding premolar sites
in the contra-lateral jaw quadrant were left non-grafted. After 2 weeks of healing, the dogs
were perfused with a fixative, the mandibles removed, the experimental sites dissected,
demineralized, sectioned in the mesio-distal plane and stained in hematoxyline–eosine.
Results: The central portion of the non-grafted sockets was occupied by a provisional
matrix comprised of densely packed connective tissue fibers and mesenchymal cells. Apical
and lateral to the provisional matrix, newly formed woven bone was found to occupy most
of the sockets. In the apical part of the grafted sockets, no particles of the xenograft could
be observed but newly formed bone was present in this portion of the experimental site.
In addition, limited numbers of woven bone trabeculae occurred along the lateral socket
walls. The central and marginal segments of the grafted sockets, however, were occupied
s
by a non-mineralized connective tissue that enclosed Bio-Oss particles that frequently
were coated by multinucleated cells.
s
Conclusions: The placement of Bio-Oss Collagen in the fresh extraction wound obviously
delayed socket healing. Thus, after 2 weeks of tissue repair, only minute amounts of newly
formed bone occurred in the apical and lateral borders of the grafted sockets, while large
amounts of woven bone had formed in most parts of the non-grafted sites.
Date:
Accepted 5 April 2008
To cite this article:
Araújo M, Linder E, Lindhe J. Effect of a xenograft
on early bone formation in extraction sockets:
an experimental study in dog.
Clin. Oral Impl. Res. 20, 2009; 1–6.
doi: 10.1111/j.1600-0501.2008.01606.x
In previous experiments in dogs (Cardaropoli et al. 2003; Araújo & Lindhe 2005), it
was observed that healing of an extraction
socket included (i) early formation of woven bone (modeling) and (ii) the subsequent replacement of this immature bone
with lamellar bone and marrow (remodeling). Healing of the edentulous site was
further characterized by (iii) loss of bundle
bone in the walls of the socket and (iv) a
marked reduction in the height of the
buccal bone crest. Similar observations
c 2009 The Authors. Journal compilation c 2009 Blackwell Munksgaard
were reported from retrospective and prospective studies in man (Pietrokovski &
Massler 1967; Schropp et al. 2003; Pietrokovski et al. 2007; for review see Chen
et al. 2004).
Different approaches were used to prevent the post-extraction ridge reductions.
Such methods included the utilization of
various graft materials and application
techniques (e.g. Becker et al. 1998; Artzi
et al. 2000; Froum et al. 2002; Carmagnola
et al. 2003; Nevins et al. 2006).
1
Araújo et al . Early bone formation in extraction sockets
In a recent study by Araújo et al. (2008),
the dog model was used to study healing of
an extraction socket that had been grafted
s
with Bio-Oss Collagen. It was observed
that the placement of the xenograft in the
fresh extraction socket after a 3-month
period of healing appeared to have interfered with the process of bone modeling
and remodeling. Thus, while the nongrafted sites underwent marked resorption
during the 3-month interval, the dimension of the walls of the grafted sockets as
well as the profile of the edentulous ridge
remained unchanged. The newly formed
hard tissue in the marginal portion of the
grafted sites, however, contained a large
s
number of Bio-Oss particles that were
surrounded by immature woven bone. A
more detailed analysis of the newly formed
tissues in the two differently treated sockets further indicated that the process of
tissue remodeling had progressed further
in the non-grafted than in the grafted sites.
Thus, while about 50% of the tissue volume in the non-grafted sites was occupied
by bone marrow, in the grafted site bone
marrow represented only about 25% of the
tissue volume. This indicates that the graft
may in fact have delayed healing.
The objective of the present experiment
was to evaluate the effect on early wound
healing and bone modeling of the placement of a xenograft in the fresh extraction
socket in dogs.
Grafted sites
In one quadrant of the mandible, a graft
s
consisting of Bio-Oss Collagen (Geiss
tlich , Wolhusen, Switzerland) was placed
in the fresh extraction wounds (Fig. 1) in a
manner previously described (Araújo et al.
2008). The marginal portion (about 2 mm)
of the buccal bone wall of the distal sockets
was also covered with the biomaterial.
Non-grafted sites
The corresponding premolar sites in the
contra-lateral jaw quadrant were exposed
and managed in the manner described
above. No biomaterial was, however,
placed in the fresh extraction sockets.
The flaps were replaced in the grafted
and non-grafted sites and were retained
with interrupted sutures. The sutures
were removed after 1 week. Mechanical
tooth cleaning was performed on days 3, 7
and 10 after surgery.
After 2 weeks of healing, the dogs were
euthanized with an overdose of Ketamin
(Agener União) and perfused, through the
carotid arteries, with a fixative containing
a mixture of 5% glutaraldehyde and 4%
formaldehyde (Karnovsky 1965). The
mandibles were removed and placed in
the fixative. Each experimental site, including the distal socket area, was diss
sected using a diamond saw (Exact
Apparatebeau, Norderstedt, Hamburg,
Germany), and subsequently demineralized in a 10% solution of EDTA. The
Material and methods
The ethical committee of the State University of Maringá approved the research
protocol. Five beagle dogs about 1 year old
and weighing between 10 and 12 kg each
were used. During surgical procedures, the
animals were anesthetized with intravenously administered Ketamin (10%,
8 mg/kg; Agener União, São Paulo, Brazil).
Pocket and crestal incisions were made
in the posterior premolar region in both
quadrants of the mandible. Buccal and
lingual full thickness flaps were elevated
to disclose the alveolar crest. The canal of
the mesial roots of the third and fourth
mandibular premolars was reamed and
filled with gutta-percha. The premolars
were subsequently hemi-sected with the
use of fissure burs. The distal roots were
carefully removed with the use of elevators.
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Clin. Oral Impl. Res. 20, 2009 / 1–6
blocks were dehydrated in ethanol and
isopropanol and embedded in paraffin. Serial sections representing the experimental
sites were cut in a mesio-distal plane and
parallel to its long axis. The microtome
was set at 6 mm. From each site, three
sections, representing the central part of
the socket and about 20 mm apart, were
selected for the histological examination.
The sections were stained in hematoxyline–eosine
Histological examination
The histological examinations were pers
formed in a Leitz DM-RBE microscope
(Leica, Wetzlar, Germany) equipped with
s
an image system (Q-500 MC ; Leica).
The composition of the newly formed
tissue in the extraction socket was determined using a point counting procedure.
Thus, a lattice comprising 100 light points
(modified from Schroeder & MünzelPedrazzoli 1973) was superimposed over
the tissue in the healing socket, and the
percentage area occupied by (i) mineralized
bone, (ii) bone marrow, (iii) provisional
matrix, (iv) granulation tissue and (v) Bios
Oss particles was determined (magnification 200). In addition, the number of
s
Bio-Oss particles in the socket that were
in direct contact with multinucleated cells
was determined and expressed as percens
tage of the total number of Bio-Oss particles identified.
Mean values and standard deviations of
the different variables were calculated
using the dog as the statistical unit.
Results
Healing was uneventful at all sites. The
clinical examination of the experimental
sites that was performed after 2 weeks (Fig.
2) disclosed that a slightly invaginated and
modestly inflamed soft tissue covered the
socket entrance.
Gross histological observations
Fig. 1. Clinical photographs illustrating the graft of
s
Bio-Oss Collagen placed in the fresh extraction
socket. Note that the graft material also covers the
marginal portion of the buccal wall of the socket.
The connective tissue of the mucosa covering the grafted as well as the non-grafted
sockets was rich in mesenchymal cells,
vascular structures and clusters of inflammatory cells.
The central portion of the non-grafted
sockets (control site; Fig. 3) was occupied
by a provisional matrix comprised of
c 2009 The Authors. Journal compilation c 2009 Blackwell Munksgaard
Araújo et al . Early bone formation in extraction sockets
Fig. 4. Microphotograph representing the provisional matrix in the non-grafted site. Note the
densely packed connective tissue fibers and cells;
V, vessel. Hematoxyline–eosine stain; original magnification: 200.
Fig. 2. Clinical photographs illustrating a site
s
grafted with Bio-Oss Collagen after 2 weeks of
healing. Note the slightly invaginated crestal surface
and the slightly inflamed soft tissue.
Fig. 6. Microphotograph representing the woven
bone in the non-grafted site. The trabeculae of
woven bone were lined with osteoblasts and occasional isolated osteoclasts (arrows). BM, primitive
bone marrow; V, vessel; WB, woven bone. Hematoxyline–eosine stain; original magnification:
200.
Fig. 5. Microphotograph representing the mineralization front of the woven bone in the non-grafted
site. Note that the woven projections had initiated
the formation of a primary spongiosa (primary
osteons and enclosed vascular structures). PM, provisional matrix; V, vessel; WB, woven bone. Hematoxyline–eosine stain; original magnification:
200.
Fig. 3. Microphotograph of a mesio-distal section
representing a non-grafted site. Note that most of
the alveolar socket is occupied by woven bone and
provisional matrix. PM, provisional matrix; GT,
granulation tissue; WB, woven bone. Hematoxyline–
eosine stain; original magnification: 16.
densely packed connective tissue fibers and
mesenchymal cells (Fig. 4). Apical and
lateral to the provisional matrix, newly
formed woven bone was found to occupy
most of the socket (Fig. 3). Several of the
bone projections formed primary osteons
and enclosed vascular structures (Fig. 5).
The trabeculae of immature bone were
lined with osteoblasts and occasionally
isolated osteoclasts, residing in resorption
bays, could be observed on the surface of
the newly formed bone (Fig. 6).
No particles of the xenograft could be
observed in the apical part of the grafted
sockets (test site; Fig. 7), but newly formed
immature bone was found to occupy this
portion of the post-extraction wound. In
addition, limited numbers of trabeculae of
woven bone occurred along the lateral
walls of the sockets. The central and marginal segments of the wound were occupied
by a connective tissue that enclosed the
s
Bio-Oss particles (Fig. 7). This connective
c 2009 The Authors. Journal compilation c 2009 Blackwell Munksgaard
Fig. 7. Microphotograph of a mesio-distal section
representing a grafted site. Note that the central
and marginal segments of the sockets were occupied
s
by a connective tissue that enclosed Bio-Oss particles (asterisks). PM, provisional matrix; WB, woven
bone. Hematoxyline–eosine stain; original magnification: 16.
tissue had the features of a provisional
matrix (rich in mesenchymal cells, fibers
and vessels) but small amounts of mononuclear leukocytes could consistently also
be observed. In addition, the provisional
matrix harbored a multitude of large multinucleated cells that were in direct contact
with and occupied substantial portions of
the periphery of many of the graft particles
(Figs 8 and 9). Segments of the graft that
3 |
Clin. Oral Impl. Res. 20, 2009 / 1–6
Araújo et al . Early bone formation in extraction sockets
Fig. 8. Microphotograph representing the provisional matrix in the grafted site. The provisional
matrix harbored large multinucleated cells (arrows)
that were in direct contact with and occupied different portions of the periphery of many of the graft
s
particles. Bp, Bio-Oss particles; PM, provisional
matrix. Hematoxyline–eosine stain; original magnification: 200.
Fig. 10. Microphotograph representing the provisional matrix in a grafted site. Note that the Bios
Oss particle was not only in direct contact with
multinucleated cells (arrows) but also with provisional matrix or newly formed woven bone (arrows
heads). a, artifact; Bp, Bio-Oss particles; PM,
provisional matrix; WB, woven bone. Hematoxyline–eosine stain; original magnification: 400.
Fig. 12. Microphotograph representing a higher
magnification of a multinucleated cell present in a
s
shallow invagination on the surface of a Bio-Oss
particle in the provisional matrix of a grafted site.
s
Bp, Bio-Oss particle. Hematoxyline–eosine stain;
original magnification: 1000.
Table 1. Mean values (SD) of the proportions (%) of the different tissues in the
grafted and non-grafted alveolar sockets
Grafted
site
Granulation
tissue
Provisional
matrix
Mineralized
bone
s
Bio-Oss
Non-grafted
site
3.7 (0.8)
3.1 (0.5)
62.7 (12.6)
49.1 (8.2)
14.7 (5.9)
47.8 (15.6)
18.9 (9.8)
–
Discussion
Fig. 9. Microphotograph representing a higher magnification of multinucleated cells (arrows) that
s
coated the entire periphery of a Bio-Oss particle
s
in a grafted site. Bp, Bio-Oss particle. Hematoxyline–eosine stain; original magnification: 1000.
were not occupied by the multinucleated
cells were found to be in direct contact
with provisional matrix or newly formed
mineralized bone (Fig. 10). In the lateral
portions of the socket, several adjacent Bios
Oss particles were frequently found to be
‘connected’ (bridged) by zones of immature
bone (Fig. 11). There were no obvious signs
of active degradation of the bovine mineral
and only at a few sites could multinucleated cells be observed in shallow invaginations on the surface of the graft (Fig. 12).
Morphometric measurements
The percentage area occupied by the various tissues in the alveolar socket is presented in Table 1. The proportion of
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Clin. Oral Impl. Res. 20, 2009 / 1–6
Fig. 11. Microphotograph representing the lateral
portions of the socket in a grafted site. Note few
s
multinucleated cells at the surface of the Bio-Oss
s
particles and that several adjacent Bio-Oss particles
were bridged by newly formed woven bone. Bp, Bios
Oss particles; V, vessel; WB, woven bone. Hematoxyline–eosine stain; original magnification:
400.
granulation tissue was 3.7 0.8% (SD)
in the grafted and 3.1 0.5% in nongrafted sites. The proportions of provisional matrix were 62.7 12.6% (grafted
sites) and 49.1 8.2% (non-grafted sites),
and the corresponding proportions of
mineralized bone were 14.7 5.9% and
s
47.8 15.6%. The Bio-Oss particles occupied 18.9 9.8% of the tissue present
in the grafted sockets. The percentage of
s
Bio-Oss particles that were in direct contact with multinucleated cells was
53 12.2%.
The present experiment indicated that the
early phase of hard tissue formation was
retarded in extraction sockets that, immediately after tooth removal, had been
s
grafted with Bio-Oss Collagen. It appeared
that this delayed wound healing and bone
modeling may have been influenced by the
multinucleated cells that occurred in tissues harboring the xenograft. Thus, in the
grafted sites, substantial amounts of newly
formed bone could only be detected in the
apical portion of the socket where the graft
material was absent. In the remaining
portions of the grafted sockets, a mildly
inflamed provisional matrix surrounded
s
the majority of the Bio-Oss particles, the
surface of which was frequently, but not
always, coated with multinucleated cells.
In isolated areas of the grafted sites, multinucleated cells were absent and the foreign
material occasionally surrounded by the
woven bone that bridged adjacent granules
of the bovine bone.
c 2009 The Authors. Journal compilation c 2009 Blackwell Munksgaard
Araújo et al . Early bone formation in extraction sockets
In the non-grafted control sites, large
amounts of woven bone had formed in
most compartments of the socket. This
finding is in agreement with observations
from similar experiments that investigated
tissue modeling and remodeling in extraction sockets as well as in mechanically
produced defects in the alveolar ridge in
dogs (Cardaropoli et al. 2003, 2005; Araújo
& Lindhe 2005).
Similar amounts of new bone had formed
in the apical segments of the test and
control sites, while in the remaining portions of the grafted sockets, only minute
amounts of immature bone could be found.
There are reasons to assume that following
root extraction and graft placement, the
ensuing flow of blood into the cone-shaped
s
socket forced the Bio-Oss Collagen material in marginal direction. A void was
hereby established in the apical zone of
the socket that could house a coagulum
that apparently was unaffected by the
translocated foreign material. Hence, in
this apical portion of the test socket as
well as in the entire non-grafted socket,
tissue modeling evidently followed a normal patter, i.e. the clot was replaced with
granulation tissue, provisional matrix and
primary spongiosa (Cardaropoli et al.
2003).
In the non-mineralized portions of the
newly formed tissue in the grafted sockets,
large multinucleated cells were found to
surround a substantial number of the Bios
Oss granules. Thus, 450% of the granules were more or less completely coated
by multinucleated cells. In the remaining
s
portions of the graft, the Bio-Oss particles
were surrounded either by a leukocytecontaining provisional matrix or occasionally newly formed woven bone. In such
locations, multinucleated cells were conspicuous by their absence.
The occurrence of multinucleated cells
s
on the surface of Bio-Oss material was
previously described (e.g. Piatelli et al.
1999; Merkx et al. 2000; Tadjoedin et al.
2003; Houshmand et al. 2007; Simion
et al. 2007), and the cells were identified
as osteoclasts and their presence related to
the resorption and gradual elimination of
the graft material (Berglundh & Lindhe
1997; Araújo et al. 2001; Cardaropoli
et al. 2005). It has not been made clear,
however, whether the multinucleated cells
found on the surface of this xenograft are
indeed active osteoclasts as suggested by,
e.g., Piatelli et al. (1999), Tadjoedin et al.
(2003), Tapety et al. (2004) or non-active,
impaired osteoclasts cells as suggested by
Taylor et al. (2002). It is documented that
multinucleated cells originate from mononuclear phagocytes that belong to the hematopoietic line of stem cells (Bredan &
Xing 2007). Such mononuclear phagocytes
(macrophages) may fuse and differentiate
into osteoclasts or giant cells as reported by
Vignery (2000) who claimed that while
osteoclasts develop on bone surfaces, other
multinucleated cells such as giant cells
differentiate ‘primarily in chronic inflammatory sites in response to bacterial invasion and foreign bodies such as implants
. . ..’ In the tissue sampled from the grafted
sites of the current experiment, the multinucleated cells on the graft surface were
almost never found to reside in resorption
bays (Fig. 13), while morphologically similar cells present on adjacent surfaces of host
bone were almost consistently located in
characteristic Howship’s lacunae and were
classified as active osteoclasts.
It has been documented that a foreign
body reaction can be elicited to a xenograft
that is clinically non-immunogenic, nontoxic and chemically inert (for review see
Luttikhuizen et al. 2006). Furthermore, it
was proposed (Ratner 2001) that such a
reaction may occur during early phases of
wound healing. The presence of multinucleated cells in the granulation tissueprovisional matrix in the grafted sockets
of the present experiment indicated that
the xenograft particles may have been recognized as being foreign to the host, and
that a foreign body reaction may have been
elicited. The early phase of such a reaction
Fig. 13. Microphotograph representing a higher
magnification of multinicleated cells (arrows) on
the graft surface in the provisional matrix of a grafted
site. Note the multinucleated cells were present on a
s
smooth non-invaginated surface. Bp, Bio-Oss particle. Hematoxyline–eosine stain; original magnification: 1000.
is associated with inflammatory processes
(Vignery 2000; Ratner 2001; Luttikhuizen
et al. 2006) that may impair hard tissue
deposition. This may explain the delayed
formation of bone that was observed in the
graft-containing areas of the extraction
socket, and that the multinucleated cells
found on the surface of the xenograft were
giant cells.
Most of the graft particles present in the
test sites were surrounded either by a dense
provisional matrix or newly formed woven
bone. In such locations, multinucleated
cells were conspicuous by their absence.
In a previous experiment in the dog (Araújo
et al. 2008), socket grafting was performed
and healing evaluated 3 months after tooth
extraction. In sections from this longer
term study, multinucleated cells were
never observed at the surface of the xenos
graft, but most of the Bio-Oss granules
were in direct contact with immature woven bone. Hence, in the interval between 2
weeks and 3 months of healing, the multinuclear cells may have completed their
function, undergone apoptosis and disappeared.
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