The International Journal of Periodontics & Restorative Dentistry

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The Influence of Bio-Oss Collagen on Healing of an Extraction Socket: An Experimental Study in the Dog

Mauricio Araújo, DDS, PhD* Following tooth extraction, the eden- Elena Linder, LT** tulous site of the alveolar process will Jan Wennström, DDS, PhD** undergo both quantitative and quali- Jan Lindhe, DDS, PhD** tative changes.1–5 Thus, during healing, the bundle bone will disappear and eventually be replaced with 3 The objective of the present experiment was to evaluate the effect on hard tissue trabecular bone and marrow. modeling and remodeling of the placement of a xenograft in fresh extraction Furthermore, the walls of the socket will be reduced in both height and sockets in dogs. Five mongrel dogs were used. Two mandibular premolars (4P4) were hemisected in each dog, and the distal roots were carefully removed. In one width.4,6 The change is often more pro- socket, a graft consisting of Bio-Oss Collagen (Geistlich) was placed, whereas the nounced in the buccal than in the contralateral site was left without grafting. After 3 months of healing, the dogs lingual/palatal compartments of were euthanized and biopsies sampled. From each experimental site, four ground extraction sites.2,6 sections (two from the mesial root and two from the healed socket) were pre- Different approaches have been pared, stained, and examined under the microscope. The presence of Bio-Oss advocated to preserve or improve the Collagen failed to inhibit the processes of modeling and remodeling that took dimension and contour of the ridge fol- place in the socket walls following tooth extraction. However, it apparently pro- lowing tooth extraction, including the moted de novo hard tissue formation, particularly in the cortical region of the use of implants,5,7–10 various graft extraction site. Thus, the dimension of the hard tissue was maintained and the 11–15 profile of the ridge was better preserved. The placement of a biomaterial in an materials, and/or barrier mem- 7,16 extraction socket may promote bone modeling and compensate, at least tem- branes. One particular xenograft porarily, for marginal ridge contraction. (Int J Periodontics Restorative Dent comprised of deproteinized bovine 2008;28:123–135.) bone mineral (Bio-Oss, Geistlich) has recently been widely used in the treat- ment of ridge defects,17,18 in sinus floor elevation procedures,19–21 and in *Department of Dentistry, State University of Maringá, Paraná, Brazil. extraction sockets.11,18,21 In some of **Institute of Odontology, The Sahlgrenska Academy at Göteborg University, Gothenburg, these studies, socket grafting appar- Sweden. ently was successful, whereas in other

Correspondence to: Dr Mauricio Araújo, Rua Silva Jardim, 15/sala 03, 87013-010 Maringá- reports the benefits of such therapy Paraná, Brazil; phone: +55-44-3224-6444; e-mail:[email protected]. were less clear.

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Figs 1a and 1b Clinical photographs illustrating a hemisected mandibular premolar (a, left) and a site with the distal root removed (b, right).

Fig 2a (left) A graft of Bio-Oss Collagen has been placed in the fresh extraction site. The socket was filled (and packed) with the graft material. Note the presence of graft material on the outside of the buccal bone wall.

Fig 2b (right) The mobilized buccal and lingual flaps have been replaced and retained with interrupted sutures.

The objective of the present Pocket incisions were made in the (Fig 2b). The sutures were removed experiment was to evaluate the effect posterior premolar region in both after 10 days. of the placement of a xenograft in fresh quadrants of the mandible. Buccal and The corresponding premolar site extraction sockets in dogs on hard lingual full-thickness flaps were ele- in the contralateral quadrant was tissue modeling and remodeling. vated to expose the alveolar crest. Two exposed and managed in the manner

premolars (4P4) were hemisected (Fig described. However, no biomaterial 1a) with the use of fissure burs. The was placed in the fresh extraction Method and materials canal of each mesial root was reamed socket. and filled with gutta-percha. The distal The ethical committee of the State roots were carefully removed (Fig 1b) University of Maringá approved the with the use of elevators. Specimen preparation research protocol. Five mongrel dogs, In one quadrant of the mandible, about 1 to 2 years old and weighing a graft consisting of Bio-Oss Collagen After 3 months of healing, the dogs between 13 and 15 kg each, were was placed in the fresh extraction were euthanized with an overdose of used. During surgical procedures, the wound (Fig 2a). The socket was filled ketamine and perfused, through the animals were anesthetized with intra- (and packed) with the graft material. In carotid arteries, with a fixative con- venously administered ketamine 10% addition, the marginal portion of the taining a mixture of 5% glutaraldehyde (8 mg/kg, Agener União). Throughout buccal bone wall was covered with and 4% formaldehyde.22 A portion of

the experiment the animals received Bio-OssCollagen. The mobilized buc- the crown of the mesial root of 4P4 was mechanical plaque removal every cal and lingual flaps were replaced and removed to expose the gutta-percha other day. closed with interrupted sutures in the root canal. The mandibles were

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Figs 3a and 3b Schematic drawings (buccolingual view) illustrating the various landmarks from which the measurement at the tooth (t) (a, left) and socket (s) (b, right) sites R C were made. BCt/BCs = buccal crest of tooth LCs LCt (t) or socket (s); C-C = long axis of the V V BCt extraction socket; LCt/LCs = lingual crest of tooth (t) or socket (s); R-R = long axis of the BCs root; V = vertical distance between BCt/BCs and LCt/LCs.

C R

Socket Tooth

removed and placed in the fixative. reduced to a thickness of about 20 to The following landmarks were Each experimental site, including the 30 µm by microgrinding and polishing identified: mesial root and the distal socket area, and were then stained in toluidine blue was dissected using a diamond saw and Ladewig fibrin stain.25 • CEJ: cementoenamel junction (Exakt Apparatebau). The tissues were • BCt(s): crest of the buccal bone processed for ground sectioning wall at the tooth (t) and socket (s) according to methods described by Histologic and histomorpho- sites Donath and Breuner23 and Donath.24 metric examinations • LCt(s): crest of the lingual bone The samples were dehydrated in wall at the tooth (t) and socket (s) increasing grades of ethanol, infiltrated Histologic examinations were per- sites with Technovit 7200 VLC-resin (Kulzer), formed with a Leitz DM-RBE micro- • A: apex of the mesial root polymerized, and sectioned using scope (Leica) equipped with an image • BM: base of the mandible a cutting-grinding unit (Exakt system (Q-500 MC, Leica). It was rec- Apparatebau). ognized that the mesial and distal root The long axis of the root (R-R) or

From each experimental site, four cones of 4P4 projected into the alveo- the center of the socket (C-C) was sections (two from the mesial root and lar process with a certain degree of determined. The levels of BCt(s) and two from the healed socket) were pre- separation. However, the shape and LCt(s) along R-R or C-C were identified pared. The sections were cut in the dimension of the alveolar process at and the vertical distance (V) between buccolingual plane and were acquired the mesial and distal roots were pre- the buccal and lingual crests deter- from the central area of either the root sumed to be similar. mined (Fig 3). or the socket. The sections were

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Figs 4a and 4b Schematic drawings (buccolingual view) illustrating measurements made to determine the cross-sectional area of the apical, middle, and coronal thirds of LCs C R the alveolar process at the tooth (a, left) and LCt socket (b, right) sites. A = apex of the root; Coronal BM = base of mandible; a-a = line, perpen- BCs Coronal BCt dicular to R-R, that separates the alveolar Middle process from the base part of the mandible. Middle (For additional abbreviations see legend in Apical C Fig 3.) R Apical a a A a a BM A BM

Socket Tooth

Fig 5 Clinical photograph illustrating the mucosa covering the edentulous ridge after 3 months. The soft tissues appeared to be clinically healthy.

On the tooth site, a line (a-a) per- tion of the ridge, the outline of the alve- The composition of the newly pendicular to R-R prepared at the level olar process obtained at the tooth site, formed tissue in the extraction socket of the root apex (A) separated the base including its apical, middle, and coro- was determined using a point count- of the mandible from the alveolar nal portions, was projected over the ing procedure. Thus, a lattice com- process (Fig 4). A second line con- section using a-a as the reference level prising 100 light points (modified from necting BCt and LCt represented the (see Fig 4). The area occupied by each Schroeder and Münzel-Pedrazzoli26) marginal border of the alveolar portion (apical, middle, and coronal) was superimposed over the tissue, and process. The image of the alveolar was measured with a cursor and the percentage area occupied by min- process was subsequently divided into expressed in square millimeters. The eralized bone, bone marrow, provi- three equal portions: apical, middle, relative alteration in the size of the alve- sional connective tissue (matrix), and and coronal. The cross-sectional area olar process that had occurred in each Bio-Oss particles was determined occupied by each portion was mea- dog after tooth extraction was esti- (magnification ϫ200). Means and stan- sured with a cursor and expressed in mated by subtracting the value dard deviations were calculated using square millimeters. obtained at the extraction site from the the dog as the statistical unit. To estimate the size of the cross- corresponding value at the tooth site. sectional area of the edentulous por-

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CEJ CEJ/aJE aJE

Fig 6a (left) Microphotograph of a bucco- Fig 6c Higher magnification of right box lingual section representing a tooth site in Fig 6a. At the buccal aspect, the aJE was (toluidine blue; original magnification ϫ0.7). located below the CEJ (Ladewig fibrin stain; original magnification ϫ5). Fig 6b (above) Higher magnification of left box in Fig 6a. At the lingual aspect, the aJE was located at the CEJ (Ladewig fibrin stain; original magnification ϫ5).

Results Histologic observations Furthermore, the buccal crest was located apical to the lingual crest. All experimental sites healed unevent- Tooth sites fully. Overt signs of soft tissue inflam- At both the buccal and lingual aspects Extraction sites mation (swelling and redness) were of the mesial roots, the gingival margin In both the grafted and nongrafted seen during the first few weeks of heal- was located coronal to the CEJ (Fig 6a). (coagulum) sites, a thick, well-kera- ing. After 3 months, the mucosa cov- The connective tissue adjacent to the tinized mucosa covered the healed ering the edentulous ridge and the junctional epithelium harbored small socket. The connective tissue was char- gingival tissues at adjacent teeth infiltrates of inflammatory cells. At the acterized by the presence of a dense appeared to be clinically healthy (Fig 5). lingual aspect, the apical portion of network of collagen fibers. A few the junctional epithelium (aJE) was scattered inflammatory cells were located at the CEJ (Fig 6b), whereas at observed in the mucosa. the buccal aspect (Fig 6c), the aJE was The old bone of the buccal and consistently located below the lingual crests at both grafted and non- CEJ. The lingual bone wall was grafted sites exhibited signs of mod- markedly wider than the buccal wall. eling and remodeling. This was

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NB NB

OB OB BB

Fig 7a (left) Microphotograph of a buccolingual section representing a nongrafted site. Note that the entrance of the socket was “closed” by a bridge of mineralized bone that con- nected the buccal and lingual crests (toluidine blue; original magnification ϫ0.7). BB = buccal bone; LB = lingual bone; arrows = bone crests.

Figs 7b and 7c (above) Higher magnifications of the areas outlined in Fig 7a. The dotted lines separate the old bone (OB) from the newly formed hard tissue (NB). The lingual (b, left) as well as the buccal (c, right) bone walls exhibited signs of modeling and remodeling (Ladewig fibrin stain; original magnification ϫ5).

evidenced by the presence of (1) lingual (Fig 7b) as well as the buccal and buccal (Fig 8c) walls of the socket osteoclasts in socket walls as well as in bone walls (Fig 7c) exhibited signs of and (2) in direct contact with the bio- the newly formed hard tissue, (2) bone remodeling, indicated by the presence material in most areas. In discrete areas multicellular units, and (3) secondary of large numbers of secondary of the newly formed bone, however, osteons with characteristic reversal osteons. The middle and apical por- particles of the biomaterial were lines in the socket walls. The buccal tions of the socket were occupied by embedded in a provisional matrix crest of the old bone wall was located bone marrow and small amounts of (arrow in Fig 8b). Bio-Oss particles could markedly apical to the lingual crest. lamellar bone. also be observed outside the hard tis- At the nongrafted sites, the At four of the five grafted sites, a sue compartment (Fig 9a). In such loca- entrance of the socket was “closed” by dome-shaped portion of newly formed tions, graft particles were surrounded a bridge of mineralized bone that con- mineralized bone occupied the socket by newly formed bone (Fig 9b) that was nected the buccal and lingual crests. entrance (Fig 8a). This hard tissue com- lined by osteoblasts. The more central The newly formed hard tissue of this prised woven bone, parallel-fibered portion of the healed socket was occu- bridge (Fig 7a) comprised woven bone bone, some lamellar bone, and Bio- pied by mineralized bone (woven and with primary osteons and parallel- Oss particles. The newly formed bone lamellar bone), Bio-Oss, and minute fibered bone. Small amounts of lamel- appeared to be (1) in direct continuity amounts of provisional connective lar bone could also be observed. The with the old bone in the lingual (Fig 8b) tissue and bone marrow (see Fig 8a).

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NB BCg

LB OB OB

Fig 8a (left) Microphotograph of a buccolingual section representing a grafted site. Note the presence of a dome-shaped bridge of hard tissue at the socket entrance. The marginal portion of this newly formed hard tissue was located coronal to the old bone crest and comprised woven bone, parallel-fibered bone, lamellar bone, and Bio-Oss particles (toluidine blue; original magnification ϫ0.7). BB = buccal bone; LB = lingual bone; arrows = old bone crests; BCg = marginal termination of newly formed hard tissue.

Figs 8b and 8c (above) Higher magnifications of the areas outlined in Fig 8a. The newly formed bone (NB) appeared to be in direct continuity with the old bone (OB) in the lingual (b, left) as well as in the buccal (c, right) wall of the socket and appeared to be in direct contact with the biomaterial (blue particles) (Ladewig fibrin stain; original magnification ϫ5). Dotted lines separate old bone from the newly formed bone.

Fig 9a (left) Microphotograph of the marginal portion of a grafted site. Particles of CNT the biomaterial (P) could be observed outside the hard tissue compartment in the healed ridge (Ladewig fibrin stain; original magnification ϫ10). CNT = connective tis- P P sue; NB = new bone. NB Fig 9b (right) Higher magnification of the P area outlined in Fig 9a. The Bio-Oss parti- NB cles (P) were surrounded by newly formed P bone (arrows) lined with osteoblastlike cells (Ladewig fibrin stain; original magnification ϫ20). NB = new bone. NB

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Table 1 Mean relative alteration (% in Table 2 Mean composition (% ± SD) of the comparison to the tooth containing newly formed tissue in the alveolar process ± SD) in the surface extraction socket area (mm2) at different portions of Tissue type Coagulum site Bio-Oss site the edentulous ridge* Mineralized bone 50.5 ± 7.3 58.1 ± 10.7 Area Coagulum site Bio-Oss site Bone marrow 49.5 ± 7.4 26.7 ± 14.4 Apical +3.8 ± 2.6 +1.7 ± 5.0 Provisional matrix – 3.3 ± 3.1 Middle +7.5 ± 7.9 +5.1 ± 7.5 Bio-Oss – 12.2 ± 9.1 Marginal –30.1 ± 20.7 +1.7 ± 5.1 *+ indicates increase in cross section area; – indicates reduction in area.

Histometric measurements alterations (between 1.7% and 7.5%; the proportion of newly formed bone Table 1). At the marginal portion of marrow. Thus, in the grafted sites the In all specimens the crest of the buc- the nongrafted sites, however, there volume occupied by bone marrow was cal bone wall was located apical to the was a marked reduction on the dimen- 26.7% ± 14.4%, whereas the corre- corresponding lingual bone crest. At sion of the ridge during the 3 months sponding proportion in the nongrafted the tooth site, the mean vertical dis- of healing. Thus, in comparison to the coagulum sites was 49.5% ± 7.4%. The tance (LCt – BCt) between the crest of tooth site, about 30% of the surface amount of mineralized bone present in the buccal and lingual bone walls was area in this portion was lost. In the Bio- the socket varied between 58.1% ± 0.6 ± 0.1 mm, whereas at the non- Oss grafted sites, such a reduction of 10.7% (grafted sites) and 50.5% ± grafted and grafted extraction sites the marginal hard tissue area did not 7.3% (nongrafted sites). In grafted sites, the corresponding distances (LCs – occur. 12.2% ± 9.1% of the tissue volume was BCs) were 2.1 ± 0.5 mm and 1.9 ± 0.6 occupied by Bio-Oss particles. mm, respectively. Placement of Bio- Oss Collagen in the fresh extraction Morphometric measurements socket thus failed to prevent resorption Discussion of the buccal crest. The composition of the tissue in the Following tooth extraction, the extraction socket after 3 months of The present experiment confirmed buccolingual cross-sectional area in healing is described in Table 2. The previous observations documenting the apical and middle portions of the most pronounced difference between that, following the loss of one or more alveolar ridge underwent only minor the grafted and nongrafted sites was teeth, the edentulous ridge will

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undergo marked change. The bundle control sites suffered a reduction of bone will gradually disappear and the more than 20%. dimensions of the marginal portion of the ridge will decrease substantially. Furthermore, ridge reduction will Elimination of the biomaterial become more pronounced in the buccal than in the lingual/palatal com- The placement of Bio-Oss Collagen partment. The current animal study in fresh extraction sockets in the pres- furthermore demonstrated that the ent study apparently promoted hard placement of a xenograft (Bio-Oss tissue formation in the crest region. In Collagen) in fresh extraction sockets this context it should be realized that failed to inhibit the processes of mod- this newly formed hard tissue cap con- eling and remodeling that took place tained a large number of Bio-Oss par- in the bone walls of the ridge follow- ticles that were surrounded by and/or ing tooth extraction. The biomaterial, integrated with immature woven bone. however, apparently promoted de This observation, which is in agree- novo hard tissue formation, particu- ment with data previously published larly at the marginal portion of the from studies in humans and ani- extraction sites. Therefore the dimen- mals,11,14,18,19,27,28 shows that the elim- sions of the hard tissue walls were ination of Bio-Oss is a slow process maintained and the profile of the ridge that may require many years. It is was preserved. believed that the xenograft is eventually replaced with host bone during the process of remodeling,29 although Ridge preservation the precise mechanism is not fully understood. The observation that the placement of a Bio-Oss Collagen graft in the fresh extraction socket could prevent ridge Hard tissue cap reduction is in agreement with findings presented by Nevins et al.15 They In the biopsy material it was observed studied “the fate of the buccal wall of that Bio-Oss particles were present in extraction sockets of teeth with promi- large numbers, even in locations coro- nent roots” in nine subjects scheduled nal to the dome-shaped hard tissue for extraction (n = 36 maxillary anterior cap. Several of these particles (see Figs teeth). Following tooth extraction, 19 8 and 9) were obviously surrounded by of the sockets were grafted with Bio- woven bone, and osteoblastlike cells Oss. Computerized tomographic were present in what appeared to be scans were made after tooth extraction a provisional matrix. It is suggested and then after 30 to 90 days of healing. that, during continued healing, these The authors reported that 15 of 19 biomaterial particles may become inte- Bio-Oss treated sockets experienced a grated with and further enhance the reduction of less than 20% of the buc- dimension of the bone crest. In other cal plate, while as many as 12 of 17 words, they may promote additional

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Fig 10a (left) Microphotograph of the BB P CNT buccal surface of the buccal wall of a grafted site. Note the presence of Bio-Oss particles (P) in a location outside the periosteum. PR (Ladewig fibrin stain; original magnification ϫ10). BB = buccal bone; CNT = connective tissue; PR = periosteum. P P Fig 10b (right) Higher magnification of the area outlined in Fig 10a, viewed with polarized light. Remnants of the biomaterial PR were consistently entrapped in a connective P tissue capsule (Ladewig fibrin stain; original magnification ϫ20). P = Bio-Oss particle.

hard tissue formation and further The socket enhance the dimension of the crest. Thus, it is proposed that during later A comparison of the two differently phases of socket healing, qualitative as treated sockets with respect to tissue well as quantitative alterations may composition (see Table 2) indicated that occur in the grafted sites. the process of tissue remodeling had During the surgical procedure, Bio- progressed further in the nongrafted Oss Collagen was placed not only in the than in the grafted sites. Thus, while socket but also on the outside of the 50% of the tissue volume in the non- marginal portion of the buccal wall (see grafted sites was occupied by bone Fig 2a). During healing, a portion of marrow, in the grafted sites, bone mar- this graft material remained in this loca- row represented only about 27% of the tion. Examination of the sections, how- tissue volume. This observation is in ever, revealed that such Bio-Oss parti- agreement with data previously pre- cles were always located lateral to the sented by Wetzel et al,30 Diés et al,31 periosteum of the buccal wall. Berglundh and Lindhe,17 and Zitzmann Furthermore, they were consistently et al32 and indicates that, during heal- surrounded by connective tissue cap- ing, Bio-Oss may occupy an area that sules (Fig 10) and were thus not would otherwise house the bone mar- engaged in new bone tissue formation. row. Taken together, the present and

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Fig 11 Microphotograph of a buccolingual section representing a grafted site in which there was limited de novo bone formation. At the socket entrance, a multitude of Bio-Oss particles (arrows) were present in a dense connective tissue matrix (Ladewig fibrin stain; original magnification ϫ0.7). BB = buccal bone; LB = lingual bone.

previous findings indicate that, whereas were present in a dense connective placement of a biomaterial in a con- tissue (Fig 11). The profile of the crest tained hard tissue defect may promote of this ridge was not dome-shaped hard tissue formation and defect reso- but invaginated. The reason why occa- lution, the graft may in fact delay heal- sionally the biomaterial failed to pro- ing. This hypothesis is supported by mote hard tissue formation in the data previously presented by Schmid et socket entrance is currently not under- al,33 Hämmerle et al,34 Slotte and stood. It is suggested, however, that in Lundgren,35 and Araújo et al29 in dif- such incompletely healed sites coag- ferent animal models. Provided this ulum formation following root extrac- assumption is correct, an extended tion may have been compromised. period of healing may be required to Alternatively, the wound may have determine (1) the ultimate fate of the become contaminated and the coag- biomaterial and (2) whether the con- ulum degraded early, thus jeopardizing tinued remodeling may alter the dimen- new bone formation. sion and profile of the edentulous ridge. In one of the grafted extraction sites, de novo bone formation was limited, and in the socket entrance of such sites, a multitude of Bio-Oss particles

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Volume 28, Number 2, 2008