Susanne Heberer
Bassem Al-Chawaf
Detlef Hildebrand
John J. Nelson
Katja Nelson
Authors’ affiliations:
Susanne Heberer, Bassem Al-Chawaf, Katja
Nelson, Clinic for Oral and Maxillofacial Surgery,
Clinical Navigation and Robotics, Charité-Campus
Virchow Clinic, Berlin, Germany
John J. Nelson, Department of Pathology,
University of South Alabama, Mobile, AL, USA.
Detlef Hildebrand, Private Practice, Berlin,
Germany
Correspondence to:
Katja Nelson
Clinic for Oral and Maxillofacial Surgery
Charité-Campus Virchow Clinic
Augustenburger Platz 1, 13353 Berlin, Germany
Tel.: þ 49 30 4 50 55 50 22
Fax: þ 49 30 4 50 55 59 01
e-mail: katja.nelson@charite.de
Date:
Accepted 3 May 2008
To cite this article:
Heberer S, Al-Chawaf B, Hildebrand D, Nelson JJ,
Nelson K. Histomorphometric analysis of extraction
sockets augmented with Bio-Oss Collagen after a
6-week healing period: A prospective study. Clin. Oral
Impl. Res. 19, 2008; 1219–1225
doi: 10.1111/j.1600-0501.2008.01617.x
c 2008 The Authors. Journal compilation


c 2008 Blackwell Munksgaard
Histomorphometric analysis of
extraction sockets augmented with
Bio-Oss Collagen after a 6-week
healing period: A prospective study
Key words: analysis, biomaterials, clinical research, morphometric, socket preservation,
tissue physiology, wound healing
For a predictable esthetic outcome of
implant-retained restoration after tooth
removal, the biology of the healing of ex-
traction sockets needs to be considered
(Quirynen et al. 2007). Based on a number
of studies including human and animal
experiments, it is known that there are a
series of events involved in the process
of healing, such as: (1) formation and
maturation of blood clot, (2) infiltration of
immature mesenchymal cells, and (3) es-
tablishment of a provisional matrix from
which bone formation results (Amler 1969;
Cardaropoli et al. 2003; Araújo & Lindhe
2005). The various stages of the process of
healing in mandibular extraction sockets of
canines show an initial phase with a boost
of bone formation within the first 30 days
and a subsequent resorption of this newly
formed bone to about 15% of the initial
amount and gradual replacement by the
bone marrow (Cardaropoli et al. 2003).
After the removal of teeth, ridge alterations
in width and height occur based on resorp-
tive processes of the newly formed bone
within the socket and also of the original
bone in canine models (Cardaropoli et al.
2003; Araújo & Lindhe 2005) and humans
(Atwood 1963; Winkler 2002; Schropp
et al. 2003b). The increased reduction
in width can be approximately 50% of
the original dimension after 12 months
(Schropp et al. 2003a, 2003b) based on a
pronounced resorption of the buccal
wall (Araújo & Lindhe 2005). Immediate
implant placement, originally thought to
prevent this resorption, shows no evident
decrease of the resorption rate or pattern in
clinical studies or animal experiments
(Schropp et al. 2003a, 2003b; Botticelli
et al. 2004; Covani et al. 2004; Araújo &
Lindhe 2005). Several studies have pro-
posed the use of heterologous graft material
such as hydroxyapatite, b-Tri-calcium
phosphate, polylactide sponge, and depro-
teinized bovine bone mineral as a ridge-
preservation technique during bone healing
(Carmagnola et al. 2003; Serino et al. 2003;
Luczyszyn et al. 2005; Rothamel et al.
2007). Bovine bone mineral displays osteo-
conducive properties forming an effective
bone/graft matrix when used in defect
regeneration, sinus floor elevation, and
repair of periodontal defects for the place-
ment of implants (Nemcovsky et al. 2002;
Norton et al. 2003; Esposito et al. 2006).
The efficiency of a heterologous bone sub-
stitute placed in extraction sockets has
been evaluated in experimental and clinical
studies regarding bone formation and the
substitute’s influence on the resorption
pattern (Artzi et al. 2000; Carmagnola
et al. 2003; Fugazzotto 2003, 2005; Serino
et al. 2003) and in defect sites with Bio-Oss
Collagen (Cardaropoli et al. 2005). The
healing period in all the previous studies
1219
Heberer et al . Bio-Oss Collagen augmented extraction sockets at 6 weeks
mentioned encompassed three or more
months before histomorphometric evalua-
tion was performed that revealed sufficient
bone formation rates of up to 80%.
Limited information is available on
the rate of bone formation in extraction
sockets of humans filled with Bio-Oss
spongiosa granules (a bovine bone substi-
tute) with the addition of 10% highly
purified porcine collagen (Bio-Oss Col-
s
lagen ) after shortened healing periods of
less than 3 months. The aim of the present
study was to assess the amount of new
bone formation in the human extraction
socket after 6 weeks as well as the amount
and mode of incorporation of Bio-Oss par-
ticles at this time point.
Material and methods
The study protocol was approved by the
Ethics Committee of the Charité Univer-
sity Medicine in Berlin, Germany.
Patients and surgical procedure
Sixteen patients (10 females and 6 males)
with a mean age 50.5 years (ranging from
28 to 69 years) participated in this prospec-
tive study. The patients were referred for
the removal of teeth for endodontic rea-
sons. Teeth with evident periapical radi-
olucency and/or periapical abscess were
excluded from this study. Patients with a
severe periodontitis or active periodontal
lesions as well as severely resorbed sockets
with a remaining height o5 mm were not
included. All patients were healthy, not
having any systemic disease or taking reg-
ular medications. A subsequent implant
procedure was planned for all of the extrac-
tion sites. The extraction procedure was
performed under local anesthesia without
the elevation of a mucoperiosteal flap;
therefore, no primary wound closure was
performed. Meticulous care was taken to
avoid surgical trauma of the surrounding
tissue by using a periotome and the appro-
priate dental forceps. For consideration in
the study, all extraction sockets had to
be intact (4-wall), with no alveolar wall
loss. A thorough curettage of all soft tissue
debris in the alveolus was performed to
ensure the removal of all granulation tissue
and to stimulate bleeding from the osseous
s
base. Thereafter, Bio-Oss Collagen (Geis-
tlich Pharma AG, Wohlhusen, Switzer-
1220 | Clin. Oral Impl. Res. 19, 2008 / 1219–1225
land) was applied, not exceeding the
height of the alveolar crest, into the extrac-
tion site without pressure and care was
taken to ensure that the collagen was
saturated with blood. The Bio-Oss Col-
s
lagen was cut to the appropriate dimen-
sion of the alveolar socket to enable
uncondensed placement with a dental for-
ceps (Aesculap AG & Co KG, Tuttlingen,
Germany). The patients were clinically
evaluated at days 1, 7, and 30 post-
operatively for the assessment of complica-
tions such as inflammation, mucosal
erythema, wound dehiscences, or loss of
graft material.
At the time of implant placement, 6
weeks post-operatively, a mucoperiosteal
flap was raised, the site of extraction was
clearly identified, and a core biopsy was
taken from the center of the extraction site
with a minimum depth of 8 mm. For this,
a trephine bur (+ 2 mm) (Straumann AG,
Basel, Switzerland) was used for the retrie-
val of the bone biopsy for histologic evalua-
tion, followed by dental implant placement
according to the manufacturer’s surgical
protocol. For implant placement, Camlog
RootLine implants (Camlog Biotechnolo-
gies, Wimsheim, Germany) or Straumann
ITI (Straumann AG, Basel, Switzerland)
implants were utilized. The mucoperios-
teal flaps were closed with interrupted
sutures (5-0 Monocryl, Ethicon, Hamburg,
Germany).
Histological evaluation
Before histological preparation, the tissue
samples were marked with blue ink
(Marker II/Superfrost, Precision Dynamics
Corp., San Fernando, CA, USA) at the
coronal side to identify the coronal and
apical region. Bone biopsy specimens
(length 8–10 mm) obtained from the
grafted areas were fixed in 4% formalin
for 2 days and then decalcified in 17%
nitric acid for 12 h (Callis 2002). After
routine tissue processing in a Pathcenter
(Thermo Shandon, Frankfurt a.M.,
Germany), tissues were embedded in par-
affin and 5 mm thick serial sections were
prepared and stained with Hematoxylin–
Eosin and Masson’s trichrome. The two
most central sections were obtained from
each specimen. The sections were line-
scanned using ScanScope T3 (Aperio Tech-
nologies Inc., Vista, USA) with a resolution
of 0.25 mm/Pixel and a  40 objective. For
c 2008 The Authors. Journal compilation


c 2008 Blackwell Munksgaard
the qualitative analysis of the remodeling
process, the stained preparations were
examined under a light microscope (Axio-
Phot I) at a magnification of up to  40.
Two regions of interest (ROI) were deter-
mined within each specimen, located
within the same proximity within the
specimens, in the apical and the coronal
portion. Each ROI was subdivided into four
regions in which the amount of new bone
and Bio-Oss particles as well as fibrous
tissue or bone marrow was calculated by
a single experienced observer who was
blinded to the clinical data using the digital
imaging system AXIO VISION 4.6 (Zeiss,
Jena, Germany). The intra-observer relia-
bility of the histomorphometric measure-
ments was based on recording the blindly
assessed data of each slide at three different
time points. A stage micrometer 25 þ 50/
10 mm (Zeiss, Göttingen, Germany) was
placed diagonally across the image for
calibration before histologic evaluation.
The relative volumes of provisional matrix
(connective tissue including mesenchymal
cells embedded in a fibrous matrix), viable
bone, and bone marrow (fibroadipose tis-
sue) were calculated in every section at
 40 magnification. Viable bone (new
bone) was defined as, the presence of
mineralized tissue matrix containing osteo-
cytes within lacunae. Descriptive histolo-
gic appearance of the total specimens was
assessed.
Statistics
The intraclass correlation coefficient (ICC)
was used to determine the intra-observer
reliability (SPSS 13.0, SPSS Inc., Chicago,
IL, USA). The histological and histomor-
phometrical data were descriptively ana-
lyzed. Comparative statistical analysis
between the apical and coronal region of
the specimens was performed using the
Wilcoxon signed-rank test with the soft-
ware version SPSS 13.0 (SPSS Inc.).
Results
For all patients (n ¼ 16) with 18 extraction
sites, the time of implant placement was
6 weeks after the grafting procedure. All
extraction sites, except one, healed un-
eventfully and showed no signs of inflam-
mation. In one patient, one surgical site
infection after the extraction and grafting
 Heberer et al . Bio-Oss Collagen augmented extraction sockets at 6 weeks

Table 1. Mean percentage of the tissues found in the histologic specimen with regard to nants in the biopsies obtained from these
localization regions, respectively. In three specimens of
Gender Localization Localization New Bio-Oss Fibrous
the maxilla, the connective tissue com-
within jaw (FDI) within specimen bone (%) particles (%) tissue (%)
prised fibroadipose tissue (Fig. 1); in these
M 26 Coronal 37 17 46
biopsies the amount of bone consisting of
Apical 53 3 44
F 16 Coronal 27 34 38 lamellar and woven bone (Fig. 2) showed
Apical 38 27 35 an average of 47%, varying between 42%
F 26 Coronal 26 3 70 and 49%, whereas the remaining Bio-Oss
Apical 28 8 63
particles were estimated at 6%, 18%, and
27 Coronal 15 3 82
Apical 23 4 73 24%. Four specimens predominantly
M 16 Coronal 20 18 62 showed provisional matrix ranging from
Apical 52 1 47 67% to 77%, accompanied by small
F 37 Coronal 24 11 56
amounts of newly formed bone ranging
Apical 45 14 53
M 16 Coronal 53 17 30 from 9 to 19% and Bio-Oss particles from
Apical 60 4 36 3 to 14% (Figs 3–5). The remaining biop-
F 16 Coronal 7 21 72 sies (n ¼ 10) displayed an average of 32%
Apical 50 10 40
M 16 Coronal 1 22 77
(14–56%) of new bone formation and 19%
Apical 1 10 89 (7–30%) of Bio-Oss remnants as well as
F 46 Coronal 41 10 57 50% (31–64%) of connective tissue (Fig.
Apical 26 16 58 6). There was a variation of the amount of
F 16 Coronal 16 17 66
Apical 36 12 68 tissues in the apical compared with the
M 16 Coronal 33 36 30 coronal portion of the biopsies. The apical
Apical 52 11 37 portion (Fig. 7) of the specimens consisted
M 16 Coronal 1 55 44
of a mean of 40% of new bone formation
Apical 43 1 72
F 15 Coronal 25 25 50 within a range of 19–63%. Up to 10% of
Apical 42 10 58 remnant Bio-Oss particles were found in
F 14 Coronal 34 7 59 this region, ranging from 3% to 32%, and
Apical 63 6 31
the connective tissue consisted of 50% of
F 13 Coronal 1 23 76
Apical 19 3 78 the specimen with a range of 19%–78%.
F 16 Coronal 29 28 43 The coronal region (Fig. 8) had a mean of
Apical 50 32 18 20% new bone formation (1–53%) and
20% of remaining Bio-Oss particles (1–
55%), with 60% of provisional matrix
procedure occurred and a re-entry was study was 0.889, with a 95% CI of (30–91%) visible. The rate of newly formed
performed to remove all material from the 0.721–0.974, indicating an excellent relia- bone was significantly different between
socket. This site was excluded from further bility of the measurements. All specimens the apical and the coronal region
analysis. The distribution of the sites were free of inflammatory cells, except (P ¼ 0.002). The amount of connective tis-
within the jaw is given in Table 1. Of the one; this specimen showed a focal lympho- sue and Bio-Oss remnants did not show a
17 sites, 12 were located in the molar cytic inflammatory infiltrate in the coronal significant difference between the apical
region of the maxilla and two in the molar region with bone formation adjacent to the and the coronal region within the speci-
region of the mandible. Two sites were area. The mean overall new bone forma- mens (P ¼ 0.4 and 0.1).
located in the premolar region and one in tion was 28% (range 9–57%) while the Early phase matrix with red blood cells
the anterior of the maxilla. The clinical amount of Bio-Oss remnants was 11% and neutrophil granulocytes embedded in a
appearance of the augmented area showed (range 3–31%). Connective tissues consist- network of fibrin were not visible in any of
soft tissue closure after 40 days in all cases. ing of collagen and fibroblasts were present the specimens; rather, a maturing provi-
Seventeen implants were placed in 16 in the grafted sites, comprising 54% (range sional matrix, if it was not yet bone, with
patients, respectively, in 17 sites. 31–77%) of tissue. Table 1 summarizes the oriented collagen fibers and a developing
After elevation of the mucoperiosteal histologic and morphometric evaluation. vasculature was present.
flap before implant placement, all extrac- The specimens collected from the molar
tion sites were clearly differentiable from region (n ¼ 12) showed a mean of 30% of
the original alveolar crest, allowing the newly formed bone (range 11–57%), 15% Discussion
retrieval of samples from the center of the (range 3–31%) of Bio-Oss particles, and
extraction socket. A total of 17 surgical 56% (range 33–77%) of connective tissue. The present histomorphometric investiga-
sites were quantitatively analyzed in 16 The Bio-Oss Collagen-grafted areas in the tion of Bio-Oss Collagen-filled extraction
patients. The ICC determined for the in- molar region (n ¼ 2) of the mandibula dis- sockets demonstrates marked de novo bone
tra-observer reliability trial of the histo- played 19% and 33% of newly formed formation after a healing period of 6 weeks.
morphometric technique used for this bone and 23% and 13% of Bio-Oss rem- The findings are consistent with early hu-

c 2008 The Authors. Journal compilation

c 2008 Blackwell Munksgaard 1221 | Clin. Oral Impl. Res. 19, 2008 / 1219–1225
Heberer et al . Bio-Oss Collagen augmented extraction sockets at 6 weeks
Fig. 1. Hematoxylin and Eosin Staining of a speci-
men with 440% of new bone formation and mature
bone marrow without hematopoetic elements (mag-
nification  2).
man studies showing equivalent time points
for the formation of bone in unfilled extrac-
tion sockets, although these studies did not
document the rate of bone formation as
they did not perform any histomorpho-
metric analysis (Boyne 1966; Amler 1969).
One experimental animal study of ex-
traction sockets in the mandible is avail-
able to give comparable data (Cardaropoli
et al. 2003). Studies in canine models have
shown a bone formation rate of up to 80%
after 30 days, which is equivalent to a
40-day healing period in humans as the
physiologic bone turn-over in dogs is 1.5 
that of humans (Cardaropoli et al. 2003;
Pearce et al. 2007). The average bone for-
mation rate found in the specimens ob-
tained within the current investigation is
lower than that found in the extraction
1222 | Clin. Oral Impl. Res. 19, 2008 / 1219–1225
Fig. 2. Bio-Oss particle (arrows) surrounded by mature lamellar bone and woven bone (Hematoxylin and
Eosin  40).
sockets in the mandible of dogs in the
previous studies mentioned. In 20% of
the defects evaluated, over 40% of mature
lamellar bone with the bone marrow was
seen, suggesting an advanced stage of
remodeling, whereas only two sockets
showed a bone formation rate o10% sur-
rounded by a mature provisional matrix
with the onset of bone formation. In the
study performed on dogs, two defect sites
were evaluated for each time point (1, 3, 7,
14, 30, 60, 90, 120, and 180 days) and the
specimens retrieved at 30 days showed a
high rate of bone formation; thus, these
might represent the extraction sites with a
high bone formation rate. The considerable
variation in bone formation within the
sockets evaluated cannot be elucidated
within this study and might be due to a
difference in individual factors influencing
bone physiology. Nicotine, known to be an
inhibitor of osteogenesis, can be excluded
as none of the patients smoked (Rosen
et al. 1996; Glowacki et al. 2008; Ziran
et al. 2007).
The biopsies obtained within this study
demonstrate a partial area of the healing
socket, allowing the assessment of the
healing process of the apical and coronal
region. Whether bone formation was also
initialized from the sides of the socket
cannot be determined from the data of
this study. The marginal entrance has
been described to show a hard tissue bridge
in studies with primary wound closure
(Cardaropoli et al. 2005). The specimens
analyzed showed low bone formation in
the most coronal region, in concordance
to the results found in other studies in
which surgical soft tissue closure was
not performed (Boyne 1966; Amler 1969;
Cardaropoli et al. 2003). This might be
c 2008 The Authors. Journal compilation


c 2008 Blackwell Munksgaard
attributed to the fact that the periosteum
could not contribute to the formation of
the provisional matrix. In this study, the
extraction sockets filled with the Bio-Oss
Collagen were left to heal openly and
wound closure was achieved by gradual
lateral epithelial overgrowth. Epithelial in-
vagination or proliferation into the extrac-
tion socket was described in unfilled
extraction sockets in humans with an in-
complete wound closure after 21 days and a
not yet complete fusion of the touching
adjacent epithelium after 32 days (Amler
1969). Experimental animal studies sug-
gest that the degree of invagination with
Bio-Oss Collagen-filled mandibular defects
seems to be decreased in comparison
with unfilled defects, suggesting a
placeholder or a scaffolding function for
the epithelialization by the heterologous
material (Cardaropoli et al. 2005). In this
study, after 40 days, wound closure was
seen in all patients with varying degrees of
thickness of the overlying mucosa. A quan-
tification of the thickness and the degree of
invagination of the epithelium cannot be
concluded from this study, as it was not
evaluated.
Therefore, the bone formation could
only be initiated from the apical or lateral
regions of the extraction socket. As evi-
denced in the study by Amler (1969), the
bone formation is seen first in the apical
region of the socket. The provisional ma-
trix was predominant in the coronal region
and Bio-Oss remnants embedded in it,
without signs of acute inflammation.
Bone formation in the human socket has
been described to take place as early as
9–10 days (Boyne 1966; Amler 1969) after
the extraction, with at least two-thirds of
the socket filled with trabeculae after 38
 Heberer et al . Bio-Oss Collagen augmented extraction sockets at 6 weeks

Fig. 4. Area (a) of Figure 3 in higher magnification (  20). Mature, oriented collagen fibers visible with
fibroblasts and beginning bone formation.

Fig. 3. Biopsy predominantly displaying provisional

matrix. Bio-Oss remnants are visible in the coronal
region (a) and islands of beginning bone formation
located throughout the central and apical portion (b)
Fig. 5. Area (b) of Figure 3 (magnification  20, Toluidine blue-stain) showing newly woven bone with
(Toluidine blue stain,  2).
osteoblasts and ongoing bone formation embedded in oriented collagen fibers.

days. The study by Amler (1969) does not
describe the surgical procedure or the loca-
tion of the extraction sites analyzed, but it
can be concluded that no primary tissue
closure was performed in their study as the
fusion of the epithelium is discussed with
regard to the observation period.
The successful formation of bone in
extraction sockets in rodents has been
correlated to the existence of cells from
the periodontal ligament (PDL), whereas
studies in canines and rodents have not
shown any correlation (Lin et al. 1994;
Cardaropoli et al. 2005). In this study, all
PDL was removed from the extraction
sockets as they were instrumented thor-
oughly after root removal, minimizing the
importance of the PDL for the formation of
bone in human extraction sockets.
Human extraction sockets filled with
bovine bone mineral investigated after a
healing period of 3 months show only
slightly higher rates of bone compared
with this study with a 6-week healing
period (Artzi et al. 2000). Existing animal
studies suggest that there might be a boost
of bone formation within the first few
weeks after extraction and that after a
prolonged period of missing mechanical
load there is onset of resorption. The pro-
cess of osseointegration is known to en-
hance bone density by stimulation of the
remodeling process, which has been de-
scribed as the regional acceleratory phe-
nomenon (RAP) (Frost 1994). Therefore,
it is necessary to acquire data of human
extraction sockets over various time points
to determine the optimal time point for the
placement of implants.
The degree of compression with which
the Bio-Oss Collagen was applied may be
crucial for the amount of Bio-Oss particles
within a defined space and therefore for the
rate of osteogenesis. There was no primary
wound closure after the uncompressed ap-
plication of the Bio-Oss Collagen, allowing
a possible displacement of the Bio-Oss
particles from the extraction socket and
accounting for the low amount of Bio-Oss
remnants found in this study. A higher
amount of Bio-Oss remnants were found
in defects filled with Bio-Oss Collagen in a
canine study with primary wound closure
(Cardaropoli et al. 2005) as well as in hu-
man extraction sockets filled with bovine
bone mineral (Artzi et al. 2000) after 3 and
9 months of healing, respectively.
The bone formation rate in the extraction
socket found after only 6 weeks is high
when compared with augmentation proce-
dures with bovine bone mineral in the sinus.
This might be due to the fact that there is a
more favourable blood supply as the sur-
rounding walls are in close proximity, re-
sulting in a smaller distance to the center
(Artzi et al. 2000; Yildirim et al. 2000).
This descriptive study provides data
showing that the bone formation in human
extraction sockets filled with Bio-Oss Col-
s
lagen displays a variation in their histolo-
gic appearance after a healing period of 6
weeks. This study demonstrates sockets
presenting bone formation rates similar to
those found after a 3-month healing period
as well as sites predominantly presenting
mature provisional matrix, which is
known to precede the formation of bone,
whereas no sites were found to show gran-

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c 2008 Blackwell Munksgaard 1223 | Clin. Oral Impl. Res. 19, 2008 / 1219–1225
Heberer et al . Bio-Oss Collagen augmented extraction sockets at 6 weeks
Fig. 6. This histologic picture resembles the appear-
ance of the majority of the specimens obtained from
extraction sockets after a 6-week healing period. It
shows bone formation in the apical region (b) and
mature provisional matrix surrounding Bio-Oss par-
ticles in the coronal region (a) with a minor focus of
lymphocytes at the surface of the specimen (Hema-
toxylin and Eosin,  2).
ulation tissue with inflammatory cell in-
filtrates. This study does not allow a con-
clusion regarding the osteoconductivity of
s
Bio-Oss , but it allows the assumption that
1224 | Clin. Oral Impl. Res. 19, 2008 / 1219–1225
Fig. 7. Area (a) of Figure 6 at  20 magnification. Bone formation around the Bio-Oss remnants next to an
islands of chronic inflammatory cells (lymphocytes) and provisional matrix with a slit-like blood vessel in the
upper left corner.
Fig. 8. Area (b) of Figure 6. Woven bone surrounding and streaking the barely visible Bio-Oss particle (arrows),
with provisional matrix in between (magnification  40, Hematoxylin and Eosin stain).
it does not hinder early bone formation. Acknowledgement: All materials
Bone formation in extraction sockets with used in this study were purchased
no primary wound closure is initiated from by the Charité University Hospital,
the apical region as this shows a signifi- and it is therefore free of any
cantly higher rate of new bone formation commercial interest. We would like
compared with the coronal region. Future to thank Mrs Kruse-Boitschenko
studies should focus on different time for her technical assistance and
points with sockets not augmented with a Dipl. Math. G. Siebert for her help
heterologous material. with statistics.
c 2008 The Authors. Journal compilation


c 2008 Blackwell Munksgaard

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