J Periodont Res 2016 © 2016 John Wiley & Sons A/S.

All rights reserved Published by John Wiley & Sons Ltd

JOURNAL OF PERIODONTAL RESEARCH

doi:10.1111/jre.12402
Review Article
S. A. Danesh-Sani1,
Histomorphometric results S. P. Engebretson1, M. N. Janal2
1
Department of Periodontology and Implant

of different grafting
Dentistry, New York University College of
Dentistry, New York, NY, USA and
2
Department of Epidemiology and Health
Promotion, New York University College of

materials and effect of Dentistry, New York, NY, USA

healing time on bone

maturation after sinus floor
augmentation: a systematic
review and meta-analysis
Danesh-Sani SA, Engebretson SP, Janal MN. Histomorphometric results of
different grafting materials and effect of healing time on bone maturation after
sinus floor augmentation: a systematic review and meta-analysis. J Periodont Res
2016; doi: 10.1111/jre.12402. © 2016 John Wiley & Sons A/S. Published by John
Wiley & Sons Ltd

The aim of this systematic review was to evaluate histomorphometric variables,

the amount of new bone (NB), residual graft (RG) particles and soft tissue
(ST), related to various grafting materials and assess the effect of graft healing
time on different histomorphometric outcomes. Studies that were published
before October 2015 were electronically and manually searched in three data-
bases. We included human studies that reported the amount of NB, RG and
ST in the biopsies taken from the grafted sinuses. Based on the applied graft-
ing materials, extracted data were categorized into different groups. Further-
more, extracted data were classified into three groups based on healing time:
(i) ≤ 4.5 mo; (ii) 4.5–9 mo; and (iii) ≥ 9–13.5 mo. The search provided 791
titles. Full text analysis was performed for 258 articles resulting in 136 studies
that met the inclusion criteria. Autogenous bone (AB) resulted in the highest
amount of NB and lowest amount of RG compared to other grafting materi-
als. Based on this meta-analysis, a significant difference was noticed in the
amount of NB formation in grafts with a healing time of > 4.5 mo when com- Seyed Amir Danesh-Sani, DDS, Department of
pared to the grafts with less healing time. However, when comparing biopsies Periodontology and Implant Dentistry, New
taken at 4.5–9 mo of healing (average = 6.22 mo) to the ones taken at ≥ York University College of Dentistry, 345 E
24th St, New York, NY 10010, USA
9–13.5 mo (average = 10.36 mo), no significant difference was noticed in the Tel: 2032152487
amount of NB formation of various grafts except allografts that resulted in a Fax: 2129927040
significantly higher percentage of NB at 9.5 mo of healing. Based on histomor- e-mail: sds521@nyu.edu

phometric analysis, AB results in the highest amount of NB formation in com-
parison to the other grafting materials. Bone substitute materials (allografts,
alloplastic materials and xenografts) seem to be good alternatives to autoge-
nous bone and can be considered as grafting materials to avoid disadvantages
Key words: biomaterials; bone regeneration;
guided bone regeneration; histomorphometry;
maxillary sinus floor augmentation; sinus floor
augmentation
Accepted for publication June 11, 2016
2 Danesh-Sani et al.
related to AB, including morbidity rate, limited availability and high volumet-
ric change. Combining AB with alloplastic materials and xenografts brings no
significant advantages regarding NB formation.
Alveolar bone resorption following
tooth extraction makes the implant
treatment planning more challenging
by compromising the bone volume
required to ensure the stability of
dental implants (1).
Maxillary sinus floor elevation is
one of the routine pre-prosthetic sur-
gical procedures performed for bone
augmentation in the posterior maxilla.
There are two main techniques for
this procedure: the transalveolar (cre-
stal) and the lateral window. How-
ever, several authors have published a
variety of modifications to these tech-
niques (2).
The transalveolar osteotome sinus
floor elevation procedure, first
described by Summers, includes green-
stick fracture of sinus floor, subse-
quent elevation of the membrane and
placement of grafting material and
implant (3). This technique is a well-
established surgical option for patients
with more than 5 mm residual bone
height (2). Various studies reported
high survival rate, ranging between
93.5% and 100%, for the implants
placed with this technique (4).
Lateral window sinus augmentation
was first described by Tatum and sub-
sequently, Boyne and James in 1980
(5,6). In this approach, entry into the
sinus was made through the lateral
wall to access the sinus. This technique
has been recognized as a successful
approach for the augmentation of the
severely resorbed ridges in the poste-
rior maxillary region, resulting in a
high survival rate of implants (2,5,6).
Different types of grafting materials
have been used for sinus augmenta-
tion including autograft, allograft,
xenograft, alloplastic materials and
growth factors. The grafting material
should be osteogenic, osteoinductive,
osteoconductive and volumetrically
stable to provide us with the optimal
outcome (7,8). Selecting the ideal
grafting material for the sinus aug-
mentation is a controversial subject.
Histomorphometric studies of
maxillary sinus augmentation showed
that the amount of newly formed
bone (NB), residual graft (RG) parti-
cles and soft tissue (ST) components
(i.e. bone marrow and/or connective
tissue) are not the same with different
grafting materials (9).
The amount of NB is an important
criteria to evaluate grafting materials,
as higher bone volume and bone den-
sity results in a higher bone–implant
contact and eventually higher survival
of implants (10). Histomorphometric
analysis is considered the gold stan-
dard method to estimate the amount of
NB, RG and ST in grafted sites (11).
The purpose of the current system-
atic review of the literature and meta-
analysis was to evaluate histomorpho-
metric variables (NB, RG, ST) related
to various grafting materials from a
large group of patients and assess the
effect of graft healing time on differ-
ent histomorphometric outcomes.
Material and methods
A detailed protocol was designed
according to guidelines of the
PRISMA (Preferred Reporting Items
for Systematic Review and Meta-ana-
lysis) statement and MOOSE (Meta-
analysis Of Observational Studies in
Epidemiology) (12,13). The clinical
questions were organized according to
the these guidelines.
Eligibility criteria
Inclusion criteria—For inclusion, the
studies were required to meet the fol-
lowing criteria:
1 Histomorphometric data needed to
be present after the sinus floor ele-
vation procedure.
2 Comparative and non-comparative
prospective studies.
3 Human clinical studies.
4 Studies conducted in five or more
patients that contained relevant his-
tomorphometric data.
Exclusion criteria—The exclusion crite-
ria were as follows:
1 Case reports.
2 Incomplete data (studies presenting
mean values without standard devi-
ation).
3 Studies that were not published as
full reports, such as conference
abstracts and letters to editors.
Information sources and search strat-
egy—An electronic search was con-
ducted on PubMed CENTRAL,
EMBASE and the Cochrane Library
up to and including 1 October 2015.
The following search terms were used:
((maxillary sinus) OR (sinus)) AND
((floor augmentation) OR (floor) OR
(augmentation) OR (grafting) OR
(floor elevation) OR (lift)) AND ((his-
tolog*) OR (morphometric) OR (mor-
phometry) OR (histomorphometric)
OR (biops*) OR (Histomorphome-
try)). We restricted our searches to
human studies published in English.
In addition, bibliographies of previous
reviews were also evaluated to be cer-
tain that no appropriate articles were
missed.
In addition, a hand search of rele-
vant studies published in dental jour-
nals between January 1990 and
October 2015 was performed. The
journals included were International
Journal of Oral and Maxillofacial
Implants, European Journal of Oral
Implantology, Clinical Oral Implants
Research, International Journal of
Oral and Maxillofacial Surgery, Bri-
tish Journal of Oral and Maxillofacial
Surgery, Journal of Oral and Maxillo-
facial Surgery, Oral Surgery Oral
Medicine Oral Pathology Oral Radiol-
ogy and Endodontology, International
Journal of Oral and Maxillofacial Sur-
gery Clinical Implant Dentistry and
Related Research, Dental Clinics of
North America, Journal of Prosthetic
Dentistry, Journal of Clinical Peri-
odontology, Journal of Oral

Implantology, Journal of Craniofacial
Surgery, Journal of Periodontology
and Journal of Craniomaxillofacial
Surgery.
Study selection and data collection—Eli-
gibility assessment was performed
through title and abstract analysis
and full text analysis. Two reviewers
(SD, SE) screened titles and abstracts
for possible inclusion in the review,
according to the inclusion criteria.
After selection, the full text papers
were read in detail by two reviewers
independently to check whether they
met all inclusion criteria. Reasons for
study exclusion were recorded.
Authors independently extracted data
using a pre-standardized data extrac-
tion form. The concordance between
reviewers was evaluated by means of
the Cohen’s Kappa coefficient. Dis-
agreements were resolved by discus-
sion and consensus.
Primary outcome—Percentage of NB
based on histomorphometric analysis
of the biopsies, as a percentage of the
whole field of view.
Secondary outcome—Percentage of RG
and ST components based on histo-
morphometric analysis of the biopsies,
as a percentage of the whole field of
view.
Risk of bias assessment—All compara-
tive and non-comparative prospective
studies, except for randomized con-
trolled trials, were assessed by the
Newcastle–Ottawa Scale indepen-
dently, by a blinded examiner, to
evaluate the quality of such studies
(14). Statistical heterogeneity was
assessed using the Q statistic and the
Ι2 statistic.
Publication bias was assessed quali-
tatively and quantitatively. Qualitative
analysis assessed the criteria for deter-
mining the quality of the research.
Publication bias was assessed quanti-
tatively using an effective sample-size
funnel plot and Egger’s test.
The random effects meta-analytical
model was used to evaluate the
pooled estimate of effect from various
studies with significant heterogeneity.
The authors of the included studies
Histomorphometric results of grafting materials
were contacted to provide missing
information as required.
Data analysis
Based on the applied grafting materi-
als, extracted data were categorized
into different groups including: auto-
genous bone (AB); AB + platelet-rich
plasma (PRP); Allograft (AG);
AG + growth factors/stem cells (GS);
alloplastic materials (AP), AP + GS,
AP + AB; Xenograft (XG); XG +
GS; and XG + AB. Furthermore,
extracted data were classified into
three groups based on healing time:
(i) ≤ 4.5 mo (average = 3.43 mo); (ii)
4.5–9 mo (average = 6.22 mo); and
(iii) ≥ 9–13.5 mo (average = 10.36 mo).
For each group (grafting material)
and subgroup (healing time), weighted
means and standard deviations were
obtained either directly from the
paper or calculated where possible.
For prospective comparative studies
involving more than one study group,
each study group was considered as a
single entry.
Results
A total of 758 articles were identified
after electronic searching of databases
while hand-searching relevant bibli-
ographies yielded 33 articles. After
excluding duplicate articles and 492
studies that did not satisfy the selec-
tion criteria, we reviewed the full texts
of 258 articles. After the final analysis
of the full text articles, 122 were
excluded, resulting in 136 articles
included for review. The article selec-
tion process is presented in Fig. 1.
Fig. 1. Flow diagram (PRISMA format) of the screening and selection process.
3
The kappa value for inter-examiner
agreement in selecting the included
studies was 0.87, showing high con-
cordance between the authors who
selected the articles.
If a meta-analysis for one group or
subgroup would be based on only one
or two investigations, the result would
almost repeat the outcomes of the sin-
gle study. Therefore, it is reasonable
to exclude groups with a limited num-
ber of studies. Table S1 summarizes
the characteristics of included studies.
In all studies, implants were placed
following a staged protocol, except 10
studies in which implants were placed
at the same time of a sinus augmenta-
tion procedure (15–25). In four stud-
ies, implants were placed either
simultaneously with or after healing
of sinus augmentation (15,17,18,24).
With regard to the use of a mem-
brane over the lateral window, four
studies used non-absorbable mem-
branes (26–29), 46 studies did not use
membrane for at least one of the
groups included in the study, 13 arti-
cles did not provide sufficient infor-
mation about the use of a membrane.
In all other studies, a resorbable
membrane was used (Table S1).
Table 1 presents histomorphometric
variables related to various grafting
materials at different healing times.
Comparison of histomorphometric
variables related to various grafting
materials was performed in each time
frame (Table 2). Owing to a limited
number of studies and excessive varia-
tions between findings, we did not
perform meta-analysis to compare
various histomorphometric variables
between different grafting materials at
4 Danesh-Sani et al.

≤ 4.5 mo of healing. Figures 2 and 3 NB in different time periods (Table 2).

Autogenous bone
show forest plots summarizing esti- Histomorphometric data about
mates of the effects of various grafting Table S2 presents studies using AB as amount of RG and ST were not
materials on the amount of NB and grafting material in 362 sinuses. Com- reported in most studies at various
RG, at 4.5–9 mo of healing, under pared to AB, each grafting material healing times. AB was mixed with PRP
the random effects model. results in a significantly less amount of in six studies. Owing to limited number
of studies at various time frames and
Table 1. Histomorphometric variables related to various grafting materials at different excessive variations between findings,
healing times we did not perform meta-analysis to
compare the amount of NB and other
No. sinuses NB (mean  SD) RG (mean  SD) ST (mean  SD)
histomorphometric variables between
Studies using autogenous bone mixture of AB + PRP to AB alone.
≤ 4.5 Healing time
27 19.31  26.5 18.39  3.18 68.74  24.27
4.5–9 Healing time Allograft
226 43.15  59.23 17.73  33.41 47.57  40.44 Table S2 presents studies using allo-
≥ 9 Healing time
graft bone as grafting material in 384
109 44.28  59.3 0.3  0.5 55.45  22.92
Studies using allograft sinuses. Various allograft materials
≤ 4.5 Healing time were used including freeze-dried bone
51 30.99  46.06 34.47  36.34 24.12  41.9 allograft, demineralized freeze-dried
4.5–9 Healing time bone allograft and fresh frozen bone.
218 25.02  55.36 25.32  34.36 50  63.75 AG was used in combination with
≥ 9 Healing time calcium sulfate, bovine bone (BB),
115 32.69  23.48 14.88  27.02 50.6  11.67
AB, PRP, two different concentra-
Studies using alloplastic materials
≤ 4.5 Healing time tions of bone morphogenic protein
25 17.59  28.55 27.73  60.85 46.89  8.13 (BMP) 2, and mesenchymal stem cells
4.5–9 Healing time in different studies (Table S2).
421 29.27  20.1 25.85  26.42 43.41  31.26
≥ 9 Healing time
117 32.45  45.75 28.72  20.41 42.7  9.94 Alloplastic bone substitutes
Studies using xenograft
Table S2 presents studies using AP
≤ 4.5 Healing time
184 19.38  29.43 35.22  40.15 41.11  31.81 bone substitutes as grafting material
4.5–9 Healing time in 563 sinuses. Various AP were used
604 26.82  26.54 29.33  46.74 44.86  21.26 including beta-tricalcium phosphate
≥ 9 Healing time (TCP), bioglass, calcium carbonate,
163 29.14  18.64 25.39  49.47 44.86  21.26 calcium sulfate, titanium granules,
Studies using xenograft + autogenous bone
synthetic hydroxyapatite (HA), coral-
≤ 4.5 Healing time
38 19.17  22.31 24.71  17.13 50.99  17.87
derived HA, mixture of HA and TCP.
4.5–9 Healing time Algae-derived HA was used in five
338 32.7  48.35 22.76  43.82 47.39  35.59 studies (24,28–31), in one of those
≥ 9 Healing time (28), HA was mixed with AB (10 : 1)
47 34.61  29.68 23.3  30.02 46.5  17.83 and applied with and without PRP in
Studies using alloplastic materials + autogenous bone the grafted sinuses. In the Bosshardt
≤ 4.5 Healing time
et al. (32) study, HA was combined
28 26.98  16.37 20.76  10.69 52.76
4.5–9 Healing time with a silica gel matrix and soaked in
98 28.33  22.35 23.5 + 29.33 48.32 + 15.93 blood while it was mixed with BMP-2
≥ 9 Healing time in one study (33). Mixture of HA and
61 34.28  24.91 17.56  36.08 49.19  20.59 TCP was used with different propor-
Studies using allograft + xenograft tions (Table S2). A 3 : 2 HA/TCP
4.5–9 Healing time mixture was used more routinely and
27 14.52  24.11 25.33  33.93 57.79  44.99
combined with fibrin sealant in one
≥ 9 Healing time
10 15.54  12.01 16.39  11.32 64.44  22.83 study (34). De Leonardis & Pecora
Studies using autogenous bone + PRP (35) used calcium sulfate with two dif-
≤ 4.5 Healing time ferent techniques for application of
28 22.74  36.77 19 76 the material. In one study, titanium
4.5–9 Healing time granules were used as a grafting mate-
16 21.03  25.76 – –
rial (21). Stavropoulos et al. (36) used
NB, new bone; RG, residual graft; ST, soft tissue; PRP, platelet-rich plasma. TCP in combination with rhGDF-5.
 Histomorphometric results of grafting materials 5

Table 2. Comparison of histomorphometric variables related to various grafting materials at different healing times

New bone Residual graft Soft tissue components

Healing time (mo) Healing time (mo) Healing time (mo)

Comparison groups ≤ 4.5 4.5–9 ≥ 9–13.5 ≤ 4.5 4.5–9 ≥ 9–13.5 ≤ 4.5 4.5–9 ≥ 9–13.5

AB-AG NR p < 0.001 p = 0.001 NR p = 0.13 NR NR NR NR

AB-AP NR p < 0.001 p < 0.001 NR p = 0.02 NR NR NR NR
AB-XG NR p < 0.001 p < 0.001 NR p = 0.04 NR NR NR NR
AG-AP NR p = 0.02 p = 0.13 NR p = 0.84 p < 0.001 NR p < 0.001 p < 0.001
AG-XG NR p = 0.36 p = 0.16 NR p = 0.27 p < 0.001 NR p < 0.001 p = 0.01
AP-XG NR p = 0.1 p = 0.75 NR p = 0.19 p = 0.34 NR p = 0.64 p = 0.5
HA-HA + TCP NR p = 0.29 NR NR p = 0.006 NR NR NR NR
AP-AB + AP NR p = 0.69 p = 0.06 NR p = 0.47 NR NR NR NR
XG-AB + XG NR p = 0.08 NR NR p = 0.03 NR NR NR NR

AB, autogenous bone; AG, allograft; AP, alloplast; XG, xenograft; HA, hydroxyapatite; NR, not reported; TCP, tricalcium phosphate;
XG, xenograft.

Fig. 2. Forest plots of the studies presenting the estimates of the effects of various grafting materials on the amount of new bone, after
4.5–9 mo of healing, under the random effects model. AB, autogenous bone; AG, allograft; AP, alloplast; HA, hydroxyapatite; TCP, tri-
calcium phosphate; XG, xenograft.
6 Danesh-Sani et al.
Fig. 3. Forest plots of the studies presenting the estimates of the effects of various grafting materials on the amount of residual graft parti-
cles, after 4.5–9 mo of healing, under the random effects model. AB, autogenous bone; AG, allograft; AP, alloplast; HA, hydroxyapatite;
TCP, tricalcium phosphate; XG, xenograft.
Xenografts
Table S2 presents studies using XG as
grafting material in 951 sinuses. Vari-
ous XG materials were used including
BB, porcine bone and equine bone.
In two studies, small particles and
large particles of BB were compared
(37,38). In four studies, a combination
of BB and synthetic cell-binding pep-
tide was used (26,39–41). BB was also
used in combination with osteoinduc-
tive materials including BMP-2,
BMP-7, PRP, stem cells, platelet-
derived growth factor (PDGF) and
PRF (Table S2). Only one study
mixed BB with venous blood (42).
Effect of adding autogenous bone to bone
substitute materials—AB was used in
combination with allograft bone in
two studies only (43,44).
AB was used in conjunction with
AP including TCP, HA, calcium sul-
fate, bioglass and polymer in 15 stud-
ies. Table S2 presents various ratios
of the mixtures between AB and AP.
AB was used in combination with
bovine and porcine bone with the
ratio of the mixture varied from 1 : 1
(AB/BB) to 1 : 10. Hallman et al.
(45) used a mixture of AB/BB (1 : 4)
and fibrin glue as grafting material.
The addition of AB to AP and XG
resulted in no significant change in
the amount of NB, compared to their
single use at 4.5–9 mo of healing
(pAP = 0.69; pXG = 0.08) (Table 2).
Effect of adding growth factors/stem cells
to grafting materials—Stem cells and
different growth factors used in com-
bination with grafting materials,
including BMP-2 (4.2 mg, 8.4 mg),
BMP-7, PRP, PRF, rhGDF-5,
PDGF, fibrin sealant and stem cells.
The effect of adding GS to other
grafting materials could not be evalu-
ated due to limited numbers of studies
and excessive variations between find-
ings.
Effect of healing time on the amount of
new bone formation—We evaluated the
effect of healing time on the amount
of NB by comparing three different
healing times of biopsies taking from
sinuses grafted with AB, AG, AP, XG,
AP + AB and XG + AB. Average
healing time periods for each grafting
material are summarized in Table S2.
Owing to the limited number of stud-
ies, other combinations of grafting
materials and healing time period of
≤ 4.5 were not included in comparisons
except for the studies using XG.

Biopsies taken from sinuses grafted
with XG + GS provide us data about
NB at ≤ 4.5 and 4.5–9 mo of healing
only (Table S2).
When comparing biopsies taken at
4.5–9 mo of healing (aver-
age = 6.22 mo) to the ones taken at
≥ 9–13.5 mo (average = 10.36 mo),
only AG resulted in a significantly
higher percentage of NB. Other graft-
ing materials showed a higher amount
of NB in biopsies taken at ≥ 9–
13.5 mo, but the difference was not
statistically significant (p = 0.06).
When comparing biopsies taken at
≤ 4.5 mo of healing to the ones taken
at 4.5–9 mo, XG resulted in a signifi-
cantly higher percentages of NB
(pXG = 0.001). When comparing biop-
sies taken at ≤ 4.5 mo of healing to
the ones taken at ≥ 9–13.5 mo, XG
resulted in a significantly higher
amount of NB (p < 0.001).
Discussion
The histomorphometric analysis has
the capability to assess precisely the
inter-phase between the NB and RG
particles (38). The present systematic
review investigated histomorphometric
data (NB, RG and ST) in biopsies
taken at different time periods from
sinuses grafted with various grafting
materials to assess graft maturation at
different time frames.
In the present systematic review,
AB resulted in the highest percentage
of NB in comparison to other grafting
materials. AB has been considered as
“gold standard” of grafting materials
as it is osteogenic, osteoinductive
and osteoconductive (2). However,
increased morbidity rate and limited
availability are the main disadvan-
tages related to AB as a grafting
material (2,9).
The results of previous reviews sub-
stantiate the finding that implant sur-
vival with bone substitute materials
(BSM) are equal or better than that
achieved with AB (46). The lower sur-
vival rate of implants placed into
sinuses grafted with AB may be
attributed to the high resorption rate
of AB (9,46). Depending on the origin
of the AB, subsequent bone resorp-
tion may vary. In a recent systematic
Histomorphometric results of grafting materials
review, Shanbhag et al. (47) assessed
the volumetric changes of grafted
sinuses over time and found that the
highest amount of volume reduction
is associated with AB, up to 45%, fol-
lowed by allografts and other grafting
materials. These findings are in agree-
ment with the outcomes of the current
review that showed AB resulted in the
lowest amount of residual bone in
comparison to other BSMs. AG
resulted in the lowest percentage of
residual bone in comparison to AP
and XG, while AP and XG showed
no significant difference in the amount
of residual bone (Table 2). It is
important to know that a reduction
in the graft volume should be
expected with application of any
grafting materials, particularly in the
earlier phase of graft maturation (47).
Based on our findings, it is recom-
mended to over-build the grafted site
when using AB or AG as grafting
materials to compensate for the
shrinkage related to these materials.
Minimum graft volumetric change
was found related to XG and AP
(47). Even though some studies found
that multinucleated giant osteoclasts-
like cells surround BB particles during
early phases of healing, but long-term
maintenance of the xenogeneic bone
RG was shown histologically at
11 years by Mordenfeld et al. and at
9 years by Traini et al. (48–50). How-
ever, sufficient long-term data are
needed to verify whether volumetric
changes are limited to the initial post-
operative period (6 mo–2 years) or
not (47).
One interesting finding in the cur-
rent study is the amount of vital bone
in the grafted sinuses that ranges
between 19% and 44%. This shows
that more than 50% of the grafted
site is either RG particles or ST
rather than vital bone. In addition,
based on a previous systematic review
that showed 95% survival rate for
implants placed into grafted sinuses
with bone substitutes, we can indi-
rectly conclude that with an average
29% vital bone and 25% RG, 95%
survival rate of implants can be
expected (46). However, it is not pos-
sible to design a study that shows
minimum amount of vital bone
7
required for high implant survival and
evaluates implant survival rate based
on the histomorphometric data. The
previous conclusion on the amount of
vital bone and implant survival rate is
only based on comparison of results
from evidence-based reviews and it is
possible to obtain the same or higher
implant survival rate with even
< 29% vital bone.
Comparing AG, AP and XG, no
significant difference was noticed in
the amount of NB in various healing
time periods except AP resulting in a
small but significantly higher NB
compared to AG at 4.5–9 mo of heal-
ing (Table 2).
It has been postulated that the ST
related to b-TCP particles consists of
osteoblasts and osteoclasts, which
may have possible beneficial effect for
maturation and healing of the grafted
area (51). Therefore the b-TCP con-
stituent of HA + TCP mixture may
increase the osteogenic potential of
this material by maintaining bone
remodeling cells in place (52). Owing
to the limited number of studies and
excessive heterogeneity, we could not
compare HA to TCP biopsies. Inter-
estingly, addition of TCP to HA
resulted in a slight decrease in the
amount of NB compared to HA
alone, at 4.5–9 mo of healing, but not
to a significant level. Furthermore,
higher resorption of grafting materials
in sites treated with the HA + TCP
mixture may be explained by the
capability of TCP to recruit osteo-
clasts to the site (Table 2) (53).
It is noteworthy to mention that
various types of allograft showed dif-
ferent histologic and clinical behavior
that is influenced by their processing
and composition. Both demineralized
freeze-dried bone allograft (FDBA)
and mineralized FDBA have been
used for sinus augmentation and
showed their ability to function as an
osteoconductive scaffold for NB for-
mation (27,54). Unlike mineralized
FDBA, some studies found osteoin-
ductive potential related to demineral-
ized FDBA, as a direct effect of
BMPs (55,56). Clinical properties of
allografts are also affected by their
processing and composition. In con-
trast to mineralized FDBA,
8 Danesh-Sani et al.
demineralized allografts showed
higher resorption rate and lower volu-
metric stability (27,57). Unfortu-
nately, due to small number of studies
and excessive variations between their
findings, we could not analyze various
allograft types separately.
Some studies found incomplete
mineralization of allogeneic–xeno-
geneic graft after 6 mo of healing,
recommending to increase the healing
time up to 12 mo to improve the
quality of the grafted bone (58). Some
authors hypothesized that as BSMs
are osteoconductive rather than osteo-
genic and osteoinductive, a longer
healing time is needed to obtain a
similar amount of NB as that found
with AB (59). In the present review,
all grafting materials showed a higher
amount of NB in biopsies taken at
≥ 9–13.5 mo (average = 10.36 mo)
compared to the ones taken at 4.5–
9 mo (average = 6.22 mo), but the
difference was statistically significant
in AG only. However, we found sig-
nificant difference in the amount of
NB when comparing biopsies taken at
≤ 4.5 mo of healing (aver-
age = 3.43 mo) to the ones taken at
4.5–9 mo or longer healing time.
These findings reveal that with an
increasing healing time, the amount
of NB formation would increase and
the grafted sinuses healed for an aver-
age time of 6 mo or longer showed a
significantly higher amount of bone
formation in comparison to the ones
that healed for an average time of
3.4 mo. However, the main dilemma
for clinicians is whether if they should
choose the 6 mo healing period or
wait for a longer healing time when
doing sinus augmentation. Based on
our findings, there was no significant
difference in the amount of bone for-
mation between the earlier healing
time (average = 6.22 mo) and longer
healing time (average = 10.36 mo), if
the sinus is grafted with AB, AP or
XG. Therefore, clinicians would not
achieve a significantly higher amount
of vital bone by waiting up to 10 mo
if the sinus is grafted with AB, AP or
XG. However, it is recommended to
increase the healing period if allograft
is used as a grafting material as it is
the only biomaterial that showed a
significantly higher amount of bone
formation after longer healing period.
When comparing the histomorphome-
tric data related to allografts at differ-
ent healing periods (6.1 vs. 9.7 mo of
healing), we noticed approximately
10% decrease in the amount of RG
and 7.5% increase in the amount of
NB after 9.7 mo of healing, which
shows a higher remodeling capacity of
allografts during this time in compar-
ison to other bone substitutes.
Regardless of graft type, the bucco-
palatal distance of the sinus cavity
influences the mineralization and heal-
ing of grafting materials (44,60). The
amount of vital bone formation is
inversely proportional to bucco-pala-
tal sinus width (60). In addition, wide
and large maxillary sinus heals and
mineralizes slower than narrow and
small sinus (44).
Several studies evaluated the clini-
cal efficacy of AB + BB mixture as a
grafting material in maxillary sinus
floor augmentation (61). The efficacy
of BSMs as sinus grafting materials
has been proved by the histologic
findings that show a pattern called
“bone bridging”; meaning that RG
particles are surrounded and being
interconnected by bridges of NB (2).
The rational of using composite graft,
combination of AB and BSM, is to
take advantage of the properties of
both combined materials. The BSMs
can provide us more stable graft with
lower resorption rate and volumetric
changes, while AB is beneficial to the
graft as it provides a source of osteo-
progenitor cells, and inorganic and
organic matrices for osteoconduction
and osteoinduction (62). AB revascu-
larizes in about 4 mo of healing,
which may shorten the healing time
required for the vascularization and
subsequent maturation of newly
formed bone tissue of combined AB
and BSM (61,63). In addition, com-
bining AB and BSM avoids using
extraoral sources of AB, which usu-
ally required general anesthesia,
increasing morbidity, time and cost of
the procedure (64).
While other investigations claimed
that along with adding AB, the
amount of NB would consequently
improve, this postulation, however,
could not be supported by this meta-
analysis and the effect of adding AB
to AP or XG appeared to be not sig-
nificant. However, it is important to
consider factors that may affect the
histomorphometric variables of the
AB + BSM mixture, including: (i)
source of AB: histomorphometric
variables of grafted sites with AB sig-
nificantly affected by the nature of
donor site (65). Crespi et al. (66)
found a significantly higher amount
of vital bone in sinuses grafted with
calvarial vs. iliac bone. When evaluat-
ing intraoral donor sites of AB, chin
bone results in less vital bone in com-
parison to the retromolar region (65).
(ii) Various proportions of BB/AB
may affect the histomorphometric
variables of grafted sites however,
there are limited comparative studies
published, to our knowledge.
The addition of AB to XG and AP
resulted in a decrease in the amount
of residual bone compared to its sin-
gle use after 4.5–9 mo of healing,
which can be explained by the follow-
ing reasons: (i) it appeared that AB
has the highest resorption rate due to
its capability of activating the cascade
of osteoclasts recruitment, and this
could affect the resorption rate of
other grafting materials surrounded
by AB (65), and (ii) for the same rea-
son, the AB part of combination
graft, AB + BSM, resulted in a mini-
mum amount of residual bone after
healing time leading to lesser amount
of combination graft residual bone
graft.
Biomimetic and stem cell technolo-
gies have been introduced to the field
of implant dentistry in the past dec-
ade with a goal of achieving the same
or better results to that of AB and
avoiding complications related to the
using of AB (2).
BMP is the most powerful osteoin-
ductive growth factor that can accel-
erate differentiation of the
osteoprogenitor cells to osteogenic
cells, resulting in faster bone forma-
tion (67,68). BMP-2 has been exten-
sively used in spinal fusion surgery
before its introduction to the dental
market. Boyne et al. and Triplett
et al. (67,68), evaluated efficacy of
BMP-2 by conducting various

randomized, clinical trials, and found
implant survival rates similar to that
of AB.
However, it is important to con-
sider drawbacks related to the appli-
cation of BMP, including shrinkage
of the graft, high cost and immature
bone quality and poor bone density
at early time intervals (2). Different
studies try to combine BMP-2 with
BSMs to resolve issues with poor
density and graft shrinkage (69,70).
However, Tarnow et al. (69) found
higher resorption of allografts when
combined by BMP-2. In addition,
Kao et al. (70) showed negative effect
of adding BMP-2 to BB on bone for-
mation and found that sinuses
grafted with BMP-2 + BB resulted in
less NB formation than those with
BB alone.
PRP can be obtained by the cen-
trifugation of freshly drawn autoge-
nous venous blood and is considered
a rich source of growth factors,
including transforming growth factor
b, platelet-derived angiogenesis factor,
PDGF, insulin-like growth factors,
and extracellular matrix components
and vascular endothelial growth fac-
tor (71). The major growth factor of
PRP is PDGFßß, which also has been
produced as recombinant human
PDGFßß. While some studies showed
positive effects of using PRP on ST
and hard tissue healing, three evi-
dence-based reviews have not sup-
ported claims for improved histologic
outcomes in maxillary sinus augmen-
tation (71–73).
Application of biomimetic and stem
cell technologies may reduce the time
necessary for graft maturation, as
shown in previous studies, but it is
unlikely to result in any dramatic
change on the amount of NB forma-
tion (74,75). In the current review, the
effect of adding GS to other grafting
materials could not be evaluated due
to limited numbers of studies and
excessive variations between findings.
In addition, different concentrations
of growth factors affect the quality of
the bone and emphasize the need for
further clinical studies to evaluate the
effect growth factors on histomorpho-
metric variables of grafting materials
(76).
Histomorphometric results of grafting materials
A number of studies reported a
great potential for bone formation in
the sinus without using bone grafting
materials (77,78). The sinus cavity
acts as a contained defect surrounded
by the bony walls nourishing the graft
materials that helps bone healing
takes place with greater ease; unless
otherwise affected by complications
such as perforation of Schneiderian
membrane and sinusitis (77,79). The
excluded compartment, developed by
the membrane elevation and main-
tained by implants or synthetic scaf-
folds, contained blood clot that
eventually allowed bone formation
according to the principle of guided
tissue regeneration (80).
While many clinicians using barrier
membrane over the lateral window
osteotomy, fewer studies have com-
pared histomorphometric findings
achieved with and without barrier
membranes (81–83). Tarnow et al.
(81) showed that using a barrier mem-
brane resulted in a significantly higher
amount of NB formation compared
to the sites without membrane. How-
ever, a recent systematic review
showed that the application of a
membrane did not substantially affect
the amount of bone formation (84). It
is important to consider different con-
founding factors that may affect the
amount of bone formation in sinus
including lateral window osteotomy
size, width of the sinus and, last but
not least, the residual alveolar bone
height (84,85).
The present systematic review has
several limitations: (i) histologic simi-
larities between NB and RG particles
in sites grafted with AB, compromised
the accurate calculation of the per-
centage of NB; (ii) most of included
studies did not provide information
regarding residual ridge height
between sinus floor and the alveolar
ridge. Residual ridge acts as a nour-
ishment wall to the grafted sinus that
affects the amount of NB formation.
Therefore, thick residual bone, with
more cancellous bone, has more
potential of bone regeneration in
comparison to thin cortical layer of
atrophic bone; (iii) the number of
studies included was limited to com-
pare various histomorphometric
9
variables between different grafting
materials at ≤ 4.5 mo of healing; and
(iv) another possible confounding fac-
tor, which may affect the histomor-
phometric variables related to the
grafting materials, was the method of
taking biopsy cores that can be har-
vested from the lateral wall or alveo-
lar crest. In addition, size of the core
(diameter and height) and area of the
biopsy (apical, central or crestal)
could be influential on the amount of
NB formation.
Conclusions
The following conclusions can be
drawn from this systematic review.
Histomorphometric variables (NB,
RG, ST) of various grafting materials
are important to consider before their
application in sinus augmentation
procedures as they may define the
quality, density and volumetric stabil-
ity of the future graft. AB resulted in
the highest amount of NB and lowest
amount of RG compared to other
grafting materials. Except for AP that
showed higher amount of NB than
AG after 4.5–9 mo, none of the
BSMs showed a significant superiority
regarding NB. Except for AG that
showed a lower amount of residual
bone than other BSMs after ≥ 9–
13.5 mo, none of other BSMs showed
a significant difference in amount of
RG.
Combining AB with AP and XG
brings no significant advantages
regarding NB formation, rejecting
hypothesis that the AB may have a
role in favoring NB formation after
adding to BSMs.
Based on this meta-analysis, a sig-
nificant difference was noticed in the
amount of NB formation in grafts
with healing time of > 4.5 mo when
compared to the grafts with less time
during healing. However, when com-
paring biopsies taken after 4.5–9 mo
of healing (average = 6.22 mo) to the
ones taken after ≥ 9–13.5 mo (aver-
age = 10.36 mo), no significant differ-
ence was noticed in the amount of
NB formation of various grafts except
AG that resulted in a significantly
higher percentage of NB after ≥ 9–
13.5 mo of healing. Biomimetic
10 Danesh-Sani et al.
enhancement factors and stem cells
may upregulate bone formation and
reduce the healing time. In the current
review, the effect of adding GS to
other grafting materials could not be
evaluated due to limited numbers of
studies and excessive variations
between findings. This is not to say
that the application of GS does not
lead to satisfactory outcomes. It may
be said, however, that they have less
evidence supporting their use at the
present time.
To achieve a better understanding
of histomorphometric variables
related to various grafting materials,
more randomized, controlled clinical
trials with sufficient statistical power
controlling different confounding fac-
tors, are required.
Acknowledgements
No external funding was available for
this study. The authors claim to have
no financial interest, either directly or
indirectly, in the products or informa-
tion listed in the paper.
Conflict of interest
Authors declare that they have no
conflict of interest.
Supporting Information
Additional Supporting Information
may be found in the online version of
this article:
Table S1 Characteristics of included
studies.
Table S2 Histomorphometric vari-
ables related to various grafting mate-
rials at different healing times.
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