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Molecular, Cellular and Pharmaceutical Aspects of Bone Grafting Materials and

Membranes During Maxillary Sinus-lift Procedures. Part 1: A General Overview

Article  in  Current Pharmaceutical Biotechnology · December 2016

DOI: 10.2174/1389201017666161221155237

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 Send Orders for Reprints to reprints@benthamscience.ae 19
Current Pharmaceutical Biotechnology, 2017, 18, 19-32

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ISSN: 1389-2010 Volume 17, Number 14
eISSN: 1873-4316

Current
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Molecular, Cellular and Pharmaceutical Aspects of Bone Grafting Materi- Biotechnology

als and Membranes During Maxillary Sinus-lift Procedures. Part 1: A Impact

Factor:
1.802

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BENTHAM
SCIENCE

Giovanna Iezzi1, Adriano Piattelli1,*, Alessandra Giuliani2, Carlo Mangano3, Licia Manzon4,
Marco Degidi5, Flavia Iaculli1, Antonio Scarano6, Antonella Filippone7 and Vittoria Perrotti1

1
Department of Medical, Oral and Biotechnological Sciences, Dental School, University G. D’Annunzio of Chieti-
Pescara, Chieti, Italy; 2Department of Odontostomatologic and Specialized Clinical Sciences – Section of Biochemistry,
Biology and Physics, Polytechnic University of Marche, Ancona, Italy; 3Private Practice, Gravedona (CO), Italy;

y
4
Sapienza University of Rome, Rome, Italy; 5Private Practice, Bologna, Italy; 6Center for Research on Ageing and

nl
Translational Medicine, CeSI-MeT, University of Chieti-Pescara, Chieti, Italy; 7Department of Neurosciences and Im-
aging, Section of Radiological Sciences, University G. D’Annunzio of Chieti-Pescara, Chieti, Italy

O
Abstract: Sinus augmentation procedure has been demonstrated to be a highly predictable treatment in
posterior maxilla atrophy. All the surgical interventions in the maxillary region require deep knowledge

n
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of anatomy and possible anatomical variations. In this article, pre-operative and post- operative assess-
ments of sinus cavity as well as novel approaches to deepen our knowledge of the behavior of bone sub-

tio
stitute materials are described. The awareness of the patient’s morphologic conditions enables exact
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planning of invasive surgery and aids to avoid complications. Pre- operative radiologic evaluation of the
region before sinus lift is advisable both for a planning of the sinus augmentation and for selection and

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ARTICLE HISTORY alignment of the optimum placement of implants. On the orthopantomography it is possible to measure
the vertical dimension of graft, but not the volume and 3D changes. Cone-beam computed tomography
al

Received: February 06, 2016

Revised: March 26, 2016
Accepted: November 25, 2016
(CBCT) has become the “gold standard” to plan a comprehensive implant treatment and to achieve a
tri
post-operative assessment. A computer-aided design/computer-aided manufacturing (CAD/CAM) tech-
on

DOI: nique is proposed to produce custom-made block grafts for sinus lift procedure, and a customized cut-
Current Cardiology Reviews

10.2174/13892010176661612211552
37 ting guide to accurately place the lateral wall and ease membrane elevation. This procedure allows to
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reduce intervention time, to precisely adapt the scaffold, to reduce risk of complications and to improve
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operation quality. Recently, a novel approach has been used to deepen our knowledge of the behavior of
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BSBs: by means of synchrotron micro-tomography (SCT). It is a 3-D analyzing method, suitable to ex-
amine the dynamic and spatial arrangement of regenerative phenomena in complex anatomical struc-
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tures such as bone, where tissues with several morphologies (alveolar process, unmineralized extracellu-
lar matrix, regenerated vessels, etc.) compete to achieve the final goal of bone regeneration.
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Keywords: Bone, grafting materials, radiography, sinus cavity.

1. INTRODUCTION different bone substitute materials prior or simultaneously

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with implant placement [2]. All the surgical interventions in

Crestal bone resorption and pneumatization of the maxil-
the maxillary region need deep knowledge of anatomy and
lary sinus are often observable after loss of upper posterior
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possible anatomical variations in order to avoid pitfalls as

teeth. The edentulous posterior maxilla in these cases, usu-
ally shows an insufficient bone quantity for the replacement
of missing teeth with dental implants. One of the common
methods to achieve adequate bone volume tissue to allow a
successful implant placement is sinus lift [1]. Clinical suc-
cess has been obtained by grafting the maxillary sinus with
*Address correspondence to this author at the Department of Medical, Oral
and Biotechnological Sciences, Dental School, University G. D’Annunzio
of Chieti-Pescara, Via dei vestini 31, 66100 Chieti, Italy; Tel: 0039
08713554083; Fax: 00 08713554076; E-mail: apiattelli@unich.it
well as an accurate preoperative diagnosis.
1.1. Sinus Cavity: Anatomical and Radiographical
Insights
The maxillary sinus is a wide pyramidal cavity with thin
walls. In partially edentulous patients, teeth loss produces
remodeling and resorption of the adjacent alveolar bone,
often lead to the atrophy of the ridge. Atrophy-related re-
sorption of the alveolar process results in a vertical bone
loss, while progressive sinus pneumatization brings to an

1873-4316/17 $58.00+.00 © 2017 Bentham Science Publishers

20 Current Pharmaceutical Biotechnology, 2017, Vol. 18, No. 1
excavation of the alveolar process from the cranial aspect
[3]. Dental implants supply prosthetic anchorage, but to
reach this goal, sufficient bone quality and quantity in the
implantation site are needed. To overcome the problem cor-
related to the alveolar bone resorption of the maxillary eden-
tulous region a sinus lift procedure can be applied [1, 4, 5].
Sinus augmentation procedure has been demonstrated to
be a highly predictable treatment in posterior maxilla atrophy
[6-19]. The sinus cavity is an important model of osteogenic
chamber for new bone formation [20].
The awareness of the patient’s morphologic conditions
enables precise planning of invasive surgery and aids to
avoid complications [21-26]. The presence of anatomical
variations within the maxillary sinus, such as septa, seems to
enhance the risk of sinus elevation procedure [3, 27-29].
Therefore, radiologic evaluation of the region prior a sinus
augmentation procedure is advisable both to permit for plan-
ning of the elevation and for selection and alignment of the
ideal placement of implant [30].
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1.2. Diagnostic Tools
Conventional imaging compresses 3-dimensional (3D)
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anatomy into a 2-dimensional (2D) image, greatly limiting
diagnostic performance [31, 32]. As a matter of fact, it pro-
vides important characteristics of the tooth and its surround-
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ing tissues in the mesio-distal (proximal) plan only, whereas
similar features presenting in the bucco-lingual plane (i.e. the
third dimension) may not be fully recognized [33]. Diagnos-
al
tic information in the missing “third dimension” is of par-
ticular relevance in surgical planning [34, 35], where the
on
thickness of the cortical plate and its relationship to key ad-
jacent anatomical structures, such as the maxillary sinus,
should be understood [36]. Panoramic radiographs allow an
assessment of the vertical dimension of graft, but do not
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supply information concerning volume and 3D changes [37].
Maestre-Ferrin et al. [38] compared the results of pano-
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ramic radiographs and computed tomography (CT) scans to
define the prevalence, location and size of sinus septa. The
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authors showed that panoramic radiographs led to an errone-
ous diagnosis in 46.8% of the cases and concluded that,
whenever a maxillary sinus lift is planned, a thorough study
of the affected sinus should be made using CT. Multidetector
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CT (MDCT) is a very usual imaging technique, which allows
the capture of information through a spiral movement of the
radiation source and the detectors around the region of inter-
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est [39]. As a result of spiral, volumetric acquisition, MDCT
units have very short examination times and isotropic images
can be reformatted in any plane [40]. On the other hand,
MDCT imparts relatively high radiation dose to the patients
[40].
A further development and improvement of CT equip-
ment have inspired researchers and clinicians to use it as
low-dose CT: this is the cone-beam CT (CBCT) [39]. CBCT
was introduced in the last decade for maxillofacial imaging
and firstly reported in the literature by Mozzo et al. [41].
Nowadays, CBCT imaging is a widely-used imaging method
in dentomaxillofacial radiology, allowing accurate 3D imag-
ing of hard tissue structures [36]. CBCT scanners use a
Iezzi et al.
tightly collimated narrow cone-shaped X-ray beam, instead
of a fan-shaped X-ray beam used in MDCT [42]. It implies
that images data are recorded in a single gantry rotation
(180°- 360°), where the X-ray source and 2D detectors move
synchronously around the patient’s head [36]. The height and
diameter of the field of view (FOV) vary from small to large
field examination [36, 42, 43].
The radiation dose from CBCT is generally lower than in
MDCT, but generally higher than in conventional dental
radiography. The dose is dependent on the equipment type
and exposure settings, especially the FOV, exposure time (s),
tube current (mA) and the energy/potential (kV) [36]. There-
fore, the personnel using a CBCT device must have appro-
priate knowledge of and training in patient radiation dose
related to the specific device they are using, the specific pa-
y
tient they are studying and the specific examination they
performing [36]. This emphasizes the importance of optimiz-
nl
ing and standardizing imaging parameters in CBCT. Beyond
a lower radiation dose, lower costs and easier availability,
CBCT shows a higher contrast resolution when comparing
with MDCT. As a matter of fact, CBCT has excellent high-
contrast resolution as a result of small size (> than 0.076
n
mm) and geometry of voxel [36, 42]. However, CBCT has
two major disadvantages with respect to MDCT. The first is
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the poor soft tissue resolution: it means that CBCT can be
used for sinus imaging when soft tissue contrast resolution is
not mandatory. If soft tissue evaluation is needed MDCT or
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magnetic resonance imaging (MRI) is indicated [36]. The
second is a fair accurate conversion of density values in
Hounsfield units (HU) [36]. It has been demonstrated that
large errors can be seen when using the grey values in a
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quantitative way [36, 44]. This implies that, although it could
be possible to obtain pseudo-Hounsfield units from certain
is
CBCT, alternative methods of assessing bone tissue should
be further investigated [44]. According to the previous con-
siderations, CBCT has become the “gold standard” to plan a
comprehensive implant treatment and to achieve a post-
operative assessment. Nevertheless, we have to keep in mind
the patient’s history, clinical information and previous im-
ages have to be available before CBCT imaging. Moreover,
conventional radiographies, such as including panoramic and
intraoral radiographies are still the basic imaging methods
and CBCT should be used in more demanding cases, such as
sinus floor augmentation [36].
1.3. Preoperative Assessment
When performing invasive technique in the maxilla, such
as sinus lift and bone grafting, some complications have
been described [21-26]. In these cases, an accurate diagnosis
is needed prior to dental implant treatment planning.
Dental panoramic radiographs allow a complete observa-
tion of the maxillary sinus as well as the evaluation of the
relationship between the level of the sinus floor and alveolar
bone [45]. Unfortunately, their 2D nature limit the 3D visu-
alization of the anatomical structures. Moreover, soft tissue
of the maxillary sinus cannot be adequately observed on
panoramic radiographs [45]. CBCT can correctly visualize
teeth and adjacent anatomical structures with hard tissue
high resolution, in spite of the lower radiation dose levels
than MDCT [45].
Molecular, Cellular and Pharmaceutical Aspects of Bone Grafting Materials
It is of crucial importance to pay attention to imaging of
the maxillary sinus. In fact, symptoms commonly do not
appear at the early stages of some lesions in the maxillary
sinus. Therefore, the diagnosis is usually made casually
when images of the area are obtained for other purposes [45].
Shiki et al. [40] showed that subjects expecting to undergo
implant-supported rehabilitations of the maxilla had a two
times greater prevalence of maxillary sinusitis than subjects
with a chief compliant other than implant planning [45].
However, non-significant differences were found in area
occupying lesions, discontinuity of the sinus floor, fluid re-
tention, bone thickening, antroliths, sinus opacification and
foreign bodies between the two groups [45].
Orhan et al. [46] showed that using CBCT the prevalence
of maxillary sinus segments with septa was 58%. The loca-
tion of septa assessed in their study showed a higher preva-
lence (69.1%) in the middle region than in the anterior and
posterior ones [46]. The mean height of septa was 5.5 ± 2.64
mm. When comparing CBCT and panoramic radiographs,
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the detection rate of internally located septa, pneumatization
and anteriorly located space occupying lesions was signifi-
cantly reduced on panoramic radiographs. Moreover, a sig-
detection rate on panoramic radiographs and septa height
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nificant association was observed between the change in the
[45]. With decreasing height of septa, the detection rate on
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panoramic radiographs was gradually reduced. The threshold
for clear observation of the septa by height was about 5 mm
[45]. Similarly, a significant association was demonstrated
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between the change in the detection rate on panoramic radio-
graphy and the length of the major axis of space occupying
lesions (including maxillary sinusitis, retention cysts, radicu-
on
lar cysts). Particularly, if the height of the major axis of
space occupying lesions was < 4 mm, the detection rate on
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panoramic radiographs was significantly lower [45]. A
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significant association was observed between the change in
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the detection rate on panoramic radiographs and the width of
mucosal thickening in the maxillary sinus. If the width of
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mucosal thickening was < 3 mm, the detection rate on pano-
ramic radiographs was significantly reduced, whereas with
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increased width over 10 mm the detection rate on panoramic
radiographs increased gradually [45]. It has been suggested
that the threshold value to define a pathological sinus mem-
brane was 2 mm or above [47].
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It is useful to remind that above the maxillary sinus septa
and maxillary sinus disease, artery within the side wall of the
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maxillary sinus is a further anatomical border that can repre-
sent a problem during sinus lift procedure. As a matter of
fact, an injury in the maxillary sinus and maxillary sinus
septa can result in failure of the grafted material in case of
perforation of the sinus membrane during the surgery [48].
On the contrary, the artery running along the side wall of the
maxillary sinus is intraosseous artery anastomosing with the
infraorbital artery and the posterior superior alveolar artery
[48]. This can be impaired in performing the bony window
for bone substitute material. Its damage, although not life-
threatening being a small vessel, can interfere with the eleva-
tion of the maxillary sinus membrane and fixation of the
grafting material by reducing the visual field of surgery with
blood [48]. Therefore, the artery course and position play a
Current Pharmaceutical Biotechnology, 2017, Vol. 18, No. 1 21
central role in determining the success rate of maxillary sinus
grafting. Park et al. [48] showed that the CT detection rate of
the posterior superior alveolar artery was 52.9% and the dis-
tance from the inferior border of the artery to the alveolar
ridge was 16.4 ± 3.5 mm. The authors concluded that the
probability of determining the artery with CT is 55%.
Moreover, they suggested that if it is not identified, setting
the upper border of the bony window in the premolar region,
instead of the molar region, since the lower limit is suggested
to improve the success rate of the maxillary sinus grafting by
minimizing damage [48]. Other authors [49] suggested to
limit the superior limit of the lateral window up to 18 mm
from the ridge to elude any possible vascular damage.
Although the incidence of malignant incidental lesions is
relatively low [45] the lack of soft tissue contrast for CBCT
y
should be underlined. It means that in doubtful cases, MDCT
or better MRI should be used.
nl
Another application of preoperative assessment is the
evaluation of the mean height of the usable bone in edentu-
lous maxilla. Residual ridge resorption following tooth ex-
traction is unavoidable process in posterior maxilla area [50].
Nimigean et al. [51] classified the average height of the
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available bone in the edentulous maxilla into three classes.
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Class 1 had a residual bone height of 10 mm, usually found
in edentulism of no more than 5-years standing. Class 2 had
a residual bone height of 5-10 mm, usually found in edentu-
lism of 5-10 mm. Class 3 indicated a bone height of 0-5 mm,
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usually found in edentulism of more than 10 years [50]. Si-
nus augmentation is recommended to be performed in class 2
and 3. Another application in preoperative phase may be the
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CBCT volume analysis of the maxillary sinus to define the
volume of graft material to use (Figs. 1-5).
2. BIOMATERIALS
Bone substitute materials (BSB) are available in unlim-
ited amounts, in different shapes and size, but they require
longer healing periods in comparison to autologous bone due
to the reduced biological potential as they are cell-free. Tis-
sue engineering procedures have allowed to successfully use
osteoconductive scaffolds as carriers for mesenchymal stem
cell and growth factors to promote tissue regeneration, accel-
erate bone formation and osseointegration of dental implants
[52]. At present, allografts and xenografts materials are con-
sidered a valid alternative [53] though compared to autolo-
gous bone, they show smaller area of regenerated bone [54],
lower defect regeneration, slower remodeling, slower or ab-
sent osteoclastic activity [55] and higher failure rate. Several
different BSBs or combinations thereof have been used in
sinus floor augmentation procedures, and the amount of vital
bone seems to be an accurate indicator to evaluating the
healing potential of the various materials [53, 56-65]. The
issue of which is the best filling material for the sinus cavity
has, then, relevant importance in clinical practice [20].
BSBs play a key role in dental practice due to their use in
several fields of oral surgery and implant dentistry, e.g. to fill
bone defects after tooth extraction, cysts or bone tumors re-
moval, to treat peri-implant defects and in sinus floor aug-
mentation procedures.
22 Current Pharmaceutical Biotechnology, 2017, Vol. 18, No. 1 Iezzi et al.

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Fig. (1). No nasal turbinate hypertrophy neither alterations or anatomical variants of the osteomeatal complex can be observed.

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Fig. (2). CBCT image showing right sinus membrane thickening can be observed as well as a scarce quantity of alveolar bone tissue.
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Fig. (3). CBCT image showing moderate thickening of the sinus membrane and poor residual crestal bone.
Molecular, Cellular and Pharmaceutical Aspects of Bone Grafting Materials Current Pharmaceutical Biotechnology, 2017, Vol. 18, No. 1 23

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Fig. (4). CBCT image showing: it is possible to observe a reduced bone thickness in the anterior area as well as and alveolar crest of 2-3 mm
in height.

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Fig. (5). CBCT image showing antral artery is not evident in the paraxial sections.
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A BSB used in bone regeneration procedures should:
1) Act as a scaffold to guide the bone formation;
2) Possess pore volume, pore interconnectivity and
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ized host bone is necessary. This fact allows an adequate
blood supply (angiogenesis), followed by osteogenesis [67].
An ideal BSB, besides other characteristics, should be

able to be completely resorbed and replaced by newly

pores size adequate to allow invasion of blood ves-
formed bone. The capability to produce new bone must be
sels;
correlated with the resorption rate of the BSB. The correla-
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3) Present mechanical characteristics similar to the tis-
sues that have to be regenerated [14, 17, 57, 60].
BSBs should be histologically evaluated to analyze the
bone healing processes [61]. Ideally, BSB should have bio-
logic stability, provide volume maintenance, induce the for-
mation of bone and allow for bone remodeling [61]. Ex-
tremely important is the macro- and microporosity of the
BSB, and the interconnecting pore structure, which plays a
crucial role in the bone tissue osteoconduction and vasculari-
zation of the grafted materials, supporting in such a way the
proliferation and differentiation of osteoblasts and the in-
growth of newly formed bone into the grafted material parti-
cles [66]. In order to guarantee the success of the grafted
materials a close contact between the BSB and the vascular-
tion between the timing for the resorption and replacement of
BSB by vital bone is not yet fully understood [68].
3. CUSTOM MADE POROUS SCAFFOLDS FOR
BONE REGENERATION
Surgery of the maxillary sinus is strictly related to the
variable anatomical aspect of its inner part, that should be
tridimensionally identified [21-26]. Despite the diagnostic
progress, currently, sinus augmentation techniques still need
bone substitute materials to be manually cut, shaped and
formed at the time of grafting, resulting in an expensive and
time-consuming process [69]. Furthermore, placing the lat-
eral wall during lateral sinus elevation is still an intuitive
24 Current Pharmaceutical Biotechnology, 2017, Vol. 18, No. 1
process, strictly linked to the surgeon ability [70]. Neverthe-
less, during sinus lift procedure, inaccurate osteotomy cuts
defining the lateral window may cause sinus membrane per-
foration, especially when the membrane is thin and the anatomi-
cal environment is demanding [63]. Recently, a computer-aided
design/computer-aided manufacturing (CAD/CAM) technique
to generate custom-made block grafts for sinus lift, and a
customized cutting guide to accurately place the lateral wall
and ease membrane elevation has been developed.
According to Mangano et al. [69], CAD/CAM procedure
involves three stages: the virtual planning and design of the
custom-made scaffold and the customized cutting guide; the
manufacture of the scaffold and the guide; and the sinus ele-
vation procedure. CBCT datasets of the posterior edentulous
maxilla are acquired and consequently uploaded in the digi-
tal imaging and communications in medicine (DICOM) for-
mat into a specific 3D reconstruction software (MimicsR,
Materialize, Leuven, Belgium) [69]. The hard tissue thresh-
old is selected so that only bone is reconstructed from the
slices. The software is able to carry out an accurate 3D re-
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construction of the maxilla and the sinus; subsequently, an
anatomically-shaped, custom-made scaffold for maxillary
sinus augmentation is drawn [69]. The 3D geometries of the
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maxilla and the scaffold are then saved as stereolithographic
(STL) files. Subsequently, these files are transferred to a 3D
CAD program (RhinocerosR, Robert McNeel & Associates,
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Seattle, WA, USA). This software is used to pre-surgically
outline the optimal lateral borders of the maxillary sinus for
bone grafting surgery [69]. The maxillary sinus is outlined in
al
3D, and the software is used to trace the desired lateral win-
dow and osteotomy cuts in 3D. The cutting paths are verified
in all planes of space to ensure that the planned osteotomy
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cuts would maximize the operator's ability to begin Schnei-
derian membrane reflection, therefore obtaining the optimal
customized cutting guide [69]. This cutting guide is designed
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such that it would precisely fit onto the bone surface and
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would have a slit conforming to the simulated osteotomy
plane. The 3D geometry of the cutting guide is then saved as
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a separate STL file [69].
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3.1. Manufacture of the Custom-Made Scaffold and the
Cutting Guide
As previously reported [69], the 3D geometry of the ana-
tomically-shaped, custom-made scaffold is imported into a
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proprietary CAM software, used to create a set of tool-paths
for fabrication on a proprietary computer- numerical-control
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(CNC) milling machine. A biomaterial block is then placed
in the CNC milling machine and milled into the precise
shape of the 3D project. In this way, an anatomically-shaped,
custom-made scaffold is obtained. Finally, the same CAD/
CAM procedure can be used to fabricate a surgical polytetra-
fluoroethylene (PTFE) device, composed of a customized
cutting guide, based on preoperative simulations [69].
Thanks to recent enhancement in CAD technology,
linked to advanced 3D cutting machinery, it is now possible
to cut a block of bone graft into the most proper shape, that
has been preoperatively calculated using 3D simulation [69,
71]. Recently, an investigation has been conducted using a
block of porous HA, possessing very good osteoconductivity
and mechanical features appropriate for machine-cutting; it
Iezzi et al.
was preoperatively cut into a highly accurate 3D shape,
based on the preoperative simulation using CAD/CAM tech-
nologies [69]. Additionally, a customized CAD/CAM os-
teotomy template was designed and manufactured before
surgery, based on preoperative simulations. Five patients
underwent bilateral sinus floor augmentation; the guide was
fitted onto the bone, and an osteotomy was performed
through the slit. The bone window was outlined and the bony
window fragment was moved medially, the sinus membrane
was reflected and elevated and the space created; then, the
anatomically-shaped custom-made HA block was inserted
into the sinus, and its position was assessed by postoperative
radiograph, showing the exact filling of the empty defect
[69]. Six months after surgery, implants were positioned.
Two years later, all implants were in function with the ab-
sence of clinical or prosthetic complications.
y
This procedure allows to reduce intervention time, to
nl
precisely adapt the scaffold, to reduce risk of complications
and to improve operation quality. However, the dimensions
of the custom-made block are linked to the size of the out-
lined lateral bony window, complicating the filling of the
space between the old and the new floor with the CAD/CAM
block alone with the risk of small defects during the grafting.
n
This limit, nevertheless, could be simply overcome by using
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particulate grafts in association with the custom-made,
CAD/CAM block.
This technique is required in a larger cohort of subjects to
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validate the outcomes; anyway, computer-controlled fabrica-
tion via CAD/CAM technology can represent the ideal alter-
native in automating scaffold development, providing for
variations in the shapes and requirements of different tissues
tri
and also size changes between different individuals [72]. In
the near future, the accessibility of custom-made scaffolds
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engineered from the patient's own stem cells could revolu-
tionize the way to treat bone defects in implantology [69]
(Figs. 6-10).
4. ANGIOGENESIS
Angiogenesis is a process that determines the sprouting
of new blood vessels from pre-existing vessels. The degree
and speed of vascularization are the key determinants in the
bone graft survival. The healing processes of the injured site
need the presence of a higher oxygen content, of nutrients,
and the removal of the cellular debris. To evaluate the pres-
ence of blood vessels in a tissue, it is necessary to count the
microvessels (Microvessel Density -MVD) [73]. MVD
seems to be correlated with the expression of the Vascular
Endothelial Growth Factor (VEGF). This correlation has
been supported by the studies on tumors conducted in our
laboratory [74]. VEGF seems to be the major mechanism
that influences angiogenesis and consequently osteogenesis
during bone repair [67] promoting neovascularization, bone
turnover, osteoblast migration [75]. VEGF is stimulated by
Bone Morphogenetic Protein (BMP) and seems to regulate
the angiogenesis at each stage of bone formation [76]. MVD
has already been used to evaluate the presence of blood ves-
sels and the angiogenetic properties of BSBs [77, 78]. Some
studies showed a higher value of MVD and a higher percent-
age of newly formed bone in sites augmented using BSB
than in nonaugmented sites [79].
Molecular, Cellular and Pharmaceutical Aspects of Bone Grafting Materials Current Pharmaceutical Biotechnology, 2017, Vol. 18, No. 1 25

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Fig. (6). CBCT data of edentulous maxilla of patient.

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Fig. (7). The virtual planning of customized cutting guide.

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5. RESORPTION PATTERN
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The ideal biomaterial should reabsorb slowly after

Fig. (8). The anatomically-shaped custom-made hydroxyapatite
block grafted into the sinus.
placement and should integrate in the surrounding bone. His
degradation rates should correspond to the rate of tissue re-
generation to guarantee the original volume and strength of
the biomaterial in the time and should be, finally, totally re-
placed by new bone [80]. It is of great interest the long-term
outcome of grafting material. It is important to understand
whether grafted particles can interfere with the regeneration
process and with the long-term prognosis of dental implants
that are inserted into this bone-graft composite. In literature,
there is no unanimous view about long term anorganic bo-
vine bone resorb ability and about his performance over long
time. Several authors argue that anorganic bovine bone
(ABB) is resorbable over time as they have observed the
26 Current Pharmaceutical Biotechnology, 2017, Vol. 18, No. 1
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Fig. (9). The CBCT after 6 months.
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Fig. (10). Rx after insertion of implants.
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presence on the particle surface of osteoclasts, resorption
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lacunae or the progressive increase of newly formed bone
with the decrease over time of the residual particles in the
specimen in vivo [14, 81-83]. Other authors describe only the
signs of resorption or a decreased density of the graft over
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time [84]. Doubtless it is a very low resorption rate over a
long period of time [53, 82, 85, 86]. Perrotti et al. [87] re-
ported that osteoclasts are generated on, attached to, and
N
resorb bovine bone (Bio-Oss) in vitro, although more slowly
than native bone. The osteoclasts activity depends on the
microenvironment of osteoclast-substratum interface. To
resorb a substrate, osteoclasts’ membrane has to be sealed to
it by cell receptors and protein of the integrin family, in such
a way the acid secreted by osteoclasts determines mineral
release from the substratum surface [58]. High calcium ions
concentration on surface particles produces an increase in the
cellular calcium levels that results in osteoclasts inhibition,
detachment of the osteoclasts from the bone surface and con-
sequently bone resorption inhibition also after many years
[82, 88]. Elemental analysis has shown a relatively high cal-
cium content of the ABB particles compared to natural bone
which might have influence in the resorption process [89].
Iezzi et al.
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The long-lasting persistence of bovine grafting particles
might also be explained by a bonding mechanism able to
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maintain the biomechanical integrity of bone/biomaterial
during remodeling/ repair process [77]. Other authors have
stated that ABB is non-resorbable [58, 90, 91] neither after
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11 years [92]. These authors did not find any macrophages
and mast cell on the granules or resorption lacunae on bone-
substitute surface [90, 92]. Mordenfeld et al. [92] claimed
that the reported variations of graft particles over time may
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depend on many factors, such as the surgery including pres-
sure at position of the grafting material, the initial percentage
is
of particles in the graft, the particles size, the bone type (cor-
tical or cancellous), the use of blood or saline, the biopsy
technique, the histological preparation technique or the dif-
ferent biological response in animal studies. However,
doubtless, it is preferable for dental implant integration and
for implant prognosis to place implants in native natural
bone and it has been demonstrated that bovine HA particles
in contact with the titanium surface should reduce mechani-
cal support for dental implants [93]. Anyway, irrespective of
ABB particles resorb ability, histological reports [86, 94] on
human implants retrieved from sinuses grafted with ABB
have shown no contact between the biomaterial particles and
the dental implant surface that was always surrounded and
covered by newly-formed bone, achieving a very high BIC
percentage. No epithelial cells or connective tissue resulted
at the interface, no inflammatory cells were observed adja-
cent to the particles or at the bone-implant interface, no gaps
were present at interface. Newly formed bone was constantly
in tight contact with the bone substitutes particles. Conse-
quently, ABB degradation does not seem to be crucial to
achieve osseointegration and even if ABB particles are not
completely resorbed and replaced by newly formed bone,
there will be no adverse effects on the osseointegration of
implants [86, 94]. The lack or the slow resorption could be
an advantage to maintain the initial volume of the grafted
area over time, while autogenous bone graft has shown, in
some cases, after 8 months of healing, a resorption of more
than 50% of the original volume [11].
Molecular, Cellular and Pharmaceutical Aspects of Bone Grafting Materials Current Pharmaceutical Biotechnology, 2017, Vol. 18, No. 1 27

6. POSTOPERATIVE ASSESSMENT CBCT offers a secure technique for 3D visualization of

Changes of augmented bone over time should be exactly
measured to guarantee the predictability of sinus floor eleva-
tion, since loss of height and width may interfere with the
following placement of dental implants.
Concerning bone substitute materials, it has been demon-
strated that autologous bone is completely resorbed over
time, mostly if the graft is retrieved from the iliac crest [95,
96]. Many bone substitutes have been proposed and used
during the last 2 decades, aiming to decrease morbidity of
the sinus lift procedure and avoiding the need for a second
surgical site [97, 98].
Panoramic radiographs allow to estimate the vertical di-
mension of graft, but do not supply data about volume and
the variations in the volume of newly-formed bone after si-
nus floor elevation. Several computer-based software pro-
grams are currently available. Volumetric changes of grafted
maxillary sinus have been previously estimated by CT scan,
both on humans [99] and on animals [100], demonstrating
the predictability of the tool regarding graft prognosis.
Moreover, CT is also helpful to plan the implantation time,
to decide the size of implants, to precisely measure the bone
grafting volume [100], as well as to accurately evaluate the
3D change of the graft material during the healing period.
Volumetric data obtained by CBCT demonstrated high accu-
racy of estimation with a relative error below 1% with re-
spect to the same measurement carried out during surgery
[101, 102]. The variation of the bone volume has been pre-
cisely appreciated thanks to spatial resolution of CBCT

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3D changes [37]. (voxel size: > 0.1 mm). Therefore, CBCT is a fast, simple,

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Fig. (11). Panorex CBCT. Maxillary sinus augmentation (left) performed with biomaterial. Neither inflammatory reaction or thickening of
sinus mucosa can be observed.
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on

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Fig. (12). CBCT. Maxillary sinus augmentation (left) performed with biomaterial. The biomaterial is well circumscribed as no scattered par-
ticles scattered into the sinus can be detected.
28 Current Pharmaceutical Biotechnology, 2017, Vol. 18, No. 1
nl
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Fig. (13). Sagittal and coronal sections after sinus augmentation. No nasal turbinate hypertrophy neither obstructions of the ostiomeatal com-
plex can be observed. Panorex. sinus lift (left).
al
relatively accurate, and promising approach to quantifying
on
long-term changes in the grafted area [103]. Further efforts
are needed in order to standardize and make reproducible 3D
is
analyzing software program for CBCT quantitative evalua-
tion such as volume analysis.
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Conventional histological evaluation and corresponding
histomorphometric measurements may be helpful to better
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understand the behavior of BSB by providing a qualitative
and quantitative of the bone healing. Specifically, evalua-
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tions on the influence of the BSBs on bone structure and on
the activities of the cells involved in the regeneration/
remodeling process can be undertaken (Figs. 11-13).
ot
N
Fig. (14). HT (rearranged by Fig. 5B of Ref. [100]). Sub-volume of
a Human Mandible 3D reconstruction: all other phases were virtu-
ally removed except for bone (white) and vessels (red).
Iezzi et al.
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Recently, a novel approach has been used to deepen our
tri
knowledge to evaluate the behavior of BSBs: synchrotron
micro-tomography (SCT) [104]. It is a 3-D analyzing
method, dedicated to assess the dynamic and spatial ar-
rangement of regenerative phenomena in complex anatomi-
cal structures such as bone, where tissues with several mor-
phologies (alveolar process, unmineralized extracellular ma-
trix involvement, regenerated vessels) compete to achieve
the final goal of bone regeneration [105, 106]. Traditionally,
absorption imaging with SCT is conducted with almost no
distance between sample and detector. In this context, among
the several techniques available, SRT is used increasingly to
achieve quantitative information concerning the mineral con-
tent of different areas of bone. In fact, the polychromatic
source and cone-shaped beam geometry complicate assess-
ment of bone mineral density by CBCT. Because absorption
is strictly related to the amount of mineral in bone, a suitable
calibration is able to precisely relate the reconstructed gray
levels in SRT images, obtained using a monochromatic X-
ray beam, to the local bone mineral density [107]. Homoge-
neous materials with a low attenuation coefficient (like such
as collagen, unmineralized extracellular matrix, vessels,
nerves, etc.) or heterogeneous materials with a narrow range
of attenuation coefficients (like the case of heterologous
bone scaffolds or for graded mineralized bone) produce in-
sufficient contrast for absorption imaging. In this case, the
imaging quality can be increased using phase contrast tomo-
graphy (PCT) with a wider distance between sample and
detector [107, 108]. Additionally, whereas PCT is based on a
single distance between the detector and the sample, holoto-
mography (HT) includes imaging at different distances, then
Molecular, Cellular and Pharmaceutical Aspects of Bone Grafting Materials
combining the phase shift information to generate 3D recon-
structions. HT is helpful when the material of interest has
very small changes in attenuation coefficients, which lead to
unsatisfactory imaging outcomes even with phase contrast
techniques [109] (Fig. 14).
CONCLUSION
The present article shows the importance of a deep
knowledge of anatomy and possible anatomical variations of
sinus cavity, thus the role of a proper radiological assessment
of the region before sinus augmentation procedure to avoid
complications and for a successful outcome of the sinus ele-
vation procedure. Despite those advances, the choice of the
best bone substitute materials still remains crucial. There-
fore, an overview of all the biomaterials that can be used
with success in maxillary sinus elevation will be conducted
in Part 2 of the article.
CONFLICT OF INTEREST
O
Like most specialists in the implant and biomaterial field
of research, the authors of this article are currently involved
in experimental studies with various dental implants and
biomaterial companies. However, this general literature re-
view work focuses only on general established knowledge in
se
the clinical and biological aspects of these materials and
U
therefore coauthors do not have any conflict of interest to
report for this work.
al
ACKNOWLEDGEMENTS
This work was partially supported by the Ministry of
on
Education, University, Research (M.I.U.R.), Rome, Italy and
by the Program PRIN (Prot. 20102ZLNJ5), M.I.U.R., Rome,
Italy.
rs
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