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Aim. Hydroxyapatite (PA) has a chemical composition and physical structure very similar to natural bone and therefore it has been considered to be the ideal biomaterial able to ensure a biomimetic scaffold to use in bone tissue engineering. The aim of this study is to clinically test hydroxyapatite used as osteoconductive biomaterial in the treatment of periodontal bone defects. Clinical and radiological evaluations were conducted at 6, 12 and 18 months after the surgery.
Materials and methods. Forty patients with 2- and 3-wall intrabony pockets were enrolled in this study. PPD, CAL, radiographic depth (RD) and angular defects were preoperatively measured. After surgery, patients were re-evaluated every 6 months for 18 months. Statistical analyses were also performed to investigate any differences between preoperative and postoperative measurements.
Results. Paired t-test samples conducted on the data obtained at baseline and 18 months after, showed significant (p&lt;0.01) differences in each measurement performed. The role of preoperative RD was demonstrated to be a significant key factor (p&lt;0.01). A relevant correlation between preoperative PPD and CAL gain was also found.
Conclusions. Within the limitations of this study, the absence of anatomical variables, except the morphology of the bone defect, emphasizes the importance of the proper surgical approach and the graft material used
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Biomimetic hydroxyapatite used in the treatment of periodontal intrabony pockets: clinical and radiological analysis
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L. Fortunato
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Biomimetic hydroxyapatite used in the treatment of periodontal intrabony pockets: clinical and radiological analysis
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                                                                                                    Original article



     Biomimetic hydroxyapatite used in the treatment
     of periodontal intrabony pockets: clinical and
     radiological analysis

     Michele Mario Figliuzzi, MD, DDS, PhD1                 Conclusions. Within the limitations of this study,
     Amerigo Giudice, MD, DDS, PhD1                         the absence of anatomical variables, except the
     Settimia Pileggi, MD1                                  morphology of the bone defect, emphasizes the
     Francesco Scordamaglia, MD1                            importance of the proper surgical approach and
     Massimo Marrelli, MD, DDS2                             the graft material used.
     Marco Tatullo, MD, DDS, PhD2#
     Leonzio Fortunato, MD, DDS, PhD1#                      Key words: biomimetic, hydroxyapatite, intrabony
                                                            pockets, clinical, radiological.

     1 Department of Periodontics and Oral Sciences,
     University “Magna Graecia” Catanzaro, Italy            Introduction
     2 Maxillofacial Unit, Calabrodental Clinic, Crotone,

     Italy                                                  Bone substitutes represent one of the most widely
                                                            used options for the regeneration of bone defects de-
     # These Authors contributed equally to this            veloped after a severe periodontal disease.
     article.                                               According to Ripamonti (1), correct bone regenera-
                                                            tion is mainly based on 4 factors:
     Corresponding author:                                  • osseo-inductive abilities
     Michele Mario Figliuzzi                                • scaffold able to support bone regeneration
     Department of Periodontics and Oral Sciences,          • mesenchymal stem cells able to be simulated by
     University “Magna Graecia”                                 these signals and able to differentiate towards the
     Via T. Campanella 115                                      osteoblast phenotype
     88100 Catanzaro, Italy                                 • appropriate timing of growth and proper environ-
     E-mail: figliuzzi@unicz.it                                 ment. Grafting materials are commonly classified,
                                                                based on the potential osteogenic activity, into:
                                                                osteogenic, osteoinductive and osteoconductive
     Summary                                                    materials (2).
                                                            Autogenous bone is the only graft material showing os-
     Aim. Hydroxyapatite (PA) has a chemical compo-         teogenic, osteoinductive and osteoconductive abilities.
     sition and physical structure very similar to natur-   However, the limited amount of bone obtainable from
     al bone and therefore it has been considered to        an intra-oral donor site, as well as the morbidity follow-
     be the ideal biomaterial able to ensure a bio-         ing surgery of the donor site and the fast resorption of
     mimetic scaffold to use in bone tissue engineer-       the autogenous bone graft represents some of the most
     ing. The aim of this study is to clinically test hy-   important limitations of this surgical procedure (3).
     droxyapatite used as osteoconductive biomaterial       On the other hand, according to Berglundh & Lindhe
     in the treatment of periodontal bone defects.          (4), heterologous grafting materials possess only os-
     Clinical and radiological evaluations were conduct-    teoconductive properties. Among these materials, the
     ed at 6, 12 and 18 months after the surgery.           bovine bone matrix was the most investigated in peri-
     Materials and methods. Forty patients with 2- and 3-   odontal-related literature. This class of grafting mater-
     wall intrabony pockets were enrolled in this study.    ial showed a long resorption time, since bovine bone
     PPD, CAL, radiographic depth (RD) and angular de-      matrix particles were found even after more than 9
     fects were preoperatively measured. After surgery,     months (5).
     patients were re-evaluated every 6 months for 18       Homologous bone graft holds intermediate features:
     months. Statistical analyses were also performed to    studies on DBDFA reported that the freeze-drying
     investigate any differences between preoperative       process causes demineralization of the mineralized
     and postoperative measurements.                        component, so freeing the BMPs able to regulate
     Results. Paired t-test samples conducted on the        MSCs differentiation towards osteoblast phenotype (6).
     data obtained at baseline and 18 months after,         Scientific progress has developed new synthetic bio-
     showed significant (p<0.01) differences in each        materials. Studies on grafting materials based on hy-
     measurement performed. The role of preoperative        droxyapatite showed controversial outcomes: some
     RD was demonstrated to be a significant key fac-       Authors (7) demonstrated that the hydroxyapatite
     tor (p<0.01). A relevant correlation between pre-      grafted in a bone defect induces new bone formation,
     operative PPD and CAL gain was also found.             without fibrotic tissue formation.

     16                                                                       Annali di Stomatologia 2016;VII (1-2): 16-23

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     Biomimetic hydroxyapatite used in the treatment of periodontal intrabony pockets: clinical and radiological analysis


     On the contrary, other studies (8) demonstrated that
     hydroxyapatite works as an inert filling material, with
     no evidence of osteogenesis activity.
     According to literature, the geometry of the grafting
     material could represent a differentiating key-factor
     able to influence the clinical outcomes. In fact, sever-
     al studies demonstrated that the surface geometry is
     a critical factor for cell adhesion and differentiation (9,
     10).
     In the light of these chemical and physical features,
     biomaterials with a surface geometry similar to hu-
     man bone represent the last generation of synthetic
     devices. These materials are supposed to produce
     molecular signalling able to modify the environment,
     so to facilitate a physiologic bone regeneration (11).         Figure 1. Preoperative probing.
     Additionally, their stoichiometric instability potentially
     allows a fast and complete resorption (12).
     Aim of this study was to clinically and radiographically       evaluated and in all the reported cases the periodon-
     evaluate the regenerative properties of synthetic hy-          tal surgery was indicated to have a probing pocket
     droxyapatite in the surgical treatment of periodontal          depth (PPD) reduction, clinical attachment level
     intrabony defects.                                             (CAL) gain and defect filling. All patients were in-
                                                                    formed about the procedures and a signed informed
                                                                    consent form was obtained.
     Materials and methods

     This study was carried out with 40 patients affected           Clinical data
     by periodontal disease: the main inclusion criterion
     was that patients presented at least one periodontal           The clinical data were evaluated, by means of a cali-
     intrabony defect. Patients were enrolled at the “Poli-         brated periodontal probe (Click-Probe®, Kerr, Bioggio,
     clinico Universitario Mater Domini”, in the Department         Switzerland), at the beginning of the study (baseline)
     of Dental Diseases of the University “Magna Grecia”            and 6, 12 and 18 months after the surgery (Fig. 1).
     of Catanzaro. This study was approved by the Uni-              In this study we evaluated the probing pocket depth
     versity Ethical Committee (n.997 of 17/Septem-                 (PPD), measured from the free gingival margin to the
     ber/2010).                                                     bottom of the pocket together with the Gingival Re-
     The research was performed following the principles            cession index (REC), measured from the Cement-
     of the Declaration of Helsinki on experimentation in-          Enamel Junction (CEJ) to the free gingival margin,
     volving human subjects.                                        and the clinical Attached Level (CAL), which is the
                                                                    sum of PPD+REC.

     Inclusion criteria
                                                                    Surgical Procedure
     From January 2008 to July 2009, 40 patients affected
                                                                    Antibiotic therapy (Amoxicillin and Clavulanic Acid 2g
     by at least one intrabony defect were selected con-
                                                                    a day for 6 days, starting the day before the surgery)
     secutively. Defects showed the following characteris-
                                                                    and antiseptic therapy with Chlorhexidine 0.2% rinses
     tics: real 2- or 3-walls defects (radiographic intrabony
     component > 4mm), probing pocket depth (PPD) >
     7mm, angular defect <30°.
     Inclusion criteria were:
     1. age >18
     2. good oral hygiene
     3. non smokers
     4. no systemic disease
     5. no previous periodontal surgery
     6. no chronic assumption of NSAIDs
     7. no allergy related to the used materials
     8. no use of drugs such as nifepidine, steroids, al-
         lantoin, estrogens, cyclosporine, bisphosphonates
     9. no pregnancy during the whole period of the
         study.
     The selected patients underwent a non-surgical peri-
     odontal treatment. After one month, patients were re-          Figure 2. X-ray of the intrabony defects.


     Annali di Stomatologia 2016;VII (1-2): 16-23                                                                           17
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     M. M. Figliuzzi et al.


     for 8 days were administered to patients. Before
     surgery, an X-ray was performed with the “parallel
     cone” technique (Fig. 2). After the local anesthesia
     (Mepivacain plus Adrenalin 1:100.000, Pierrel Italia),
     according to Cortellini et al. (13) an intrasulcular inci-
     sion, was made with a blade (Beaver 64, Becton,
     Dickinson & Co, USA) between the mesial and distal
     tooth. The flap was raised at a split thickness. Granu-
     lation tissue was removed with ultrasonic tools and
     curettes. Defect morphology (2- or 3- walls) was char-
     acterised after flap elevation and the surgical de-
     bridement (Fig. 3).
     Once the defect depth was measured, a topical thera-
     py on the root surface was performed with tetracy-
     cline 0.5%. In addition, a biomaterial made by hydrox-        Figure 5. Flap sutured and coronally repositioned.
     yapatite was customised to this bone defect (Engi-
     pore®, Finceramica, Faenza, Italy) (Fig. 4). We fill the
     bone defect with the biomaterial to be investigated,
     no membrane was used to cover this graft, while the
     flap was coronally repositioned (Poliglycolic Acid, di-
     ameter 4.0, Distrex Spa Italia) (Fig. 5). In all the re-
     ported cases, a periodontal dressing was placed to
     preserve the flap. After 8 days, periodontal dressing
     and sutures were removed and patients were careful-
     ly visited in order to evaluate the healing process.
     Clinical and radiographic controls were performed 6,
     12 and 18 months after surgery by an independent
     trained examiner (Figs. 6-9).

                                                                   Figure 6. Clinical control at 6 months from baseline.


                                                                   Radiographic analysis

                                                                   Standard X-ray analyses were performed by using a
                                                                   custom-made resin bite with the “parallel cone” tech-
                                                                   nique, at the baseline and 6, 12 and 18 months after
                                                                   surgical therapy. The radiographic depth of the intra-
                                                                   bony defect (RD) was evaluated as a vertical dimen-
                                                                   sion between the projection of the coronal bone crest
                                                                   onto the root surface and the most apical bone level
                                                                   where the periodontal ligament was considered to
                                                                   have a normal width.
                                                                   A computerised measuring technique was applied to
                                                                   digital periapical radiographs. The evaluation of the
     Figure 3. Assessment of defect after flap elevation and de-
     bridement.




     Figure 4. Defect filled with the biomaterial.                 Figure 7. Intraoral X-rays at 18 months from baseline.


     18                                                                               Annali di Stomatologia 2016;VII (1-2): 16-23

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     Biomimetic hydroxyapatite used in the treatment of periodontal intrabony pockets: clinical and radiological analysis


                                                                    significant differences between RD, PPD, REC and
                                                                    CAL values before surgery and the same variables
                                                                    18 months after surgery.
                                                                    A general linear model was achieved in order to eval-
                                                                    uate the role of variables preoperative RD, angular
                                                                    and number of bone walls on the realisation of the
                                                                    dependent variable (Bone Gain, calculated as RD at
                                                                    18-month follow-up- preoperative RD). In particular,
                                                                    we measured direct and indirect effects between the
                                                                    variables included in the model. Pearson’s correlation
                                                                    coefficient was calculated to determine the relation-
                                                                    ship between CAL Gain (calculated as CAL at 18-
                                                                    month follow-up - preoperative CAL) and PPD values.

     Figure 8. Clinical control at 18 months from baseline.
                                                                    Results

                                                                    Forty patients were observed (24 females, 16 males),
                                                                    aged from 18 to 65 years old (mean 42.2 ± 4.97
                                                                    years old).
                                                                    Intraoperative evaluations assessed that 17 cases
                                                                    showed 2-wall defects and 23 cases showed 3-wall
                                                                    defects.
                                                                    No patient reported intra-operative or post-operative
                                                                    pain.
                                                                    No patient dropped out during the study.


                                                                    Clinical evaluation

                                                                    As reported in Table 1, clinical results at 18 months
                                                                    showed a complete filling of the defect, with a mean
                                                                    PPD of 3 mm, and a mean CAL of 3.3 mm.
                                                                    Paired sample t-tests carried out on PPD, REC and
     Figure 9. Control probing at 18 months from baseline.          CAL before surgery and after 18 months showed
                                                                    strongly (p<0.01) significant differences for each
                                                                    measurements performed between pre- and post (18
     defect sizes were assessed in mm and performed us-             months) operative steps.
     ing an image analysis software with RVG equipment              The Pearson coefficient shows a relevant correlation
     (CDR Dicom 4.5, Schick Technologies, Long Island               (0.797) between preoperative PPD and CAL gain.
     City, NY).

                                                                    Radiographic evaluation
     Statistical analysis
                                                                    The radiographic evaluation was performed by ana-
     Paired sample t-test was carried out to evaluate any           lysing both the radio-opacity on digital periapical radi-

     Table 1. Clinical and radiographic mean values (mm values) at the time of surgery, 6, 12 and 18 months from baseline.

                 Pre-operative                6-months follow-up   12-months follow-up           18-months follow-up
     PPD             10.52                           4.57                 5.30                         2.98
                    SD: 1.36                        SD: 0.65             SD: 0.67                     SD: 0.50

     CAL             11.77                           4.84                 5.59                         3.32
                    SD: 1.37                        SD: 0.65             SD: 067                      SD: 0.54

     REC             1.26                            0.288                0.34                         0.35
                    SD: 0.75                        SD: 0.44             SD: 0.43                     SD: 0.49

     Rx Depth        8.95                            2.41                 2.35                         1.10
                    SD: 1.46                        SD: 0.60             SD: 0.44                     SD: 1.02


     Annali di Stomatologia 2016;VII (1-2): 16-23                                                                           19
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     M. M. Figliuzzi et al.


     ographs and the defect depth in mm measured from                of synthetic materials, mostly hydroxyapatites, is
     the bone crest to the bottom of the defect, during the          growing every day because of their mechanical prop-
     surgery and after 6, 12 and 18 months.                          erties very similar to human bone characteristics. So
     At baseline, the angular defect was 23.05° on aver-             these “Miming bone materials” were studied for their
     age (SD: 1.64). At the following follow-ups, these da-          ability to trigger the Guided Tissues Regeneration
     ta resulted in 0. In fact, after 6 months, the biomateri-       (GTR) mechanisms (15-17).
     al showed a radio-opacity very similar to the sur-              The present study was aimed to evaluate the capabil-
     rounding bone. At 12 months, the radio-opacity was              ity of new bio-mimetic hydroxyapatite biomaterial to
     even more similar to surrounding bone, while at 18              treat the complex periodontal intrabony defects. Hy-
     months it was indistinguishable from the native bone            droxyapatite (PA) has a composition and structure
     tissue and was well integrated. On the pre-surgery              very similar to natural bone tissue and therefore it
     digital periapical radiographs, the depth of the defect,        has been considered to be the ideal biomaterial to
     evaluated from the bone crest to the bottom of the              use in bone tissue engineering, also in the light of its
     defect, was on average 8.9 mm. This value de-                   osteoconductivity and a likely osteoinductivity.
     creased to an average of 2.4 mm, 2.3 mm and 1.1                 PA has already been proven to show good biocom-
     mm. On the digital periapical radiographs performed             patibility with many human cells and tissues, probably
     6, 12 and 18 months after the surgery, there were               thanks to its similarity to collagen (18).
     several (p<0.01) significant differences shown.                 Nano-structured hydroxyapatite presents chemical
     Our linear model was built to determine how the vari-           and morphologic properties similar to natural bone.
     ables preoperative RD, angular and number of walls              PA porosity was demonstrated to reach 90% of the
     were crucial in contributing to the achievement of              entire volume, with macro-pores ranging between
     bone gain, and it showed interesting results (R                 200 and 500 μm, and pores of interconnection rang-
     Squared: 0.84). The single effect of preoperative RD            ing between 80 and 200 μm. Additionally, its Ca/P
     was strongly significant (p<0.01), while the other sin-         (Calcium/Phosphate) ratio is almost to the same as
     gle effects and all the cumulative effects played no            the natural bone Ca/P ratio. These features allow the
     statistically significant role (Tab. 2).                        material to present a geometric configuration similar
                                                                     to natural bone and, according to Ripamonti et al.
                                                                     (12), allow this material to adsorb the bioactive pro-
     Discussion                                                      teins and the grow factors concentrated in the clot. It
                                                                     allows the progressive releasing of these factors,
     Bone regeneration mechanisms depend on mechani-                 able to induce migration, adhesion and proliferation
     cal factors and physical factors such as humidity,              of cells inside the pore network and to promote a
     mineral content, density, porosity, collagen fiber ori-         faster angiogenesis and a more effective osteo-gene-
     entation and interfacial bonding between constituents           sis inside these pores (19-21). Theoretical data was
     (14).                                                           confirmed by clinical outcome (22). In fact, according
     In the field of periodontal tissue regeneration, the use        to several studies (23-26), new generation hydroxya-


     Table 2. Analysis of variance, tests of between-subjects effects - dependent variable: bone gain.

     Source                                               Type III Sum     Df         Mean               F              Sig.
                                                          of Squares                  Square
     Corrected Model                                      299.306          29         4.338              2.281          0.007
     Intercept                                            2635.376         1          2635.376           1386.027       0.000
     Rx depth preop                                       136.729          12         11.394             5.992          0.000
     Angle preop                                          4.745            11         0.431              0.227          0.994
     Number of walls preop                                1.692            1          1.692              0.890          0.353
     Rx depth preop * Angle preop                         9.649            23         0.420              0.221          1.000
     Rx depth preop * Number of walls preop               2.276            6          0.379              0.199          0.974
     Angle preop * Number of walls preop                  4.548            5          0.910              0.478          0.789
     Rx depth preop * Angle preop *
     Number of walls preop                                3.278            5          0.656              0.345          0.881
     Error                                                57.042           10         1.901389
     Total                                                6510.750         40
     Corrected Total                                      356.348          39
     R Squared = 0.840 (Adjusted R Squared = 0.472)
     Df: degrees of freedom
     F: statistical result of F Test

     20                                                                               Annali di Stomatologia 2016;VII (1-2): 16-23

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     Biomimetic hydroxyapatite used in the treatment of periodontal intrabony pockets: clinical and radiological analysis


     patites demonstrated high osteo-conductive proper-             membranes alone was reported (23).
     ties when used in sinus-lift procedure and in vertical         However, the lack of a control group suggests the
     ridge-augmentation of atrophic posterior mandible              need to perform further clinical trials.
     (27). Moreover, the osseointegration period was con-           In our clinical study no statistical differences regard-
     firmed to range between 9 and 18 months. On the                ing the probing depth reduction values, the clinical at-
     other hand, bovine bone matrix showed, in the same             tachment level (CAL) gain and the defect fill were ob-
     conditions, a longer resorption time, even with contro-        served, both in contained (3 wall) and non-contained
     versial histomorphometrical outcomes (28).                     (2 wall) periodontal defects. Even if such clinical out-
     At the end of this study, the reported outcomes                comes are not investigated by histology assay, it can
     showed a strong bone regeneration, with a bone re-             be argued that the periodontal defects can be suc-
     generation mean value of 7.85±1.9 mm. These data               cessfully regenerated only by means of the tested
     report a bone regeneration slightly higher than the            biomaterial without any use of membrane.
     outcome reported by Trombelli et al. (6) which com-            Statistical analyses found no statistically differences
     pared different grafting materials, and the outcome            in tree-wall intrabony pockets compared to two-wall
     reported by Sculean et al. (28) which used bovine              defects. These data are in agreement with Cortellini &
     bone matrix with or without membrane. It might be              Tonetti (29), which described the same healing pat-
     explained because of the bio-mimetic properties of             tern in three- and two-wall intrabony pockets.
     the hydroxyapatites associated to the surgical tech-           Furthermore, after having analyzed the results, we
     nique used and to proper soft tissue management.               found that angular defects seemed not to influence
     Split thickness flap used has ensured an adequate              the final outcomes of the study; we have to consider,
     blood supply to the soft tissues during the surgical           however, that the inclusion criteria required a preop-
     treatment and the possibility to replace the gingival          erative angular defect <30°.
     flap more coronally.                                           On the other hand, the length of the defect appeared
     The surgical technique used exploited the reparative           to be another key factor: in fact, the better results
     and regenerative properties of underlying bone tis-
                                                                    were demonstrated in the deeper defects.
     sue, given that periosteum is rich in totipotential sta-
                                                                    Results of the reported study seem to disagree with
     minal cells. Moreover, this flap technique allowed for
                                                                    Needleman et al. (34), which stated that a better
     complete flap stability, which is a key condition to ob-
                                                                    healing can be obtained in the three-wall defects.
     tain good healing of the tissues (29).
                                                                    At the end of our study, the marginal soft tissue level
     Trombelli et al. (6) and Cortellini & Tonetti (29), ac-
                                                                    was found to be healed more coronally than we ex-
     cording to a Literature systematic review, stressed
                                                                    pected. REC reduction after surgery might be ex-
     the importance of the surgical approach. In fact, it
                                                                    plained by the overfilling of the defect, to maintain an
     was shown that a minimally invasive technique with
                                                                    adequate space, and by the possibility to move and
     or without regenerative materials resulted in signifi-
                                                                    suture coronally the flap, to obtain a perfect soft tis-
     cant clinical and radiographic improvements. In this
                                                                    sue closure and the stability of the coagulum for a
     light, our results from the present study showed that,
     by using the nano-structured hydroxyapatite as filling         proper healing process. This data seems to be in
     biomaterial, a membrane might not be a critical factor         contrast with the Literature (35) which suggests to
     for bone regeneration, even in non-containing bone             place the soft tissues at the same level or slightly api-
     defects.                                                       cally after the surgery.
     The data from published controlled clinical studies do
     not seem to clearly indicate improved clinical out-
     comes related to probing pocket depth (PPD) reduc-             Conclusions
     tion, clinical attachment level (CAL) gain and defect
     fill when the combination of grafting materials and a          In the presented study, the absence of anatomical
     covering membrane is compared with the membrane                determinants, with the exception of the length of the
     alone or with the grafting materials alone (30-33). It         defect, might suggest the importance of surgical ap-
     was shown that treatment of intrabony defects with a           proach and of the grafting material used as well. With
     complicated, non-containing morphology by using                an accurate patients selection and the proper surgical
     membranes and grafting materials showed better                 technique, the here investigated biomaterial gives an
     clinical outcomes if compared with the use of the              important aid in the treatment of periodontal intrabony
     membranes alone (30, 33). Such better clinical out-            defects, leading to a normalisation of the clinical and
     comes are confirmed by more suggestive histological            radiological parameters. These assumptions were
     pictures describing a good bone repair, after the sur-         supported by histological evidence, as previously
     gical technique combining grafting materials and               demonstrated by Figliuzzi et al. (36).
     membranes in non-containing periodontal defects.
     Otherwise, in containing bone defects (i.e. fenestra-
     tion defects, three-wall intrabony defects or Class II         Source of Funding
     furcation defects) no additional advantage by a com-
     bination of grafting materials and barrier membranes           The study was self-funded by the Authors and their
     compared with grafting materials alone or barrier              institutions.



     Annali di Stomatologia 2016;VII (1-2): 16-23                                                                           21
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     M. M. Figliuzzi et al.


     Acknowledgements                                                              mation of calcium phosphate collagen composites trough min-
                                                                                   eralization of collage matrix. J Biomed Mater Res. 2000;
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     We highly appreciated the skills and commitment of
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     Dr. Audrenn Gautier in the supervision of the study, Dr.
                                                                                   pling of osteogenesis and angiogenesis in bone substitute
     Marco Clementini and Dr. Gaia Rosa Pellegrini for the                         healing – A brief overview. Journal of Anatomy. 2011;10: 12-
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     Annali di Stomatologia 2016;VII (1-2): 16-23                                                                                        23
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