10.59987/ads/2010.1.2-7
Aim. The aim of this study is to evaluate the capability of Hyaloss™ matrix (Fab – Fidia Advanced Biopolymers – Pd – Italy), a biomaterial based on hyaluronic acid, used as organic scaffold in bone repair in post-extractive defects.
Materials and methods: 20 post-extractive sockets were selected, with similar size defects in the same patient and in the same hemiarch. Hyaluronic acid with high molecular weight (Hyaloss™ matrix, Fab – Pd – Italy) was mixed with autologous bone obtained using Safescraper ® curve (Meta – Re – Italy) to repair post-extractive sites. Safescraper® is a cutting edge system that allows to the collection of autologous bone without using traditional, incision-based collection techniques, which could cause discomfort to the patient.
Results: Clinical and hystological evaluations were performed, four months after grafting, in the maxilla and in the mandible. From a clinical point of view Hyaloss™ matrix mixed with autologous bone and patient’s blood becomes a substance similar to gel, which is easy to insert in to the defect. From a hystological point of view, in the treated site there is the presence of an erosive activity, with accelerated angiogenetic and bone remodelling activities.
Conclusions: The preliminary results show an acceleration of the bone deposit process and of its remodelling due to the presence of Hyaloss™ matrix, which, from a clinical point of view, improves the handling and application of the bone matrix inside the defects and, from a hystologic point of view makes it possible to obtain bone regeneration in less time when it is used with autologous bone.
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G. Nicolini 
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Annali di stomatologia
bone graft
Bone-defects healing by high-molecular hyaluronic acid: preliminary results
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G. Nicolini 
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Bone-defects healing by high-molecular hyaluronic acid: preliminary results
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1
    Bone-defects healing by high-molecular
    hyaluronic acid: preliminary results




                                                                                                      i
                                                                                                    al
                                                                                                  on
    Alberto Baldini, DDS1                                          clinical point of view, improves the handling and appli-
    Davide Zaffe, MD2                                              cation of the bone matrix inside the defects and, from a
    Gabriella Nicolini, PhD1                                       hystologic point of view makes it possible to obtain
                                                                   bone regeneration in less time when it is used with au-
    1University of Milano-Bicocca, Milan, Italy                    tologous bone.




                                                                                                zi
    Department of Neurosciences
    and Biomedical Technologies                                    Key words: autologous bone, hyaluronic acid, bone,
                                                                   bone defect healing, bone graft.
    (M. Baldoni)




                                                                       na
    2University of Modena and Reggio Emilia,
    Modena, Italy
    Department of Anatomy and Hystology,                           Introduction
    Human Anatomy Section (D. Zaffe)




                                                                     er
                                                                   Numerous biologic processes could take place following a tooth
    Corresponding author:                                          extraction, with important changes of the anatomy of the post-
    Dott. Alberto Baldini                                          extractive site (Trombelli, 2008).
    Centro Medico Polispecialistico Baldini Srl                    Processes involved in the healing of the extraction socket have
    Via S.Orsola, 5
    24100 Bergamo, Italy
    Tel.: 035/271935 - Fax: 035/694280
                                                             nt    been evaluated in animal experimental situations (Lekic, 2001;
                                                                   Sato, 2007) and in human models (Boyne,1966).
                                                                   The anatomo-morphologic situation of the empty socket in-
                                                   iI
    E-mail: alberto.baldini@unimib.it                              volves a vertical and horizontal bone reabsorption which mod-
                                                                   ifies the morphologic aspect with a decrease in height, in the
                                                                   thickness of the alveolar bone and gingival collapse (Schropp,
                                                                   2003; Trombelli, 2008).
                                      on

                                                                   At the end of the involutional processes the socket could re-
                                                                   sult unsuitable for the implant diameter. At this point the cli-
    Summary                                                        nician has to deal with surgical problems difficult to solve and,
    Bone-defects healing by high-molecular hyaluronic              the insertion of the implant could be unsatisfying from an aes-
    acid: preliminary results.                                     thetic point of view (Carlino, 2008).
                             i


                                                                   For instance the positioning of graft material or the use of mem-
                          iz



    Aim. The aim of this study is to evaluate the capability of    branes to cover and prevent outer communication (Adriaens,
    Hyaloss™ matrix (Fab – Fidia Advanced Biopolymers –            1999). Some authors do not agree with the insertion of graft
    Pd – Italy), a biomaterial based on hyaluronic acid, used      material in post-extractive sites because it seems to interfere
           Ed




    as organic scaffold in bone repair in post-extractive de-      with the normal healing process of the bone in the areas where
    fects.                                                         the implant is to be inserted (Becker, 1996; Buser,1998; Artzi,
    Materials and methods: 20 post-extractive sockets were         2000).
    selected, with similar size defects in the same patient        Much research, performed on human models using dem-
    and in the same hemiarch. Hyaluronic acid with high mo-        ineralized freeze-dried bone allograft (DFDBA) (Becker,
    lecular weight (Hyaloss™ matrix, Fab – Pd – Italy) was         1996) and deproteinized natural bovine bone mineral (Bio-Oss)
    mixed with autologous bone obtained using Safe-                (Carmagnola, 2001), have demonstrated the presence of par-
IC




    scraper® curve (Meta – Re – Italy) to repair post-extrac-      ticles of grafted material in the alveolar sockets even 6-9
    tive sites. Safescraper® is a cutting edge system that         months after their insertion. Other authors (Lekovic, 1997) have
    allows to the collection of autologous bone without            demonstrated that using reabsorbable membranes made of
    using traditional, incision-based collection techniques,       polylactic and polyglicolic acid material can lower the reab-
C




    which could cause discomfort to the patient.                   sorption of the bone.
    Results: Clinical and hystological evaluations were per-       Bone grafting is a common option in treating bone defects and
    formed, four months after grafting, in the maxilla and in      reconstructing alveolar bone before an implant insertion. Every
    the mandible. From a clinical point of view Hyaloss™           grafting material, homologous, xenologous, heterologous or
    matrix mixed with autologous bone and patient’s blood          synthetic, has some drawbacks, even if they have a distinc-
©




    becomes a substance similar to gel, which is easy to in-       tive feature: availability on demand. Autologous bone is “gold
    sert in to the defect. From a hystological point of view, in   standard” for bone grafting (Jakse, 2001) since it does not pro-
    the treated site there is the presence of an erosive ac-       duce adverse reactions and has optimal biocompatible re-
    tivity, with accelerated angiogenetic and bone remodel-        modelling patterns and osteoinductive capabilities (Bunger,
    ling activities.                                               2003; Hu, 2004). Bone has been used in blocks (Misch, 1992)
    Conclusions: The preliminary results show an accelera-         or in particulates (Missori, 2002), alone (Dahlin, 1988 ) or un-
    tion of the bone deposit process and of its remodelling        der a membrane protected space in guided bone regenera-
    due to the presence of Hyaloss™ matrix, which, from a          tion (GBR) procedure (Simion, 1998) or mixed with other graft

    2                                                                                     Annali di Stomatologia 2010; I (1): 2-7
    Bone-defects healing by high-molecular hyaluronic acid: preliminary results


    materials (Hallman, 2002). Controversy remains as to whether         simple, linear structure, due to the repetition of the dimer glu-
    cortical or spongy bone is the material of choice for autolo-        curonic acid/N-acetylglucosamin. Numerous studies (Toole,
    gous bone graft.                                                     2001; Huang, 2003; Chen, 1999; Weigel, 1988; Peattle,
    Particulated bone can be harvested in many ways. The most            2004; Peattle, 2002) highlighted the roles of hyaluronic acid
    common method is to mill large bone portions ( Springer, 2004).      in the inflammatory response, in antimicrobic and osteoinductive
    Treatment of transplants with the bone mill or lifting transplants   activities. These activities are particularly important in bone re-




                                                                                                             i
    by rotating electrical instruments seem to reduce the amount         generation, especially in repairing bone defects (Slevin,




                                                                                                           al
    of viable bone cells supplied. Some authors collect bone dur-        2002; Pilloni, 2003; Graber,1999; Sasaki, 1995; Savani 2001).
    ing implant surgery (Zaffe, 2007), however they need an im-          Hyaluronic acid, once it is inserted, is quickly metabolized and
    plant site. The use of a bone collector represents an un-            therefore its effect lasts only a short time.




                                                                                                         on
    common technique. Bone collectors were proposed many                 HYAFF®-11 (Fidia- Abano Terme- Pd) has been created to sta-
    years ago (Widmark, 2000), but they have been continuous-            bilize this polymer, which derives from bacterial hyaluronic acid.
    ly redesigned, renewed, studied and proposed to achieve the          From HYAFF®-11 it is possible to obtain Hyaloss™matrix, which
    most effective and practical use (Zaffe, 2007).                      is the subject of our study and which, once it has been de-
    The aim of this study has been to evaluate, from a clinical per-     hydrated, becomes similar to a fibrous felt (Fig. 2).




                                                                                                       zi
    spective, if the hyaluronic acid mixed with cortical autologous      Surgery: following a local anaesthesia and elevation of a
    bone particles harvested from intraoral sites can prevent or         vestibular and palatal or lingual flap, the teeth are delicately
    reduce the bone reabsorption after tooth avulsion, compared          extracted. The sockets, after the extraction of radicular rests,




                                                                             na
    with control cases when only autologous bone is inserted, and        have been carefully cleaned using alveolar spoons to remove
    make a hystological evaluation of the quantity and the qual-         the granulation tissue (Fig. 3). In this research we decided to
    ity of the bone tissue developed in the post-extractive sock-        perform a surgical extraction and to insert Hyaloss™matrix and
    et 4 months after the graft insertion with microradiography and      autologous bone and suture in the test site and simple suture
    Sem analysis.                                                        and the application of autologous bone, collected using safe-




                                                                           er
                                                                         scraper, in the control site.
                                                                         In this study Hyaloss™matrix was mixed with autologous bone
    Materials and methods                                                to fill post-extractive cavities. The autologous bone was col-
                                                                         lected using Safescraper® (Meta – RE), a new device which
    Selection of the patients: we selected 10 patients (6 females
    and 4 males), aged between 25 and 55, who needed tooth ex-
    tractions due to periodontal or endodontic problems. It was
    necessary to insert in their sockets osteointegrated implants
                                                                   nt    allows the possibility to obtain large quantities of bone par-
                                                                         ticulate with a slightly invasive surgical operation. The Safe-
                                                                         scraper®curve (Meta – RE – Italy) is used to repair post-ex-
                                                                         tractive sites. Safescraper® is a cutting edge system to col-
                                                        iI
    to substitute at least two teeth. In particular we decided to con-   lect autologous cortical bone with a slightly invasive method,
    sider sockets in the same hemiarch which could allow the in-         without using techniques which can cause great discomforts
    sertion of 10 mm long implants. So there was no need to re-          to the patient. With this method allows to the collection of great
    sort to GBR (Guided Bone Regeneration) to correct bone de-           quantities of cortical and autologous bone (from 2 to 5 cc) (Fig.
                                         on

    fects following tooth extractions, to favour a correct insertion     4). Using Hyaloss™matrix as adjuvant of the autologous bone
    of the implant in the socket after the avulsion of the compro-       in the regeneration process improves the graft handling and
    mised teeth.                                                         the application of bone matrix obtained inside the defects. Dur-
    Patients should not have systemic disorders. We also excluded        ing the collection process the intertwined lamellae of bone, mix
    from this study patients who showed, through anamnesis or            directly with blood, allowing Hyaloss™matrix to hydrate and
                               i


    radiography, symptoms or pathologies of nasal and paranasal          to form a high density bone concentrate which can be used
                            iz



    sinuses, in case of implant insertion near the maxillary sinus.      as a very good filler in regeneration therapy (Fig. 5). Patients
    Before being inserted in to the protocol, we informed the pa-        were treated with chlorhexidine-dicluconate 0,2% twice a day
    tients about the kind of research they were going to be sub-         for two weeks. They were also asked to undergo antibiotic ther-
           Ed




    dued to and they signed the informed consent. Every patient          apy for 6 days, while an analgesic was suggested only in case
    received basic information for adeguate control of bacterial         of post-operative pain. Stitches were removed a week after
    plaque and oral hygiene. We evaluated the general state of           the excision. Four months after bone and Hyaloss™matrix
    health through anamnesis: an eventual hypothesis regarding           graft, after local anaesthesia and elevation of a buccal and lin-
    implant rehabilitating treatment was considered through a clin-
    ical evaluation of the stomatognathic apparatus. The subjects
    representing potential candidates for this study were subjected
IC




    to the following controls:
    standard haematochemical evaluation, to rule out every
    systhemic pathology which was unknown at the moment of
    the anamnesis;
C




    radiographic evaluation through orthopantomography (OPT),
    teleradiography of the skull in latero-lateral projection (Tele L-
    L) and computerized axial tomography plus dentalscan (TAC
    – Dentalscan), to identify the atrophy class, the possible
    pathologies of the maxillary sinus and to plan a detailed sur-
©




    gical excision.
    The aim of this research has been to study the activity of a
    biopolymer, based on hyaluronic acid, used as scaffold to re-
    pair bone defects.
    Hyaluronic acid is a natural polysaccharide with high molec-
    ular weight (>5MDa), which is normally present in great quan-
    tities in amorphous, extracellular matrixes such as basal lam-
    inae, connective matrixes and synovial fluid (Fig. 1). It has a      Figure 1 - Hyaluronic acid.


    AAnnali di Stomatologia 2010; I (1): 2-7                                                                                             3
    A. Baldini et al.


    gual flap, fixtures were inserted in post-extractive sites and
    in control sites treated only with autologous bone (Fig. 6).
    Biopsies: during the preparation of the implant site a surgical
    trephine of 3 mm diameter and 6 mm long was used to collect
    bone cores. Following the surgical protocol to prepare the im-
    plant site for the insertion of fixtures, the site was widened to




                                                                                                          i
    receive implants of 3,7 mm diameter and 10 mm or more long.




                                                                                                        al
    Biopsies were fixed in 4% paraformaldehyde in 0.1 M phos-
    phate buffer pH 7.2 for 1 h at room temperature and then de-
    hydrated and embedded in methyl methacrylate (PMMA) at




                                                                                                      on
    4°C, as reported elsewhere. Longitudinal thin (5-µm-thick) and
    thick (200-µm-thick) sections were obtained from biopsies us-
    ing an Autocut 1150 bone microtome (Reichert-Jung-D) and            Figure 4 - Safescraper device for bone harvesting near the bone
    a diamond saw microtome (1600, Leica, D), respectively. Thick       defect.
    sections were reduced to 100 µm and X-rayed (microradi-




                                                                                                    zi
    ographed). Thin sections have been stained with toluidine blue,
    trypanblue, solochrome cyanin/nuclear fast red as reported          collection procedure allows the harvesting of great quantities
    elsewhere. Microradiographs and thin sections were analyzed         of cortical autologous bone (2 to 5 cc). Therefore the use of




                                                                            na
    and photographed using an Axiophot Zeiss microscope un-             Hyaloss™matrix in autologous bone grafting improves han-
    der ordinary or polarized light.                                    dling and application inside the defect. During the collection
                                                                        process the intertwined lamellae of bone, mixed with blood and
                                                                        Hyaloss™matrix, form a high density bone concentrate
    Results                                                             which can be used as a very good filler in regeneration ther-
                                                                        apy. Hyaluronic acid, thanks to its own features, helps to im-




                                                                          er
    From a clinical point of view Hyaloss™matrix mixed with au-         prove the tissue repairing processes, creating an ideal envi-
    tologous bone and patient’s blood becomes a substance sim-          ronment for the recovery and restoration of connective and
    ilar to gel, which is easy to insert in to the defect. The bone     bony tissues.

                                                                  nt
                                                       iI
                               i        on
                            iz
           Ed




    Figure 2 - Hyaff’s molecule.
IC
C
©




    Figure 3 - Radiographic control of two post extractive sites be-    Figure 5 - Autologous cortical bone mixed with hyaluronic acid
    fore the grafting.                                                  ready to be inserted in to the bone socket.


    4                                                                                         Annali di Stomatologia 2010; I (1): 2-7
    Bone-defects healing by high-molecular hyaluronic acid: preliminary results


                                                                          gy, using both its physiochemical and biological properties.
                                                                          It interacts with other macromolecules and plays a predom-
                                                                          inant role in tissue morphogenesis, cell migration, differenti-
                                                                          ation and adhesion (Toole, 1991; Turley, 1989; Toole, 2001).
                                                                          Up to today hyaluronic acid has been used prevalently in pe-




                                                                                                              i
                                                                          riodontology and oral pathology (Ballini, 2009; Vandebogaerde,




                                                                                                            al
                                                                          2009).
                                                                          In his protocol of research Ballini (Ballini, 2009) analyzed the
                                                                          osteoinductive effect of hyaluronic acid as an adjuvant in the
                                                                          grafting processes to produce bone-like tissue, employing au-




                                                                                                          on
                                                                          tologous bone obtained from intraoral sites, to treat intrabony
                                                                          defects without covering membrane, in 9 patients. The clini-
                                                                          cal results showed an average increase in clinical attachment
                                                                          and suggest that autologous bone combined with hyaluron-
                                                                          ic acid seems to have good capabilities in accelerating new




                                                                                                        zi
                                                                          bone formation in the intrabony defects.
                                                                          In the Vandebogaerde work (Vandebogaerde, 2009) 19
    Figure 6 - The implants (Swiss Plus 3,75x12 mm) at 3 months           deep periodontal defects were analyzed. One year after the




                                                                              na
    grafting. The mesial implant is the control case (only cortical au-   treatment, the average PPD has been reduced to 5,8 mm, gin-
    tologous bone), the distal implant is the treated case (autologous    gival recession increased to 2.0 mm and the attachment in-
    cortical bone and hyaluronic acid).                                   crease was to 3.8 mm, using esterified hyaluronic acid
                                                                          (Hyaloss™ matrix).
    During sutures removal, no important tissue inflammation was          In our protocol we wanted to evaluate the clinical effectiveness




                                                                            er
    observed. A 10 day follow-up post-operative clinical assess-          of the use of Hyaloss™matrix with autologous bone in filling
    ment demonstrated a gingivitis grade of 0 or 1. Thanks to the         post-extractive defects and the following insertion of implants.
    bacteriostatic properties of the tested polymer, a more effective     The clinical criteria of reference to evaluate the success of the
    control of the surgical wound and non bacterial contamination         osteointegration are those suggested by Albrektsson (Al-
    of the surgical site were observed in all instances (Pilloni,
    2003).
    Post operative radiographs showed absence of bone re-
    modelling and satisfactory filling of the defects with Hyaloss™
                                                                    nt    brektsson, 1986 ) and modified by Buser (Buser, 1997). In par-
                                                                          ticular: lack of inflammatory signs or infection during clinical
                                                                          examination, lack of mobility, lack of peri-implantar radio-
                                                                          transparency. In all the evaluated sites we successfully inserted
                                                         iI
    and autologous bone in all the post-extractive sites. From a          implants following the above-mentioned criteria.
    hystological point of view the first results showed the presence      As a matter of fact the clinical and biological characteristics
    of a rich network of bone trabeculae, having a very high TBV.         of these defects favour the bone filling of the post-extractive
                                          on

    The newly formed bone was made mainly of woven structures             sites, while good regenerative activity was obtained in all sit-
    and showed few erosive activities. Comparison with control            uations. Our results confirm that bone harvesting with a man-
    sites indicated a preliminary prevail of bone amount produced         ual collector achieves good clinical success in extraction sock-
    by Hyaloss™matrix (Figs 7-8).                                         et healing (Zaffe, 2007). Also very interesting is the use of
    A total amount of 20 fixtures were placed with a 100% suc-            hyaluronic acid (Hyaloss™ matrix) which, as confirmed by hys-
                                i


    cess rate at the moment of prosthetic delivery.                       tologic evaluations, allows a better and faster healing process.
                             iz



                                                                          The preliminary results of our study seem to confirm the ones
                                                                          obtained through an experimental protocol performed on an-
    Discussion                                                            imals, which has a similar approach (Muzaffer, 2006).
            Ed




                                                                          In this study, two cavities of 3 mm diameter and depth were
    Thanks to its complex interactions with matrix components and         created in the right tibia of 30 adult rabbits. Following the pro-
    cells, hyaluronic acid has played multifaceted roles in biolo-        tocol, one of the cavities of the tibia is filled with hyaluronic
IC
C
©




                                                                          Figures 7 and 8 - (Hyaloss) Microradiographies of biopsies from
                                                                          maxillary post-extractive sites of the same patient, 4 months after
                                                                          grafting. The control shows an amount of bone higher than the
                                                                          Hyaloss treated site. Microradiography of the biopsy of the
                                                                          Hyaloss treated site: we can observe that the bone trabeculae
                                                                          seem to be particularly thick but show a large amount of vascu-
                                                                          lar neo-cavities.


    Annali di Stomatologia 2010; I (1): 2-7                                                                                             5
    A. Baldini et al.


                                                                        Conclusions

                                                                        The properties of hyaluronic acid are very useful in the re-
                                                                        generation therapy as adjuvant of autologous bone grafting.
                                                                        When it comes into contact with the patient’s blood or a saline
                                                                        solution, Hyaloss™matrix becomes a substance similar to gel,




                                                                                                              i
                                                                        which is easy to insert in to bone defects




                                                                                                            al
                                                                        Hyaloss™ matrix is easy to use because the clinician can ad-
                                                                        just it to suit every bone defect and every size to fill. The bio-
                                                                        chemical properties of this material allows a better healing and




                                                                                                          on
                                                                        post-operative follow-up.
                                                                        This preliminary study, with clinical and histological evalua-
                                                                        tions, shows an acceleration of bone deposition activities and
                                                                        of bone remodelling due to the presence of hyaluronic acid
                                                                        ,which can reduce the time required for bone regeneration




                                                                                                        zi
                                                                        when associated with autologous cortical bone.

    Figure 9 - Toluidine blue staining highlights living osteocytes
    (black arrow) both in newly formed bone and in grafted autolo-




                                                                               na
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©




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    6                                                                                             Annali di Stomatologia 2010; I (1): 2-7
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    Annali di Stomatologia 2010; I (1): 2-7                                                                                                   7
