10.59987/ads/2011.3-4.3-9
Hyaluronic acid (HA) is an ubiquitous form of non-sulphated glycosaminoglycan of the extracellular matrix of all mammalian connective tissues. It is mainly present during tissue’s formation or during most of initial tissue’s repair processess. Cell migration, adhesion and differentiation are only part of several unique biological characteristics of HA which have been under investigation in the past decades.
Aim of the study. Evaluate the possible positive effect of an esterified form of HA on gingival tissues in mild chronic periodontitis patients, seeking for the reduction of all the periodontal disease clinical parameters PLI (Plaque Index), BOP (Bleeding on Probing), PPD (Probing Pocket Depth), GI (Gingival Index), PAL (Probing Attachment Level).
Materials and methods. The study is an open, intrapatient, controlled, single center pilot clinical trial including 19 adult patients with mild chronic periodontitis and shallow pockets (&lt; 4 mm) in at least two different quadrants. One quadrant was treated with HA gel after regular toothbrushing (test), the other without (control).
Results. Although oral hygiene itself had a similar positive influence on the improvement of all the clinical indexes for test and control, the treatment with HA gel showed a greater effect almost always statistically significant. BOP in the HA gel treated areas had a decrease of 92.7% and GI of 96.5%, whereas controls 75.8% and 79.0% respectively. The difference of PPD in both areas was statistically significant (p&lt;0.01) in favour of the HA gel treated zone. Also PAL and Pl were reduced more with gel than with oral hygiene alone, although this did not reach a statistical significant difference.
Conclusion. It appears that an esterified gel form of HA has shown an effect in reducing the gingival inflammation when used as an adjunct to mechanical home plaque control and that it could be successfully used to improve the periodontal clinical indexes. This pilot study will gain substantial scientific significance when both a higher number of patients can be utilized and also by adding any possible further biological information, as with immunocytochemistry and histology
application/pdf
1971-1441
181
3-4
en
A. Polimeni 
https://creativecommons.org/licenses/by-nc-nd/4.0
Annali di stomatologia
Evaluation of the efficacy of an hyaluronic acid-based biogel on periodontal clinical parameters. A randomized-controlled clinical pilot study
Text.Serial.Journal
https://www.annalidistomatologia.eu/ads
2
Original Article
2022-08-18
2022-08-18
2011-12-01
2023-12-04
3-9
Ann Stomatol (Roma)
A. Polimeni 
2011
10.59987/ads/2011.3-4.3-9
3
1971-1441
3-4
en
9
Evaluation of the efficacy of an hyaluronic acid-based biogel on periodontal clinical parameters. A randomized-controlled clinical pilot study
https://www.annalidistomatologia.eu/ads/article/download/181/162
2
                                                                                                              Original article



    Evaluation of the efficacy of an hyaluronic
    acid-based biogel on periodontal clinical
    parameters. A randomized-controlled




                                                                                                                li
    clinical pilot study




                                                                                                             na
    Andrea Pilloni, MD, DDS, MS*                                  crease of 92.7% and GI of 96.5%, whereas controls
    Susanna Annibali, MD, DDS#                                    75.8% and 79.0% respectively. The difference of PPD
    Francesco Dominici, DDS*                                      in both areas was statistically significant (p<0.01) in




                                                                                                          io
    Carlo Di Paolo MD, DDS§                                       favour of the HA gel treated zone. Also PAL and Pl were
    Marco Papa, DDS§                                              reduced more with gel than with oral hygiene alone,
    Maria Antonietta Cassini, DDS*                                although this did not reach a statistical significant dif-




                                                                                   az
    Antonella Polimeni, MD, DDS§                                  ference.
                                                                  Conclusion. It appears that an esterified gel form of
                                                                  HA has shown an effect in reducing the gingival in-
    “Sapienza” University of Rome, Rome, Italy                    flammation when used as an adjunct to mechanical
    Department of Oral and Maxillofacial Sciences                 home plaque control and that it could be successful-




                                                                                 rn
    * Periodontics Unit                                           ly used to improve the periodontal clinical indexes. This
    # Oral Surgery Unit
                                                                  pilot study will gain substantial scientific significan-
    § Gnathological Unit
                                                                  ce when both a higher number of patients can be uti-
    § Pediatric Dentistry Unit
                                                                  lized and also by adding any possible further biological




                                                                      te
                                                                  information, as with immunocytochemistry and hi-
                                                                  stology.
    Corresponding author:
    Dott. Andrea Pilloni
    Department of Oral
                                                              In  Key words: extracellular matrix, hyaluronan, perio-
                                                                  dontal disease.
    and Maxillofacial Sciences
    Via Caserta, 6 - 00161 - Rome, Italy
    Phone +39 06 44230809
                                                                  Introduction
                                                 ni
    E-mail: andrea.pilloni@uniroma1.it
                                                                  In normal conditions the gingival tissues carry out typical
                                                                  functions of fibrous tissues, although presenting features
                                             io


    Summary                                                       very similar to soft tissues.
                                                                  The “ground substance”, which is the supporting structu-
    Hyaluronic acid (HA) is an ubiquitous form of non-sul-        re of the extracellular matrix and is formed by a highly struc-
                                   iz



    phated glycosaminoglycan of the extracellular matrix          tured net of proteoglycans in perfect equilibrium one ano-
    of all mammalian connective tissues. It is mainly pre-        ther, gives the gingival tissues a typical firm consistency.
    sent during tissue’s formation or during most of ini-         In this context, hyaluronic acid or hyaluronan (HA), an ubi-
                                                                  quitous nonsulphated glycosaminoglycan, plays a funda-
                  Ed




    tial tissue’s repair processess. Cell migration, adhe-
    sion and differentiation are only part of several unique      mental role (2). In fact, it has been shown that among gin-
    biological characteristics of HA which have been un-          gival diseases, periodontal disease is characterized by the
    der investigation in the past decades.                        loss of the normal gingival properties. Many studies
    Aim of the study. Evaluate the possible positive effect       show that the most important alterations are related to the
    of an esterified form of HA on gingival tissues in mild       reduction of the normal structural balance of the extra-
    chronic periodontitis patients, seeking for the reduc-        cellular matrix (21,24).
 IC




    tion of all the periodontal disease clinical parameters       In particular, the endogenous hyaluronan component re-
    PLI (Plaque Index), BOP (Bleeding on Probing), PPD            sults to be lacking within the epithelium and the gingival
    (Probing Pocket Depth), GI (Gingival Index), PAL              connective tissue with a consequent structural failure and
    (Probing Attachment Level).                                   loss of normal features of the gingiva (2,4,7). It was de-
C




    Materials and methods. The study is an open, intra-           monstrated that in patients with chronic periodontitis, the-
    patient, controlled, single center pilot clinical trial in-   re is a rapid loss of high molecular weight of hyaluronic acid
    cluding 19 adult patients with mild chronic perio-            due to enzymatic digestive processes (3). Hyaluronidase,
    dontitis and shallow pockets (< 4 mm) in at least two         an enzyme released by micro-organisms of bacterial pla-
©




    different quadrants. One quadrant was treated with HA         que, plays an essential role in such mechanism (14). The
    gel after regular toothbrushing (test), the other without     supply of constituents that can be utilized by the regene-
    (control).                                                    rating tissues in order to re-establish their internal struc-
    Results. Although oral hygiene itself had a similar po-       ture is, therefore, strictly necessary (10).
    sitive influence on the improvement of all the clinical       In the dental literature, HA has been shown to be bacte-
    indexes for test and control, the treatment with HA gel       riostatic with respect to periodontal pathogens (18) and ef-
    showed a greater effect almost always statistically si-       fective in vitro when both intramembranous and endo-
    gnificant. BOP in the HA gel treated areas had a de-          chondral models of osteogenesis are utilized (12,17). More

    Annali di Stomatologia 2011; II (3-4): 3-9                                                                                 3
    A. Pilloni et al.


    recently HA appears to be effective for the treatments of         be treated with HA gel or by normal oral hygiene proce-
    gingivitis (19).                                                  dures. Following initial assessment and after ensuring an
    An HA derivative, in esterified form, by maintaining the cha-     adequate oral hygiene, HA gel was applied after scaling
    racteristics of biocompatibility and biointeractivity of hya-     and root planning on the treated area (one quadrant) mas-
    luronic acid, (1,8), seems to be able to re-establish the         saging the gingiva with a soft-bristles toothbrush for 2-3
    ground substance’s normal equilibrium. Furthermore, it pos-       minutes and then asking the patient to eliminate the ex-




                                                                                                                     li
    sesses a very good bio-adhesiveness and fits tightly to the       cess by rinsing once with tap water. The other randomi-
    gingival mucosa, to be then rapidly incorporated into the         zed selected quadrant (contralateral) was considered as




                                                                                                                  na
    epithelial layers (29). When compared to HA, the esteri-          control and treated by normal oral hygiene procedures.
    fied form is more resistant to enzymatic biodegradation (20).     The treatment was repeated daily by the patient who has
    Based upon such premises, a benzylic ester of hyaluro-            been adequately instructed by the investigator for a total
    nic acid (HYAFF®, Anika Therapeutics Srl), for the treat-         period of three weeks. The patient was asked to return to




                                                                                                               io
    ment of gingival inflammation, has been developed in a gel        the office after 7, 14 and 21 days to assess parameters
    form for clinical use. The aim of this clinical pilot study is    for tolerability and efficacy.
    to evaluate the efficacy of an esterified gel form of HA on       Initial, control and final visits comprised: treatment com-
    the reduction of clinical indexes typically present in the ini-   pliance, assessment of concomitant medications, objec-




                                                                                       az
    tial stages of periodontal disease.                               tive oral exam, gingival tenderness or pain, root sensiti-
                                                                      vity, evaluation of clinical indexes (BOP, PAL, PPD, PLI, GI).
                                                                      Control and final visits included respectively safety details
    Materials and methods                                             as adverse events and overall judgement of the investigator




                                                                                     rn
                                                                      about tolerability and efficacy of HA gel.
    The study is an open, intra-patient, controlled, single cen-
    ter pilot clinical trial including 19 adult patients with mild    Statistics
    chronic periodontitis: 10 male (55,6%), 9 female (44,4%),         No statistical considerations were made in order to defi-




                                                                          te
    with an age range of 20-75 (mean 41,9 ±15,1).                     ne the sample size, considering a pilot study.
    After ethical committee approval received, at initial scree-      Baseline, demographic and anamnestic data and effica-
    ning visit, patients who fulfilled the selection criteria and     cy data were summarized by means of descriptive stati-
    with shallow pockets (< 4 mm) in at least two different qua-      stics such as mean, standard deviation, standard error, mi-
    drants, were included in the study. One quadrant was trea-
                                                                  In  nimum and maximum value, frequency distributions.
    ted with HA gel (test), the other without (control).              Although it was not planned, statistical comparison between
    Patients had to return for the control visits after 7, 14 and     the two zones at baseline and at different visits after tre-
    21 days. The selection of study population has been ba-           atment, was performed by mean of Paired Wilcoxon test
    sed on the following criteria:                                    or Paired t-test. Before performing statistical analysis of
                                                    ni

    • patients affected by mild adult periodontitis;                  data, the criteria for the identification of the population for
    • patients with shallow pockets (PPD <4mm), present in at         the efficacy analysis were defined. The following three po-
        least two different quadrants of the oral cavity (PSR 4);     pulations were identified:
                                          io


    • patients in good general health;                                1. Safety population: All patients who receive at least one
    • no smokers;                                                         application of HA gel;
    • patients with given informed consent.                           2. Intention-to-Treat population (ITT): All patients of sa-
                                 iz



    The exclusion criteria were:                                          fety population who are assessed at least at one con-
    • patients who did not collaborate and/or were not tru-               trol visit;
        stworthy;                                                     3. Per-Protocol population (PP): All patients of Intention-
                  Ed




    • smokers;                                                            to-treat population who have no major protocol viola-
    • PPD >4mm.                                                           tions.
    Patients were withdrawn from the study for the following          Major protocol violations (that could affect efficacy) were
    reasons: patient request, failure to return to two consecutive    classified following the definition here below:
    control visits, protocol violation, insufficient patient com-         1. Patients with poor compliance;
    pliance, serious adverse event, other reasons which had               2. Patients with no (or not recorded) periodontal di-
    to be justified.                                                           sease;
 IC




    Efficacy of the gel under investigation was assessed by               3. Patients without shallow pockets.
    measuring the following variables:                                Data were transferred on a database by means of
    • Reduction of BOP (Bleeding on probing);                         SAS/FSP software. Checks for inconsistencies and im-
    • Gain of PAL (Probing Attachment Level);                         plausibility were made via computer.
C




    • Reduction of PPD (Probing Pocket Depth);
    • Reduction of PLI (Plaque Index);
    • Reduction of GI (Gingival Index);                               Results
©




    Treatment Procedures                                              Study population
    During the initial visit oral hygiene habits of the patients      Of the 19 patients enrolled in the study eighteen were as-
    were assessed and an accurate exam of the oral cavity to          sessed at all visits, while one patient (5.3%) withdrew be-
    detect any visible alteration of oral tissues was performed.      fore completing the study because he did not return for the
    Measurement of clinical indexes (BOP, PAL, PPD, PLI, GI)          final visit. No patient was excluded from the study and no
    was also performed and patient was also questioned re-            patient was excluded from the analysis of efficacy that was
    garding root sensitivity and gingival pain. The two affec-        performed on all 19 individuals. (Safety, ITT and Per-Pro-
    ted zones were randomly assigned by the investigator to           tocol population were the same).

    4                                                                                        Annali di Stomatologia 2011; II (3-4): 3-9
    Evaluation of the efficacy of an hyaluronic acid-based biogel on periodontal clinical parameters.
    A randomized-controlled clinical pilot study

    Table 1 - Demography                                             Table 2 - Age distribution.

                                                     HA-gel                                                  HA-gel Number (%)
           Number of patients                             19                  Number of patients                     19
                  SEX                                                               <18                            0 (0,0)




                                                                                                                   li
                  Male                             10 (55,6%)                      18<30                          5 (26,3)
                 Female                             9 (44,4%)                      30<40                          3 (15,8)




                                                                                                                na
                                                                                   40<50                          5 (26,3)
                   AGE                                                             50<60                          4 (21,1)
                  Mean                                 41,9                        60<65                           1 (5,3)
                    SD                                 15,1                         >65                            1 (5,3)
                    ES                                  3,5




                                                                                                             io
                  Range                               20-75
                     N                                  19
                                                                     Baseline Data




                                                                                       az
              WEIGTH (kg)                                            Demographic characteristic of the patients (mean, stan-
                Mean                                  68,2           dard deviation, standard error, minimum and maximum va-
                  SD                                  14,7           lue) are reported in Tables 1 and 2. Ten patients were ma-
                  ES                                   3,4           les, 9 females with an average of 41.9±15.1 years. Three
                Range                              49,5-106,0




                                                                                     rn
                                                                     patients received some medications before entering the
                   N                                   19            study, for a total of five drugs, while two patients received
                                                                     concomitant drugs also during the treatment period.
              HEIGTH (cm)                                            The two zones, test and control, appeared to be compa-




                                                                         te
                 Mean                                171,3           rable for PAL, PPD, PI and GI. The same unbalance was
                  SD                                  7,0            present for BOP, with a greater average score in the test
                  ES                                  1,6            selected sites (39.6%), compared to the control sites
                 Range                              150-180          (29.3%) (p=0.03). The two affected areas were random-
                   N                                  19
                                                                In   ly assigned by the investigator to be treated with HA gel
                                                                     or by normal oral hygiene procedures.
                                                                     Although in favour of the control, this unbalance did not af-
                                                                     fect the comparability of the two groups.
    Protocol Deviations
                                                       ni
    Neither major nor minor protocol deviations were registered      Patient Compliance
    in the study. Consequently Safety, ITT and Per-Protocol po-      All 19 patients (100%) applied the gel as prescribed. Oral
    pulation were identical.                                         hygiene compliance was very good in 94.7% of them.
                                             io
                                   iz



    Table 3 - Bop (bleeding on probing) during treatment.

                BOP                              Baseline               T7                       T14                   T21
                  Ed




        (Bleeding on Probing)                                     (after 7 days)           (after 14 days)       (after 21 days)

    HA-gel
                  Mean                             39,6               20,8                       5,2                    2,9
                   SD                              29,6               16,7                       4,1                    4,3
                   SE                              6,8                 3,8                       1,0                    1,0
                  Range                          8,3-100             0-58,3                    0-12,5                 0-12,5
 IC




                    N                               19                 19                        19                     18

    Control
                  Mean                             31,1               22,9                      11,6                    7,1
C




                   SD                              21,2               16,3                      10,5                    6,8
                   SE                               4,9                3,7                       2,4                    1,6
                  Range                          8.3-83,3           4,1-54,1                   0-33,3                 0-29,1
                    N                               19                 19                        19                     18
©




           Difference between
              treatments (*)                       8,47               -2,09                    -6,44                   -4,18

               Paired t-test                       1,97               -0,50                    -2,65                  -2,84
                 p-value                           0,06                0,62                     0,02                   0,01

    (*) HA-gel/control

    Annali di Stomatologia 2011; II (3-4): 3-9                                                                                  5
    A. Pilloni et al.


                                                                 to 22.9±16.3 % after one week, to reach the minimum va-
                                                                 lue of 7.1±6.8 % at the end of the study (percent decrea-
                                                                 se = 75.8 %). Both at 14 and at 21 days, the difference
                                                                 between the two zones was statistically significant, with
                                                                 p=0.02 and p=0.01 respectively (Table 3, Figure 1).




                                                                                                               li
                                                                 PAL (Probing Attachment Level)
                                                                 At baseline, the average of PAL was comparable in the two




                                                                                                            na
                                                                 zones (2.2±0.7 and 2.0±0.5 respectively for test and con-
                                                                 trol). This index decreased during treatment period in both
                                                                 areas, but even if the decrease was greater in the HA gel
                                                                 treated zones the difference between the two groups did




                                                                                                         io
                                                                 not reach the statistical significance at any time. After 21
                                                                 days the averages were respectively 1.9±0.8. and 2.0 +
                                                                 0.4 (Table 4, Figure 2).




                                                                                 az
    Figure 1 - Mean (SD) of BOP during the study.

    Table 4 - PAL (Probing Attachment Level) during treatment.




                                                                               rn
                   PAL
        (Probing Attachment Level)           Baseline              T7                      T14                       T21

    HA-gel




                                                                     te
                 Mean                           2,2                2,1                     2,0                       1,9
                  SD                            0,7                0,7                     0,8                       0,8
                  SE                            0,2                0,2                     0,2                       0,2
                 Range                        0,8-4,3            0,8-3,5                 0,6-3,4                    0-3,1
                   N                            19
                                                                 In19                      19                        18

    Control
                 Mean                           2,0                2,0                     2,0                       2,0
                                                    ni
                  SD                            0,5                0,5                     0,5                       0,4
                  SE                            0,1                0,1                     0,1                       0,1
                 Range                        1,1-2,7            1,2-2,6                 1,2-2,6                   1,3-2,6
                   N                            19                 19                      19                        18
                                          io


            Difference between
               treatments (*)                   0,19              0,11                    -0,01                     -0,07
                                 iz



               Paired t-test                    1,44              1,04                    -0,06                     -0,55
                 p-value                        0,17              0,31                     0,95                      0,59
                  Ed




    (*) HA-gel/control
 IC
C




    Figure 2 - Mean (SD) of PAL during the study.                Figure 3 - Mean (SD) of PPD values during the study
©




    BOP (Bleeding on Probing)                                    PPD (Probing Pocket Depth)
    In the treated areas the average of BOP was 39.6±29.6        At baseline the average of PPD was comparable in the two
    % at baseline, which decreased to 20.8±16.7 % after one      zones: 3.3±0.6 and 3.3±0.6 respectively for test and con-
    week, then reaching the minimum value after 21 days:         trol. After seven days of treatment the index decreased with
    2.9±4.3 % (percent decrease = 92.7 %). In the control are-   both treatments, but in the HA gel treated areas it reached
    as the average was 31.1±21.2 % at baseline, decreased        a lower average than in the control ones: 2.8±0.6 vs.

    6                                                                                  Annali di Stomatologia 2011; II (3-4): 3-9
    Evaluation of the efficacy of an hyaluronic acid-based biogel on periodontal clinical parameters.
    A randomized-controlled clinical pilot study

    Table 5 - PPD (Probing Pocket Depth) during treatment.

                 PPD                             Baseline                T7                     T14                     T21
        (Probing Pocket Depth)                                     (after 7 days)         (after 14 days)         (after 21 days)

    HA-gel




                                                                                                                   li
                  Mean                              3,3                 2,8                     2,4                      2,5
                   SD                               0,6                 0,6                     0,7                      0,7




                                                                                                                na
                   SE                               0,1                 0,1                     0,2                      0,2
                  Range                           2,5-4,5             1,9-4,1                 1,3-3,8                  1,3-3,7
                    N                               19                  19                      19                       18




                                                                                                             io
    Control
                  Mean                              3,3                 3,1                     2,8                     3,0
                   SD                               0,6                 0,6                     0,9                     0,7
                   SE                               0,1                 0,1                     0,2                     0,2




                                                                                      az
                  Range                          2,35-4,3             2,3-4,4                  0-4,2                   2-4,4
                    N                               19                  19                      19                      18

           Difference between




                                                                                    rn
              treatments (*)                       0,02                -0,29                   -0,42                    -0,47

               Paired t-test                       0,20                -3,29                   -2,42                   -3,36
                 p-value                           0,85                <0,01                    0,03                   <0,01




                                                                          te
    (*) HA-gel/control                                         In
    3.1±0.6 (p < 0.01). At the end of treatment the difference        and control. This index decreased during treatment in both
    was still significantly in favour of the HA gel treated zone      areas, but even if the decrease was greater in the HA gel
    (p<0.01) (Table 5, Figure 3).                                     treated zone the difference between the two groups did not
                                                       ni
                                                                      reach the statistical significance at any time. After 21 days
    PLI (Plaque index)                                                the averages were respectively 4.6±4.3 % (percent de-
    At baseline the average of PLI was comparable in the two          crease = 87.8 %) and 8.1±9.1 % (percent decrease = 78.1
    zones: 37.6±20.6 % and 37.0±22.6 % respectively for test          %) (Table T6, Figure 4).
                                             io
                                   iz



    Table 6 - PLI (Plaque Index) during treatment

                   PLI                           Baseline                T7                     T14                     T21
                  Ed




              (Plaque Index)                                       (after 7 days)         (after 14 days)         (after 21 days)

    HA-gel
                  Mean                             37,6                12,7                     4,3                      4,6
                   SD                              20,6                 9,8                     5,9                      4,3
                   SE                               4,7                 2,2                     1,4                      1,0
                  Range                          8,3-83,3              0-31                   0-20,8                   0-12,5
 IC




                    N                               19                  19                      19                       18

    Control
                  Mean                             37,0                15,4                     6,0                      8,1
C




                   SD                              22,6                16,4                    10,7                      9,1
                   SE                               5,2                 3,8                     2,5                      2,2
                  Range                          12,5-83,3            0-70,8                  0-45,8                   0-37,5
                    N                               19                  19                      19                       18
©




           Difference between
              treatments (*)                       0,62                -2,72                   -1,69                    -3,46

               Paired t-test                       0,17                -1,11                   -0,85                    -1,66
                 p-value                           n.s.                 n.s.                    n.s.                     n.s.

    (*) HA-gel/control

    Annali di Stomatologia 2011; II (3-4): 3-9                                                                                   7
    A. Pilloni et al.


    Table 7 - GI (Gingival Index) during treatment.

                    GI                        Baseline                       T7                      T14                       T21
             (Gingival Index)                                          (after 7 days)          (after 14 days)           (after 21 days)

    HA-gel




                                                                                                                         li
                 Mean                            20,0                       4,5                      1,6                       0,7
                  SD                             18,8                       6,6                      3,0                       2,1




                                                                                                                      na
                  SE                              4,3                       1,5                      0,7                       0,5
                 Range                           0-75                      0-25                     0-8,3                     0-8,3
                   N                              19                        19                       19                        18




                                                                                                                   io
    Control
                 Mean                            21,0                      10,2                      3,6                        4,4
                  SD                             14,3                      11,2                      3,9                        3,3
                  SE                              3,3                       2,6                      0,9                        0,8




                                                                                           az
                 Range                          0-62,5                     0-50                    0-12,5                      0-10
                   N                              19                        19                       19                         18

           Difference between




                                                                                         rn
              treatments (*)                    -1,01                      -5,68                    -1,98                     -3,68

               Paired t-test                    -0,20                      -1,82                    -2,92                     -4,17
                 p-value                         n.s.                       0,09                     0,01                     <0,01




                                                                              te
    (*) HA-gel/control                                             In
                                                      ni
                                           io


    Figure 4 - Mean (SD) of Plaque Index during the study.                Figure 5 - Mean (SD) of Gingival Index during the study.
                                  iz



    GI (Gingival index)                                                   biomaterial. No visible alterations of oral tissues were seen
                  Ed




    At baseline the Gingival Index was, on average, com-                  during the study in the treated areas with HA gel.
    parable in the two zones, with a mean value of 20.0±18.8              Both gingival reddening and pain were in favour of HA gel
    % in the one to be treated with HA gel and 21.0±14.3 %                at all visits, although they do not reach statistical signifi-
    in the control. After one week the GI was reduced to                  cance. Subjective judgement of patient on symptomatic
    4.5±6.6 in the testy and to 10.2±11.2 % in the control.               evolution during the treatment period improved more in HA
    The very large variability in both groups did not allow this          gel zones than in the control zones, reaching a positive re-
    difference, strongly in favour of HA gel, to be significant.          sult (100.0 %) at the end of treatment compared with the
 IC




    Statistical significance was reached at 14 and 21 days                results (66.7 %) of the control zones. The difference bet-
    of treatment with p<0.01. At 21 days the percent reduction            ween treated and control zone values are significant at all
    from basal average level in the HA gel areas was 96.5                 visits. (p<0.01).
    % while in the control once it was 79.0 % (Table 7, Fi-               Root sensitivity showed a higher decrease in HA gel trea-
C




    gure 5).                                                              ted zones and the taste of the product was positive at the
                                                                          end of the study for all patients.
                                                                          Furthermore, investigator’s overall judgement on tolerability
    Discussion                                                            of HA gel was completely positive and no adverse event
©




                                                                          occured, confirming the safety of the product.
    In this study HA gel has been tested on 19 patients affected          All efficacy indexes had a decrease in the HA gel treated
    with mild chronic periodontal disease, with shallow poc-              zone, a decrease which was significant in comparison with
    kets in at least two different quadrants , comparing the ma-          normal oral hygiene used in the control zones for BOP, PPD
    terial with normal oral hygiene.                                      and GI.
    Based upon the obtained results it is important to notice that        In fact even if the oral hygiene had a positive influence
    all the evaluated parameters for assessing the tolerability           on the outcome of all the clinical indexes measured in the
    of HA gel, the principal aim of this study, are in favour of the      study, the treatment with HA gel showed a greater effect

    8                                                                                            Annali di Stomatologia 2011; II (3-4): 3-9
    Evaluation of the efficacy of an hyaluronic acid-based biogel on periodontal clinical parameters.
    A randomized-controlled clinical pilot study

    almost always statistically significant. BOP in the HA gel                       and immune response in wound healing. J Periodontol 2001;
    treated areas had a decrease of 92.7% and the correlated                         72(9):1192-200.
    GI of 96.5%, respectively 75.8% and 79.0% in the con-                      10.   Haase HR, Bartold PM. Enamel matrix derivative induces matrix
                                                                                     synthesis by cultured human periodontal fibroblast cells. J Peri-
    trol areas. The difference of PPD in both areas was sta-
                                                                                     odontol 2001; 72(3):341-8.
    tistically significant (p<0.01) in favour of the HA gel trea-              11.   Kaneko S, Ohashi,K, Soma K, Yanagishita M. Occlusal hypofunction
    ted zone.




                                                                                                                                       li
                                                                                     causes changes of proteoglycan content in the rat periodontal lig-
    Also PAL and Pl diminished more with gel than with oral                          ament.” J Periodontal Res 2001;36(1):9-17.
    hygiene, although it does not reach a statistical significant




                                                                                                                                    na
                                                                               12.   Kang MK, Sison J, Nachnani S, Pilloni A and Bernard GW. Low mo-
    difference. The investigator’s overall judgement on effica-                      lecular weight hyaluronic acid enhances osteogenesis of adult rat
    cy of HA gel was positive in 84.3% of the treated patients.                      bone marrow cells in vitro. Int. J. of Oral Biology 1998; , 23: 149-
                                                                                     155.
                                                                               13.    Kirkham J, Robinson C, Smith AJ, Spence,A. The effect of Peri-
                                                                                     odontal disease on sulphatated glycosylaminoglycan distribution




                                                                                                                                 io
    Conclusion
                                                                                     in the sheep periodontium, Archs Oral Biology 1992; 37, n°12: 1031-
                                                                                     1037.
    In conclusion, it appears that the treatment with HA gel has               14.    Last KS, Embery G. Hyaluronic acid and hyaluronidase activity in
    shown an effect in reducing the gingiva inflammation and




                                                                                                    az
                                                                                     gingival exudate from sites of acute ulcerative gingivitis in man. Archs
    that it could be successfully used to improve the the pe-                        Oral Biol 1987; 32, n°11: 811-815.
    riodontal clinical indexes.                                                15.   Last KS, Stanbury JB, Embery G. Glycosaminoglycans in human
    Additionally, the effect of hyaluronan seems to be, from the                     gingival crevicular fluid as indicators of active periodontal disease.
    patient’s side, more beneficial by reducing, in the test si-                     Arch Oral Biol 1985;30(3):275-81.




                                                                                                  rn
    tes, both staining and change of taste or calculus forma-                  16.   Matsukawa,F. Biochemical analysis of extracellular matrix in
                                                                                     bovine periodontal ligament. J Osaka Dent Univ 1994; 28(1-2):45-
    tion which occur with current traditional adjunctive thera-
                                                                                     55.
    py using products such as clorhexidine. This is a further                  17.   Pilloni A, Bernard GW(1998) “The effect of hyaluronan on mouse
    help for the clinician for suggesting prolonged applications                     intramembranous osteogenesis in vitro” Cell. Tissue Res. 294(2),




                                                                                     te
    of the product without adverse reactions. Furthermore, the                       323-33
    improvement of the clinical inflammatory signs on the test                 18.   Pirnazar P, Wolinsky L, Nachnani S, Haake S, Pilloni A, Bernard
    sites can be also explained from recent data (18) showing                        GW. Bacteriostatic effects of Hyaluronic Acid. Journal of Peri-
    a bacteriostatic effect of hyaluronan on oral bacteria. Fu-                      odontology 1999; vol. 70, N°4.
    ture research will be necessary in order to evaluate the hi-
                                                                           In  19.   Pistorius A, Martin M, Willershausen B, Rockmann P. The clinical
    stological changes where the new attachment is formed                            application of hyaluronic acid in gingivitis therapy. Quintessence Int.
                                                                                     2005 Jul-Aug; 36(7-8):531-8.
    to understand its quality and characteristics.
                                                                               20.   Pritchard K, Lansley A B, Martin G P, Helliwell M, Marriott C and
                                                                                     Benedetti L. Evaluation of the bioadhesive properties of hyaluro-
                                                           ni
                                                                                     nan derivatives: detachment weight and mucociliary transport rate
    References                                                                       studies. International journal of pharmaceutics 1996; 12: 137-145.
                                                                               21.   Purvis JA. Molecular size distribution of proteoglycans in human
     1. Abatangelo G. Hyaluronan (Hyaluronica acid): an overview. In Pro-            inflamed gingival tissue. Archs Oral Biology 1994; n°7: 513-519.
                                                io


        ceedings of a Workshop held at the annual Meeting of European          22.   Sato R, Yamamoto H, Kasai K, Yamauchi M. Distribution pattern of
        Society for Biomaterials, Pisa September 10th 1994, 8-18.                    versican, link protein and hyaluronic acid in the rat periodontal lig-
     2. Bartol, PM, Page RC. Proteoglycans of the periodontium: structure,           ament during experimental tooth movement. J Periodontal Res 2002;
                                     iz



        role and function. J Perio Res 1987; 22: 431-444.                            37(1):15-22.
     3. Bartold PM, Page RC. The effect of chronic inflammation on gin-        23.   Shibutani T, Imai K, Kanazawa A, Iwayama Y. Use of hyaluronic acid
        gival tissue proteoglycans and hyaluronic acid. J Oral Pathol 1986;          binding protein for detection of hyaluronan in ligature-induced pe-
        15: 367-374.                                                                 riodontitis tissue. J Periodontal Res 1998; 33(5):265-73.
                   Ed




     4. Bartold PM, Page RC. Hyaluronic acid synthesized by fibroblasts        24.    Smith AJ, Addy M, and Embery M. Gingival crevicular fluid gly-
        cultured from normal and chronically inflamed human gingivae. Coll           cosaminoglycan levels in patients with chronic adult periodontitis.
        Relat Res 1986; 6(4):365-77                                                  J Clin Periodontology 1995; 22: 355-361.
     5. Bartold PM, Wiebkin OW, Thonard JC. Behavior of hyaluronic acid        25.   US Patent 4, 851, 521: Esters of hyaluronic acid.
        from gingival epithelium and connective tissue on the analytical ul-   26.   Utoh E., Okazaki J., Gonda Y. Analysis of hyaluronic acid in human
        tracentrifuge. Connect Tissue Res 1984; 12(3-4):257-64.                      gingival crevicular fluid using high-performance liquid chromatog-
     6. Bartold PM, Wiebkin OW, Thonard JC. Molecular weight estima-                 raphy. J Osaka Dent Univ 1998; 32(1):1-7.
 IC




        tion of sulfated glycosaminoglycans in human gingivae.”Connect         27.   William DF, Campoccia D. In vitro and in vivo biocompatibility of
        Tissue Res 1982; 9(3):165-72.                                                hyaluronic acid derivatives. In Proceedings of a Workshop held at
     7. Bartold PM. Platelet-derived growth factor stimulates hyaluronate            the annual Meeting of European Society for Biomaterials, Pisa Sep-
        but not proteoglycan synthesis by human gingival fibroblasts in vit-         tember 10th 1994, 30-37.
        ro. J Dent Res. Nov 1993;72(11):1473-80.                               28.   Yan F, Marshall, R, Wynne S, Xiao Y, Bartold, PM. Glycosamino-
C




     8. Benedetti L, Cortivo R, Berti T, Berti A, Pea F, Mazzo M, Moras M            glycans in gingival crevicular fluid of patients with periodontal class
        and Abatangelo G. Biocomptaibility and biodegradation of differ-             II furcation involvement before and after guided tissue regenera-
        ent hyaluronan derivatives (Hyaff) implanted in rats. Biomaterials           tion. A pilot study. J Periodontol 2000; 71(1):1-7.
        1993; 14: 1154-1160.                                                   29.   Zhong SP, Campoccia D, Doherty PJ, Williams RL, Benedetti L,
©




     9. Engstrom PE, Shi XQ, Tronje G, Larsson A, Welander U, Frithiof               Williams DF. Biodegradation of hyaluronic acid derivatives by
        L, Engstrom GN. The effect of hyaluronan on bone and soft tissue             hyaluronidase. Biomaterials 1994; 15 (5): 359-365.




    Annali di Stomatologia 2011; II (3-4): 3-9                                                                                                             9
