Hyaluronic Acid in Papillary Reconstruction
Condition: Interdental Papillary Reconstruction
Study type: Interventional
Phase: Phase 4

Summary: 
      Hyaluronic acid (HA) has been used as a dermal filler in medicine for many years. It also has
      umpteen benefits in terms of aiding in rapid healing and resolution of inflammation. Thus in
      the present study, HA has been used at the test site to fill papillary recession defects. At
      the control site saline was injected as the placebo.
    

Detailed description: 
      INTRODUCTION Periodontal diseases, trauma, treatment of periodontal diseases and iatrogenic
      causes lead to papillary tissue loss in the interproximal area.1 Management of soft tissue
      deformities in the interproximal space can be advocated through several surgical and
      non-surgical techniques. The non-surgical approaches - orthodontic, prosthetic and
      restorative procedures modify the interproximal space, thereby altering the soft tissue
      morphology. The surgical techniques aim to recontour, preserve or reconstruct the soft tissue
      between teeth and implants. Surgical techniques, due to their invasive and unpredictable
      nature and limited blood supply/ minimal access makes regeneration of deficient papilla a
      highly sensitive procedure.2 Hyaluronic acid (HA) is a high molecular weight polysaccharide
      that plays a vital role in the functioning of extracellular matrices, including those of
      mineralized and non-mineralized periodontal tissues. HA helps in tissue hydrodynamics, cell
      migration/ proliferation, anti-inflammatory role and facilitates healing.3 HA has shown
      anti-inflammatory, anti-edematous and anti-bacterial effects in the treatment of gingivitis
      and periodontitis.4 Deviating from these utilities, HA also plays an important role in the
      non surgical facial rejuvenation through bioengineered hyaluronic acid derivatives. The
      exquisite role of bioengineered hyaluronic acid derivatives for soft tissue augmentation in
      gingival deficiencies has not been researched enough. Based on this beneficial effect of HA
      in dermatology, the present triple blind split mouth randomised clinical trial was planned to
      evaluate the injection of HA dermal filler as a minimally invasive treatment modality for the
      reconstruction of lost interdental papilla.

      The aim of the present study was to evaluate the efficacy of hyaluronic acid dermal filler
      for interproximal papillary augmentation in Nordland's Class I and Class II5 interdental
      papillary recession defects.

      MATERIALS AND METHODS:

      PARTICIPANTS:

      15 adult patients from the out-patient department of Department of Periodontology,
      Krishnadevaraya College of Dental Sciences, Bangalore, India, aged between 25-75 years were
      recruited among those seeking treatment for esthetics in the maxillary anterior region due to
      interdental papilla recession, from July 2013 to September 2014. The details of the study and
      the procedure were explained to the patients and an institutional review board approved
      informed consent was obtained from each patient, affiliated to Rajiv Gandhi University of
      Health Sciences (ACA/DCD/SYN/KCODS - B/PG/2012-2013) (02_D012_36683).

      INTERVENTIONS Papillary augmentation with HA dermal fillers was considered as the test group
      and this was compared with saline injection (placebo) for the control group. The study was
      conducted in full accordance with the declared ethical principles (World Medical Association
      Declaration of Helsinki, version VI, 2002) and was approved by the Institutional review board
      of Krishnadevaraya College of Dental Science and Hospital, affiliated to Rajiv Gandhi
      University of Health Sciences, Bangalore.

      This study was conducted by 2 investigators and one operator, one of the investigators and
      the operator were blinded. The unblinded investigator performed the randomisation and
      allocation of the test and control groups, whereas all the study measurements and assessment
      were performed by the blinded investigator and operator. The patients were not informed and
      had no way to decipher the test or the control group. Both the investigators assessed the
      following clinical outcomes.

      STUDY DESIGN The design of this study is a unicenter, triple blind, placebo controlled split
      mouth randomised controlled clinical trial according to the Consolidated Standards of
      Reporting Trials (CONSORT) criteria, 2010 (Fig 1). All patients completed an initial therapy
      that included oral hygiene instructions and scaling and root planning. 2 similar sites in
      each patient i.e. a total of 30 interdental papillary recession area were selected and
      treated. One of the patients failed to complete the follow up visits and hence was excluded
      from the study.

      DATA COLLECTION Data collection included baseline clinical measurements and photographs taken
      perpendicular to the site at baseline, 3 weeks, 3 months and 6 months.

      The radiographs were taken using a positioning device and an intraoral periapical radiograph
      grid at baseline and 6 months. Study impressions of sites were taken at baseline.2 At
      baseline and all subsequent study visits the below mentioned clinical parameters were
      recorded by the examiner using a standardized acrylic stent and University of North Carolina
      (UNC 15) probe , i.e. papillary recession depth (distance from the contact point to gingival
      margin was measured to the nearest millimeter- CP -GM); Interproximal width (distance from
      the mesial height of contour to the distal height of contour of the interproximal
      tissue-IPW); Width of the keratinized gingiva (schiller's potassium iodide solution-KTW);
      Facial gingival recession of the two adjacent teeth11; Radiographic Analysis of papillae
      height (vertical distance from the tip of the interdental papillae, using radiopaque material
      to mark it to the tip of the crest of the alveolar bone)12; Plaque index (PI)13; Gingival
      Bleeding Index (GBI)14; Gingival Index (GI)15 and photographic analysis of the intraoral
      photographs taken using Image analysis software. (Digimiser∗)6

      OUTCOMES:

      Two different treatment methods were compared, HA filler (n=15) and saline (n=15). The
      primary outcome that was assessed in the study was the papillary recession reduction
      (pRecRed). pRecRed was calculated in millimeters and in percentage papillary coverage(PPC).
      The percentage of complete papillary coverage (CPC) in each group was assessed.

      The formula used to calculate the percentage papillary coverage was as follows-

      Baseline (CP-GM) - 6 month (CP-GM)

      ---------------------------------------------- x 100 Baseline (CP-GM) The primary outcomes
      were also assessed with a photogrammetric analysis using Digimiser software∗. Image analysis
      consisted of several steps: image identification, image scaling, calibration, and
      measurement. The ideal image was selected and scaled to standard (1:1) magnification. The
      photograph was calibrated and standardised to the actual clinical dimensions by feeding a
      known clinical dimension (the 1mm markings of UNC-15∗∗∗periodontal probe in the photograph)
      into the software. Determination of the distance from the contact point to the gingival
      margin was done (CP-GM) .The ideal height of the interdental papillary recession was measured
      as the distance between the lines joining the apical tip of the papilla to the contact point
      of the teeth. The primary outcome measurement i.e. papillary recession depth was assessed
      using the computerized software tools.

      The following secondary outcomes were also measured change in interproximal width2; width of
      the keratinized gingiva9; facial gingival recession of the two adjacent teeth11; radiographic
      height of papillae height using12; Plaque index13; Gingival Bleeding Index14 and Gingival
      Index15.

      PRE-TREATMENT PROCEDURES:

      Initial therapy that included scaling and root planning was completed prior to the treatment
      procedure.10 The patients who demonstrated ≤ 20 % O'Leary Plaque Index were subjected to the
      study protocol.2 Occlusal interferences were identified and eliminated through occlusal
      adjustments, and hard acrylic bite guards were constructed for those patients with
      parafunctional habits. The study was designed so that extraneous factors such as oral hygiene
      and compliance were controlled within each subject.

      RANDOMIZATION:

      Randomization sequence was generated by a computer program. Allocation concealment was
      achieved using a sealed coded opaque envelope containing the treatment of the specific
      subject. The unblinded investigator opened the sealed envelope containing treatment
      assignment as Test site (treatment with HA filler) or Control Site (treatment with placebo)
      prior to the treatment procedure and allotted the cases to operator accordingly. The patient
      and investigator and operator were blinded to the treatment performed.

      PROCEDURE:

      6 weeks after the initial therapy, patients were scheduled for the procedure.16 Local
      Anesthetic solution (2% Lignocaine HCl with adrenaline 1:80000) was administered.17 About 0.2
      ml of a commercially available hyaluronic acid based gel was injected 2-3 mm coronal to the
      apical tip of the receded interdental papilla (Fig 2). Injections were performed using 23
      gauge X 25mm intraoral injection needles . The concentration of HA gel used was 20 mg/ml.6
      The area was gently massaged to ensure that the filler was uniformly distributed. Care was
      taken to fill each papilla to full correction (100% of defect). After the treatment the
      individual patient syringes were capped and stored in a refrigerator with patient names and
      details. The needle was discarded. Patients were seen three weeks after the initial treatment
      and if augmentation was still deemed necessary, another injection of 0.2ml was injected up to
      three times.6 In the control site the same protocol was performed, however with saline.
      Patients were recalled and all the clinical and radiographic parameters were recorded after
      three months and six months.

      SATATISTICAL ANALYSIS:

      A sample of 14 recessions in each group (test and control), were included. The analysis was
      performed by a blind examiner. Statistical analysis was undertaken with SPSS (version10.0.5)
      package. Normality of data was tested using Shapiro-Wilk test. The intergroup comparisons
      were done using student 't' test and chi square test, with Mann Whitney U test as post hoc
      test. Intergroup comparison at different recall visits was done using Mann Whitney U test.
      The intergroup comparison of the photogrammetric analysis; mean papillary recession reduction
      between test and control at baseline and 6 months was compared using student 't' test with
      Mann Whitney U test as post hoc test. Intragroup comparison between baseline and the follow
      up visits values were done using the one was ANOVA test and Kruskal Wallis test. Comparison
      between the clinical analysis and image analysis was done using chi square test.

      DISCUSSION The attempt to use dermal fillers for papillary augmentation is scarcely reported
      in the existing literature. Only one study has evaluated the effect of HA filler on
      interdental papilla reconstruction and noted that injection of hyaluronic acid gel is safe
      and significantly decreased the interdental black triangle in the esthetic zone.3 Application
      of non-invasive techniques such as the use of commercially available hyaluronic acid gel can
      replace the conventional invasive methods.

      This split mouth clinical study consisted of 15 patients with Nordland and Tarnow's Class I
      and Class II6 papillary loss that were treated with either HA gel (test) or saline (control)
      for papillary augmentation.

      Significantly 28.6% of the sites in test group showed CPC whereas no sites in the control
      group showed CPC. The results are in agreement with that of Becker et al. 2010 who achieved
      21.4% CPC similarly by injection of a HA gel for papillary augmentation.3 CPC was noted by
      Nordland et al 200818, where he used a microsurgical technique to reconstruct the lost
      interdental papilla, Tinti C et al. 200219 used Ramp mattress suture to augment the papilla,
      Carnio et al. 200420 - interposed subepithelial connective tissue graft and Geurs et al10
      showed 57.9% of CPC. Various other authors have also reported CPC with different
      techniques.21-24 55.4% of PPC was achieved with HA augmentation, which is similar to 42.1%
      PPC achieved by Geurs et al. 201210 who used micronized acellular dermal matrix allograft for
      papillary reconstruction. Another similar study has shown a significant papillary fill post
      operatively.2 No significant differences were noted in both the groups as regards to the
      interproximal width. A similar trend was noted by Mcguire & Scheyer 2007.2 There were no
      significant changes in the dimensions of the keratinized gingiva in both the groups.

      Image analysis system to measure changes in root coverage has also been successfully employed
      in previous literature.26 Identification of the anatomic CEJ, accuracy of determining the
      probing pocket depth/ papillary height/ width etc. can be subjected to manual errors.
      Calibrated photogrammetric analysis can reduce subjective measurement errors. The current
      study reported no significant differences between clinical and photogrammetric analysis. 26
      Literature review reveals that the split mouth randomised controlled clinical trial with a
      duration of more than or equal to 6 months assessing complete papillary coverage as the
      primary outcome in papillary reconstruction for papillary recession defects is rarely
      documented. However, there is frequent reporting of primary outcome variable like PPC,
      pRecRed, change in papillary index scores and the casual mention of significant papillary
      gain. Due to the inconsistent and insufficient data available regarding papillary
      reconstruction, it was difficult to compare the results of the current trial.

      Hyaluronic acid gel§§§ is generated by Streptococcus species of bacteria and is chemically
      cross-linked and has a concentration of 20 mg/mL. Hyaluronic acid fillers are less allergy
      prone and produce favourable results.27 Hyaluronic acid forms the natural physiological
      constituent of the ground substance of connective tissue of the gingival mucosa, and hence
      can be considered for the treatment of papillary deficiency. Patients on blood thinning
      agents might experience mild bruising, therefore eliminating any blood thinning agents for at
      least 7 days before injection is preferred.28 HA acts as a matrix, provides lubrication and
      increases volume through its aqueous and pliable framework that suspends and adheres to
      collagen, elastin and numerous proteins like fibrinogen, fibrin, fibronectin and collagen
      bind to HA.29 HA integrates well into the adjacent gingiva with excellent esthetic results.
      Microcirculatory perfusion is enhanced with HA.30 The plumping of the interdental papilla on
      injecting the defect with a HA filler could be explained by the fact that HA has a unique
      rheological property and is highly hydrophilic and can bind to upto 1000 times more water
      than its molecular-weight.31 HA injection has shown to increase denovo collagen synthesis,
      hypothesized to be the result of fibroblast stretching. As HA is degraded novel collagen
      synthesis replaces the HA resulting in longer lasting correction.32 CPC achieved and
      maintained in the current trial can be attributed to the hydrophilpic nature and collagen
      synthesizing property of HA filler. The cross linking prevents its degradation in the body.
      The high level of cross linking alters the ability of water to bind to HA and thereby creates
      tissue lift.28 HA increases the cell division and the tubulin concentration which helps in
      the proliferation of fibroblasts through the cell cycle.33 HA also acts as biomaterial
      scaffold for other molecules, such as BMP-2 and PDGF-BB.4 Smooth-gel dermal fillers like HA
      offer longer-lasting correction of defects than bovine collagen etc. The insoluble gel
      portion that persists in the skin and gingiva after injection is the amount of HA that
      contributes to the clinical effect.34 The product in trial being a smooth gel HA dermal
      filler offers long lasting correction and achieves natural look post injection.35 Nearly all
      the subjects achieved optimal correction with only a single injection of 0.2ml of HA dermal
      filler.6 The commonly employed injection techniques for dermal fillers (serial puncture,
      linear threading, fanning and cross hatching) was not employed in the current trial owing to
      the limited area and minimal access to the interdental papillary region. The product that is
      used in the current study is 1.8% sodium salt hyaluronic acid. It has been successfully used
      in the treatment of nasolabial folds with no adverse events.36 Results from this study
      evaluating the use of a commercially available injectable gel for correcting deficient
      papillae between teeth are successful and promising and minimally invasive. This study had a
      follow up period of 6 months as compared to the study of Becker et al. 20106 which had a
      follow up period of 6-25 months based on the patient compliance. It is interesting to note
      that all patients considered treatment to be painless.

      Traditional gingival augmentation uses epithelial/ connective tissue graft harvested from the
      palate that can cause considerable discomfort for the patient which is successfully avoided
      with HA dermal filler.

      Randomized clinical trials with a longer follow up time period and a larger sample size are
      to be undertaken to further justify the use of HA dermal filler for the augmentation of
      papillary deficiency.
    

Intervention name(s): Hyaluronic acid filler
Intervention type(s): Procedure
Intervention description(s): Papillary augmentation with HA dermal fillers was considered as the test group
Intervention MeSH terms: Hyaluronic Acid
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment