Adjunctive Hyaluronic Acid Gel in Non-Surgical Periodontal Treatment of Patients With Diabetes Mellitus

The Effect of Hyaluronic Acid on Non-Surgical Periodontal Treatment in Patients With Diabetes Mellitus

The goal of this clinical trial is to evaluate whether the adjunctive use of hyaluronic acid (HA) improves periodontal healing in people with diabetes mellitus and periodontitis. The effects of HA on biomolecules and bacteria levels will be assessed during the follow-up period.

The main questions the study will answer are:

• Will periodontal sites treated with non-surgical periodontal treatment (NSPT) plus HA gel show better clinical periodontal parameters than sites treated with only NSPT in patients with diabetes and periodontitis?
• will HA gel have additional effect on reducing inflammation or collagen markers, and bacteria levels during follow-up?

Researchers will compare periodontal sites receiving NSPT with adjunctive HA gel application to sites receiving NSPT alone to determine whether HA provides additional clinical, biochemical and microbiological benefits.

Participants will:

• provide recent HbA1c test results.
• then, the participants will receive full-mouth NSPT then, randomization will be performed for the selected jaw for test sites. These two interproximal test sites will additionally receive HA application.
• attend follow-up visits at 1, 3 and 6 months for clinical periodontal measurements and to provide gingival crevicular fluid samples (GCF) and subgingival samples.

The GCF samples will be evaluated for interleukin-34 (IL-34) and beta C-terminal telopeptide (β-CTX) levels and subgingival samples for periodontal pathogens.

Study Overview

• Status: Not yet recruiting
• Conditions: Diabetes Mellitus; Periodontitis; Hyaluronic Acid; Oral Microbiota; IL-34; β-CTX
• Intervention / Treatment: Procedure: Scaling and root planing; Device: Hyaluronic Acid (HYADENT BG)

Detailed Description

This study is a randomized controlled split-mouth clinical trial that investigates the clinical, biochemical, and microbiological effects of adjunctive Hyadent BG® gel application into selected interproximal periodontal pocket sites after non-surgical periodontal treatment (NSPT) in patients with diabetes mellitus (DM) and stage III/IV periodontitis.

Periodontitis is a chronic inflammatory disease characterized by the progressive destruction of the tooth-supporting tissues. DM is an important modifying factor for periodontal disease progression and treatment response. Hyperglycemia-related alterations in host immune response, collagen metabolism, microvascular function, and wound healing may contribute to increased periodontal inflammation and delayed periodontal healing. Therefore, adjunctive local approaches that may enhance the response to NSPT are clinically relevant in this patient population.

Hyaluronic acid (HA) is a naturally occurring glycosaminoglycan found in periodontal tissues and the extracellular matrix. Because of its hydrophilic, viscoelastic, anti-inflammatory, and wound-healing properties, HA has been investigated as an adjunctive agent in periodontal therapy. In this study, HA gel will be applied locally into periodontal pockets after scaling and root planing to evaluate whether it provides additional benefit beyond NSPT alone.

The study will include a total of 23 patients with DM and Stage III/IV periodontitis who applied to the Department of Periodontology, Faculty of Dentistry, Marmara University. Eligible participants will receive detailed information regarding the study procedures, and written informed consent will be obtained prior to enrollment.

TREATMENT PROCEDURES

Before treatment, recent HbA1c and fasting plasma glucose (FPG) test results will be obtained. Two days before NSPT, radiographic and full-mouth clinical evaluations will be carried out to determine which jaw will be included in the study. Intraoral photographs will be taken, and impressions of the related jaw will be taken for stent fabrication. One day before NSPT, clinical measurements of the related sites with the stent will be repeated. NSPT will be completed in three sessions within two weeks. Before starting NSPT, baseline pooled gingival crevicular fluid (GCF) samples and then pooled subgingival microbiological samples will be collected sequentially from the related sites of the selected jaw. Then oral hygiene instructions will be provided, followed by full-mouth supragingival and subgingival scaling using ultrasonic and hand instruments in two weeks time. At the last session of NSPT, test sites (non-adjacent sites with ≥6 mm pocket depth) for adjunctive use of HA gel will be randomly determined by a toss of a coin from the selected jaw, and HA will be applied subgingivally.

All patients will be followed up at the 1-, 3-, and 6-month intervals.

Periodontal Clinical Measurements

At baseline and at 1, 3, and 6 months, full-mouth clinical measurements will be performed. Periodontal clinical measurements will be recorded at six sites per tooth-mesiobuccal, midbuccal, distobuccal, mesiolingual, midlingual, and distolingual-using a Williams periodontal probe (Hu-Friedy).

Plaque Index (PI): Dental plaque accumulation will be assessed after air drying the teeth using a periodontal probe and visual inspection, according to the PI system developed by Silness and Löe.

Gingival Index (GI): The gingival inflammatory status will be assessed using the GI developed by Löe and Silness.

Probing Depth (PD): PD will be measured as the distance from the free gingival margin to the base of the periodontal pocket by inserting the periodontal probe to the pocket base.

Clinical Attachment Level (CAL): CAL will be recorded by measuring the distance from the cemento-enamel junction to the base of the pocket.

Bleeding on Probing (BOP) (%): BOP will be assessed 25-30 seconds after pocket probing. Sites showing bleeding will be recorded as positive (+), while those without bleeding will be recorded as negative (-).

Collection of GCF and Subgingival Microbiological Samples At baseline, both GCF and pooled subgingival microbiological samples will be collected after clinical measurements from test and control sites, but at follow-up visits (1st, 3rd, and 6th months) prior to clinical measurements. Before sampling, supragingival plaque will be carefully removed, then the test (n=2) and control (n=2) sites will be isolated from saliva using cotton rolls and dried. First, GCF samples will be collected. Periopaper strips will be inserted 1-2 mm into the periodontal pocket and left in place for 30 seconds at the selected sites. GCF volume will be measured. Following GCF sampling, subgingival microbiological sampling will be carried out by inserting sterile paper points (#30) to the base of the periodontal pockets and kept in place for 10 seconds. All GCF and the subgingival microbiological samples will be stored at -80°C until the day of analysis. GCF samples will be analyzed for interleukin-34 (IL-34) and beta C-terminal telopeptide (β-CTX) levels using commercially available enzyme-linked immunosorbent assay kits. IL-34 will be assessed as a marker related to local inflammatory activity, and β-CTX will be assessed as a marker of type I collagen degradation.

Quantification of A. actinomycetemcomitans, F. nucleatum, P. gingivalis, T. forsythia, and P. intermedia in subgingival microbiological samples will be performed using real-time polymerase chain reaction.

Statistical Analysis

Statistical analyses will be performed using IBM SPSS Statistics for Windows, Version 20.0 (IBM Corp., Armonk, NY, USA). A confidence level of 95% will be adopted for all analyses, and a p value of less than 0.05 will be considered statistically significant.

Due to the split-mouth study design, test and control sites within the same individual will be treated as paired samples.

Descriptive statistics for clinical parameters (PI, GI, BOP, PD, and CAL) and biochemical markers (IL-34 and β-CTX) will be expressed as mean ± standard deviation, median, and minimum-maximum values.

The normality of data distribution will be assessed using the Shapiro-Wilk test. For normally distributed variables, within-group comparisons over time (baseline, 1 month, 3 months and 6 months) will be analyzed using one-way repeated measures analysis of variance (ANOVA). When a statistically significant difference is detected, pairwise comparisons will be performed using the Tukey post hoc test.

Comparisons between test and control sites will be conducted using the paired samples t-test.

For variables that do not follow a normal distribution, within-group comparisons over time will be analyzed using the Friedman two-way analysis of variance. When significant differences are observed, pairwise comparisons will be performed using the Wilcoxon signed-rank test.

Between-group comparisons for non-normally distributed variables will be performed using the Mann-Whitney U test.

Correlations between clinical, biochemical, and microbiological variables will be evaluated using Spearman's correlation analysis. Variables found to be significant will be further analyzed using multiple linear regression to assess their independent effects.

• Study Type: Interventional
• Enrollment (Estimated): 23
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Başak Doğan; Phone Number: +905332621170; Email: basakdogan@marmara.edu.tr

Study Locations

• Turkey (Türkiye)
  • Istanbul, Turkey (Türkiye)
    • Department of Periodontology, Faculty of Dentistry, Marmara University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Individuals who sign the informed consent form
• Participants diagnosed with diabetes mellitus (HbA1c %7-7.9)
• Participants without any systemic disease other than DM
• Participants diagnosed with Stage III or Stage IV periodontitis
• Nonsmokers
• Participants with at least 15 natural teeth present in the mouth (excluding third molars)
• Participants in either of the jaws, in both quadrants, having two non-adjacent interproximal sites with probing depth and clinical attachment level ≥6 mm with no caries, restorations or furcation involvement

Exclusion Criteria:

• Individuals who do not sign the informed consent form
• Ongoing drug therapy that might have an impact on the clinical signs and symptoms of periodontitis
• Participants have received any periodontal treatment within 6 months prior to the study
• Participants who have used antibiotics within the last 3 months
• Smokers
• Participants who are pregnant or lactating

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Test; Non-surgical periodontal treatment and Hyaluronic Acid gel	Procedure: Scaling and root planing; Scaling and root planing is a conventional gold-standard treatment for periodontitis. As part of this procedure, subgingival plaque and tartar are removed and root surfaces are planed.; Device: Hyaluronic Acid (HYADENT BG); Hyaluronic acid will be locally applied to periodontal pockets as an adjunct to non-surgical periodontal therapy, aiming to support periodontal healing. After completion of scaling and root planing, the material will be delivered subgingivally to designated test sites in a split-mouth design.
Other: Control; Non-surgical periodontal treatment alone	Procedure: Scaling and root planing; Scaling and root planing is a conventional gold-standard treatment for periodontitis. As part of this procedure, subgingival plaque and tartar are removed and root surfaces are planed.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Clinical Attachment Level	Clinical attachment level (CAL) will be measured in millimeters using a periodontal probe. The change in CAL will be calculated as the difference between baseline and follow-up measurements. A decrease in CAL indicates an improvement in periodontal attachment.	Baseline, 1, 3 and 6 months after NSPT
Change in Probing Depth	Probing depth will be measured around each tooth by recording the distance in millimeters from the gingival margin to the bottom of the pocket at 6 locations (mesiobuccal, mid-buccal, distobuccal, mesiopalatal, mid-palatal, distopalatal).	Baseline, 1, 3 and 6 months after NSPT

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of Bleeding on Probing (%)	Possible score for bleeding on probing range from %0 (no sites with bleeding on probing) to %100 (all sites with bleeding on probing). Higher scores mean worse outcome.	Baseline, 1, 3 and 6 months after NSPT
Change in Plaque Index	Possible scores for Plaque Index range from 0 (no plaque) to 3 (visible plaque all around the tooth). Higher scores mean a worse outcome.	Baseline, 1, 3 and 6 months after NSPT
Change in Gingival Index	Possible score for Gingival Index range from 0 (healthy gingiva) to 3 (severe gingivitis with bleeding). Higher scores mean worse outcome.	Baseline, 1, 3 and 6 months after NSPT
Change in GCF IL-34 Levels	Change in IL-34 levels from baseline to 1, 3 and 6 months after NSPT	Baseline, 1, 3 and 6 months after NSPT
Change in GCF β-CTX Levels	Change in β-CTX levels from baseline 1, 3 and 6 months after NSPT	Baseline to 1, 3 and 6 months after NSPT
Change in level of Porphyromonas gingivalis	Change in Porphyromonas gingivalis levels in subgingival microbiological samples from baseline to 1, 3 and 6 months after NSPT.	Baseline, 1, 3 and 6 months after NSPT
Change in level of Fusobacterium nucleatum	Change in Fusobacterium nucleatum levels in subgingival microbiological samples from baseline to 1, 3 and 6 months after NSPT.	Baseline, 1, 3 and 6 months after NSPT
Change in level of Aggregatibacter actinomycetemcomitans	Change in A. actinomycetemcomitans levels in subgingival microbiological samples from baseline to 1, 3 and 6 months after NSPT.	Baseline, 1, 3 and 6 months after NSPT
Change in level of Tanerella forsythia	Change in Tanerella forsythia levels in subgingival microbiological samples from baseline to 1, 3 and 6 months after NSPT.	Baseline, 1, 3 and 6 months after NSPT
Change in level of Prevotella intermedia	Change in Prevotella intermedia levels in subgingival microbiological samples from baseline to 1, 3 and 6 months after NSPT.	Baseline, 1, 3 and 6 months after NSPT

Collaborators and Investigators

• Sponsor: Marmara University

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): July 1, 2028
• Study Completion (Estimated): July 1, 2028

Study Registration Dates

• First Submitted: May 12, 2026
• First Submitted That Met QC Criteria: June 2, 2026
• First Posted (Actual): June 8, 2026

Study Record Updates

• Last Update Posted (Actual): June 8, 2026
• Last Update Submitted That Met QC Criteria: June 2, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Periodontitis; diabetes mellitus; periodontal pathogens; Hyaluronic Acid; IL-34; Non-surgical Periodontal Treatment; Split-mouth Study; β-CTX
• Additional Relevant MeSH Terms: Endocrine System Diseases; Periodontal Diseases; Mouth Diseases; Stomatognathic Diseases; Metabolic Diseases; Glucose Metabolism Disorders; Nutritional and Metabolic Diseases; Periodontitis; Diabetes Mellitus; Digestive System and Oral Physiological Phenomena; Dentistry; Dental Physiological Phenomena; Dental Scaling; Dental Prophylaxis; Periodontics; Subgingival Curettage; Preventive Dentistry; Root Planing; Tooth Exfoliation
• Other Study ID Numbers: 09.2025.543; TDH-2026-12438 (Other Grant/Funding Number: Marmara University Scientific Research Projects Coordination Unit)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No