Hyaluronic Acid in Endodontic Microsurgery

Effectiveness of Using Cross-linked Hyaluronic Acid in Endodontic Microsurgery. A RCT

This randomized clinical trial (RCT) will evaluate the effectiveness of cross-linked hyaluronic acid as an adjunct to endodontic microsurgery in adult patients with apical periodontitis affecting maxillary or mandibular first molars. Participants previously treated with non-surgical endodontic therapy will be allocated to either endodontic microsurgery with cross-linked hyaluronic acid application (test group) or the same surgical procedure without adjunctive material (control group), with 12 months of follow-up.

The study hypothesis is that cross-linked hyaluronic acid improves soft- and hard-tissue healing, reduces postoperative inflammation and pain, and supports more stable surgical outcomes. Primary outcomes include early soft tissue healing (Early Wound Healing Score, day 4) and postoperative pain (visual analogue scale). Secondary outcomes include periapical healing assessed by blinded evaluators on periapical radiographs (Molven criteria) at 3, 6, and 12 months, and on CBCT scans (PENN 3D criteria) at 6 and 12 months, as well as cortical plate healing (RAC/B index). This study aims to provide clinical evidence on the potential regenerative and anti-inflammatory benefits of cross-linked hyaluronic acid in endodontic microsurgery.

Study Overview

• Status: Recruiting
• Conditions: Periapical Periodontitis
• Intervention / Treatment: Procedure: Hyaluronic Acid; Procedure: Endodontic microsurgery

Detailed Description

Background and Rationale:

Endodontic microsurgery is an established treatment for persistent apical periodontitis after non-surgical root canal treatment. Successful healing depends on appropriate surgical technique, infection control, and favorable soft and hard tissue regeneration. Cross-linked hyaluronic acid is a non-animal-origin biomaterial with hydrating, tissue-supportive, and bacteriostatic properties, and may support wound healing and tissue regeneration in oral surgery. In addition, it is stable at room temperature and radiolucent, which facilitates postoperative radiographic and CBCT evaluation.

The present study investigates whether adjunctive use of cross-linked hyaluronic acid during endodontic microsurgery improves clinical healing outcomes compared with standard endodontic microsurgery alone.

Scientific Question:

Does cross-linked hyaluronic acid improve hard and soft tissue regeneration in endodontic microsurgery?

Hypothesis:

The adjunctive use of cross-linked hyaluronic acid in endodontic microsurgery improves soft-tissue and bone-healing, reduces inflammation and postoperative pain, and enhances the long-term stability of surgical outcomes.

Study type: Interventional (Clinical Trial) Allocation: Randomized Intervention model: Parallel assignment Masking: Double-blinded (participant and outcome examiner/radiologist) Primary purpose: Treatment Setting: Single center Follow-up duration: 12 months

Study Population:

Adult patients (>18 years) with apical periodontitis in maxillary or mandibular first molars, previously treated with non-surgical endodontic therapy at least 12 months prior to enrollment, and meeting predefined periodontal and radiographic eligibility criteria.

Interventions:

Test Group (n=30 teeth) Endodontic microsurgery (open flap debridement) with adjunctive application of cross-linked hyaluronic acid (Hyadent BG, Regedent) into the osteotomy defect and under the flap before closure.

Control Group (n=30 teeth) Endodontic microsurgery (open flap debridement) with no adjunctive grafting/regenerative material.

Surgical Procedure (both groups):

All procedures will be performed under an operating microscope (Carl Zeiss Extaro 300) using a standardized microsurgical protocol under local anesthesia (articaine with epinephrine 1:100,000, 3.4 mL). The protocol includes:

Single flap approach (Trombelli 2009) combined with entire papilla preservation technique (Aslan et al.).

• Flap elevation
• Osteotomy with Lindemann bur under irrigation
• 3 mm root-end resection at approximately 90 degrees
• Root-end staining with 1% methylene blue
• Ultrasonic retrograde preparation
• Granulation tissue removal
• Hemostasis with epinephrine cotton pellets
• Root-end filling with mineral trioxide aggregate (MTA, Trioxident)
• Irrigation with 0.9% sodium chloride
• Periosteoplasty
• Tension-free flap repositioning and suturing with 7-0 monofilament sutures (Prolene)
• In the test group only, cross-linked hyaluronic acid will be applied via cannula to fill the osteotomy defect and placed beneath the flap prior to suturing.

Outcome Measures:

Primary Outcome: Early soft tissue healing Assessed on postoperative day 4 using the Early Wound Healing Score (EHS).

Secondary Outcomes

• Periapical healing on periapical radiographs (PA) Assessed by blinded evaluators using Molven criteria at 3, 6, and 12 months
• Periapical healing on CBCT Assessed by blinded evaluators using PENN 3D criteria at 6 and 12 months
• Cortical plate healing Assessed using the RAC/B index
• Postoperative pain Assessed using a Visual Analogue Scale (VAS).

Statistical Considerations

Sample size calculation was based on detecting a 2-point difference in the Early Wound Healing Score (range 0-10) between groups, assuming:

Alpha = 0.05 Power = 80% Standard deviation = 3 The calculated sample size was approximately 18 patients per group. To account for potential dropouts and ensure robustness, the final planned sample size is 23 patients per group. The protocol currently plans enrollment of 30 teeth per group, providing additional allowance for attrition and variability.

• Study Type: Interventional
• Enrollment (Estimated): 46
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Anton Sculean, Prof.; Phone Number: +41316840620; Email: anton.sculean@unibe.ch
• Study Contact Backup: Name: Vitaly Fuog, DMD; Phone Number: +41795378238; Email: vitaly.fuog@gmail.com

Study Locations

• Russia
  • Moscow, Russia, 127006
    • Recruiting
    • Praktika 1
    • Contact: Anton Sculean, Prof; Phone Number: +41316840620; Email: anton.sculean@unibe.ch
    • Contact: Alexandra Stähli, PD; Phone Number: +41316840620; Email: alexandra.staehli@unibe.ch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Written informed consent
• ≥18 years of age
• Apical peridontitis at maxillar or mandibular first molars ≥ 12 months after non-surgical endodontical treatment
• Full mouth plaque score (FMPS) and bleeding score (BoP) < or 20%
• Periapical lesion < or 10 mm
• Four-wall bone defect morphology

Exclusion Criteria:

• Smokers of more than 10 cigarettes a day
• Allergy to hyaluronic acid
• Pregnancy or lactation
• Uncontrolled Diabetes
• Untreated periodontal conditions
• Any conditions associated with poor compliance or failure to maintain good oral hygiene
• Acute infections lesions in areas intended for surgery
• Chemotherapy and radiotherapy treatment

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
Experimental: Test: endodontic microsurgery with hyaluronic acid; The endodontic microsurgery will be performed, then cross-linked hyaluronic acid will be added in the surgical area.	Procedure: Hyaluronic Acid; The endodontic surgery will be performed under the control of an operating microscope (Carl Zeiss Extaro 300). The operation will be performed under anesthesia, articaine + epinephrine. OFD (single flap approach Trombelli 2009 combined with entire papilla preservation technique Aslan et al., flap elevation, osteotomy, 3 mm root resection, the root cut will be made at an angle close to 90 degrees, the root cut will be coloured with methylen-blue 1%, retrograde canal preparation using ultrasonic scaler, and ultrasonic tips, granulated tissues excavation, haemostasis will be achieved by using cotton balls with epinephrine, root-end filling with mineral trioxide aggregate. Irrigation with 0.9% sodium chloride, application of cross-linked hyaluronic acid through the cannula into the osteotomy, until the bone defect is completely filled and under the flap, flap reposition tension-free, suturing using monofilament sutures 7-0 (Prolene).; Procedure: Endodontic microsurgery; The endodontic surgery will be performed under the control of an operating microscope (Carl Zeiss Extaro 300). The operation will be performed under anesthesia, articaine + epinephrine. OFD (single flap approach Trombelli 2009 combined with entire papilla preservation technique Aslan et al., flap elevation, osteotomy, 3 mm root resection, the root cut will be made at an angle close to 90 degrees, the root cut will be coloured with methylen-blue 1%, retrograde canal preparation using ultrasonic scaler, and ultrasonic tips, granulated tissues excavation, haemostasis will be achieved by using cotton balls with epinephrine, root-end filling with mineral trioxide aggregate. Irrigation with 0.9% sodium chloride, flap reposition tension-free, suturing using monofilament sutures 7-0 (Prolene).
Active Comparator: Control: mere endodontic microsurgery; Endodontic microsurgery will be performed only.	Procedure: Endodontic microsurgery; The endodontic surgery will be performed under the control of an operating microscope (Carl Zeiss Extaro 300). The operation will be performed under anesthesia, articaine + epinephrine. OFD (single flap approach Trombelli 2009 combined with entire papilla preservation technique Aslan et al., flap elevation, osteotomy, 3 mm root resection, the root cut will be made at an angle close to 90 degrees, the root cut will be coloured with methylen-blue 1%, retrograde canal preparation using ultrasonic scaler, and ultrasonic tips, granulated tissues excavation, haemostasis will be achieved by using cotton balls with epinephrine, root-end filling with mineral trioxide aggregate. Irrigation with 0.9% sodium chloride, flap reposition tension-free, suturing using monofilament sutures 7-0 (Prolene).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The healing of soft tissues will be evaluated by the Early wound healing score	The early wound healing index assesses periodontal soft tissue healing, usually around 1 week post-surgery, by evaluating flap closure, fibrin presence, and necrosis in 5 grades. It ranges from score 1 (complete healing) to score 5 (necrosis and pus)	4 days after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The postoperative pain will be evaluated by visual analogue scale VAS	The visual analogue scale is a mm scale from 0 (no pain) to 100 mm (maximal possible pain)	within the two first weeks after surgery
Periapical healing assessed on periapical radiographs according to the Molven's criteria	The Molven's criteria is a 2D radiographic classification system used to evaluate the healing outcome of apical endodontic surgery, four main categories exist: Complete Healing: Bone tissue is completely restored, and a normal periodontal ligament (PDL) space is visible. Incomplete Healing (Scar Tissue): The initial radiolucent area has reduced in size, but a small residual rarefaction remains, often characterized as a "scar". Uncertain Healing: A reduction in the size of the lesion has occurred, but it does not fit the criteria for complete or incomplete healing. Unsatisfactory Healing (Failures): The radiolucent lesion is unchanged, has increased in size, or appears newly developed, indicating failure.	3, 6, and 12 months post-surgery
Pericapial healing on cone beam computed tomography (CBCT) scans according to PENN's criteria	Healing of endodontic microsurgery assessed using CBCT imaging, categories: Complete Healing (Success): Full bone repair, with the periodontal space having a normal width. Limited Healing (Success): Bone regeneration, but the periodontal space over the resected root surface is slightly widened (but less than twice the width of non-involved root). Uncertain Healing (Failure): A small defect or continued radiolucency persists in the lamina dura around the root-end filling. Unsatisfactory Healing (Failure): No change or an increase in the size of the radiolucent area, with poor bone repair.	6 and 12 months post-surgery
Cortical plate healing	Cortical plate healing will be scored according to the RAC/B index: Score 0: Cortical plate not re-established. Score 1: Cortical plate is partially re-established. Score 2: Cortical plate is re-established	6 and 12 months post-surgery

Collaborators and Investigators

• Sponsor: University of Bern
• Investigators: Study Chair: Anton Sculean, Prof., University of Bern

Study record dates

Study Major Dates

• Study Start (Actual): February 20, 2026
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2028

Study Registration Dates

• First Submitted: March 24, 2026
• First Submitted That Met QC Criteria: March 24, 2026
• First Posted (Actual): March 30, 2026

Study Record Updates

• Last Update Posted (Actual): March 30, 2026
• Last Update Submitted That Met QC Criteria: March 24, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Endodontic microsurgery
• Additional Relevant MeSH Terms: Periodontal Diseases; Mouth Diseases; Stomatognathic Diseases; Periapical Diseases; Jaw Diseases; Periodontitis; Periapical Periodontitis; Carbohydrates; Glycosaminoglycans; Polysaccharides; Hyaluronic Acid
• Other Study ID Numbers: HA in endo surgery

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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