Bone Substitutes and NIPSA in Intrabony Periodontal Defects: A Randomized Controlled Trial

Regenerative Therapy of Intrabony Periodontal Defects Using Bone Substitutes and a Minimally Invasive Nonincised Papilla Surgical Approach - A Randomized Controlled Clinical Trial

This multicenter randomized controlled clinical trial aims to compare the clinical, radiographic, microbiological and molecular outcomes of two collagenated xenogeneic bone substitutes (GTO® and GenOs®) used in combination with the Non-Incised Papilla Surgical Approach (NIPSA) for the treatment of intrabony periodontal defects. The study will evaluate whether differences exist between the two biomaterials with respect to clinical attachment gain, defect resolution, wound healing and biological markers of regeneration.

Study Overview

• Status: Recruiting
• Conditions: Periodontitis (Stage 3); Bone Substitutes; Minimally Invasive Surgical Procedures
• Intervention / Treatment: Procedure: GTO® with NIPSA surgical approach; Procedure: GenOs® + NIPSA

Detailed Description

Background Periodontal reconstructive surgery has demonstrated favourable long-term outcomes in the treatment of intrabony periodontal defects, including challenging defects with limited remaining bony walls. Periodontitis is a chronic inflammatory disease associated with progressive destruction of the tooth-supporting tissues and alveolar bone loss. Intrabony defects are associated with an increased risk of disease progression and tooth loss and therefore represent an important therapeutic challenge.

Recent advances in minimally invasive periodontal surgery aim to improve regenerative outcomes while reducing patient morbidity. The Non-Incised Papilla Surgical Approach (NIPSA) is a minimally invasive surgical technique that provides access to the intrabony defect through an apical incision while preserving the papillary and marginal soft tissues. This approach may improve wound stability, clot protection, vascularisation, and soft tissue preservation.

In parallel, collagenated xenogeneic bone substitutes have been developed to enhance periodontal regeneration. GenOs® is a collagenated xenogeneic particulate bone substitute with a preserved collagen matrix and documented regenerative potential. GTO® is a collagenated xenogeneic bone substitute consisting of cortico-cancellous granules incorporated into a cohesive collagen gel composed of type I and III collagen. Differences in biomaterial composition and physical form may influence wound healing, tissue stability, and regenerative outcomes.

Aim The aim of this multicenter randomised controlled clinical trial is to compare the clinical, radiographic, microbiological, and molecular outcomes of GTO® and GenOs® used in combination with the NIPSA surgical approach for the treatment of intrabony periodontal defects. The study will evaluate whether the two biomaterials result in comparable improvements in periodontal regeneration and biological markers associated with bone formation and healing.

Materials and Methods This study is designed as a multicenter, parallel-group, randomised controlled clinical trial conducted at the School of Dental Medicine, University of Belgrade (Serbia), and the Department of Periodontology, University of Cagliari (Italy).

Thirty patients diagnosed with Stage III periodontitis and presenting with at least one intrabony periodontal defect with probing depth greater than 5 mm following completion of non-surgical periodontal therapy will be enrolled. Participants will be randomly allocated in a 1:1 ratio to one of two treatment groups:

Test group: GTO® combined with the NIPSA surgical technique. Control group: GenOs® combined with the NIPSA surgical technique. Allocation concealment will be achieved using sequentially numbered, opaque, sealed envelopes. The operator will be informed of the assigned biomaterial after defect preparation, while the examiner responsible for clinical measurements, radiographic assessment, and outcome evaluation will remain blinded to treatment allocation throughout the study.

Clinical parameters, including probing depth (PD), clinical attachment level (CAL), bleeding on probing (BOP), and plaque index (PI), will be recorded at baseline and 6 months after surgery. Standardized periapical radiographs will be obtained at baseline, immediately after surgery, and at 6 months.

Microbiological analysis will be performed using real-time PCR. Molecular analyses will evaluate gene expression associated with osteogenesis and bone remodelling (RANKL, OPG, ALP, RUNX2, OCN), vascularisation (VEGF, HIF-2, eNOS), and growth factors (FGF and TGF). Particular attention will be given to the RANKL/OPG ratio as a marker of the balance between bone resorption and bone formation.

Clinical Relevance This study will provide comparative evidence regarding the regenerative potential of two collagenated xenogeneic bone substitutes used in conjunction with a minimally invasive periodontal surgical approach. The findings may contribute to optimising biomaterial selection and improving treatment predictability in regenerative periodontal therapy.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Iva Z Milinkovic, DDS, PhD; Phone Number: +381113629201; Email: iva.milinkovic@gmail.com

Study Locations

• Italy
  • Italy
    • Cagliari, Italy, Italy
      • Recruiting
      • Department of Periodontology, School of Dental Medicine, University of Cagliari Cittadella Universitaria di Monserrato Monserrato (CA), Italy
      • Contact: Nicola A Valente, DDS, MS, PhD; Phone Number: +39 338 5932069; Email: navalentedds@gmail.com
• Serbia
  • Belgrade, Serbia
    • Recruiting
    • Department of Periodontology and Research Implant Center, School of Dental Medicine, University of Belgrade
    • Contact: Iva Z Milinkovic, DDS, PhD; Phone Number: +381113629201; Email: iva.milinkovic@gmail.com

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Age ≥ 18 years
• Diagnosis of Stage III periodontitis
• At least one intrabony periodontal defect with probing depth > 5 mm following completion of non-surgical periodontal therapy
• Full-mouth plaque score (FMPS) < 20%
• Full-mouth bleeding score (FMBS) < 20%
• Ability to understand the study procedures and provide written informed consent

Exclusion Criteria:

• Systemic medical contraindications to periodontal surgery
• History of head and neck radiotherapy
• Poor oral hygiene or lack of motivation/compliance
• Uncontrolled diabetes mellitus
• Pregnancy or lactation
• Treatment with antiresorptive medications or other drugs affecting bone remodeling
• Heavy smoking (>20 cigarettes/day)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: GTO® + NIPSA; Regenerative periodontal therapy using GTO® collagenated xenogeneic bone substitute in combination with the Non-Incised Papilla Surgical Approach (NIPSA).	Procedure: GTO® with NIPSA surgical approach; Regenerative periodontal surgical treatment using the Non-Incised Papilla Surgical Approach (NIPSA) combined with GTO® collagenated xenogeneic bone substitute for the treatment of intrabony periodontal defects.
Active Comparator: GenOs® + NIPSA; Regenerative periodontal therapy using GenOs® collagenated xenogeneic bone substitute in combination with the Non-Incised Papilla Surgical Approach (NIPSA).	Procedure: GenOs® + NIPSA; Regenerative periodontal surgical treatment using the Non-Incised Papilla Surgical Approach (NIPSA) combined with GenOs® collagenated xenogeneic bone substitute for the treatment of intrabony periodontal defects.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Attachment Level (CAL) gain	Change in clinical attachment level (CAL) at treated intrabony periodontal defects from baseline to 6 months following regenerative periodontal therapy using either GTO® or GenOs® in combination with the Non-Incised Papilla Surgical Approach (NIPSA).	Baseline to 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Probing Depth (PD) reduction	Change in probing depth at treated sites from baseline to 6 months.	Baseline to 6 months
Bleeding on Probing (BOP)	Change in bleeding on probing (presence/absence) at treated sites from baseline to 6 months.	Baseline to 6 months
Plaque Index (PI)	Change in plaque index (PI) from baseline to 6 months	Baseline to 6 months
Radiographic bone level changes	Change in radiographic bone level at treated sites from baseline to 6 months using standardised periapical radiographs.	Baseline to 6 months
Quantification of periodontal pathogens	Change in levels of key periodontal pathogens (Porphyromonas gingivalis, Fusobacterium nucleatum, Prevotella intermedia, Aggregatibacter actinomycetemcomitans) from baseline to 6 months assessed by real-time PCR.	Baseline to 6 months
Gene expression of osteogenic markers	Change in gene expression of markers related to osteogenesis and bone remodelling (RANKL, OPG, ALP, RUNX2, OCN) from baseline to 6 months	Baseline to 6 months
Gene Expression of Vascularization Markers	Change in gene expression of vascularisation-related markers (VEGF, HIF-2, eNOS) from baseline to 6 months	Baseline to 6 months
Growth Factor Expression	Change in expression of growth factors associated with wound healing and regeneration (FGF and TGF) from baseline to 6 months	Baseline to 6 months
Early Healing Index (EHI)	Assessment of early soft tissue healing using the Early Healing Index (EHI) at 1 week postoperatively.	1 week postoperatively
Postoperative pain and discomfort	Patient-reported postoperative pain and discomfort assessed using a visual analog scale (VAS) ranging from 0 (no pain/discomfort) to 10 (worst imaginable pain/discomfort) during the first 7 days following surgery.	Up to 7 days postoperatively

Collaborators and Investigators

• Sponsor: University of Belgrade
• Collaborators: Cittadella Universitaria
• Investigators: Principal Investigator: Iva Z Milinkovic, DDS, PhD, School of Dental Medicine, University of Belgrade, Implant Research Centre and Department of Periodontology and Oral Medicine

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): February 1, 2027
• Study Completion (Estimated): March 1, 2027

Study Registration Dates

• First Submitted: June 22, 2026
• First Submitted That Met QC Criteria: June 22, 2026
• First Posted (Actual): June 26, 2026

Study Record Updates

• Last Update Posted (Actual): June 26, 2026
• Last Update Submitted That Met QC Criteria: June 22, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: periodontitis; bone substitutes; NIPSA; regenerative treatment
• Additional Relevant MeSH Terms: Periodontal Diseases; Mouth Diseases; Stomatognathic Diseases; Periodontitis
• Other Study ID Numbers: 36/53

Drug and device information, study documents

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