Surgical Treatment of Peri-implantitis Using a Bone Substitute With or Without a Resorbable Collagen Membrane

The purpose of the study is to compare treatment outcomes of peri-implantitis defects when using a defect fill substitute (InterOss Collagen), against the treatment outcome when placing the same defect fill substitute with a resorbable collagen membrane (InterCollagen Guide). There is no current literature to suggest that placing a collagen membrane over a bone grafting material in an infrabony defect of more than 270 degrees is more effective than placing the bone graft material alone. The present study will help in understanding if such defects require an additional placement of a collagen membrane which could increase the cost of the procedure for the practitioner and the patient.

The study will be conducted at the University of Pittsburgh School of Dental Medicine Graduate Periodontics Department. A detailed description of research activities during each patient visit is provided below.

Screening Visit (V0):

Prior to starting any of the procedures, the subject will complete the informed consent interview. Patients will be screened to assess for inclusion in the study. Vitals (blood pressure and heart rate) will be measured and medical history will be discussed. Limited field of view (FOV) cone beam computed tomography (CBCT) scan will be taken and examined prior to the study to determine the presence of a 270 degree circumferential boney defect for inclusion in the study. Probing pocket depths (PPD), plaque sites, mobility and bleeding on probing (BOP) are clinical measurements that will be completed. The visit will take approximately 1.5 hours. All procedures will be performed by the faculty and Periodontics graduate resident.

Pre-surgical phase (V1):

If the patient is eligible and willing to participate in the study following the screening visit, they will return for V1. Their medical history will be reviewed, blood pressure and heart rate will be measured. Any adverse events from the previous visit will be assessed. A periapical (PA) radiograph will be taken to confirm a crater like defect \>=3mm. The prosthetic superstructures (implant crowns) will be removed followed by placement of cover screws. PPD will be measured twice (with and without the implant crown). Bleeding on Probing (BOP), suppuration, mobility, and plaque sites will be recorded. Clinical photographs will be taken of the teeth and inside of the mouth. Generalized supragingival debridement will be performed. Patients will be informed that newly fabricated crowns might be needed after the treatment as part of the study. During this visit, patients will be also re-instructed and emphasized on maintaining proper at-home oral hygiene measures with a soft-bristled toothbrush for minimizing trauma to marginal soft tissues. The visit will take approximately 2 hours. All procedures will be performed by the faculty and Periodontics graduate resident.

Surgical treatment procedures (V2) After 4 to 6 weeks, the patient will undergo regenerative surgical procedure. Their medical history will be reviewed, blood pressure and heart rate will be measured. Any adverse events since the previous visit will be assessed. The Study individuals will receive a local anesthetic as needed by the surgeon. Intra-sulcular, and if necessary, vertical releasing incisions will be made. Soft tissue flaps will be elevated at buccal and lingual aspects providing adequate access. Granulation tissue and mineralized deposits at implants will be removed using titanium curettes. The implant surfaces will be decontaminated with airflow. Once the surgical site was debrided, clinical intra-surgical measurements will be made. The measurement of peri-implant defect depth will be made clinically intra-surgically. Defects will be measured by calibrated examiners using a periodontal probe. The depth will be measured to the deepest point of the defect. This will be termed the clinical vertical defect fill (DF), and assessed at each implant site (buccal, lingual/palatal, mesial, distal) as follows: DF = (Measurement at the surgical treatment) - (Measurement at re-entry procedure). The defect resolution (DR) on the other hand will be measured as the percentage of the defect that was filled with bone at the follow up compared to the original defect depth. The horizontal defect, width of keratinized tissue, and soft tissue thickness will also be measured at this visit.

Thereafter, study individuals will be randomized to control or test groups using the SPSS randomization method (SPSS PASW 23.0 statistical software package, SPSS Inc., Armonk, NY, USA). Depending on the randomization, one of the following therapies was used: (a) (control group); bone grafting alone (InterOss Collagen) will be placed. (b) (test group); the intraosseous component will be filled with bone grafting (InterOss Collagen) and covered with a resorbable collagen membrane (InterCollagen Guide). InterOss Collagen is an FDA cleared for use in guided bone regenerative procedures. InterOss Collagen is a bovine derived anorganic hydroxyapatite collagen composite composed of 90% bovine granules and 10% collagen fibers molded in a block form. InterCollagen Guide is an FDA cleared porcine derived resorbable collagen membrane intended for periodontal and dental surgeries. In both groups, if needed, a periosteal releasing incision will be made to allow complete coverage of the wound area. In both study groups, surgical soft tissue flaps will be sutured with interrupted sutures without tissue tension using 4/0 or 5/0 PGA providing full wound closure. Clinical photographs will be taken again, and surgical video may be recorded when possible. All study individuals will receive postoperative antibiotics and prescribed post-operative pain relievers, as well as care instructions.

The postoperative medications may include:

Amoxicillin 500 mg 3 x 7 days

* Clindamycin 300 mg 4 x 7 days Ibuprofen 600 mg PRN Chlorhexidine 0.12% rinse 2 x 2 weeks Tylenol 3 (300mg-30mg)\* Medrol Dose Pack (as needed) Instructions not to wear any removable prosthesis during the healing phase * Administer if drug allergy to Amoxicillin \*Administer as alternative to Ibuprofen

The visit will take approximately 2.5-3 hours. All procedures will be performed by the faculty and Periodontics graduate resident.

4 weeks post op (V3) After 4 weeks (± 2 days), the patient will return for follow-up. Any changes to their medical history will be reviewed, blood pressure and heart rate will be measured. Any adverse events since the previous visit will be assessed. Sutures will be removed. Clinical photographs will be taken again. The visit will take approximately 0.5-1 hours. All procedures will be performed by the faculty and Periodontics graduate resident.

Re-entry procedure and replacement of superstructures (healing abutment) (V4) After 4 months of uninterrupted healing, patients will return for the re-entry procedure. Any changes to their medical history will be reviewed, blood pressure and heart rate will be measured. Any adverse events since the previous visit will be assessed. A standardized PA radiograph will be taken at this visit. Intrasulcular incision will be performed on the adjacent teeth and midcrestal incision at the implant location. Full thickness flap will be elevated, and the same defect measurements taken during the surgical procedures will be performed to obtain clinical changes in peri-implant bone levels. Where the defect fill will be measured as the difference in millimeters between the initial measurements taken at baseline and the depth of defect present at follow up. During the re-entry procedure, if the bone defect around the implant is not completely filled after V2, (it happens that we succeed to feel 60-70% of the defect, but not the whole defect), additional bone grafting material will be added after taking intra-surgical measurements. Please note the same bone graft material will be used, and will not involve additional clinical procedures, since the flap is open for the re-entry procedures. The outcome of "complete bone fill?" Yes/No will be recorded on the Visit form. Then, implant cover screws will be replaced by appropriate healing abutments, followed by single interrupted sutures for re-adaptation of the flap. Clinical photographs will be taken again, and surgical video may be recorded. Finally, a periodontal maintenance will be performed. The visit will take approximately 2 hours. All procedures will be performed by the faculty and Periodontics graduate resident. During this period, if needed new crowns will be designed, fabricated, and delivered to all patients and for all treated implants.

Post op after stage 2 (V5) Approximately 2 weeks after V4, subjects will return for V5. Any changes to their medical history will be reviewed, blood pressure and heart rate will be measured. Any adverse events since the previous visit will be assessed. Sutures will be removed. If a new crown is needed, digital impression will be taken with the Trios hand-held scanner, and patient will be referred to receive a new crown. If no new crown is needed, the old crown will be replaced at the next visit. Clinical photographs will be taken again. The visit will take approximately 1-2 hours. All procedures will be performed by the faculty and Periodontics graduate resident.

Crown placement/replacement (V6) Approximately 1 month after V5, the subjects will return for the Implant Crown replacement. Any changes to their medical history will be reviewed, blood pressure and heart rate will be measured. Any adverse events since the previous visit will be assessed. The old crown or the new crown will be placed in the treated area. A radiograph may be taken to assist in placement. The visit will take approximately 1- 2 hours. All procedures will be performed by the faculty and Periodontics graduate resident.

8 months visit (V7) For V7, subjects will return at approximately 8-months post-op. Any changes to their medical history will be reviewed, blood pressure and heart rate will be measured. Any adverse events since the previous visit will be assessed. Probing pocket depth (PPD), recession, BOP, plaque, suppuration and mobility measurement will be recorded. Radiographic measurements (bone fill) will be obtained as performed at the pre-surgical visit (time point 1). Dental prophylaxis and periodontal maintenance will be performed. Clinical photographs will be taken again. The visit will take approximately 0.5-1 hours. All procedures will be performed by the faculty and Periodontics graduate resident.

12 months visit (V8) Any changes to subject's medical history will be reviewed, blood pressure and heart rate will be measured. Any adverse events since the previous visit will be assessed. Probing pocket depth (PPD), recession, BOP, suppuration, mobility and plaque measurements will be taken as in previous visits. Radiographic measurements (bone fill) will be obtained as performed at the pre-surgical visit (time point 1) using a standardized PA radiograph. Periodontal maintenance will be performed. Clinical photographs will be taken again. The visit will take approximately 0.5-1 hours. All procedures will be performed by the faculty and Periodontics graduate resident.

Year 2:

15, 18, 21, 24 months visit (V9, V10, V11, V12) Any changes to subject's medical history will be reviewed, blood pressure and heart rate will be measured. Any adverse events since the previous visits will be assessed. Probing pocket depth (PPD), recession, BOP, suppuration, mobility and plaque measurements will be taken as in previous visits. Radiographic measurements (bone fill) will be obtained as performed at the last visit (V12, timepoint 24 months) using a standardized PA radiograph. If a patient is pregnant, the periapical x-ray will not be performed. Periodontal maintenance will be performed. Clinical photographs will be taken again. The visit will take approximately 0.5-1 hours. All procedures will be performed by the faculty and Pe

• Radiographic Marginal Bone Loss (MBL) [Time frame: 8 months]
• Radiographic Marginal Bone Loss (MBL) [Time frame: 12 months]
• Peri-Implant Bleeding on Probing [Time frame: 8 months]
• Peri-Implant Bleeding on Probing [Time frame: 12 months]
• Peri-Implant Probing Depth [Time frame: 8 months]
• Peri-Implant Probing Depth [Time frame: 12 months]
• Clinical Peri-Implant Bone Defect Fill [Time frame: 4 months]
• Clinical Peri-Implant Bone Defect Resolution [Time frame: 4 months]
• Patient Reported Pain Outcomes [Time frame: 2 weeks]
• Patient Reported Pain Outcomes [Time frame: 4 weeks]