Immediate Placement and Stabilization of Dental Implants With Tetranite® Stabilization Material in Mandibular and Maxillary Tooth Extraction Sites That Fail to Provide Adequate Primary Stability
Conditions: Adhesive Dental
Sponsor: RevBio

 
 
 
 
Pilot Study  
 
Immediate Placement and Stabilization of Dental Implants with Tetranite® Stabilization Material 
in Mandibular and Maxillary Tooth Extraction Sites that Fail to Provide Adequate Primary 
Stability 
 
 
DVAL18041 
Version 3.0 
 
December 8th, 2020 
 
 
Protocol Reviewed and Approved By: 
 
 
 
Dr. David Cochran  
 
 
Study Monitor      
 
 
 
Signature        
 
 
Date 
 
 
 
Dr. Ryushiro Sugita 
 
 
Principal Investigator      
 
 
Signature        
 
 
Date 
 
 
 
Dr. Michael Pikos  
 
 
 
Principal Investigator       
 
 
Signature        
 
 
Date 
 
 
 
Dr. George Kay  
 
 
 
Chief Science Officer   
 
 
Signature 
 
 
 
Date 
 
 
 
Dr. Alan Pollack 
  
 
 
Chairman of Clinical Advisory Board  
Signature  
 
 
 
Date 
 
 
PROPRIETARY INFORMATION 
This protocol contains information that is confidential and proprietary to RevBio. The information has been 
provided to you for the sole purpose of conducting a clinical trial for RevBio. The information may be disclosed 
to the Ethics Committee or Institutional Review Board of your institution and to personnel who are expected 
to participate in the study. The information contained in this protocol, its appendices or supplements, the 
existence of such a protocol or the fact of or content of discussions with RevBio must not be revealed to any 
other parties without the written permission of RevBio in advance, unless such disclosure is mandated by 
government laws or regulations

 
 
Protocol DVAL18041 Version 3.0 
 
Contact Information 
 
Study Monitor: 
David L. Cochran, DDS, PhD, MMSci 
University of Texas Health Science Center 
San Antonio 
Department of Periodontics, MSC 7894 
7703 Floyd Curl Drive 
San Antonio, TX 78229  
(210) 567-3604 – Phone 
(210) 567-3643 – Fax 
cochran@uthscsa.edu 
 
Principal Investigator: 
Ryushiro Sugita, DDS 
University of Texas Health Science Center 
San Antonio 
Department of Periodontics, MSC 7894 
7703 Floyd Curl Drive 
San Antonio, TX 78229  
(210) 567-0416 – Phone 
(210) 567-3761 – Fax 
sugita@uthscsa.edu 
Principal Investigator: 
Michael Pikos, DDS 
Pikos Institute  
8740 Mitchell Blvd,  
New Port Richey, FL 34655 
(727) 781-0491 – Phone 
(727) 807-6033 – Fax 
mapikos@gmail.com 

 
 
Protocol DVAL18041 Version 3.0 
 
Sponsor: 
RevBio (F/K/A Launchpad Medical) 
600 Suffolk Street 
Suite 250  
Lowell, MA 01854 
Sponsor Representatives: 
Study Manager: 
Grayson Allen 
Clinical Study Director 
600 Suffolk Street 
Suite 250  
Lowell, MA 01854 
617-947-6246 – Phone 
gallen@launchpadmedical.com 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
Protocol DVAL18041 Version 3.0 
 
Abbreviations 
Ø               
Diameter 
ADA          
American Dental Association  
ADE           
Adverse Device Effect 
AE             
Adverse Event 
ASADE      
Anticipated Serious Adverse Device Effect  
BLT          
Bone Level Tapered 
BOP           
Bleeding on Probing 
CBCT        
Cone Beam Computed Tomography  
CFR           
Code of Federal Regulations 
CRF           
Case Report Form  
DD           
Device Deficiencies  
ECRF 
 
Electronic Case Report Form 
EDC 
 
Electronic Data Capture 
FDA 
 
Food and Drug Administration 
GBR 
 
Guided Bone Regeneration  
GCP 
 
Good Clinical Practice 
GTR 
 
Guided Tissue Regeneration  
HDD        
Horizontal Dimension of Defect 
IFU 
 
Instructions for Use 
IRB 
 
Institutional Review Board 
ISO 
 
International Organization for Standardization 
ISQ 
 
Implant Stability Quotient  
ITT  
 
Intention To Treat population  
mITT 
 
Modified Intention to Treat  
mGI 
 
Modified Gingival Index 
mm 
 
Millimeter 
mSBI 
 
modified Sulcus Bleeding Index  

 
 
Protocol DVAL18041 Version 3.0 
 
Ncm 
 
Newton Centimeter  
PlI    
 
Plaque Index 
PP  
 
Per Protocol population  
PPD 
 
Probing Pocket Depth  
PSP 
 
Photostimulable Phosphor 
RFA 
 
Resonance Frequency Analysis 
SADE 
 
Serious Adverse Device Effect  
SAE 
 
Serious Adverse Event 
SAF 
 
Safety Population 
TN-SM 
 
Tetranite® - Stabilization Material 
USADE 
 
Unanticipated Serious Adverse Device Effect  
VAS 
 
Visual Analog Scale 

 
 
Protocol DVAL18041 Version 3.0 
 
Synopsis 
Study Title: 
Immediate Placement and Stabilization of Dental Implants with Tetranite®
Stabilization Material in Mandibular and Maxillary Tooth Extraction Sites that Fail
to Provide Adequate Primary Stability – A Pilot Study 
Study Protocol 
Number: 
DVAL18041 
Study Registration: 
This protocol will be registered at www.clinicaltrials.gov before enrollment
begins. 
Aim: 
The aim of this Pilot Study is to demonstrate the safety and efficacy of the use of 
Tetranite-Stabilization Material (TN-SM) to allow clinical study of the TN-SM
device in a greater number of patients.  
Primary Endpoint: 
The primary endpoint is a composite measure of implant success (after criteria
of Buser, et. al.1) at six-month post-functional loading consisting of: 
• 
Presence of the implant at its site of implantation; and, 
• 
Absence of a recurrent peri-implant infection with suppuration; and, 
• 
Absence of mobility, defined as: 
o 
Lack of implant rotation subjected to 20 Ncm of clockwise 
torque applied 15 minutes after implant placement; and. 
o 
Lack of implant rotation subjected to 35 Ncm of clockwise 
torque applied 13 weeks after implant placement; and, 
o 
No construct mobility upon palpation at 6 months post-
functional loading; and, 
• 
Absence of encapsulation defined as continuous radiolucency 
around the implant in a periapical radiograph. 
Secondary Endpoints: 
Incidence, severity and duration of device-related adverse events throughout the
12-month post-functional loading term; 
Implant success (after criteria of Buser, et. al.1, see primary endpoint) after
implants are stabilized with the TN-SM device throughout the 12-month post-
functional loading term; 
Crestal bone level maintenance assessed by analysis of two-dimensional
periapical radiographic records showing no more than a 2mm loss of height at 
the 12-month post-functional loading term;  
Dimensional changes in bone volume and changes in bone density will be
tracked and qualitatively compared at the following time points: before tooth 
extraction, at follow-up to the implant placement, six months after functional
loading of the implant, and at twelve months after functional loading of the 
implant. CBCT data will be used to perform these assessments; 
Periodontal and peri-implant tissue health satisfaction demonstrated throughout
the 12-month post-functional loading as compared to existing conditions in the 
oral cavity near adjacent teeth to the implant site and to baseline around the
implant at definitive restoration; 
Subject satisfaction after TN-SM device placement and implant uncovering (i.e.,
level of pain) as well as throughout the 12-month post-functional loading term 

 
 
Protocol DVAL18041 Version 3.0 
 
(i.e., function, level of pain, esthetics). 
Primary Analysis: 
The primary analysis will be conducted after each subject completes six months
of TN-SM device functional loading after crown placement.  
Study Design: 
Prospective, multi-center, single arm, clinical pilot study. 
Number of Subjects: 
20 subjects total, 10 subjects at each of two Research Centers 
Subject Population: 
Male or female subjects 21 years of age or older who require a tooth extraction 
and desire a replacement with a dental implant and crown reconstruction, and 
who meet all the Inclusion/Exclusion criteria listed below.  
The implant site anatomical location may be maxillary or mandibular, anterior or 
posterior; however, the residual alveolar defect must meet stability and size 
criteria. 
Inclusion Criteria: 
Screening Inclusion Criteria 
• Subjects must have voluntarily signed the informed consent form before any
study related procedures; 
• Subjects must be males or females who are a minimum of 21 years of age, 
• Subjects who require a single tooth extraction and desire a replacement with 
a dental implant. Candidate subjects may require more than one extraction,
but only one site will be considered for inclusion in the study. 
• Subjects must have opposing dentition (natural teeth, fixed or removable 
restorations); 
• Subjects must be committed to the study and the required follow-up visits; 
• Subjects must be ASA I or ASA II; 
• Planned site for implant must have at least one adjacent tooth; 
• There must be sufficient bone height crestal to critical anatomical structures, 
i.e., the inferior alveolar canal, maxillary sinus or piriform foramen, to safely
place a dental implant within the bone contours; 
• Anatomical conditions that, in the opinion of the investigator, allow an implant
crown restoration to be placed at the candidate site, e.g., sufficient 
interocclusal space, appropriate angulation of the ridge, etc. 
Extraction Site Enrollment Inclusion Criteria  
• There is at least 2mm of apical bone for positive seating of the implant; 
• Any implant site in which placement of the selected implant leaves an HDD 
greater than 2mm in at least two directions, (i.e., mesially, distally, buccally, 
or lingually) between the implant surface and the most coronal aspect of the 
osteotomy.  

 
 
Protocol DVAL18041 Version 3.0 
 
Exclusion Criteria: 
Screening Exclusion Criteria 
• 
Subjects with a systemic disease or condition affecting a major organ system 
that would preclude dental implant surgery (e.g., malignant neoplasm or 
chemotherapy in the past 6 months, uncontrolled diabetes, major infection, 
Cushing’s syndrome, metabolic bone disease, immunosuppression, blood 
dyscrasias, healing bone fracture, myocardial infarction or cerebrovascular 
accident within the last six months, etc.); 
• Subjects with any contraindications for oral surgical procedures (e.g. 
scleroderma, etc.); 
• Subjects with mucosal diseases (e.g. erosive lichen planus, mucous 
membrane pemphigoid, erythema multiforme, etc.) in the localized area around 
the study implant site; 
• Subjects with bone diseases or conditions (e.g. Paget’s disease, fibrous 
dysplasia, history of osteomyelitis, etc.) in the region of the potential study 
implant site; 
• Subjects with a history of local radiation therapy in the head/neck area or 
osteonecrosis of the jaws; 
• Subjects with any acute and untreated endodontic lesions or periodontal 
disease; 
• Subjects receiving, or having a recent or long-term history of receiving, oral or
parenteral anti-osteoclastic agents [e.g., bisphosphonates, Xgeva® and 
Prolia® (denosumab); Forteo® (teriparatide), strontium ranelate, etc.], or anti-
angiogenesis factors; 
• Subjects who have major active substance abuse problems (e.g., alcoholism, 
opiate addiction, methamphetamine abuse, etc.); 
• Subjects who are pregnant or intending to become pregnant during the 
duration of the study; 
• Subjects who are heavy smokers (defined as >10 cigarettes per day or >1 cigar 
per day or equivalent of electronic cigarette vaping) or chew tobacco;  
• Subjects with inadequate oral hygiene or who are unmotivated for adequate 
home care; 
• Subjects who have physical or mental handicaps that would interfere with the 
ability to perform adequate oral hygiene; 
• Subjects who have undergone administration of any investigational device 
within 30 days of enrollment in the study; 
• Subjects who are allergic or otherwise sensitive to any materials likely 
encountered during the course of the study (e.g. titanium, suture materials,
local anesthetics);  
• Subjects with conditions or circumstances, which, in the opinion of the
Investigator, would prevent completion of study participation or interfere with 
analysis of study results, such as history of non-compliance or unreliability 
Extraction Site Enrollment Exclusion Criteria  
• Any site into which the implant is not or cannot be placed during the same visit
as the extraction. 
• Any implant site where there is a dehiscence or fenestration of buccal or lingual 
plates of bone greater than 5mm in any direction; 

 
 
Protocol DVAL18041 Version 3.0 
 
• Any implant site in which placement of the selected implant leaves an HDD 
greater than 5mm in any direction between the implant surface and the most 
coronal aspect of the osteotomy;  
• Any site which provides primary implant stability after seating as demonstrated
by insertion torque of greater than or equal to 15 Ncm; 
• Any site into which the implant is not or cannot be placed during the same visit 
as the extraction. 
Treatment Plan for 
the Study Subjects: 
Visit  
# Procedures 
Schedule 
Screening 
1 
Informed Consent, Screening, 
Demographics, Pregnancy Test, 
Periodontal Measurements 
 
Qualifying 
Examination 
2 
History, Baseline Clinical Examination, 
Baseline Radiographs and Holder 
Fabrication, Photographs 
 
Surgery 
3 
Tooth Extraction, Enrollment, TN-SM 
Placement, Implant Placement and 
Stability Test, Health Check, 
Radiographs, Photographs 
< 45 days from 
screening 
Postoperative 
Follow-up 
4 Suture Removal, Health Check, 
Radiographs, Photographs 
2-weeks post    
TN-SM device and 
implant placement 
Implant 
Uncovering 
5 
Uncover Implant, Health Check, Stability 
Test, Radiographs, Photographs, 
Periodontal Measurements  
13-weeks post 
TN-SM device and 
implant placement 
Restorative 
Records 
6 
Health Check, Records for Fabrication 
of Definitive Restoration (Impressions or 
scans, shade, jaw relation, etc.), 
Photographs 
3-weeks post 
implant 
uncovering 
Insertion of 
Definitive 
Restoration 
(Baseline) 
7 
Insertion of Definitive Restoration, 
Health Check, Satisfaction Survey, 
Periodontal & Peri-Implant 
Measurements, Radiographs, 
Photographs  
4 - 6 months post 
TN-SM device and 
implant placement 
3-month  
Follow-up 
8 
Health check, Satisfaction Survey, 
Periodontal & Peri-Implant 
Measurements, Radiographs, 
Photographs, Implant Success  
3-months post-
functional loading 
6-month  
Follow-up – 
Primary 
Endpoint 
9 
Health Check, Satisfaction Survey, 
Periodontal & Peri-Implant 
Measurements, Radiographs, 
Photographs, Implant Success 
6-months post-
functional loading 
9-month 
Follow-up  
9.5 
Health Check, Satisfaction Survey, 
Periodontal & Peri-Implant 
Measurements, Radiographs, 
Photographs, Implant Success 
9-months post-
functional loading 

 
 
Protocol DVAL18041 Version 3.0 
 
12-Month  
Follow-up 
10 
Health check, Satisfaction Survey, 
Periodontal & Peri-Implant 
Measurements, Radiographs, 
Photographs, Implant Success 
12-months post-
functional loading 
 
15-month 
Follow-up 
11 
Health Check, Satisfaction Survey, 
Periodontal & Peri-Implant 
Measurements, Radiographs, 
Photographs, Implant Success 
15-month post-
functional loading 
 
18-month 
Follow-up 
12 
Health Check, Satisfaction Survey, 
Periodontal & Peri-Implant 
Measurements, Radiographs, 
Photographs, Implant Success 
18-month post-
functional loading 
 
21-month 
Follow-up 
13 
Health Check, Satisfaction Survey, 
Periodontal & Peri-Implant 
Measurements, Radiographs, 
Photographs, Implant Success 
21-month post-
functional loading 
 
24-month 
Follow-up 
14 
Health Check, Satisfaction Survey, 
Periodontal & Peri-Implant 
Measurements, Radiographs, 
Photographs, Implant Success 
24-month post-
functional loading 
Study Products: 
Tetranite Stabilization Material, TN-SM  
Commercially available endosseous dental implants 
Manufacturer’s recommended prosthetic components for the implant systems 
Registration Status: 
TN-SM is the experimental device under study. 
Safety: 
Study subjects will be monitored for device-attributable adverse effects during 
the scheduled examinations and at any examinations resulting from study 
subjects’ self-reported concerns. A licensed physician will evaluate any evidence 
of systemic adverse effects.  
Countries in which 
the Study will be 
Conducted: 
United States 
Number of 
Participating 
Centers: 
2 centers 
Study Monitor: 
David L. Cochran, DDS, MS, PhD 
Principal 
Investigators at 
Centers: 
Michael Pikos, DDS, Pikos Institute, 8740 Mitchell Blvd, New Port Richey, FL 
34655 
Ryushiro Sugita, DDS, University of Texas Health Science Center, San Antonio, 
TX 78229 
Estimated Date of 
Study Initiation: 
Q1 2019 

 
 
Protocol DVAL18041 Version 3.0 
 
Estimated Date of 
Study Completion: 
Q2 2020 for all subjects to reach the primary endpoint;  
Q4 2021 for all subjects to complete the follow-up phase. 
Sponsor: 
RevBio 
Compliance: 
This study and any amendments will be performed according to ISO 
14155:2011, ICH E6(R1) Guideline on Good Clinical Practice (GCP) 1996 and 
conformed to the Declaration of Helsinki (last revised Fortaleza 2013). 
Local legal and regulatory requirements include compliance with 21 CFR 50, 21 
CFR 54, and 21 CFR 56. 

 
 
 
 
 
 
Schedule of Procedures / Assessments 
Procedures: 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 9.5 
Visit 10 
Visit 11-14 
Screening 
Visit1 
Qualifying 
Exam 
Surgery 
Post-Op 
Follow-up 
Implant 
Uncovering  
Restorative 
Records 
Insertion of 
Definitive 
Restoration 
(Baseline) 
Follow-up 
Follow-up 
(Primary) 
Follow-up 
Follow-up 
Follow-ups 
every 3 
months 
 
 
< 45 days 
after 
Screening 
2 weeks 
post- 
implant 
placement 
13 weeks 
post- implant 
placement 
3 weeks 
post- 
implant 
uncovering 
4-6 months 
post-implant 
placement 
3-months 
post- 
loading  
6-months 
post- 
loading 
9-months 
post-
loading 
12-months 
post- 
loading 
15-24 
month post 
loading 
Informed Consent 
 
 
X 
 
 
 
 
 
 
 
 
 
Screening Criteria 
(Inclusion/Exclusion) 
X 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Full Mouth CBCT or Panoramic 
Radiograph 
X 
 
 
 
 
 
 
 
 
 
 
 
Radiographic Media Holder 
Fabrication 
 
X 
 
 
 
 
 
 
 
 
 
 
Tooth Extraction 
 
 
X 
 
 
 
 
 
 
 
 
 
Extraction Site Enrollment 
Criteria (Inclusion/Exclusion) 
 
 
X 
 
 
 
 
 
 
 
 
 
TN-SM Device and  
Implant Placement 
 
 
X 
 
 
 
 
 
 
 
 
 
Suture Removal 
 
 
 
X 
 
 
 
 
 
 
 
 
Implant Uncovering  
 
 
 
 
X 
 
 
 
 
 
 
 
Restoration Records  
 
 
 
 
 
X 
 
 
 
 
 
 
Insertion of Definitive 
Restoration  
 
 
 
 
 
 
X 
 
 
 
 
 

 
 
 
 
 
 
 
Assessments: 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 9.5 
Visit 10 
Visit 11 
Visit 12 
Visit 13  
Visit 14 
Screening 
Visit1 
Qualifying 
Exam 
Surgery 
Post-Op 
Follow-up 
Implant 
Uncovering  
Restorative 
Records 
Insertion of 
Definitive 
Restoration 
(Baseline) 
Follow-up 
Follow-up 
(Primary) 
Follow-up 
Follow-up 
Follow-up 
Follow-up 
Follow-up 
Follow-up 
 
 
< 45 days 
after 
Screening 
2 weeks 
post-
implant 
placemen
t 
13 weeks 
post-
implant 
placement 
3 weeks 
post-
implant 
uncovering 
4-6 months 
post-
implant 
placement 
3-months 
post- 
loading  
6-months 
post- 
loading 
9-months 
post-
loading 
12-
months 
post- 
loading 
15-
months 
post-
loading 
18-
months 
post-
loading 
21-
months 
post-
loading 
24-
months 
post-
loading 
Pregnancy Test 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Med & Dental History 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Check 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Periapical radiographs 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
CBCT – localized 
 
X3 
 
X 
 
 
X 
X 
X 
 
X 
 
 
 
X 
Intra-oral photographs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Implant stabilization  
(torque check) 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Implant success 
(Buser et al.,Error! Bookmark not defined.) 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Oral Hygiene Evaluation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Periodontal Measurements 
X 
X 
 
 
X  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Peri-Implant Measurements 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Subject satisfaction evaluation 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1 The screening assessments can be taken at several visits as long as they are performed within 45 days of the surgery. 
2 The pregnancy test must be administered before taking study required radiographs. 
3 A localized CBCT is required at screening if a full mouth panoramic radiograph is used at screening instead of the full mouth CBCT. 

Protocol DVAL18041 Version 3.0 
Page 12 of 73 
 
 
 
 
 
 
Table of Contents 
 
 
CONTACT INFORMATION ....................................................................................................................................................... 2 
ABBREVIATIONS ..................................................................................................................................................................... 2 
SYNOPSIS ............................................................................................................................................................................... 4 
SCHEDULE OF PROCEDURES / ASSESSMENTS ....................................................................................................................... 10 
TABLE OF CONTENTS ............................................................................................................................................................ 12 
1 
BACKGROUND AND RATIONALE .................................................................................................................................. 15 
2 
STUDY ENDPOINTS ...................................................................................................................................................... 19 
2.1 
PRIMARY ENDPOINT (COMPOSITE) ...................................................................................................................................... 19 
2.2 
SECONDARY ENDPOINTS.................................................................................................................................................... 20 
 
Incidence and Severity of Device Attributed Adverse Effects and Events ............................................................... 20 
 
Long Term Implant Success .................................................................................................................................... 20 
 
Crestal Bone Level Maintenance ............................................................................................................................ 20 
 
Peri-Implant Bone Stability ..................................................................................................................................... 20 
 
Periodontal and Peri-Implant Health ...................................................................................................................... 20 
 
Patient Satisfaction ................................................................................................................................................ 21 
3 
STUDY DESIGN ............................................................................................................................................................. 21 
3.1 
OVERVIEW ..................................................................................................................................................................... 21 
3.2 
INTENDED USE ................................................................................................................................................................ 21 
3.3 
INDICATIONS FOR USE ...................................................................................................................................................... 21 
3.4 
STUDY POPULATION ......................................................................................................................................................... 21 
3.5 
STUDY SAMPLE SIZE ......................................................................................................................................................... 22 
3.6 
STUDY DURATION ............................................................................................................................................................ 22 
3.7 
SCREENING CRITERIA ........................................................................................................................................................ 22 
3.8 
EXTRACTION SITE ENROLLMENT CRITERIA ............................................................................................................................. 22 
3.9 
STUDY TREATMENT PLAN .................................................................................................................................................. 23 
3.10 
POST-LOADING FOLLOW-UP VISITS ..................................................................................................................................... 24 
3.11 
STUDY ASSESSMENTS ....................................................................................................................................................... 25 
 
Implant Success .................................................................................................................................................. 25 
 
Medical and Dental History ................................................................................................................................ 25 
 
Concomitant Medication .................................................................................................................................... 26 
 
Adverse Event Check .......................................................................................................................................... 26 
 
Subject Satisfaction ............................................................................................................................................ 26 
 
Oral Hygiene Evaluation..................................................................................................................................... 27 
 
Periodontal and Peri-Implant Measurements .................................................................................................... 27 
 
Periapical Radiographs ...................................................................................................................................... 28 
 
Cone Beam Computed Tomography (CBCT) ....................................................................................................... 28 
 
Intra-oral Photographs....................................................................................................................................... 28 
4 
DEVICE DESCRIPTION ................................................................................................................................................... 32 
4.1 
STUDY PRODUCT ............................................................................................................................................................. 32 
 
General Description of the Study Device ................................................................................................................ 32 

Protocol DVAL18041 Version 3.0 
Page 13 of 73 
 
 
 
 
 
 
 
Dental Implants and Restorative Components ....................................................................................................... 32 
4.2 
INSTRUCTIONS FOR USE, HANDLING, AND LABELING ............................................................................................................... 32 
4.3 
STORAGE ....................................................................................................................................................................... 33 
4.4 
DEVICE ACCOUNTABILITY .................................................................................................................................................. 33 
4.5 
RETURN OF STUDY DEVICE................................................................................................................................................. 33 
4.6 
RISK ANALYSIS, RISK/ BENEFITS .......................................................................................................................................... 33 
4.7 
GENERAL PRECAUTIONS: ................................................................................................................................................... 33 
 
Warnings: ............................................................................................................................................................... 33 
 
Cautions/Precautions: ............................................................................................................................................ 34 
5 
STUDY PROCEDURES .................................................................................................................................................... 34 
5.1 
SCHEDULE OF PROCEDURES AND ASSESSMENTS ..................................................................................................................... 34 
5.2 
SUBJECT SCREENING AND QUALIFYING EVALUATION (VISITS 1 AND 2) ....................................................................................... 35 
 
Informed Consent ................................................................................................................................................... 36 
 
Screening Inclusion Criteria: ................................................................................................................................... 36 
 
Screening Exclusion Criteria: ................................................................................................................................... 37 
 
Pregnancy Test ....................................................................................................................................................... 38 
 
Full Mouth CBCT or Panoramic Radiograph + Local CBCT ...................................................................................... 38 
 
Fabrication of Radiographic Media Holder ............................................................................................................ 39 
5.3 
SURGICAL PROCEDURE (VISIT 3) ......................................................................................................................................... 39 
 
Tooth Extraction ..................................................................................................................................................... 39 
 
Extraction Site Enrollment Inclusion Criteria .......................................................................................................... 39 
 
Extraction Site Enrollment Exclusion Criteria .......................................................................................................... 40 
 
Surgery – TN-SM Device and Implant Placement ................................................................................................... 40 
5.4 
POST-OPERATIVE FOLLOW-UP (VISIT 4) ............................................................................................................................... 42 
5.5 
IMPLANT UNCOVERING (VISIT 5) ........................................................................................................................................ 42 
5.6 
RESTORATIVE RECORDS (VISIT 6) ........................................................................................................................................ 43 
5.7 
INSERTION OF DEFINITIVE RESTORATION (FUNCTIONAL LOADING) (VISIT 7, BASELINE) .................................................................. 43 
5.8 
3-MONTH FOLLOW-UP (VISIT 8) ........................................................................................................................................ 43 
5.9 
6-MONTH FOLLOW-UP (VISIT 9, PRIMARY ENDPOINT)........................................................................................................... 44 
5.10 
9-MONTH FOLLOW-UP (VISIT 9.5) .................................................................................................................................... 44 
5.11 
12-MONTH FOLLOW-UP (VISIT 10) ................................................................................................................................... 45 
5.12 
15-MONTH FOLLOW-UP (VISIT 11) ................................................................................................................................... 45 
5.13 
18-MONTH FOLLOW-UP (VISIT 12) ................................................................................................................................... 46 
5.14 
21-MONTH FOLLOW-UP (VISIT 13) ................................................................................................................................... 46 
5.15 
24-MONTH FOLLOW-UP (VISIT 14) ................................................................................................................................... 47 
5.16 
PROTOCOL RELATED PROCEDURES ...................................................................................................................................... 47 
 
Early Withdrawal ............................................................................................................................................... 47 
 
End of Study ....................................................................................................................................................... 48 
 
Subject Replacement Policy................................................................................................................................ 48 
 
Protocol Deviations ............................................................................................................................................ 48 
6 
EVALUATION OF ADVERSE EVENTS .............................................................................................................................. 48 
6.1 
DEFINITIONS ................................................................................................................................................................... 48 
 
Adverse Event (AE).................................................................................................................................................. 48 
 
Serious Adverse Event (SAE) ................................................................................................................................... 49 
 
Adverse Device Effect (ADE) ................................................................................................................................... 49 
 
Serious Adverse Device Effect (SADE) ..................................................................................................................... 49 
 
Unanticipated Serious Adverse Device Effect (USADE) ........................................................................................... 49 
 
Anticipated Serious Adverse Device Effect (ASADE) ............................................................................................... 49 
6.2 
ASSESSMENT OF ADVERSE EVENTS ...................................................................................................................................... 50 

Protocol DVAL18041 Version 3.0 
Page 14 of 73 
 
 
 
 
 
 
 
Seriousness ............................................................................................................................................................. 50 
 
Relationship to the Study Device ............................................................................................................................ 50 
 
Relationship to the Procedure ................................................................................................................................ 51 
 
Severity ................................................................................................................................................................... 51 
 
Outcome ................................................................................................................................................................. 51 
 
Expectedness .......................................................................................................................................................... 52 
6.3 
PROCEDURE FOR REPORTING ADVERSE EVENTS ..................................................................................................................... 54 
 
AE Reporting ........................................................................................................................................................... 54 
 
SAE Reporting ......................................................................................................................................................... 54 
 
DD Reporting .......................................................................................................................................................... 55 
 
ADE Reporting ........................................................................................................................................................ 55 
 
SADE Reporting....................................................................................................................................................... 56 
 
Additional Safety Reporting .................................................................................................................................... 56 
6.4 
MONITORING OF SUBJECTS WITH ADVERSE EVENTS ................................................................................................................ 56 
7 
ANALYSIS OF ENDPOINTS ............................................................................................................................................ 57 
7.1 
ANALYSIS OF PRIMARY ENDPOINTS ...................................................................................................................................... 57 
7.2 
ANALYSIS OF SECONDARY ENDPOINTS .................................................................................................................................. 57 
7.3 
ANALYSIS OF SAFETY ENDPOINTS ........................................................................................................................................ 57 
7.4 
GENERAL STATISTICAL METHODS ........................................................................................................................................ 58 
 
Surgery and Supporting Procedures ....................................................................................................................... 58 
 
Other Data Summaries ........................................................................................................................................... 58 
 
Subject Disposition ................................................................................................................................................. 58 
 
Missing Data ........................................................................................................................................................... 58 
8 
DATA MANAGEMENT .................................................................................................................................................. 58 
9 
STUDY MANAGEMENT ................................................................................................................................................. 59 
9.1 
REGULATORY AND ETHICAL REQUIREMENTS .......................................................................................................................... 59 
 
Informed Consent ................................................................................................................................................... 59 
 
Institutional Review Board ..................................................................................................................................... 59 
9.2 
REPORTS AND RECORD MANAGEMENT ................................................................................................................................ 59 
 
Investigator Records ............................................................................................................................................... 59 
 
Case Report Forms .................................................................................................................................................. 60 
 
Source Documents .................................................................................................................................................. 60 
 
Records/Data Retention ......................................................................................................................................... 60 
9.3 
MONITORING ................................................................................................................................................................. 60 
 
Study Initiation Visit................................................................................................................................................ 60 
 
Routine Monitoring Visits ....................................................................................................................................... 61 
 
Study Closeout Visit ................................................................................................................................................ 62 
9.4 
STUDY TERMINATION ....................................................................................................................................................... 62 
 
Center Discontinuation ........................................................................................................................................... 62 
9.5 
PROTOCOL AMENDMENTS ................................................................................................................................................. 63 
9.6 
PUBLICATIONS ................................................................................................................................................................. 63 
10 
PROTOCOL SIGNATURE PAGE ...................................................................................................................................... 64 
 

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1 
Background and Rationale 
Every year, millions of procedures involving fixation of metal objects and bone fragments to bone 
are performed worldwide.2-5 An assortment of autografts, allografts, xenografts, alloplasts, 
hardware fixation devices, as well as growth factors are currently being used to improve the 
outcomes of these procedures by aiding in immobilization, fixation, providing scaffolds, stimulating 
bone ingrowth and healing, or increasing bone volume.6 The ideal material or device, or 
combination, used in many of these procedures must be biocompatible, at least osteoconductive, 
preferably biodegradable and replaced by native bone, able to withstand loads (strong) and absorb 
shocks (tough), produce predictable results, be easy to use, and be relatively inexpensive.7 The list 
of desirable characteristics should also include the capacity to resist migration (cohesiveness), be 
used in minimally invasive procedure (injectability), adhere to living bone (wet field adherence), 
adhere to the hardware materials, accept direct bone deposition (ability to osseointegrate), and 
maintain the desirable mechanical properties throughout the useful life of the product. To date, 
such an ideal material has not been found.  
In addition to allograft products, many semi-synthetic, synthetic, and xenograft bone graft substitute 
particulate materials have entered the market. The most successful of these are calcium phosphate 
salts, e.g., hydroxyapatite and β-tricalcium phosphate because of their biocompatibility and 
similarity to the natural bone mineral. These materials are osteoconductive, inexpensive and can 
be successfully used to expand the volume of autogenous grafts.8 The physical characteristics of 
these materials, however, do not allow them to be weight bearing and many are not significantly 
biodegradable. Furthermore, particulate materials, such as bone chips and xenograft granules, 
often need to be contained by membranes or meshes to prevent migration from the application site 
and to maintain shape of the graft mass.  
Hard-setting polymeric cements were developed to retain load-bearing implantable hardware such 
as prosthetic joints.9-10 These synthetic materials have seen extensive use in orthopedics because 
they can uniquely and immediately provide load-bearing strength and toughness.7, 11 However, their 
use is controversial in some applications as they can pose several serious problems as 
biomaterials. For instance, a class of bone cement based on polymethylmethacrylate (PMMA) resin 
is a legacy material that has no chemical adherence to bone, is not resorbable, and its monomer 
has been characterized as a toxic material particularly when used in bulk.12 PMMA has also been 
known to cause serious complications related to its exothermic setting reaction,13 its effect on the 
pulmonary and circulatory system,14 and its lack of long-term hard tissue integration, 

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biodegradation and vascular penetration.15-16 Inclusion of various additives such as fibers, 
nanotubes, beads, flakes, antibiotics, barium salts, magnesium salts, hydroxyapatite, bioglass, 
silica, chitosan, and others, has been investigated with the goal of improving the mechanical and 
biochemical properties of the PMMA bone cements to produce mixed incremental improvements.17-
20 
The use of synthetics has increased in the past several decades after the development of calcium 
phosphate cements (CPCs) in the mid 1980’s.21 This class of water-based self-setting cements 
composed of various calcium phosphate salts has been described and studied as potential 
synthetic bone grafting materials. CPCs are usually composed of two calcium phosphate salts, one 
more alkaline, e.g., α-tricalcium phosphate or tetracalcium phosphate (TTCP), and the other more 
acidic, e.g., dicalcium phosphate anhydrate or monocalcium phosphate,22 which when mixed in an 
aqueous environment react with one another and precipitate as one of several intermediate pH 
calcium salts, often hydroxyapatite.23 The newer CPC formulations often add a non-calcium-
phosphate compound acidic component, e.g., polymethyl-vinyl ether-maleic acid or citric acid, etc. 
in order to improve properties of the biomaterial.24-25, 
Even though many of the non-metallic materials and devices available are osteoconductive, 
resorbable, injectable, capable of osteointegration and increasingly tougher and stronger, most are 
brittle and not strong enough for load bearing applications required for the skeleton.26-28 
On the other hand, metallic implantable fixation devices, which do have the load bearing intrinsic 
strength, are not biodegradable,29 nor do they conform to the defect shape or size. Both metal and 
resorbable (e.g. collagen) hardware, such as screws, plates, and buttons, require a significant, 
often unavailable, bone quantity and quality for successful application, thereby presenting technical 
challenges or leading to compromised results.30  
A material combining load bearing, resorbable, osteoconductive, and injectable characteristics has 
been elusive, yet another highly desirable characteristic, that of robust adherence to bone in a 
biocompatible and biodegradable material has not been described in spite of much effort expended 
and some promising results. One direction to follow is the synthetic path with known adhesives 
being applied to the biological system. A variety of cyanoacrylates,31-32 polyurethanes,33 PMMAs,34 
glass ionomers,35 as well as calcium and magnesium phosphates36 and others have been 
investigated without resulting in a broadly used clinical product for a variety of reasons spanning 
from cytotoxicity, insufficient strength of bonds formed with bone, method of use incompatible with 
osseous tissue survival, to brittleness of the material itself.7  

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Another direction followed was to adapt a naturally-occurring adhesive to bone applications. Fibrin 
clot based37 and aldehyde cross-linked collagen derivatives based38 systems have been successful 
as soft tissue adhesives but lack strength for bone applications. Attempts to directly use proteins 
involved in adhesion in nature resulted in unacceptable immune responses in vivo; however, 
biomimetic polymers based on marine organisms such as the mussel Mytilus californianus39-40 and 
the sandcastle worm Phragmatopoma californica41 have produced more promising results. The 
continuing work by Messersmith and by Lee with the mussel-inspired materials related to 
dihydroxyphenylalanine (DOPA), such as 3,4-dihydroxyhydrocinnamic acid (DOHA), dopamine, 
and nitrodopamine has led to reports of implantable soft tissue adhesive,42 underwater bonding 
and debonding by exposure to ultraviolet irradiation,43 underwater adhesion with post-
translationally modified, bioengineered proteins, and a functional osteoinductive binder for grafting 
of bone substitute particles,44 among others.  
RevBio (RB) seeks to obtain marketing approval for Tetranite™ Stabilization Material Device (TN-
SM), a calcium phosphate-based synthetic material with adhesive properties that make it suitable 
to bond metal implants to bone. The adhesive contains O-phospho-L-serine (OPLS), which is 
essential to the adhesive properties. Tetranite® is a synthetic, osteoconductive, biodegradable 
bone-adherent biomaterial. It is injectable, mildly exothermic during cure, bonds to most high 
surface energy materials, including living bone and metals such as titanium and its alloys, and is 
capable of forming durable and stable bonds in a wet environment. The components of Tetranite 
are substances that occur naturally in the human body. Tetranite technology is partly built on 
Chow’s work with calcium phosphates but is also partly inspired by a glue protein found in the sea-
dwelling sandcastle worm. The results show a robust ability to bond both metals and bone in a wet-
field 
environment 
combined 
with 
injectability, 
biocompatibility, 
biodegradability 
and 
osteoconduction.  
The stability in bone of a newly placed dental implant is critical to its success.45 Frequently, the 
conditions at presentation do not predictably guarantee that the new implant will be stable on 
placement and require reconstructive procedures aimed at rebuilding the bone through grafting.46 
This additional sequence of procedures, with an additional healing period to follow, delays the 
completion of treatment by four to six months. It also adds increased risk for post-surgical 
complications including inadequate healing and infection, as well as greater morbidity for the 
patient. Additionally, implants placed in grafted bone have a higher risk of failure to 
osseointegrate.47 The purpose of the present study is to evaluate the safety and efficacy of a single 
stage approach using Tetranite® Stabilization Material (TN-SM). The purpose of the efficacy 

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component of this study is a composite comprising: (1) First – To demonstrate and evaluate the 
ability of TN-SM to achieve immediate implant stabilization in sites otherwise unable to provide 
primary stability without requiring the delay in treatment imposed by the current multi-staged 
standard-of-care method; (2) Second - To demonstrate and evaluate the ability of TN-SM to 
achieve short-term stabilization of implants as the device undergoes initial resorption and 
replacement with new bone; and (3) Third - To demonstrate and evaluate the ability of a TN-SM 
stabilized implant to achieve implant success (after criteria of Buser, et. al.1) after 6 months of 
functional-loading while the device undergoes significant resorption, facilitates osteoconduction, 
and replacement with new bone. In addition to the Primary Endpoints of establishing the Safety 
and Efficacy of Implant Stabilization and Implant Success throughout the initial 6 months of post-
functional loading, the study also assesses several secondary endpoints over the course of the 
study and one-year follow-up, as outlined in the sections below. These include assessment of 
incidence, duration, and severity of adverse effects and events; assessment of implant success; 
assessment of bone level, volume and density changes; patient satisfaction surveys, and 
assessment of periodontal and peri-implant health integral to implant success. 
There are currently many alternatives for clinicians and patients to choose for use as bone graft 
materials. While safety and efficacy have been well established for the majority of them, success 
rates vary both in their ability to allow bone replacement and their ability to maintain volume of bony 
architecture once placed, and as healing and bone replacement occur over time. Additionally, 
where bony walls are absent, guided bone regeneration (GBR) procedures are indicated. While 
also highly successful, these GBR procedures introduce additional risk of treatment failure, post-
surgical infection and other complications, as well as increased cost and treatment time for the 
patient. While not a primary outcome of this proposed study, animal data to date have 
demonstrated soft tissue exclusion with Tetranite and, therefore, no need for barrier membranes to 
be used. Additionally, the TN-SM is dimensionally stable as it is replaced by the patient’s bone, 
thereby limiting the need for overfill or secondary grafting procedures. 
The goal of implant therapy is to provide support for a functional and esthetic restoration with a low-
risk of complication to the patient. Clinicians have many treatment decisions that impact the 
successful delivery of functional and esthetic restorations, including timing of implant placement 
and type of implant. This study will consider the clinical outcomes of using TN-SM to establish 
adequate stability for immediate implantation following extraction of natural teeth for successful 
osseointegration. The study treatments have been developed in the course of exploratory and 
pivotal preclinical large animal studies using the TN-SM device in unstable implant sites. 

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2 
Study Endpoints 
The aim of this study is to demonstrate, at a pilot level, the Safety and Efficacy of TN-SM for its 
stated indications for use to allow clinical study in a greater number of patients. It is also an aim of 
this study to test performance characteristics and capabilities of study designs, measures, 
procedures, recruitment criteria, and operational strategies that are under consideration for use in 
a larger subsequent study. 
2.1 
Primary Endpoint (Composite) 
The primary endpoint is implant success through six-months of post-functional loading. The 
implant success criteria will be collected on a per patient level and are a composite of implant 
survival, health and efficacy measures, based after criteria of Buser, et. al. 1, including: 
• 
Presence of the implant at its site of implantation; and, 
• 
Absence of a recurrent peri-implant infection with suppuration; and, 
• 
Absence of mobility, which will be assessed at multiple timepoints. Specifically, 
o Immediate stabilization (implant placement, Visit 3) is assessed by applying a torque of 
20 Ncm applied directly to the implant 15 minutes after implantation.  
o Short-term stabilization (implant uncovering, Visit 5) is assessed by applying a torque 
of 35 Ncm 13 weeks after implant insertion.  
o Continued stabilization is assessed at 6-months post-functional loading (Primary 
Follow-up, Visit 9) by applying manual palpation.    
• 
Absence of encapsulation determined by a continuous radiolucency around the implant 
assessed via periapical image. 
 
 

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2.2 
Secondary Endpoints 
 Incidence and Severity of Device Attributed Adverse Effects and Events 
The first secondary endpoint will be to demonstrate low incidence and severity as well as short 
duration of adverse device-attributed systemic effects and events as reported by study subjects 
and/or investigator/monitors throughout the 12-month post-functional loading term. 
 Long Term Implant Success 
The second secondary endpoint will be to demonstrate long-term implant success after implants 
are stabilized with the TN-SM device throughout the 12-month post-functional loading term. The 
implant success criteria will be collected on a per patient level at each timepoint and are a 
composite of implant survival, health and efficacy measures, based after criteria of Buser, et. al.1, 
including: 
• 
Presence of the implant at its site of implantation; and, 
• 
Absence of a recurrent peri-implant infection with suppuration; and, 
• 
Absence of mobility, which will be assessed by applying manual palpation; and,    
• 
Absence of encapsulation determined by a continuous radiolucency around the implant 
assessed via periapical image. 
 Crestal Bone Level Maintenance 
The third secondary endpoint will be to demonstrate crestal bone level maintenance measured 
directly by two-dimensional periapical radiographic methods showing no more than a 2mm loss of 
height at the 12-month post-functional loading term. 
 Peri-Implant Bone Stability 
The fourth secondary endpoint will be to determine if there are any dimensional changes in bone 
volume and changes in bone density which will be tracked and qualitatively compared at the 
following time points: before tooth extraction, at follow-up to the implant placement, six months after 
functional loading of the implant, and at twelve months after functional loading of the implant. CBCT 
data will be used to perform these assessments. 
 Periodontal and Peri-Implant Health 
The fifth secondary endpoint will be to demonstrate satisfactory periodontal and peri-implant 
health throughout the 12-month post-functional loading term compared to existing conditions in the 
oral cavity near adjacent teeth and to baseline around the implant at definitive restoration; 

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 Patient Satisfaction 
The sixth secondary endpoint will be to demonstrate acceptable level of subject satisfaction after 
TN-SM device placement and implant uncovering (i.e., level of pain) as well as throughout the 12-
month post-functional loading term (i.e., function, level of pain, esthetics). Patient Satisfaction 
scores will be determined by analysis of patient reports using a Visual Analog Scale.  
3 
Study Design 
3.1 
Overview 
This is a prospective, multi-center, single arm, pilot clinical study evaluating the use of TN-SM for 
implant stabilization immediately after tooth extraction. The purpose of this pilot study is to test 
performance characteristics and capabilities of study design, recruitment criteria, procedures, 
measures, and operational strategies that are under consideration for use in a subsequent, larger 
clinical pivotal study. The purpose of the subsequent study will be to provide data demonstrating 
the safety and efficacy for the use of TN-SM to provide immediate and continued stabilization of 
implants placed into otherwise unstable sites. Use of TN-SM eliminates the need for the standard 
practice of bone grafting after tooth extraction and staged implant placement, significantly 
shortening the overall length of this treatment.  
3.2 
Intended Use 
Tetranite® Stabilization Material bonds dental implants to bone in applications where additional 
mechanical stabilization is required at the time of placement. Its purpose is to augment primary 
stability of dental endosseous implants inserted into sites that lack adequate primary stability. 
Tetranite is resorbed over several months while being replaced with new bone without 
compromising implant stabilization.  
3.3 
Indications for Use 
Tetranite Stabilization Material is indicated to stabilize a dental implant in a compromised 
implantation site which requires an adjunct to hardware fixation between the implant surface and the 
bone recipient site. These sites are sockets after the recent extraction of a tooth, that include a 
surgically created osteotomy within the extraction site made in preparation for dental implant 
placement in which primary stability is unable to be achieved through conventional means. The 
adhesive is intended only as an adjunct to hardware fixation and is not intended for stand-alone use. 
3.4 
Study Population 
The study population will consist of male and female subjects at least 21 years of age. The 

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demographic data will be recorded in the study logs. Subjects will be recruited through the clinics 
where the investigators are practicing and possibly through referring dentists. There will be a 
stratified examination of inclusion/exclusion criteria applied during the patient evaluation process 
to make the process less burdensome to both the potential study subjects and the investigators: 
the first is the screening criteria of the patient overall, which will consider whole-patient and oral 
factors, while the second is the extraction site enrollment criteria, which is a more detailed 
assessment of the candidate study subject and of the specific potential study site which will be 
determined at the time of the tooth extraction and implant placement. All of the inclusion criteria 
must be met to receive the study implant. If any of the exclusion criteria are met, the potential study 
subject must be excluded from the study. 
3.5 
Study Sample Size 
This study size will enroll 20 subjects, 10 at each of the two Research Centers. The enrollment will 
be capped at 20 subjects total and will not include control subjects.  
3.6 
Study Duration 
The study is expected to enroll 20 subjects over a 6-month period. Study subjects will participate 
for 30 months (up to 6 months to reach implant loading, then 6 months to reach the primary 
endpoint, followed by another 18 months to reach 24-months follow-up). The total duration of the 
study is expected to span 36 months. 
3.7 
Screening Criteria  
Those potential subjects who appear eligible according to the Screening Inclusion and Exclusion 
Criteria will be asked to provide informed consent in writing prior to any study related procedures 
and will be considered “consented” in the study and logged in as “consented” candidates. Potential 
subjects will be evaluated based on the Screening Inclusion Criteria (Section 5.2.2) and Screening 
Exclusion Criteria (Section 5.2.3) for initial eligibility during the Screening and Examination visits. 
Subjects must fulfill all of the inclusion criteria and not meet any of the exclusion criteria to be 
eligible for the study. If the “consented” study candidate meets all the Criteria he/she will be 
scheduled for the Surgical Visit. If a “consented” study candidate does not meet all the 
Inclusion/Exclusion Criteria, his/her name will be logged in as a “screen failure”. Subject 
demographics, including age, gender, race, and ethnicity, will be documented at the Examination 
visit. 
3.8 
Extraction Site Enrollment Criteria 

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Potential subjects are permitted to have multiple teeth extractions and/or receive multiple implants 
during the surgical procedure, however only one of the sites will be enrolled as the study site. The 
study subject candidate site tooth will be extracted during the Surgical Visit, and the extraction site 
will be immediately prepared with an implant osteotomy and next evaluated for enrollment by 
application of the Enrollment Inclusion Criteria (Section 5.3.2) and Enrollment Exclusion Criteria 
(Section 5.3.3). In the case of multiple potential candidate sites, the study site will be selected by 
the investigator prior to the TN-SM device and implant placement based on which site meets the 
Extraction Site Enrollment Criteria. If multiple sites meet the criteria, the least stable qualifying site 
will be selected and enrolled as the study site.  
Once the subject meets all the Extraction Site Enrollment Criteria, he/she is considered “enrolled” 
in the study, and the status will be documented in the Enrollment Log. Any “consented” potential 
subject who at the end of the Surgical Visit does not have a single “enrolled” site, will be considered 
an “enrollment failure” and his/her name will be logged in as such. Once the number of enrolled 
subjects at a Research Center reaches ten, no further subjects will be considered or enrolled. 
Once the planned number of subjects at the study center is reached (10), no more potential subjects 
will be considered or enrolled in the study.  
3.9 
Study Treatment Plan 
Subjects enrolled in the study will have had, during the Surgical Visit, a test site which met the 
criteria of an initially placed implant demonstrating inadequate stability. After implant removal, the 
TN-SM is applied to the site and the implant is reinserted per the Tetranite IFU – Document # 
50001-00 (Appendix 1). Immediate stabilization is assessed by applying a torque of 20 Ncm applied 
directly to the implant 15 minutes after implantation. This level is a clinically relevant indicator of 
stability and is expected to be a sub-threshold and nondestructive test.48 After successful 
completion of the torque test, all implants will be closed with a cover screw and soft tissues left to 
granulate over the socket crests. Monofilament sutures will be used at the discretion of the clinician 
to approximate soft tissue margins, as needed. Photographic records will be captured of the study 
site before and after soft tissue adaptation. A standardized periapical image will be captured for 
documentation of the crestal bone level pre-extraction and after TN-SM device and implant 
placement.  
Two weeks following placement of the TN-SM device and the implant, all subjects will return for 
evaluation of the study site for healing and possible suture removal. A localized CBCT scan of the 
region of the study site will be performed and will serve as baseline. 

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All subjects will return at 13 weeks following the TN-SM device implantation to uncover the implant. 
At this point, short-term stabilization will be assessed by applying a torque of 35 Ncm to the implant. 
The test is performed at a clinically relevant torque level to demonstrate readiness for restoration 
of an implant supported prosthesis.49 A healing or standard abutment will be placed during the visit. 
A standardized periapical image for documentation of crestal bone level and for evaluation of 
indicators of encapsulation will be captured. Photographic records of the study site will be captured 
before uncovering surgery and following abutment placement and soft tissue adaptation. 
Following a three to four-week healing period, records will be obtained for fabrication of a crown 
restoration. These records will consist of the following: final impression or scan of the test site dental 
arch, an impression or scan of the opposing dental arch, a jaw relation record and a shade 
registration of the dentition. Photographic records will also be captured at this time.  
Contingent upon satisfactory stabilization, the implant will be loaded by the implant crown in 
appropriate occlusion with an abutment and crown prosthesis no sooner than four months and no 
later than six months after TN-SM device placement. A baseline standardized periapical image for 
documentation of crestal bone level and for evaluation of indicators of encapsulation will be 
captured. Photographic records will be captured of the study site before and after the crown is 
inserted from lingual (or palatal) and from buccal aspects. If the definitive restoration is inserted 
provisionally at this time, the provisional insertion date will be treated as the baseline loading date 
for the purposes of the study and the definitive insertion visit will be recorded as a separate visit.  
Any loosened implants that are identified during the course of the study will be considered a failure 
and will be removed. The remaining Tetranite material will be removed by curetting or drilling the 
osteotomy until a bleeding bone surface is obtained.  The clinician may place a wider or longer 
implant as appropriate for the tooth position.  Otherwise the site will be grafted as per a conventional 
staged approach. 
3.10 Post-Loading Follow-up Visits 
Following crown placement, all subjects will return for routine evaluation of the study site and for 
evaluation of the TN-SM device function at 3-, 6-, 9-, 12-, 15-, 18-, 21-, and 24-months of post-
functional loading. In addition to the routine elements of the site evaluation, the following 
assessments will be performed: Photographic records will be captured of the study site from lingual 
(or palatal) and buccal aspects, and the subject will also answer a satisfaction survey (pain, 
function, and esthetics) at every post-loading follow-up. A standardized periapical image for 
documentation of crestal bone level and for evaluation of encapsulation of the study will be captured 

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at 3 months and 6 months post-loading, and every 6 months thereafter (3, 6, 12, 18, and 24 
months). A CBCT scan of the region of the study site will be performed at  the 3-, 6-, 12-, and 24-
month post-loading follow-up visits. 
3.11 Study Assessments 
 Implant Success 
Implant success will be assessed at post-functional loading follow-ups. A successful implant will 
meet all of the following criteria according to Buser et al.1; including, 
• 
Presence of the implant at its site of implantation; 
• 
Absence of a recurrent peri-implant infection with suppuration;  
• 
Absence of mobility, which will be assessed at several timepoints.  Specifically, 
o Immediate stabilization (implant placement, Visit 3) is assessed by applying a torque of 
20 Ncm applied directly to the implant 15 minutes after implantation.   
o Short-term stabilization (implant uncovering, Visit 5) is assessed by applying a torque 
of 35 Ncm 13 weeks after implant insertion. 
o Long term stabilization is assessed every 3 months post-functional loading until 24- 
months post-functional loading by manual palpation.    
• 
Absence of encapsulation determined by a continuous radiolucency around the implant 
recorded in a periapical image. 
Any dental implant showing excessive bone loss, radiolucency, or infection shall be treated in the 
manner best suited to the well-being of the subject, including treatment to save the dental implant. 
Continuous radiolucency, implant loss, recurrent peri-implant infection with suppuration, or implant 
mobility shall be considered a failure for the purposes of the study. 
 Medical and Dental History 
The medical and dental history will be obtained at the screening visit and updated at each visit in 
the study. The dental history should include dental status information including a description of the 
opposing and adjacent dentition. Relevant medical history (e.g., systemic diseases, medications, 
etc.) and current medical conditions will be recorded by the investigator. The information may be 
obtained from the subject’s general physician or from oral communication with the subject.   
Any study subject who develops a medical condition during the course of the study which would 
have been considered an exclusion criterion will not be exited from the study.  Patients will continue 

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in the study and will continue to be followed except as required to ensure appropriate medical care 
for their specific conditions.  For example, patients who become pregnant during the study would 
be unable to undergo the required imaging but would be followed clinically.  Patients who develop 
cancer and require systemic chemotherapy or radiation would also continue to be followed except 
if deemed necessary to exit the study by their clinician.  
 Concomitant Medication 
Concomitant medication, procedures, and supportive therapies will be recorded at the screening 
visit. Any changes in the concomitant medications, procedures, and supportive therapies must be 
documented at each study visit until the end of the study. All prophylactic antibiotics and anesthesia 
given must be recorded on the Concomitant Medication Form. This includes the pre-rinse with 
chlorhexidine mouthwash 0.12% for 30 seconds immediately prior to the surgery. 
 Adverse Event Check  
Following surgery and at each visit until the end of the study, the Investigator will determine if any 
adverse events occurred since the last study visit by speaking with the subject and reviewing any 
dental and medical records. These Adverse Events (AEs), along with any adverse events from the 
current study visit, should be documented and reported as described in Section 6.3 of the protocol. 
In addition, the Investigator will evaluate the status of any ongoing adverse events throughout the 
study as specified in Section 6.4. 
 Subject Satisfaction 
Subject satisfaction will be assessed utilizing Visual Analog Scales (VAS) at insertion of definitive 
restoration, as well as at 3-, 6-, 9-, 12-, 15-, 18-, 21-, and 24-months post-functional loading for the 
following parameters related to the implant and restoration: 
• 
Level of pain associated with the implant and crown  
 Painful       
 
 No pain 
• 
Level of satisfaction with the function of the implant supported crown 
 Not satisfied at all  
 Highly satisfied 
• 
Level of satisfaction with the esthetics of the implant supported crown 
 Not satisfied at all  
 Highly satisfied 
Each subject will be asked to complete a VAS for each of the above parameters by the Investigator. 
The subject will be given a paper questionnaire to mark their responses on the VAS (Appendix 3). 
The subject will mark a 100 mm scale with a vertical line. A measurement will be made from the 

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left on the scale to the point of the first marking from the subject. This measurement will be recorded 
on a case report form. 
 Oral Hygiene Evaluation 
The subject’s overall oral hygiene will be evaluated at each study visit starting with the screening visit 
by choosing one of the following: “excellent”, “good”, “fair” or “poor”. 
 Periodontal and Peri-Implant Measurements 
Periodontal and peri-implant measurements will include the modified sulcus bleeding index (mSBI) 
and the pocket probing depth (PPD), as detailed below. All periodontal measurements will be 
performed using a manual, millimeter calibrated periodontal probe (UNC 15, Hu-Friedy, Chicago, 
IL, USA). The periodontal measurements will be used to assess the periodontal health of the region. 
These measurements will be made on the teeth adjacent to the study site during screening, at 
surgery, at implant uncovering, at definitive crown insertion, and at 3-, 6-, 9-, 12-, 15-, 18-, 21-, and 
24-months post-functional loading. These measurements will also be made around the study site 
implant at definitive crown insertion, and at 3-, 6-, 9-, 12-, 15-, 18-, 21-, and 24-months post-
functional loading. 
• 
Modified Sulcus Bleeding Index (mSBI): 
It will be documented if bleeding is induced at the marginal gingival tissue by running a blunt 
periodontal probe along the soft tissue wall at the orifice of the pocket. The bleeding 
tendency will be evaluated on the two adjacent teeth at 6 locations (distofacial, facial, 
mesiofacial, distolingual, lingual, mesiolingual) and assessed using the mSBI by Mombelli 
et al.2 If only one adjacent tooth is present only that tooth will be evaluated.  
• 
Score 0: No bleeding when a periodontal probe is passed along the gingival margin 
• 
Score 1: Isolated bleeding spots visible 
• 
Score 2: Blood forms a confluent red line on margin 
• 
Score 3: Heavy or profuse bleeding 
• 
Probing Pocket Depth (PPD): 
The PPD will be measured at the two adjacent teeth by recording the distance from the 
gingival margin to the bottom of the probeable pocket at six locations (distofacial, facial, 
mesiofacial, distolingual, lingual, mesiolingual). If only one adjacent tooth is present only 
that tooth will be evaluated. 

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 Periapical Radiographs 
Standardized peri-apical radiographs of the area being treated will be recorded pre-operatively, at 
surgery after device placement, during implant uncovering, at the prosthetic records visit, at 
insertion of the definitive restoration, and 3, 6, 12, 18, and 24 months post-functional loading. The 
radiographs must be of high quality and definition, so as to identify the bone contours in question. 
Ideally the entire implant should be visible on the radiograph. However, it is not essential that the 
apical end of the implant is contained within the radiograph; in case it is not, at least three threads 
from the top of the implant showing first bone-implant contact must be visible in the image. These 
radiographs will be used for crestal bone level assessment and evaluation of implant success (e.g., 
presence of encapsulation as determined by a continuous radiolucency around the implant). 
Radiographs will be digital, using either a direct sensor system or an indirect system with 
Photostimulable Phosphor (PSP) plate. The patient-specific, custom stent fabricated during the 
Qualifying Exam must be used. All settings must be noted and consistently used on subsequent 
visits. To standardize the series of periapical radiographs, the same customized sensor/phosphor 
plate holder and beam aiming device will be used throughout the study for each study implant site. 
The radiographs will be captured with the sensor/phosphor plate placed parallel to the implants and 
the X-ray beam directed perpendicular to the implants. The digital image should will be saved and 
the file name will be formatted as follows: Subject number (XX-XX), Subject initials (XXX)_Image 
date (DD MMM YYYY), i.e., 01- 01_ABC_04 Nov 2019. The files will be uploaded as a DICOM file 
into the Electronic Data Capture system. The records will contain the kV, mA, and exposure time 
settings. 
 Cone Beam Computed Tomography (CBCT) 
CBCT scans will be performed during initial diagnostic exam, during the post-operative follow-up, 
at the definitive crown insertion visit (approximately 4-6 months after implant placement), and at 
the 3-, 6-, 12-, 18-, and 24-months post functional loading follow-up visits. A diagnostic quality, 
collimated view of the region of interest, showing the entire study site as well as all tissues within 
12 to 15 mm distant will be considered acceptable. The CBCT digital records will be saved and the 
file name will be formatted as follows: Subject number (XX-XX), Subject initials (XXX)_Image date 
(DD MMM YYYY), i.e., 01- 01_ABC_04 Nov 2019. The files will be uploaded as a DICOM file into 
the Electronic Data Capture system. The records will contain the kV, mA, and collimation settings.  
 
Intra-oral Photographs 
Standardized intra-oral photographs of the area being treated will be taken throughout the study 

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for documentation of procedures as well as results. The following standard field of view scales will 
be used: 
• 
Complete dental arch - a view including the entire alveolar ridge and all teeth in the arch 
• 
Segment of the region of interest - a view centered on the implant site and including 
between 12 and 15 mm view of surrounding tissues, the long axis of the image will coincide 
with the mesio-distal direction. 
The following aspects of view will be used: 
• 
Occlusal view – a view nearly perpendicular to the occlusal plane, a mirror may be used to 
capture the image 
• 
Facial view – a view nearly perpendicular to the facial surfaces of the teeth in the area of 
interest, a mirror may be used to capture the image 
• 
Occluso-facial view – a view nearly perpendicular to the mesio-distal direction in the area 
of interest and approximately 45 degrees from the occlusal plane and the facial surface of 
the teeth 
• 
Occluso-lingual view – a view nearly perpendicular to the mesio-distal direction in the area 
of interest and approximately 45 degrees from the occlusal plane and the lingual surface of 
the teeth, a mirror may be used to capture the image 
Ideally the following clinical photographic images will be captured during the study visits as a matter 
of routine. Additional images of other significant findings will also be recorded. 
Preoperative Baseline, Visits 1, 2, or 3: 
• 
Facial view of the segment  
• 
Occlusal view of the segment 
• 
Occlusal view of the entire dental arch where implant will be placed 
• 
Occlusal view of the entire opposing dental arch 
Surgical, Visit 3: 
• 
Occlusal view of the segment after extraction 
• 
Occlusal view of the segment after trial implant placement 
• 
Occlusal view of the segment after definitive implant placement and TN-SM trim 
• 
Facial view of the segment after definitive implant placement and TN-SM trim 

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• 
Occlusal view of the segment after closure 
Post-Surgical Follow-up, Visit 4: 
• 
Occlusal view of the segment as the patient arrives 
• 
Occlusal view of the segment at end of visit 
Implant Uncovering, Visit 5: 
• 
Occlusal view of the segment as the patient arrives 
• 
Occluso-facial view of the segment with torque test hardware in place 
• 
Occluso-buccal view of the segment with the abutment in place at the end of visit 
Prosthetic Records, Visit 6: 
• 
Occlusal view of the segment as the patient arrives 
• 
Occlusal view of the segment immediately after removal of the healing abutment, if used 
• 
Facial view of the segment in full occlusion 
• 
Occluso-facial view of the segment with scan body or impression pickup hardware 
• 
Occlusal view of the segment at the end of the visit 
Crown Insertion, Visit 7: 
• 
Occlusal view of the segment as the patient arrives 
• 
Occlusal view of the segment immediately after removal of the healing abutment, if used 
• 
Facial view of the segment in full occlusion showing the definitive abutment in place, if used 
• 
Facial view of the segment in full occlusion after definitive restoration seated and adjusted 
• 
Occluso-lingual view of the segment after definitive restoration seated and adjusted 
• 
Occlusal view of the entire arch with occlusal markings displayed after definitive crown 
seated and adjusted 
Post-Loading Follow-up, Visits 8 - 14: 
• 
Occlusal view of the segment as the patient arrives 
• 
Occluso-lingual view of the segment as the patient arrives 
• 
Facial view of the segment as the patient arrives 
• 
Occlusal view of the entire arch with occlusal markings displayed 

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The photographs must be of high quality and definition, so as to identify the tissue condition and 
contours in question. These photographs will be used for evaluation of implant success (e.g., 
presence of peri-implant infection). The photographs will be saved as a .jpeg file (or equivalent) 
and the file name will be formatted as follows: Subject number (XX-XX), Subject initials 
(XXX)_Image date (DD MMM YYYY)_Image Number, i.e., 01- 01_ABC_04 Nov 2019_01. The files 
will be uploaded into the Electronic Data Capture system. 
 
 

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4 
Device Description 
4.1 
Study Product 
 General Description of the Study Device 
Tetranite Stabilization Material Device (TN-SM) is a synthetic, osteoconductive, biodegradable 
bone-adherent biomaterial. It is injectable, mildly exothermic during cure, bonds to most high 
surface energy materials, including living bone and metals such as titanium and its alloys, and is 
capable of forming stable bonds in a wet environment. 
Each capsule of TN-SM contains two pre-dosed and pre-mixed, powdered reactants, TTCP and 
OPLS, which are packaged together with a pre-dosed amount of pure water in a separate 
compartment. These capsules are packaged in a pouch which preserves its sterility, protects it from 
environmental contaminants, and allows inspection for damage through a clear panel. The 
packaging is designed to allow activation of the capsule contents, i.e., combining of the components 
and mixing of the material, without breaching the protective pouch. The mixing is accomplished 
utilizing an automatic, factory-set, dedicated triturator capable of holding the capsule in its sterile 
pouch. The packaging method allows for aseptic placement of the capsule containing mixed 
adhesive within the clinical sterile field for aseptic attachment of the capsule to a dedicated hand-
held applicator and for application to the implantation site. After mixing, the TN-SM material, as 
extruded from capsule for use, is a viscous, tacky, white liquid approximately the consistency of 
honey.  
 Dental Implants and Restorative Components 
The study clinician may select the appropriate dental implants, abutments and other restorative 
components from any legally marketed components that are labeled as compatible. The prostheses 
fabricated for the study subjects will be single crowns. 
4.2 
Instructions for Use, Handling, and Labeling 
RevBio will provide the study Research Centers with the necessary amount of product for the study. 
The product delivered for the study is to be used only for the subjects enrolled in the study and 
according to the clinical investigation plan. The study product will be used as described in the 
Tetranite IFU – Document # 50001-00 (Appendix 1). The Tetranite Stabilization Material Device 
(TN-SM) is a device designed and intended to provide immediate stabilization to dental implants. 
All device deficiencies shall be reported by the investigator to RevBio as described under section 
6.3.3. 

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4.3 
Storage 
The study product will be stored in its original container until used and its access shall be controlled. 
The study product shall be stored in a dry environment within the temperature range 15-25°C.  
4.4 
Device Accountability 
The Investigator must maintain an accurate and up-to-date accountability record of all study 
products received, used, discarded (opened, but non-used) and returned during the course of the 
study. This information shall be recorded in the Device Accountability Record Log. At each 
monitoring visit, the monitor will check the investigational device accountability for accuracy and 
completeness. At the end of the study, the monitor or RevBio’s delegate conducting the closeout 
visit will perform a final reconciliation of the device accountability (cross check between the Device 
Record Accountability Log, the shipments delivery notes and the acknowledgement of device 
receipts). 
4.5 
Return of Study Device 
After treatment of the last subject, any remaining unopened study product at site must be returned 
to RevBio and acknowledged for receipt. A copy of the acknowledgement of receipt must be filed 
in the Investigator File. 
4.6 
Risk Analysis, Risk/ Benefits 
The device risk analysis and risk assessment for the TN-SM device was conducted according to 
EN ISO 14971. Full results are included in the Risk Management Hazards Analysis (91048-00) 
dated 28 November 2018. Refer to Table 3 of this protocol for a list of anticipated adverse device 
effects (ADE) following the placement of TN-SM and insertion of dental implants. Read carefully 
the risks associated with the TN-SM device and the procedures involved in its use listed in the 
Instructions for Use 50001-00 (Appendix 1) as well as the Warning and Cautions/Precautions in 
Section 4.7.  
4.7 
General Precautions: 
 Warnings: 
• 
Avoid approaching the proximity of the inferior alveolar nerve canal during implant bed 
preparation, adhesive injection, and implant insertion. If the integrity of the canal is violated 
nerve damage may result in anesthesia, paresthesia and/or dysesthesia.  
• 
Avoid approaching the proximity of the maxillary sinus during implant bed preparation, adhesive 

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injection, and implant insertion. Placement of the Implant and/or TN-SM, or any other object, 
into the lumen of the sinus on indwelling basis could potentially result in a foreign body reaction, 
sinusitis, or a chronic infection in the sinus. 
• 
TN-SM warnings are listed in the Instructions for Use (Appendix 1). 
 Cautions/Precautions: 
• 
Particular care should be taken to assure proper implant alignment when comparatively high 
loads are expected.  
• 
A careful clinical and radiological examination of the patient should be performed prior to 
surgery to determine the psychological and physical status of the patient. Special attention 
should be given to patients who have local or systemic factors that could interfere with the 
healing process of either bone or soft tissue or the osseointegration process (e.g. bone 
metabolism disturbances, previously irradiated bone in the head or neck area, diabetes 
mellitus, anticoagulation drugs/hemorrhagic diatheses, untreated bruxism or other 
parafunctional habits, unfavorable anatomic bone conditions, tobacco abuse, untreated 
periodontal disease, acute infection of implant site, temporomandibular joint disorders, treatable 
pathologic diseases of the jaw and changes in the oral mucosa, pregnancy, and inadequate 
oral hygiene). 
• 
Sterile handling is essential. Never use potentially contaminated components. Contamination 
may lead to infections.  
• 
TN-SM precautions are listed in the Instructions for Use (Appendix 1) 
5 
Study Procedures 
5.1 
Schedule of Procedures and Assessments 
The schedule of administrative, treatment and evaluation visits will follow the matrix detailed in 
Table 1. The timing of the scheduled events listed in the table will be acceptable if it is within the 
tolerances listed. Except for the First Surgical Visit, i.e., the extraction, test device and implant 
placement visit, it is permissible for portions of the procedures to be completed on separate visits 
provided they are within the allowable schedule windows. A record of procedure and evaluation 
dates will be maintained.  
Table 1: Schedule of Procedures and Assessments  
Visit # 
Visit Name 
Visit Window 

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Visit 1 
Screening  
 
Visit 2 
Qualifying Examination 
 
Visit 3 
First Surgical  
< 45 days from screening 
Visit 4 
Post-Operative Follow-up 
2 weeks ± 3 days after implant surgery 
Visit 5 
Implant Uncovering 
13 weeks ± 1 week after implant surgery 
Visit 6 
Restorative Records 
3 weeks ± 1 week post-uncovering 
Visit 7 
Definitive Restoration (Loading) 
4 - 6 months from implant insertion 
Visit 8 
3-month follow-up 
3 months ± 2 weeks post-functional loading 
Visit 9 
6-month follow-up – Primary Endpoint 
6 months ± 1 month post-functional loading 
Visit 9.5 
9-month follow-up 
9 months ± 1 month post-functional loading 
Visit 10 
12-months follow-up 
12 months ± 2 month post-functional loading 
Visit 11 
15-months follow-up 
15 months ± 2 month post-functional loading 
Visit 12 
18-months follow-up 
18 months ± 2 month post-functional loading 
Visit 13 
21-months follow-up 
21 months ± 2 month post-functional loading 
Visit 14 
24-months follow-up 
24 months ± 2 month post-functional loading 
5.2 
Subject Screening and Qualifying Evaluation (Visits 1 and 2) 
An initial evaluation will be conducted to determine whether the subject meets the Screening 
Inclusion/Exclusion criteria and for collection of baseline data. This evaluation will include an 
appropriate medical and dental history, a clinical examination, and a radiographic evaluation. The 
screening evaluations and data collection can take place at several office visits as long as the visits 
are all within 45 days of the surgery. 
If the screening evaluations are not conducted within 45 days of the surgery, then the subject may 
be asked to re-consent and re-screen, as long as enrollment is still open. 
In particular, the subject will have the following procedures and/or evaluations performed and 
documented at this visit: 
• 
Screening Inclusion/Exclusion criteria applied 
• 
Demographics 
• 
Pregnancy test (administered before taking study required radiographs or CBCT scans) 
• 
Medical and dental history 
• 
Full mouth CBCT, or panoramic radiograph with a localized CBCT scan 
• 
Oral Hygiene Evaluation 
• 
Concomitant medications 
• 
Radiographic stent fabrication 

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• 
Intra-oral photographs 
 Informed Consent 
It is the responsibility of the investigator, or a person designated by the investigator (if acceptable 
by local regulations) to obtain informed consent in writing from each subject participating in this 
study prior to any study related procedures. As part of the informed consent discussion with a 
potential subject, the investigator must provide an adequate explanation of the overall 
requirements/procedures of the study, purpose of the study, the nature of the planned treatment, 
any alternative procedures, and possible risks, complications, or benefits of the study. The 
investigator or designee must also explain that the subjects are completely free to refuse to enter 
the study or to withdraw from the study at any time for any reason without prejudice. 
The informed consent must be approved by an Institutional Review Board (IRB) before consenting 
can begin. The informed consent form must be available in the primary language of the subject. It 
is written in accordance with the “Declaration of Helsinki” (as adopted by the 18th World Medical 
Assembly, 1964, and as amended in Tokyo (1975), Venice (1983), Hong Kong (1989), Somerset 
West (1996), Edinburgh (2000), Washington DC (2002), Tokyo (2004), Seoul (2008), and Fortaleza 
(2013) (Appendix 2)) and applicable local regulations. 
This IRB approved consent form must be personally signed and dated by the subject and the 
person obtaining consent with a witness present for the signature. Investigators should keep the 
original signed informed consent document in a secure location. A copy of the signed consent form 
should be given to the subject. The Case Report Forms (CRFs) for this study contain a section for 
documenting informed consent, and this must be completed appropriately. 
If new safety information results in significant changes in the risk/benefit assessment, the consent 
form will be reviewed and updated as necessary. All consented and enrolled subjects should be 
informed of the new information, given a copy of the revised form and give their consent to continue 
the study, unless the subject signed consent and was considered a screen failure. 
 Screening Inclusion Criteria:  
• 
Subjects must have voluntarily signed the informed consent form before any study related 
procedures; 
• 
Subjects must be males or females who are a minimum of 21 years of age, 
• 
Subjects who require a single tooth extraction and desire a replacement with a dental implant. 
Candidate subjects may require more than one extraction, but only one site will be considered 

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for inclusion in the study. 
• 
Subjects must have opposing dentition (natural teeth, fixed or removable restorations); 
• 
Subjects must be committed to the study and the required follow-up visits; 
• 
Subjects must be ASA I or ASA II; 
• 
Planned site for implant must have at least one adjacent tooth; 
• 
There must be sufficient bone height crestal to critical anatomical structures, i.e., the inferior 
alveolar canal, piriform foramen, and maxillary sinus, to safely place a dental implant within the 
bone contours; 
• 
Anatomical conditions must be present to allow an implant crown restoration to be placed at 
the candidate site, e.g., sufficient interocclusal space, appropriate angulation of the ridge, etc. 
 Screening Exclusion Criteria: 
• 
Subjects with a systemic disease or condition affecting a major organ system that would 
preclude dental implant surgery (e.g., malignant neoplasm or chemotherapy in the past 6 
months, uncontrolled diabetes, major infection, Cushing’s syndrome, metabolic bone disease, 
immunosuppression, blood dyscrasias, healing bone fracture, myocardial infarction or 
cerebrovascular accident within the last six months, etc.); 
• 
Subjects with any contraindications for oral surgical procedures (e.g. scleroderma, etc.); 
• 
Subjects with mucosal diseases (e.g. erosive lichen planus, mucous membrane pemphigoid, 
erythema multiforme, etc.) in the localized area around the study implant site; 
• 
Subjects with bone diseases or conditions (e.g. Paget’s disease, fibrous dysplasia, history of 
osteomyelitis, etc.) in the region of the potential study implant site; 
• 
Subjects with a history of local radiation therapy in the head/neck area or osteonecrosis of the 
jaws; 
• 
Subjects with any acute and untreated endodontic lesions or periodontal disease; 
• 
Subjects receiving, or having a recent or long-term history of receiving oral or parenteral anti-
osteoclastic agents [e.g., bisphosphonates, Xgeva® and Prolia® (denosumab); Forteo® 
(teriparatide), strontium ranelate, etc.], or anti-angiogenesis factors; 
• 
Subjects who have major active substance abuse problems (e.g., alcoholism, opiate addiction, 
methamphetamine abuse, etc.); 

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• 
Subjects who are pregnant or intending to become pregnant during the duration of the study; 
• 
Subjects who are heavy smokers (defined as >10 cigarettes per day or >1 cigar per day or 
equivalent of electronic cigarette vaping) or chew tobacco;  
• 
Subjects with inadequate oral hygiene or who are unmotivated for adequate home care; 
• 
Subjects who have physical or mental handicaps that would interfere with the ability to perform 
adequate oral hygiene; 
• 
Subjects who have undergone administration of any investigational device within 30 days of 
enrollment in the study; 
• 
Subjects who are allergic or otherwise sensitive to any materials likely encountered during the 
course of the study (e.g. titanium, suture materials, local anesthetics);  
• 
Subjects with conditions or circumstances, which, in the opinion of the Investigator, would 
prevent completion of study participation or interfere with analysis of study results, such as 
history of non-compliance or unreliability. 
 Pregnancy Test 
Women of child-bearing potential (women who are not surgically sterile or postmenopausal (defined 
as amenorrhea for >12 months) must perform a pregnancy test (validated over-the-counter test) at 
Visit 1, before taking study required radiographs or CBCT scans to confirm that they are not 
pregnant. The test result must be documented in the source data. A woman who is pregnant or 
planning to become pregnant at any point during the study duration cannot be enrolled in this study 
and will be considered a screening failure. 
If a woman becomes pregnant during the study, a protocol deviation form should be completed. 
The woman should be followed for the duration of the pregnancy, without the study required 
projected radiographs or CBCT until term, and the outcome of the pregnancy should be 
documented.  
 Full Mouth CBCT or Panoramic Radiograph + Local CBCT 
A panoramic radiograph or full mouth CBCT scan must be available during screening to assess the 
complete dentition and for use in surgical planning. The screening panoramic radiograph or full 
mouth CBCT scan can be taken during the screening visit or be available from a previous date 
within 6 months of the implant surgery. If a panoramic radiograph is used for screening, then a 
localized CBCT scan is also required as a baseline. 

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 Fabrication of Radiographic Media Holder 
A radiographic media holder used to capture periapical (PA) radiographs throughout the study will 
be fabricated at screening. The device will be fabricated according to the instructions provided by 
Larheim and Eggen.3 
5.3 
Surgical Procedure (Visit 3) 
This visit should be completed within 45 days of screening. In particular, the subject will have the 
following procedures and/or evaluations performed and documented at this visit: 
• 
Dental and medical history  
• 
Concomitant medication 
• 
Adverse event check 
• 
Oral hygiene 
• 
Informed consent 
• 
Tooth extraction 
• 
Enrollment Inclusion/Exclusion criteria 
• 
TN-SM device and implant placement 
• 
Implant stability by clockwise torque with maximum at 20 Ncm to confirm stabilization  
• 
Standardized periapical radiographs 
• 
Intra-oral photographs 
 Tooth Extraction 
Each potential subject will have the candidate site tooth extracted using standard procedures in an 
outpatient environment under local anesthesia. Curettage of the extraction socket will be performed 
to remove soft tissue remnants, including the periodontal ligament, granulation tissue, etc. Intra-
oral photographs will be captured. Subjects will pre-rinse with chlorhexidine mouthwash 0.12% for 
30 seconds immediately prior to the surgery. 
 Extraction Site Enrollment Inclusion Criteria 
• 
Approximately 2mm of apical bone is available for positive seating of the implant; 
• 
Placement of the selected implant leaves an HDD greater than 2mm in at least two directions, 
(i.e., mesially, distally, buccally, or lingually) between the implant surface and the most coronal 
aspect of the osteotomy.  (For the purpose of clarity, HDD is measured from the outer surface 

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of the implant to the inner aspect at the crest of the socket walls.) 
 Extraction Site Enrollment Exclusion Criteria 
• 
Any implant site where there is a dehiscence or fenestration of buccal or lingual plates of bone 
greater than 5mm in in any direction; 
• 
Any implant site in which placement of the selected implant leaves an HDD greater than 5mm 
in any direction between the implant surface and the most coronal aspect of the osteotomy;  
• 
Any site which provides primary implant stability after seating, as demonstrated by insertion 
torque of greater than or equal to 15 Ncm; 
• 
Any site into which the implant is not or cannot be placed during the same visit as the extraction. 
 Surgery – TN-SM Device and Implant Placement 
Each study subject will receive the TN-SM device to stabilize an implant in an outpatient 
environment. The procedure will be performed under local anesthesia following standard surgical 
and sterile techniques. After initial evaluation, surgical guides may be prepared in accordance with 
the surgeon’s preference and standard practices. All implants will be placed in accordance with the 
IFU of the respective implant manufacturer, with possible departure related to the placement of the 
TN-SM. Prophylactic antibiotic treatment will be given according to the investigator’s standard 
practice and shall be recorded. All prophylactic antibiotics and anesthesia given must be recorded 
on the Concomitant Medication Form. Prior to surgery, subjects should have teeth cleaned, if 
required, as per standard of care at the practice. Guided Bone/Tissue Regeneration (GBR/GTR) 
procedures will not be employed in this study as bone volume insufficiency and a large dehiscence 
are among Site Enrollment Exclusion Criteria. 
The following is a detailed list of the procedures and measurements to be performed during the 
implant placement surgery visit: 
• 
Following tooth extraction curette the socket; 
• 
Prepare the implant bed according to the standard drilling sequence recommended by the 
implant manufacturer; 
• 
Place the implant into the site according to standard procedures and apply the Extraction Site 
Enrollment Criteria to qualify the site.  
• 
Assuming the implant has insufficient insertion torque, remove the implant. Prepare and apply 
the TN-SM device to the site according to the IFU - Document 50001-00 (Appendix 1). Re-
insert the implant to its preplanned seating position into apical bone. Consistent with the IFU, 

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additional TN-SM may be applied, if necessary, to fill any residual space between the implant 
surface and surrounding bone, up to the height of crestal bone. Care must be taken to ensure 
proper final position of the implant by use of standard measures that may include manual control 
or use of a prefabricated surgical guide.  
• 
After the TN-SM device cures around the implant for 15 minutes, implant stabilization will be 
tested by applying a clockwise torque of 20 Ncm.  If the implant does not rotate with torque 
application, stabilization will be considered a success of the device and the event will be logged 
as a “success of immediate stabilization” with time since mixing noted. Should the implant rotate 
with torque application, the implant will be removed, the osteotomy refreshed with the last drill 
used prior to implant placement, and a second application of TN-SM will be prepared per the 
IFU and injected into the site along with a new implant. After the TN-SM device cures for 20 
minutes around the implant, implant stabilization will be tested a second time by applying a 
clockwise torque of 20 Ncm. If the implant does not rotate with torque application, stabilization 
will be considered a success of the device and the event will be logged as a “success of 
immediate stabilization” with time since mixing noted.  Should the implant rotate with torque 
application again after the second application, stabilization will be considered a failure of the 
device and the event will be logged as a “failure of immediate stabilization” with time since 
mixing noted. The loosened implant will be removed. The remaining Tetranite will be removed 
by curetting or drilling the osteotomy until a bleeding bone surface is obtained.  The clinician 
may place a wider or longer implant as appropriate for the tooth position.  Otherwise the site 
will be grafted as per a conventional staged approach. 
• 
The implant platform will be covered by seating a cover screw and the soft tissue will be 
reapproximated with monofilament sutures, as needed.  
The Investigator will prescribe Chlorhexidine rinse in addition to medications for infection control and 
post-operative pain control according to his/her standard practice. Standard post-operative instructions 
will be provided, including the use of Chlorexidine and antibiotics These instructions will also include a 
description of dietary restrictions to only soft foods for a period of up to two weeks following surgery.   

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5.4 
Post-Operative Follow-up (Visit 4) 
The subject will return for a post-operative visit at 14 days (± 5 days) following implant placement 
for a general assessment of wound healing and to remove sutures, if applicable. In particular, the 
subject will have the following procedures and/or evaluations performed and documented at this 
visit: 
• 
Dental and medical history  
• 
Concomitant medication 
• 
Adverse event check 
• 
Oral hygiene evaluation 
• 
CBCT - Localized 
• 
Intra-oral photographs 
• 
Suture removal, if necessary 
5.5 
Implant Uncovering (Visit 5) 
At 13 weeks (± 1 week) following implant surgery, the implant will be uncovered, the short-term 
implant stabilization will be checked, a healing or standard abutment will be placed, and the soft 
tissue adapted around the abutment. Short-term implant stabilization will be tested by applying a 
clockwise torque of 35 Ncm to the implant.  If the implant does not rotate with torque application, 
stabilization will be considered a success of the device and the event will be logged as a “success 
of short-term stabilization”. Should the implant rotate with torque application, the abutment will be 
removed, and the implant will be left and allowed to heal for an additional month and re-evaluated 
for successful integration. Lack of stabilization will be considered a failure of the device and the 
event will be logged as a “failure of short-term stabilization”. In particular, the subject will have the 
following procedures and/or evaluations performed and documented at this visit: 
• 
Dental and medical history  
• 
Concomitant medication 
• 
Adverse event check 
• 
Oral hygiene evaluation 
• 
Uncover implant, place healing abutment 
• 
Implant stability by clockwise torque with maximum of 35 Ncm to confirm stabilization  
• 
Standardized periapical radiograph 
• 
Intra-oral photographs 

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5.6 
Restorative Records (Visit 6) 
At 3 weeks (+/- 2 weeks) following uncovering impressions/records will be taken for fabrication of 
a definitive crown restoration. In particular, the subject will have the following procedures and/or 
evaluations performed and documented at this visit: 
• 
Dental and medical history  
• 
Concomitant medication 
• 
Adverse event check 
• 
Oral Hygiene Evaluation 
• 
Restorative Records 
• 
Standardized periapical radiograph  
• 
Intra-oral photographs 
5.7 
Insertion of Definitive Restoration (Functional Loading) (Visit 7, Baseline) 
At 4 - 6 months after implant surgery, and contingent upon good stability, the study implant will be 
loaded with an abutment and crown restoration in appropriate occlusion. The subject will have the 
following procedures and/or evaluations performed and documented at this visit: 
• 
Dental and medical history  
• 
Concomitant medication 
• 
Adverse event check 
• 
Oral hygiene evaluation 
• 
Periodontal measurements 
• 
Insertion of definitive restoration 
• 
Standardized periapical radiograph  
• 
CBCT - localized 
• 
Intra-oral photographs 
• 
Subject satisfaction 
5.8 
3-Month Follow-up (Visit 8) 
Subjects will return at 3 months (± 2 weeks) post-loading for brief evaluation of the implant 
supported definitive restoration and check possible adverse events. The subject will have the 

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following procedures and/or evaluations performed and documented at this visit: 
• 
Dental and medical history  
• 
Concomitant medication 
• 
Adverse event check 
• 
Oral Hygiene evaluation 
• 
Periodontal measurements 
• 
Standardized periapical radiograph 
• 
CBCT - localized 
• 
Intra-oral photographs  
• 
Implant success 
• 
Subject satisfaction 
5.9 
6-Month Follow-Up (Visit 9, Primary Endpoint) 
Subjects will return at 6 months (± 1 month) post-loading for an evaluation of the implant supported 
definitive restoration and check possible adverse events. The subject will have the following 
procedures and/or evaluations performed and documented at this visit: 
• 
Dental and medical history  
• 
Concomitant medication 
• 
Adverse event check 
• 
Oral Hygiene evaluation 
• 
Periodontal measurements 
• 
Standardized periapical radiograph 
• 
CBCT - Localized 
• 
Intra-oral photographs 
• 
Implant success 
• 
Subject satisfaction 
5.10 9-Month Follow-Up (Visit 9.5) 
Subjects will return at 9 months (± 1 month) post-loading for an evaluation of the implant supported 

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definitive restoration and check possible adverse events. The subject will have the following 
procedures and/or evaluations performed and documented at this visit: 
• 
Dental and medical history  
• 
Concomitant medication 
• 
Adverse event check 
• 
Oral Hygiene evaluation 
• 
Periodontal measurements 
• 
Intra-oral photographs 
• 
Implant success 
• 
Subject satisfaction 
5.11 12-Month Follow-Up (Visit 10) 
Subjects will return at 12 months (± 2 month) post-loading for an evaluation of the implant supported 
definitive restoration and check possible adverse events. The subject will have the following 
procedures and/or evaluations performed and documented at this visit: 
• 
Dental and medical history  
• 
Concomitant medication 
• 
Adverse event check 
• 
Oral Hygiene evaluation  
• 
Periodontal measurements 
• 
Standardized periapical radiograph  
• 
CBCT - Localized 
• 
Intra-oral photographs 
• 
Implant success 
• 
Subject satisfaction 
5.12 15-Month Follow-Up (Visit 11) 
Subjects will return at 15 months (± 2 month) post-loading for an evaluation of the implant supported 
definitive restoration and check possible adverse events. The subject will have the following 
procedures and/or evaluations performed and documented at this visit: 

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• 
Dental and medical history  
• 
Concomitant medication 
• 
Adverse event check 
• 
Oral Hygiene evaluation  
• 
Periodontal measurements 
• 
Intra-oral photographs 
• 
Implant success 
• 
Subject satisfaction 
5.13 18-Month Follow-Up (Visit 12) 
Subjects will return at 18 months (± 2 month) post-loading for an evaluation of the implant supported 
definitive restoration and check possible adverse events. The subject will have the following 
procedures and/or evaluations performed and documented at this visit: 
• 
Dental and medical history  
• 
Concomitant medication 
• 
Adverse event check 
• 
Oral Hygiene evaluation  
• 
Periodontal measurements 
• 
Standardized periapical radiograph  
• 
Intra-oral photographs 
• 
Implant success 
• 
Subject satisfaction 
5.14 21-Month Follow-Up (Visit 13) 
Subjects will return at 21 months (± 2 month) post-loading for an evaluation of the implant supported 
definitive restoration and check possible adverse events. The subject will have the following 
procedures and/or evaluations performed and documented at this visit: 
• 
Dental and medical history  
• 
Concomitant medication 
• 
Adverse event check 

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• 
Oral Hygiene evaluation  
• 
Periodontal measurements 
• 
Intra-oral photographs 
• 
Implant success 
• 
Subject satisfaction 
5.15 24-Month Follow-Up (Visit 14) 
Subjects will return at 24 months (± 2 month) post-loading for an evaluation of the implant supported 
definitive restoration and check possible adverse events. The subject will have the following 
procedures and/or evaluations performed and documented at this visit: 
• 
Dental and medical history  
• 
Concomitant medication 
• 
Adverse event check 
• 
Oral Hygiene evaluation  
• 
Periodontal measurements 
• 
Standardized periapical radiograph  
• 
CBCT - Localized 
• 
Intra-oral photographs 
• 
Implant success 
• 
Subject satisfaction 
5.16 Protocol Related Procedures 
 Early Withdrawal 
Any subject may withdraw from the study at any time without prejudice and will be offered an 
alternative treatment for his/her dental condition. Subjects will be advised of the need for the 
prescribed follow-up visits for their ongoing care, well-being, and collection of any safety data. 
The Investigator may withdraw any subject from the study in the case of: 
• 
Non-compliance with the protocol 
• 
Failure to attend the follow-up visits 
• 
Serious Adverse Event (SAE) or adverse event, which in the opinion of the Investigator prevents 

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the subject’s further participation in the study. 
The subject withdrawal will be documented on a study termination form and must include the 
reason for the subject withdrawal. Efforts should be made to capture the primary study endpoint for 
each subject prior to withdrawal, if possible.  
 End of Study 
Once the subject is seen for the final visit at 24-months post-functional loading, the subject will 
have completed the study. This will be documented on a study completion form. 
 Subject Replacement Policy 
Subjects withdrawn from the study after enrollment will not be replaced. 
 Protocol Deviations 
Deviations from the procedures established in the protocol are not permitted. If a deviation occurs, 
the study center must record the deviation on the appropriate CRF. The sponsor shall be notified 
immediately of any deviations in informed consent or Inclusion/Exclusion criteria. The IRB should 
be notified according to the requirements of the local IRB. 
Any deviation from the protocol (including deviations from the expected study visit windows) may 
jeopardize the study outcome. Non-compliance of the subjects, as well as of the Investigators, may 
lead to the closure of the respective study center. 
6 
Evaluation of Adverse Events 
For the avoidance of doubt, all AE/SAEs as defined below should be collected, fully investigated 
and documented in the source document and appropriate case report form for all subjects from the 
time of the signing of the informed consent until the last protocol-specific procedure. Documentation 
includes dates of event, treatment, outcome, assessment of seriousness and causal relationship 
to the device and/or study procedure (rationale to be provided). 
6.1 
Definitions 
 Adverse Event (AE) 
An AE is defined as any untoward medical occurrence, unintended disease or injury, or any untoward 
clinical signs (including abnormal laboratory findings) in subjects, users or other persons, whether or 
not related to the investigational medical device or surgical procedure. This definition includes events 
related to the investigational medical device or events related to the procedures involved. For users or 
other persons, this definition is restricted to events related to investigational medical devices. 

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 Serious Adverse Event (SAE) 
Any adverse event that: 
• 
led to a death 
• 
led to a serious deterioration in the health of the subject, that either resulted in 
o a life-threatening illness or injury, or 
o a permanent impairment of a body structure or a body function, or 
• 
in-patient or prolonged hospitalization, or 
• 
medical or surgical intervention to prevent life-threatening illness or injury or permanent 
impairment to a body structure or a body function, 
• 
led to fetal distress, fetal death, or a congenital abnormality or birth defect 
NOTE: A planned hospitalization for a pre-existing condition, or a procedure required by the 
protocol, without serious deterioration in health, is not considered to be a serious adverse event. 
NOTE: Implant failures requiring the removal of the implant are to be considered a serious adverse 
event.  
 Adverse Device Effect (ADE) 
An ADE is an adverse event related to the use of an investigational medical device. This definition 
includes adverse events resulting from insufficient or inadequate instructions for use, deployment, 
implantation, installation, or operation, or any malfunction of the investigational medical device. 
This definition includes any event resulting from use error or from intentional misuse of the 
investigational medical device. Any adverse event which the clinical investigator believes has 
even a possible relationship to the device will be classified as an ADE. 
 Serious Adverse Device Effect (SADE) 
An SADE is an adverse device effect that has resulted in any of the consequences characteristic 
of a serious adverse event. 
 Unanticipated Serious Adverse Device Effect (USADE) 
An USADE is a serious adverse device effect which by its nature, incidence, severity or outcome 
has not been identified in the current version of the risk analysis report. 
 Anticipated Serious Adverse Device Effect (ASADE) 
An ASADE is a serious adverse device effect which by its nature, incidence, severity or outcome 

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has been identified in the risk analysis report. 
Table 2: Summary of the classification for adverse events 
Adverse 
Events 
Non-Device Related 
Device Related 
Non-serious 
Adverse Event  
(AE) 
Adverse Device Effect  
(ADE) 
Serious 
Serious Adverse Event 
(SAE) 
Serious Adverse Device Effect  
(SADE) 
Anticipated 
Unanticipated 
Anticipated Serious 
Adverse Device Effect 
(ASADE) 
Unanticipated Serious 
Adverse Device Effect 
(USADE) 
 
6.2 
Assessment of Adverse Events 
In the event of an adverse event, the investigator or another suitably qualified clinician who is 
trained in recording and reporting AEs and have been delegated to this role (such delegation must 
be captured in the study site delegation log) must review all documentation (e.g., hospital notes, 
laboratory and diagnostic reports) relevant to the event. Each adverse event should be assessed 
for seriousness, relationship to the study device or the procedure, severity, outcome, and 
expectedness, as described below, by the Investigator. 
 Seriousness 
An adverse event will be described as serious if it meets the definition in Section 6.1.2. The rationale 
for the assessment shall be provided in a short narrative. 
 Relationship to the Study Device 
The investigator should assess the relationship of the adverse event to the implanted product (e.g., 
TN-SM device and dental implant) and provide the rationale in a short narrative. The relationship 
should be assessed using the following categories: 
• 
Definitely related – There is a reasonable causal and temporal relationship between the 
treatment with the study device and the adverse event. 
• 
Possibly related – The causal and temporal relationship between the treatment with the study 

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device and the adverse event is less likely; however, the determination that there is no 
relationship cannot be made. 
• 
Not related – A causal relationship with device application can be definitely excluded. By 
definition, all AEs/ADEs, with a start date before the surgery procedure at Visit 2 must be 
assigned a “not related” relationship with study device. 
NOTE: Device deficiencies that might have led to an SAE are always related to the medical device. 
 Relationship to the Procedure 
The investigator should assess the relationship of the adverse event to the implant procedure (e.g. 
placement of TN-SM device and the dental implant) and provide the rationale in a short narrative. 
The relationship should be assessed using the categories described in Section 6.2.2. 
 Severity 
Each adverse event should be assessed by the investigator for its severity, or the intensity of an 
event experienced by a subject, using the following: 
• 
Mild – discomfort noticed, but no disruption in daily activities; the event is easily tolerated by 
the subject 
• 
Moderate – discomfort severe enough to reduce or affect normal daily activity 
• 
Severe – Inability to work or perform normal daily activity and/or the subject’s life is at risk from 
the adverse event 
The maximum severity observed is to be recorded, except if there is a significant worsening in an 
AE/ADE severity after device intake, then the change will be tracked as a new AE/ADE record as 
follows: 
• 
The same wording describing the original AE/ADE must be used. 
• 
Outcome of the initial entry should be designated as 'worsened'. 
• 
The end date of the previous AE/ADE must equal the start date of the new AE/ADE. 
 Outcome 
The outcome should reflect the status of the adverse event at the time of recording. 
• 
Resolved - The subject fully recovered from the event without any sequelae. This option also 
applies when it is unknown whether there are sequelae. 
• 
Resolved with sequelae - The subject’s condition stabilized despite the persistence of sequelae 
(e.g., lesion or medical condition which is a consequence of the event). This option does not 

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apply to irreversible congenital anomalies (see under “ongoing”). 
• 
Ongoing - The subject has not yet recovered from the event. By convention, in the case of an 
irreversible congenital anomaly, the “Ongoing” option should be chosen and understood as “Not 
recovered/Not resolved“. The same applies to conditions that are not yet resolved, but are 
controlled by medication (e.g., diabetes, epilepsy) and therefore may not have any symptoms. 
• 
Worsened - The severity of the AE/ADE increased. 
• 
Fatal - The event is related to a death; whether it caused death or contributed to it. If the subject 
died of a different cause, prior to resolution of the AE/ADE, the outcome of this AE/ADE should 
be designated “Ongoing”, and not “Fatal”, and an end date should not be specified. 
• 
Unknown - Knowledge of the current status of the AE/ADE is truly not available to the 
investigator (i.e. event was ongoing at last observation, but no further contact with the subject 
could be established). However, all efforts should be made to determine the outcome of any 
AE, especially that of an SAE/SADE. 
 Expectedness 
If the adverse event is judged to be related to the device, the investigator will make an assessment 
of expectedness based on knowledge of the reaction and any relevant product information as 
documented in the IFU and current protocol. The event will be classed as either; 
• 
Expected - the reaction is consistent with the effects of the device listed in the IFU and protocol; 
• 
Unexpected - the reaction is not consistent with the effects listed in the IFU and protocol. 
The table below presents the potential expected adverse device effects following the placement of 
TN-SM and insertion of dental implants. 
Table 3: List of expected ADEs following the placement of TN-SM and insertion of dental implants 
Biological complications 
Nature of effect 
Severity 
(mild, moderate, severe) 
Frequency 
(very rare, rare, 
probable, frequent) 
• 
Peri-implant mucositis 
 
Bleeding (BOP Bleeding On Probing) 
Mild 
Probable 
Bruising 
Mild 
Frequent 
Delayed healing of the gum 
Mild 
Rare 
Inflammatory papillary hyperplasia 
Mild 
Probable 

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Gingival/mucosal hyperplasia 
Mild 
Probable 
Pain 
Mild to Moderate 
Probable 
Recession/dehiscence of the gum 
Moderate 
Rare 
Redness 
Mild 
Probable 
Suppuration 
Moderate 
Rare 
Swelling/gingival inflammation 
Mild 
Probable 
• 
Peri-implantitis 
Bleeding (BOP Bleeding On Probing) 
Mild 
Probable 
Bone loss around implant 
Moderate 
Probable 
Bruising 
Mild 
Frequent 
Infection at implant site without suppuration (not recurrent) Mild to Moderate 
Rare 
Infection at implant site with suppuration (not recurrent) 
Moderate 
Rare 
Recurrent infection at implant site without suppuration 
Moderate to Severe 
Rare 
Recurrent infection at implant site with suppuration 
Moderate to Severe 
Rare 
Systemic infection 
Severe 
very rare 
Pain 
Mild to Moderate 
Probable 
Swelling 
Mild 
Probable 
• 
Bone integration deficiency 
Early loss/exfoliation (within 2 weeks after surgery) 
Moderate 
Rare 
Late loss/exfoliation (after prosthetic restoration) 
Moderate 
Rare 
Implant mobility (tactile horizontal or vertical) 
Moderate 
Rare to Probable 
Crestal ridge height bone loss 
Mild to Moderate 
Rare 
Fibrous tissue around implant  
Moderate 
Rare 
Ectopic bone growth 
Moderate 
very rare 
• 
Non-plaque related 
Chronic pain in connection with the dental implant 
mild to moderate 
Rare 
Foreign body sensation 
Mild 
Rare 
Material allergy 
Moderate 
very rare 
Oro-sinus or oro-nasal intrusion/fistula 
Severe 
Rare 

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Permanent paresthesia, dysesthesia 
Severe 
very rare 
Temporary or permanent paresthesia in the jaw 
Severe 
Rare 
Mechanical complications 
Loosening of dental implant  
Mild 
Probable 
Loss of dental implant   
Mild 
Probable 
Migration of TN-SM 
Mild 
Probable 
Fracture of TN-SN 
Moderate 
Rare 
Other complications 
Aspiration of implant 
Severe 
Very Rare 
Swallowing of implant 
Severe 
Very Rare 
Aesthetic problem 
Mild 
Probable 
Aspiration of component(s) (other than implant) 
Severe 
Rare 
Jaw, bone fracture 
moderate to severe 
very rare 
Phonetic difficulties 
mild to moderate 
Rare 
Swallowing of component(s) (other than implant) 
Severe 
very rare 
Hypersensitivity (adjacent teeth) 
Mild 
Rare 
6.3 
Procedure for Reporting Adverse Events 
Adverse event reporting will begin at the time a subject provides written informed consent and ends 
after a subject withdraws from the study or completes the final study visit. For screen failure 
subjects, any AEs, ADEs, and DDs that occur from the time of informed consent up until the date 
on which the subject is deemed ineligible for the study will be recorded on a case report form. Only 
one AE/SAE case report form should be completed per event. To ensure patient confidentiality, the 
following reports will include the patient number only. 
 AE Reporting 
In the occurrence of an AE, data should be entered into the AE case report form in the EDC system 
within five working days of awareness of the event. Safety reporting to the IRB should occur 
according to the requirements of the local IRB. 
 SAE Reporting 
In the occurrence of a serious adverse event (SAE), expedited reporting requirements are followed. 

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The SAE case report form should be completed in the EDC within 24 hours of awareness of the 
event. RevBio will receive an automated notification generated by the EDC system. Safety reporting 
to the IRB should occur according to the requirements of the local IRB. It is recognized that in many 
cases SAEs will be treated in a medical rather than a dental environment and the investigator may 
not have immediate knowledge of the event. The investigator should report an SAE as soon as 
he/she has knowledge of the event within the above time frame irrespective of when the actual 
event occurred. 
 DD Reporting 
The Investigator should report all device deficiencies to RevBio by submitting a description to the 
following email address: reg_complaints@launchpadmedical.com 
If appropriate, the product shall be returned in appropriate packaging by courier (trackable method) 
directly to: 
Regulatory Affairs  
RevBio 
600 Suffolk Street, Suite 250 
Lowell, MA 01854 
 
When a device deficiency leads to a potential AE (e.g. bleeding, pain, swelling, infection, peri-
implantitis) the AE case report form in the database needs to be completed in a timely manner. 
Moreover, device deficiencies with SADE potential (e.g. nerve encroachment, sinus perforation, 
etc.) must be recorded in the SAE case report form and follow the expedited reporting requirements 
(within 24 hours). 
 ADE Reporting 
Adverse device effects must be recorded and submitted to RevBio by completing the AE case 
report form in the EDC system within five working days of awareness of the event. Safety reporting 
to the Institutional Review Board (IRB) should occur according to the requirements of the local IRB.  
Bone loss reporting: Continuous substantial reduction of the peri-implant bone level is a sign of 
failure of the implant system. The first European Workshop on Periodontology specified an average 
marginal bone loss of less than 1.5 mm bone loss within the first year after the insertion of the 
prosthesis, and thereafter less than 0.2mm annual bone loss as criteria for measuring success.50 
This has been a standard and a basis for success criteria since it was defined in 1993. A more 
recent systematic review article in 2012 reported 2 mm of bone loss being universally acceptable 

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at one year.51 Based on this information and since this is a pilot study, the central radiologist will 
flag any bone level changes that are greater than 2 mm in the first year post-functional loading. 
The study manager will review the flagged values and discuss with the principal investigator 
whether the bone level change will be reported as an ADE. 
 SADE Reporting 
In the occurrence of a serious adverse device effect, expedited reporting requirements are followed. 
The SAE case report form should be completed within 24 hours of awareness of the event in the 
EDC system. RevBio will receive an automated notification generated by the EDC system. 
The product safety officer at RevBio will work with the Investigator to determine whether the event 
is anticipated (ASADE) or unanticipated (USADE). In case of USADE, the investigator must 
promptly notify its reviewing IRB as soon as possible, but no later than ten (10) working days after 
first learning of the event. 
Since this is a multi-center study, RevBio will inform investigators at all participating centers of any 
reported USADEs related to this protocol and the study device. Copies of such external USADE 
reports should be forwarded to the IRB for review and a copy must be kept in the investigator site 
files. 
 Additional Safety Reporting 
RevBio will report additional safety information to the centers that is relevant to the protocol or study 
device and may affect the risk/benefit ratio, the rights, safety or welfare of subjects, or the integrity 
of the study. Such reports may include notification of any changes to the instructions for use, any 
publications or interim reports, or any product recalls. 
6.4 
Monitoring of Subjects with Adverse Events 
Any AE that occurs during the course of this study must be monitored and followed-up by the 
investigator until one or more of the following have occurred: 
• 
The AE is resolved, 
• 
Pathological laboratory findings have returned to normal, 
• 
Steady state has been achieved, or 
• 
It has been shown to be unrelated to the study products. 
The outcome of an event will be pursued until resolution or until the last data queries are issued 
following the subject’s last study visit. For screen failure subjects, ongoing AEs, ADEs, and DDs 

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must be followed and updated until the date the subject is deemed a screen failure. For subjects 
documented as lost to follow-up, ongoing AEs, ADEs, and DDs will not be followed. It is the 
responsibility of the sponsor to cooperate with the investigator to assure that any necessary 
additional therapeutic measures and follow-up procedures are performed.  
The Clinical Events Committee (CEC) will be an independent board who will not be participating in 
the study and will adjudicate SAEs reported in the study.   
7 
Analysis of Endpoints 
7.1 
Analysis of Primary Endpoints 
The primary endpoint in this pilot study will be summarized descriptively and no hypothesis tests 
are planned. 
7.2 
Analysis of Secondary Endpoints 
All secondary endpoints will be summarized descriptively, and no hypothesis tests are planned. 
Secondary endpoints include implant success, dimensional changes of bone around the localized 
region of the implant as determined from radiographic data (periapical and CBCT), qualitative bone 
density changes in the localized region of the implant as determined from CBCT data, changes in 
periodontal health measurements, and subject satisfaction (esthetics, function, and level of pain). 
The radiographic data will be sent to a centralized location to be evaluated by a single reader using 
a calibrated measuring tool. The images will be provided to the evaluator individually coded and 
randomized by a third party to make the identity of the subject and the time point of image capture 
not identifiable by the evaluator, rendering the evaluator blinded. A central radiologist will assess 
evidence of encapsulation, bone dimensional changes and density values from the radiographs. 
7.3 
Analysis of Safety Endpoints 
For analysis of safety endpoints, summary tables and/or listings will be provided for all adverse 
events by event category. Adverse events will also be summarized by relationship to the study 
device, implant procedure, by seriousness, severity and by outcome. Adverse events leading to 
discontinuation from the study will be tabulated. Except where indicated, a subject reporting the 
same adverse event more than once will be counted once when calculating the number and 
percentage of subjects with that particular event. Except where indicated, if a subject reports the 
same adverse event more than once, the strongest relationship to the procedure and/or device 
recorded for the event will be presented. 
Adverse events that occurred in screen failure subjects will be presented separately. 

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7.4 
General Statistical Methods 
Only descriptive statistics will be used, including mean, standard deviation, and range. 
 Surgery and Supporting Procedures 
Detailed information regarding the surgical procedure will be presented in listings. This will include 
information on crestal bone measurements, bone quality, evaluation of primary stability, and soft 
tissue procedures. 
Details regarding other supportive procedures in the study will be presented in listings, including 
suture removal, second stage surgery, soft tissue procedures, impressions, temporary prosthesis 
placement, and definitive prosthesis placement. 
 Other Data Summaries 
Concomitant medications will be presented in listings and also summarized by drug category. 
Protocol deviations will be summarized by deviation type and study center. 
 Subject Disposition 
A detailed description of subject disposition will be provided using a CONSORT diagram and 
summaries of subjects falling in various subgroups of interest, such as enrolled but did not receive 
study treatment and early withdrawals. All enrolled subjects entered in the study will be accounted 
for in the summary. 
 Missing Data 
Every effort will be made to minimize the amount of missing data. If a subject drops out of the study 
prior to completing their primary endpoint assessment, every effort will be made to measure their 
primary endpoint immediately prior to discontinuation if possible.  No missing data will be imputed. 
8 
Data Management 
The general data management procedures are described below, details can be found in the Data 
Management Plan. Required clinical data for this study will be collected and recorded in the clinical 
database using an electronic case report form for all study subjects from whom informed consent 
is obtained. Research Center numbers and subject numbers will be used to track subject 
information throughout the registry. The Principal Investigator or authorized designee is 
responsible for the timely completion and electronic signature of all electronic case report forms. 
The information entered into the database will be checked systematically by the data management 
for inconsistent, illogical and/or missing data using electronic and manual validation checks defined 

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in the Data Validation Plan. If validation of data leads to discrepancies, data management will 
generate electronic queries. The timely resolution of the queries is under the responsibility of the 
monitor and the investigators at the Research Center. The query process is an ongoing process 
starting with the first data entered into the database. The electronic clinical data system used for 
this study has a security system that prevents unauthorized access to the data and any deletion of 
data (audit and edit trail). 
9 
Study Management 
9.1 
Regulatory and Ethical Requirements 
 Informed Consent 
Informed consent will be obtained from all subjects prior to study participation as described in 
Section 5.2.1. 
 Institutional Review Board 
Prior to initiation of any study procedures, the protocol and informed consent will be submitted to 
an IRB for review and approval. In addition, any amendments to the protocol or informed consent 
will be reviewed and approved (if necessary) by the IRB. The sponsor must receive a letter 
documenting the IRB approval at the center prior to the initiation of the study at the center. 
The investigator is responsible for providing the appropriate reports to the IRB during the course of 
the clinical study. This will include the following: 
• 
Informing the IRB of the study progress periodically as required, but at a minimum annually 
• 
Reporting any unanticipated serious adverse device effects within 10 working days of becoming 
aware of the event 
• 
Reporting any deviations from the protocol that adversely affect the risk/benefit ratio, the rights, 
safety, or welfare of the participants, or integrity of the study 
• 
Providing any other reports requested by the IRB 
9.2 
Reports and Record Management 
 Investigator Records 
The following will be required from the investigator prior to the initiation of the study: 
• 
A signed confidentiality agreement 
• 
Signed and dated curriculum vitae of the investigator(s) and a copy of his/her dental license 
• 
Signed financial disclosure 

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• 
A signed copy of the final protocol and any amendments 
• 
A signed copy of the clinical study agreement with the sponsor 
• 
IRB approval letter and IRB approved informed consent document 
 Case Report Forms 
The investigator will be responsible for the accuracy of the data entered on the Electronic Case 
Report Forms (eCRFs). The investigator will also allow a RevBio representative and/or regulatory 
bodies to review the data reported on the case report form with the source documents as far as is 
permitted by local regulations. 
 Source Documents 
Source documents are defined as the original point of entry of a specific data point. Source 
documents will include, but are not limited to, progress notes, electronic data, computer printouts, 
radiographs, and recorded data from automated instruments. All source documents pertaining to 
this study will be maintained by the investigator and made available for inspection by authorized 
persons. 
 Records/Data Retention 
Original radiographs, photographs, and study documents will be maintained at the research center 
in a file established for this study. All study documentation needs to be stored at the research center 
for at least fifteen (15) years following the completion of the study, as specified by the sponsor. The 
investigator should have access to the study documents in order to answer any queries associated 
with the study. All other study records will be kept by RevBio once the study has been completed. 
These records will be maintained at RevBio according to RevBio’s standard operating procedures. 
9.3 
Monitoring 
RevBio will assign a qualified individual to monitor the study. The general monitoring procedures 
for this study are described below, details can be found in the Monitoring Plan. 
 Study Initiation Visit 
Once a Research Center receives IRB approval, the monitor will schedule a site initiation visit in 
order to make sure all study documents are in place and that all the site personnel that will 
participate in the study are trained on the study procedures. The monitor will ensure during the 
study initiation that the investigator clearly understands and accepts the responsibilities and 
obligations of conducting a clinical study: 
• 
Understands the clinical protocol and relevant items outlined in the protocol (including 

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Inclusion/Exclusion criteria, AE and SAE reporting requirements); 
• 
Understands and accepts the obligations to obtain informed consent; 
• 
Understands how to document study data (especially the importance of having supporting 
documentation for AE assessment); 
• 
Understands the information outlined in the investigator’s brochure, including proper device 
usage 
• 
Understands aspects of study device accountability (i.e. how to obtain the device, how to store 
the device, how to document device receipt, usage and return); 
• 
Understands and accepts the obligation to obtain IRB review and approval of the protocol and 
informed consent, and to ensure continuing review of the study by the IRB; 
• 
Has adequate facilities and access to an adequate number of suitable subjects to conduct the 
study 
 Routine Monitoring Visits 
Monitoring visits will be scheduled and conducted periodically, but at a minimum annually to review 
the following: 
• 
The study is in compliance with the currently approved protocol/ amendment(s); deviations will 
be discussed with the responsible investigator, documented, and reported to the sponsor and 
IRB (according to the IRB policy); 
• 
The study is in compliance with Good Clinical Practice (GCP) and with the applicable regulatory 
requirements; 
• 
Only authorized investigators/ clinical personnel are participating in the clinical investigation; 
• 
Device accountability including adequate supply at center, proper storage, and documentation 
of device traceability; 
• 
The reported study data entered on CRFs are accurate, complete, and verifiable from source 
documents 
• 
All adverse events and serious adverse events are reported correctly. In cases where there is 
missing information about an adverse event or missing evidence to support the investigator’s 
assessment, a monitor will review and discuss the adverse event with the responsible 
investigator; 
• 
The reason for a subject’s withdrawal has been documented 

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The investigator will allow RevBio to have access to all study documents during each monitoring 
visit for a thorough review of the study’s progress. 
 Study Closeout Visit 
After the last subject has completed the study and the database has been cleaned, the closeout 
visit will be conducted at the center. The following tasks should be completed by RevBio or the 
monitor: 
• 
Review any outstanding questions from the Clinical Investigation Report and organize the 
signature process; 
• 
Ensure that the documentation and clinical investigation requirements were met; 
• 
Collect outstanding documents; 
• 
Ensure that adverse events were reported to the IRB according to the IRB’s policy; 
• 
Ensure that device accountability is complete; 
• 
Organize the archiving of all study-related documents and remind the investigator of the 
obligation to retain the records 
9.4 
Study Termination 
At study termination, a Clinical Investigation Report will be prepared by the sponsor, even if the 
study was terminated prematurely. 
The study can be terminated early at the discretion of the investigator or the sponsor in the case of 
any of the following: 
• 
Occurrence of adverse device effects unknown at the start of the study with respect to their 
nature, severity, and duration, or the unexpected excessive incidence of known adverse device 
effects; 
• 
New scientific knowledge obtained after the start of the study showing the ethical claim of the 
study is no longer valid 
 Center Discontinuation 
The study Center will be closed and the study terminated under the following circumstances: 
• 
The Center is not recruiting a sufficient number of subjects or is unlikely to recruit a sufficient 
number of subjects; 
• 
The Center does not respond to study management requests; 

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• 
Repeated protocol violations have been discovered that effect the integrity of the study or the 
study data 
9.5 
Protocol Amendments 
Once the first subject has entered the study, any part of this study plan can be amended upon 
agreement of the sponsor and the participating principal investigators throughout the clinical 
investigation. Protocol changes will be kept to a minimum. Only those changes that are deemed 
essential to the successful completion of the protocol will be considered. 
The reasons and justifications for the amendment will be included with each amended section of 
the document, and the amendment will include a version number and date. Once the investigator 
and the sponsor have accepted the changes, a written amendment to the protocol will be sent to 
the investigator for signature. 
All significant protocol changes affecting the scientific soundness of the study or the rights, safety, 
or welfare of subjects which occur after the initial IRB approval, must be submitted for approval by 
each center to the IRB as an amendment to the original protocol before the changes can be 
implemented by the Investigator. Each investigational center will send a copy of the IRB approval 
letter for the amendment to RevBio. 
Requests for clarifications to the protocol shall be discussed with the study monitor. The clarification 
statements will be sent to each investigator and will be kept in the appropriate file. 
9.6 
Publications 
Analysis of data will be conducted by RevBio and the final report will be prepared by RevBio with 
input from the investigators. Any publications or presentations utilizing the data from this study must 
be reviewed by RevBio prior to submission according to the time frame specified in the clinical 
study agreement. 
 
 

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10 Protocol Signature Page 
 
Protocol: DVAL18041 
Title:  
Immediate Placement and Stabilization of Dental Implants with Tetranite® Stabilization 
Material in Mandibular and Maxillary Tooth Extraction Sites that Fail to Provide 
Adequate Primary Stability 
Version: 
3.0 
I have read the foregoing protocol and agree to conduct the study as outlined. I agree that the 
examinations and follow-up visits required by the study protocol are in accordance with the 
standard treatment plan for dental implant subjects. 
 
Signature: 
 
 
   
Dr. Ryushiro Sugita 
UT Health Science Center – San Antonio 
 
Date 
 
 
Signature: 
 
 
 
Dr. Michael Pikos 
Pikos Institute 
Date 
 
 
Received by Sponsor: 
 
 
Printed Name of Study Director 
Signature of Study Director 
Date 

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References 
 
1. 
Buser, D.; Weber, H. P.; Bragger, U.; Balsiger, C., Tissue integration of one-stage ITI implants: 3-
year results of a longitudinal study with Hollow-Cylinder and Hollow-Screw implants. Int J Oral Maxillofac 
Implants 1991, 6 (4), 405-12. 
2. 
Ray, N. F.; Chan, J. K.; Thamer, M.; Melton, L. J., 3rd, Medical expenditures for the treatment of 
osteoporotic fractures in the United States in 1995: report from the National Osteoporosis Foundation. J 
Bone Miner Res 1997, 12 (1), 24-35. 
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Baldwin, K.; Morrison, M. J., 3rd; Tomlinson, L. A.; Ramirez, R.; Flynn, J. M., Both bone forearm 
fractures in children and adolescents, which fixation strategy is superior - plates or nails? A systematic 
review and meta-analysis of observational studies. J Orthop Trauma 2014, 28 (1), e8-e14. 
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Murray, C. M., Thomson, W.M., Leichter, J.W., Dental implant use in New Zealand: A 10-year 
update. New Zealand Dental Journal 2016, 49-54. 
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McAnany, S. J.; Baird, E. O.; Qureshi, S. A.; Hecht, A. C.; Heller, J. G.; Anderson, P. A., 
Posterolateral Fusion Versus Interbody Fusion for Degenerative Spondylolisthesis: A Systematic Review 
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Sarkar, S. K.; Lee, B. T., Hard tissue regeneration using bone substitutes: an update on innovations 
in materials. Korean J Intern Med 2015, 30 (3), 279-93. 
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Farrar, D. F., Bone adhesives for trauma surgery: A review of challenges and developments. 
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Jensen, S. S.; Chen, B.; Bornstein, M. M.; Bosshardt, D. D.; Buser, D., Effect of enamel matrix 
derivative and parathyroid hormone on bone formation in standardized osseous defects: an experimental 
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Tsukeoka, T.; Suzuki, M.; Ohtsuki, C.; Sugino, A.; Tsuneizumi, Y.; Miyagi, J.; Kuramoto, K.; Moriya, 
H., Mechanical and histological evaluation of a PMMA-based bone cement modified with gamma-
methacryloxypropyltrimethoxysilane and calcium acetate. Biomaterials 2006, 27 (21), 3897-903. 
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Mousa, W. F.; Kobayashi, M.; Shinzato, S.; Kamimura, M.; Neo, M.; Yoshihara, S.; Nakamura, T., 
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Heini, P. F.; Berlemann, U.; Kaufmann, M.; Lippuner, K.; Fankhauser, C.; van Landuyt, P., 
Augmentation of mechanical properties in osteoporotic vertebral bones--a biomechanical investigation of 
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Leggat, P. A., Smith, D.R., Kedjarune, U., Surgical Applications of Methyl Methacrylate: A Review 
of Toxicity. Archives of Environmental & Occupational Health 2009, 63 (3), 207-212. 
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Serbetci, K., Korkusuz, F., Hasirci, N., Thermal and mechanical properties of hydroxyapatite 
impregnated acrylic bone cements. Polymer Testing 2004, 23 (2), 145-155. 
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Donaldson, A. J.; Thomson, H. E.; Harper, N. J.; Kenny, N. W., Bone cement implantation 
syndrome. Br J Anaesth 2009, 102 (1), 12-22. 
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Tsukimura, N.; Yamada, M.; Aita, H.; Hori, N.; Yoshino, F.; Chang-Il Lee, M.; Kimoto, K.; Jewett, 
A.; Ogawa, T., N-acetyl cysteine (NAC)-mediated detoxification and functionalization of poly(methyl 
methacrylate) bone cement. Biomaterials 2009, 30 (20), 3378-89. 
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Provenzano, M. J., Murphy, K.P., Riley III, L.H., Bone Cements: Review of Their Physiochemical 
and Biochemical Properties in Percutaneous Vertebroplasty. AJNR Am J Neuroradiol 2004, 25, 1286-
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Ormsby, R.; McNally, T.; O'Hare, P.; Burke, G.; Mitchell, C.; Dunne, N., Fatigue and biocompatibility 
properties of a poly(methyl methacrylate) bone cement with multi-walled carbon nanotubes. Acta Biomater 
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Khandaker, M.; Vaughan, M. B.; Morris, T. L.; White, J. J.; Meng, Z., Effect of additive particles on 
mechanical, thermal, and cell functioning properties of poly(methyl methacrylate) cement. Int J 
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19. 
Topoleski, L. D.; Ducheyne, P.; Cuckler, J. M., Flow intrusion characteristics and fracture properties 
of titanium-fibre-reinforced bone cement. Biomaterials 1998, 19 (17), 1569-77. 
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Serbetci, K., Hasirci, N., Recent Developments in Bone Cements. In Biomaterials in Orthopedics, 
Yaszemski, M. J., Trantolo D.J., Lewandrowski, K.U., Hasirci, V., Altobello, D.E., Wise, D.L., Ed. Marcel 
Dekker, Inc: 2004; pp 241-280. 
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Brown, W. E., Chow, L.C., A new calcium phosphate water-setting cement. Cements Research 
Progress 1986, 352-379. 
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Bohner, M.; Lemaitre, J.; Ring, T. A., Effects of Sulfate, Pyrophosphate, and Citrate Ions on the 
Physicochemical Properties of Cements Made of β-Tricalcium Phosphate-Phosphoric Acid-Water 
Mixtures. Journal of the American Ceramic Society 1996, 79 (6), 1427-1434. 
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Gruniger, S. E., Evaluation of the biocompatibility of a new calcium phosphate setting cement. J 
Dent Res 1984, 63, 200. 
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Khashaba, R. M.; Moussa, M. M.; Mettenburg, D. J.; Rueggeberg, F. A.; Chutkan, N. B.; Borke, J. 
L., Polymeric-calcium phosphate cement composites-material properties: in vitro and in vivo investigations. 
Int J Biomater 2010, 2010. 
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Yokoyama, A.; Yamamoto, S.; Kawasaki, T.; Kohgo, T.; Nakasu, M., Development of calcium 
phosphate cement using chitosan and citric acid for bone substitute materials. Biomaterials 2002, 23 (4), 
1091-101. 
26. 
Bercier, A.; Goncalves, S.; Lignon, O.; Fitremann, J., Calcium Phosphate Bone Cements Including 
Sugar Surfactants: Part One-Porosity, Setting Times and Compressive Strength. Materials (Basel) 2010, 
3 (10), 4695-4709. 
27. 
Zakaria, S. M.; Sharif Zein, S. H.; Othman, M. R.; Yang, F.; Jansen, J. A., Nanophase 
hydroxyapatite as a biomaterial in advanced hard tissue engineering: a review. Tissue Eng Part B Rev 
2013, 19 (5), 431-41. 
28. 
Zhang, J.; Liu, W.; Schnitzler, V.; Tancret, F.; Bouler, J. M., Calcium phosphate cements for bone 
substitution: chemistry, handling and mechanical properties. Acta Biomater 2014, 10 (3), 1035-49. 
29. 
Kraus, T.; Moszner, F.; Fischerauer, S.; Fiedler, M.; Martinelli, E.; Eichler, J.; Witte, F.; Willbold, E.; 
Schinhammer, M.; Meischel, M.; Uggowitzer, P. J.; Loffler, J. F.; Weinberg, A., Biodegradable Fe-based 
alloys for use in osteosynthesis: outcome of an in vivo study after 52 weeks. Acta Biomater 2014, 10 (7), 
3346-53. 
30. 
Kim, Y. H.; Park, J. W.; Kim, J. S., Is diaphyseal stem fixation necessary for primary total hip 
arthroplasty in patients with osteoporotic bone (Class C bone)? J Arthroplasty 2013, 28 (1), 139-46 e1. 
31. 
Kilpikari, J.; Lapinsuo, M.; Tormala, P.; Patiala, H.; Rokkanen, P., Bonding strength of alkyl-2-
cyanoacrylates to bone in vitro. J Biomed Mater Res 1986, 20 (8), 1095-102. 
32. 
Maurer, P.; Bekes, K.; Gernhardt, C. R.; Schaller, H. G.; Schubert, J., Tensile bond strength of 
different adhesive systems between bone and composite compared: an in vitro study. J Craniomaxillofac 
Surg 2004, 32 (2), 85-9. 
33. 
Fedak, P. W.; Kieser, T. M.; Maitland, A. M.; Holland, M.; Kasatkin, A.; Leblanc, P.; Kim, J. K.; King, 
K. M., Adhesive-enhanced sternal closure to improve postoperative functional recovery: a pilot, 
randomized controlled trial. Ann Thorac Surg 2011, 92 (4), 1444-50. 
34. 
Smeets, N. M.; Bakaic, E.; Patenaude, M.; Hoare, T., Injectable poly(oligoethylene glycol 
methacrylate)-based hydrogels with tunable phase transition behaviours: physicochemical and biological 
responses. Acta Biomater 2014, 10 (10), 4143-55. 
35. 
Hatton, P. V.; Hurrell-Gillingham, K.; Brook, I. M., Biocompatibility of glass-ionomer bone cements. 
J Dent 2006, 34 (8), 598-601. 
36. 
Sehlke, B. M.; Wilson, T. G.; Jones, A. A.; Yamashita, M.; Cochran, D. L., The use of a magnesium-
based bone cement to secure immediate dental implants. Int J Oral Maxillofac Implants 2013, 28 (6), e357-
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Chivers, R. A., Wolowacz, R.G.,, The strength of adhesive-bonded tissue joints. International 
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38. 
Heiss, C.; Kraus, R.; Schluckebier, D.; Stiller, A.-C.; Wenisch, S.; Schnettler, R., Bone Adhesives 
in Trauma and Orthopedic Surgery. European Journal of Trauma 2006, 32 (2), 141-148. 
39. 
Guvendiren, M.; Messersmith, P. B.; Shull, K. R., Self-assembly and adhesion of DOPA-modified 
methacrylic triblock hydrogels. Biomacromolecules 2008, 9 (1), 122-8. 
40. 
Jo, S. H.; Sohn, J. S., Biomimetic adhesive materials containing cyanoacryl group for medical 
application. Molecules 2014, 19 (10), 16779-93. 
41. 
Shao, H.; Bachus, K. N.; Stewart, R. J., A water-borne adhesive modeled after the sandcastle glue 
of P. californica. Macromol Biosci 2009, 9 (5), 464-71. 
42. 
Murphy, J. L.; Vollenweider, L.; Xu, F.; Lee, B. P., Adhesive performance of biomimetic adhesive-
coated biologic scaffolds. Biomacromolecules 2010, 11 (11), 2976-84. 
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Shafiq, Z.; Cui, J.; Pastor-Perez, L.; San Miguel, V.; Gropeanu, R. A.; Serrano, C.; del Campo, A., 
Bioinspired underwater bonding and debonding on demand. Angew Chem Int Ed Engl 2012, 51 (18), 4332-
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Choi, J. W.; Kim, N., Clinical application of three-dimensional printing technology in craniofacial 
plastic surgery. Arch Plast Surg 2015, 42 (3), 267-77. 
45. 
Nedir, R.; Bischof, M.; Szmukler-Moncler, S.; Bernard, J. P.; Samson, J., Predicting 
osseointegration by means of implant primary stability. Clin Oral Implants Res 2004, 15 (5), 520-8. 
46. 
Mesa, F.; Munoz, R.; Noguerol, B.; de Dios Luna, J.; Galindo, P.; O'Valle, F., Multivariate study of 
factors influencing primary dental implant stability. Clin Oral Implants Res 2008, 19 (2), 196-200. 
47. 
Elakkiya, S.; Ramesh, A. S.; Prabhu, K., Systematic analysis on the efficacy of bone enhancement 
methods used for success in dental implants. J Indian Prosthodont Soc 2017, 17 (3), 219-225. 
48. 
Mombelli, A.; van Oosten, M. A.; Schurch, E., Jr.; Land, N. P., The microbiota associated with 
successful or failing osseointegrated titanium implants. Oral Microbiol Immunol 1987, 2 (4), 145-51. 
49. 
Larheim, T. A.; Eggen, S., Measurements of alveolar bone height at tooth and implant abutments 
on intraoral radiographs. A comparison of reproducibility of Eggen technique utilized with and without a 
bite impression. J Clin Periodontol 1982, 9 (3), 184-92. 
50. 
Albrektsson, T., Isidor, F. In Consensus Report of Session IV., Proceedings of the First European 
Workshop  on Periodontology, , Quintessence Publishing: 1994; pp 365-369. 
51. 
Papaspyridakos, P.; Chen, C. J.; Singh, M.; Weber, H. P.; Gallucci, G. O., Success criteria in 
implant dentistry: a systematic review. J Dent Res 2012, 91 (3), 242-8. 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1 
Appendix 1 – Instructions for Use  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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2 
Appendix 2 – Declaration of Helsinki 
 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975  
35th WMA General Assembly, Venice, Italy, October 1983  
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996  
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of Clarification added) 
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added)  
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
 
 
Preamble 
The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement 
of ethical principles for medical research involving human subjects, including research on 
identifiable human material and data. The Declaration is intended to be read as a whole and each 
of its constituent paragraphs should be applied with consideration of all other relevant paragraphs. 
Consistent with the mandate of the WMA, the Declaration is addressed primarily to physicians. The 
WMA encourages others who are involved in medical research involving human subjects to adopt 
these principles. 
General Principles 
The Declaration of Geneva of the WMA binds the physician with the words, “The health of my 
patient will be my first consideration,” and the International Code of Medical Ethics declares that, 
“A physician shall act in the patient's best interest when providing medical care.”  
 

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It is the duty of the physician to promote and safeguard the health, well-being and rights of patients, 
including those who are involved in medical research. The physician's knowledge and conscience 
are dedicated to the fulfilment of this duty. Medical progress is based on research that ultimately 
must include studies involving human subjects. 
The primary purpose of medical research involving human subjects is to understand the causes, 
development and effects of diseases and improve preventive, diagnostic and therapeutic 
interventions (methods, procedures and treatments). Even the best proven interventions must be 
evaluated continually through research for their safety, effectiveness, efficiency, accessibility and 
quality. 
Medical research is subject to ethical standards that promote and ensure respect for all human 
subjects and protect their health and rights. 
While the primary purpose of medical research is to generate new knowledge, this goal can never 
take precedence over the rights and interests of individual research subjects. 
It is the duty of physicians who are involved in medical research to protect the life, health, dignity, 
integrity, right to self-determination, privacy, and confidentiality of personal information of research 
subjects. The responsibility for the protection of research subjects must always rest with the 
physician or other health care professionals and never with the research subjects, even though 
they have given consent. 
Physicians must consider the ethical, legal and regulatory norms and standards for research 
involving human subjects in their own countries as well as applicable international norms and 
standards. No national or international ethical, legal or regulatory requirement should reduce or 
eliminate any of the protections for research subjects set forth in this Declaration. 
Medical research should be conducted in a manner that minimizes possible harm to the 
environment. 
Medical research involving human subjects must be conducted only by individuals with the 
appropriate ethics and scientific education, training and qualifications. Research on patients or 
healthy volunteers requires the supervision of a competent and appropriately qualified physician or 
other health care professional. 
Groups that are underrepresented in medical research should be provided appropriate access to 
participation in research. 
 

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Physicians who combine medical research with medical care should involve their patients in 
research only to the extent that this is justified by its potential preventive, diagnostic or therapeutic 
value and if the physician has good reason to believe that participation in the research study will 
not adversely affect the health of the patients who serve as research subjects. 
Appropriate compensation and treatment for subjects who are harmed as a result of participating 
in research must be ensured. 
Risks, Burdens and Benefits 
In medical practice and in medical research, most interventions involve risks and burdens. 
Medical research involving human subjects may only be conducted if the importance of the 
Endpoint outweighs the risks and burdens to the research subjects. 
All medical research involving human subjects must be preceded by careful assessment of 
predictable risks and burdens to the individuals and groups involved in the research in comparison 
with foreseeable benefits to them and to other individuals or groups affected by the condition under 
investigation. 
Measures to minimize the risks must be implemented. The risks must be continuously monitored, 
assessed and documented by the researcher. 
Physicians may not be involved in a research study involving human subjects unless they are 
confident that the risks have been adequately assessed and can be satisfactorily managed. 
When the risks are found to outweigh the potential benefits or when there is conclusive proof of 
definitive outcomes, physicians must assess whether to continue, modify or immediately stop the 
study. 
Vulnerable Groups and Individuals 
Some groups and individuals are particularly vulnerable and may have an increased likelihood of 
being wronged or of incurring additional harm. 
All vulnerable groups and individuals should receive specifically considered protection. 
Medical research with a vulnerable group is only justified if the research is responsive to the health 
needs or priorities of this group and the research cannot be carried out in a non- vulnerable group. 
In addition, this group should stand to benefit from the knowledge, practices or interventions that 
result from the research. 
 

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Scientific Requirements and Research Protocols 
Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant sources of 
information, and adequate laboratory and, as appropriate, animal experimentation. The welfare of 
animals used for research must be respected. 
The design and performance of each research study involving human subjects must be clearly 
described and justified in a research protocol. 
The protocol should contain a statement of the ethical considerations involved and should indicate 
how the principles in this Declaration have been addressed. The protocol should include 
information regarding funding, sponsors, institutional affiliations, potential conflicts of interest, 
incentives for subjects and information regarding provisions for treating and/or compensating 
subjects who are harmed as a consequence of participation in the research study. 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial provisions. 
Research Ethics Committees 
The research protocol must be submitted for consideration, comment, guidance and approval to 
the concerned research ethics committee before the study begins. This committee must be 
transparent in its functioning, must be independent of the researcher, the sponsor and any other 
undue influence and must be duly qualified. It must take into consideration the laws and regulations 
of the country or countries in which the research is to be performed as well as applicable 
international norms and standards but these must not be allowed to reduce or eliminate any of the 
protections for research subjects set forth in this Declaration. 
The committee must have the right to monitor ongoing studies. The researcher must provide 
monitoring information to the committee, especially information about any serious adverse events. 
No amendment to the protocol may be made without consideration and approval by the committee. 
After the end of the study, the researchers must submit a final report to the committee containing 
a summary of the study’s findings and conclusions. 
Privacy and Confidentiality 
Every precaution must be taken to protect the privacy of research subjects and the confidentiality 
of their personal information. 
 

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Informed Consent 
Participation by individuals capable of giving informed consent as subjects in medical research 
must be voluntary. Although it may be appropriate to consult family members or community leaders, 
no individual capable of giving informed consent may be enrolled in a research study unless he or 
she freely agrees. 
In medical research involving human subjects capable of giving informed consent, each potential 
subject must be adequately informed of the aims, methods, sources of funding, any possible 
conflicts of interest, institutional affiliations of the researcher, the anticipated benefits and potential 
risks of the study and the discomfort it may entail, post-study provisions and any other relevant 
aspects of the study. The potential subject must be informed of the right to refuse to participate in 
the study or to withdraw consent to participate at any time without reprisal. Special attention should 
be given to the specific information needs of individual potential subjects as well as to the methods 
used to deliver the information. 
After ensuring that the potential subject has understood the information, the physician or another 
appropriately qualified individual must then seek the potential subject’s freely-given informed 
consent, preferably in writing. If the consent cannot be expressed in writing, the non- written 
consent must be formally documented and witnessed. 
All medical research subjects should be given the option of being informed about the general 
outcome and results of the study. 
When seeking informed consent for participation in a research study the physician must be 
particularly cautious if the potential subject is in a dependent relationship with the physician or may 
consent under duress. In such situations the informed consent must be sought by an appropriately 
qualified individual who is completely independent of this relationship. 
For a potential research subject who is incapable of giving informed consent, the physician must 
seek informed consent from the legally authorized representative. These individuals must not be 
included in a research study that has no likelihood of benefit for them unless it is intended to 
promote the health of the group represented by the potential subject, the research cannot instead 
be performed with persons capable of providing informed consent, and the research entails only 
minimal risk and minimal burden. 
When a potential research subject who is deemed incapable of giving informed consent is able to 
 

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give assent to decisions about participation in research, the physician must seek that assent in 
addition to the consent of the legally authorized representative. The potential subject’s dissent 
should be respected. 
Research involving subjects who are physically or mentally incapable of giving consent, for 
example, unconscious patients, may be done only if the physical or mental condition that prevents 
giving informed consent is a necessary characteristic of the research group. In such circumstances 
the physician must seek informed consent from the legally authorized representative. If no such 
representative is available and if the research cannot be delayed, the study may proceed without 
informed consent provided that the specific reasons for involving subjects with a condition that 
renders them unable to give informed consent have been stated in the research protocol and the 
study has been approved by a research ethics committee. Consent to remain in the research must 
be obtained as soon as possible from the subject or a legally authorized representative. 
The physician must fully inform the patient which aspects of their care are related to the research. 
The refusal of a patient to participate in a study or the patient’s decision to withdraw from the study 
must never adversely affect the patient-physician relationship. 
For medical research using identifiable human material or data, such as research on material or 
data contained in biobanks or similar repositories, physicians must seek informed consent for its 
collection, storage and/or reuse. There may be exceptional situations where consent would be 
impossible or impracticable to obtain for such research. In such situations the research may be 
done only after consideration and approval of a research ethics committee. 
Use of Placebo 
The benefits, risks, burdens and effectiveness of a new intervention must be tested against those 
of the best proven intervention(s), except in the following circumstances: 
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or 
Where for compelling and scientifically sound methodological reasons the use of any intervention 
less effective than the best proven one, the use of placebo, or no intervention is necessary to 
determine the efficacy or safety of an intervention and the patients who receive any intervention 
less effective than the best proven one, placebo, or no intervention will not be subject to additional 
risks of serious or irreversible harm as a result of not receiving the best proven intervention. 
Extreme care must be taken to avoid abuse of this option. 
 

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Post-Trial Provisions 
In advance of a clinical trial, sponsors, researchers and host country governments should make 
provisions for post-trial access for all participants who still need an intervention identified as 
beneficial in the trial. This information must also be disclosed to participants during the informed 
consent process. 
Research Registration and Publication and Dissemination of Results 
Every research study involving human subjects must be registered in a publicly accessible database 
before recruitment of the first subject. 
Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard to 
the publication and dissemination of the results of research. Researchers have a duty to make 
publicly available the results of their research on human subjects and are accountable for the 
completeness and accuracy of their reports. All parties should adhere to accepted guidelines for 
ethical reporting. Negative and inconclusive as well as positive results must be published or 
otherwise made publicly available. Sources of funding, institutional affiliations and conflicts of 
interest must be declared in the publication. Reports of research not in accordance with the 
principles of this Declaration should not be accepted for publication. 
Unproven Interventions in Clinical Practice 
In the treatment of an individual patient, where proven interventions do not exist or other 
known interventions have been ineffective, the physician, after seeking expert advice, with 
informed consent from the patient or a legally authorized representative, may use an 
unproven intervention if in the physician's judgement it offers hope of saving life, re-
establishing health or alleviating suffering. This intervention should subsequently be made 
the object of research, designed to evaluate its safety and efficacy. In all cases, new 
information must be recorded and, where appropriate, made publicly available. 
 
 
 
 
3 
Appendix 3 – Visual Analog Scale 
 

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