Prospective, Comparative Assessment of Alveolar Bone Augmentation Using Guidor Membrane in the Bound Edentulous Space
Phase: NA
Conditions: Bone Regeneration
Sponsor: University of North Carolina, Chapel Hill

 
Prospective, Comparative Assessment of Alveolar Bone Augmentation 
Using GUIDOR® Membrane in the Bound Edentulous Space 
 
 
NCT number NCT02387008 
Document Date November 11, 2015 
 

CLINICAL STUDY PROTOCOL 
 
 
 
 
 
 
 
 
 
 
 
PROSPECTIVE, COMPARATIVE ASSESSMENT OF 
ALVEOLAR BONE AUGMENTATION USING GUIDOR® 
MEMBRANE IN THE BOUND EDENTULOUS SPACE 
 
 
 
 
 
 
 
 
 
 
 
 
Study Product: 
GUIDOR® Membrane 
Study Code: 
13-2429 
Edition Number: Revision 04 
Date: 
November 11, 2015 

CLINICAL STUDY PROTOCOL 
 
 

 
 
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PROTOCOL SYNOPSIS 
 
Sponsor 
UNC School of Dentistry 
5501G Koury Oral Health Sciences Building 
CB #7450 
Chapel Hill, NC  27599-7450 
 
 
Coordinating and Principal Investigator  
Professor Jonathan Reside, University of North Carolina, USA 
 
Study center(s) and number of subjects planned 
The study will include a total of 60 subjects equally distributed at two centers: 
Center 1: Professor Jonathan Reside, University of North Carolina, USA 
Center 2: Professor Homa Zadeh, University of Southern California, USA 
 
 
Study timetable 
 
Estimated date of first subject 
enrolled 
Q4 2015 
Estimated date of last subject 
completed 
 
Q3 2016/Q4 2016 
Objectives 
The primary objective of this study is to investigate volumetric osseous changes at 6 
months following guided bone regeneration by calculating horizontal and vertical bone 
changes via cone beam computed tomography (CBCT). 
 
Secondary objectives of the study are to evaluate soft tissue inflammation, soft tissue 
infection, and wound dehiscence.. 
 
Study design 
The study is designed as a prospective, randomized controlled clinical trial.  Patients will 
be assigned for guided bone regeneration of a single bound edentulous site to 
treatment group A (GUIDOR® membrane with freeze-dried bone allograft), group B 
(GUIDOR® membrane alone), or group C (Bio-Gide® membrane with freeze-dried bone 
allograft). 
 

 
 
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Target subject population 
Patients in need of guided bone regeneration prior to dental implant therapy in a single, 
bound edentulous space within zone 14-24 or 34-44 will be included. 
 
Investigational product 
GUIDOR® membrane is a bioresorbable copolymer barrier membrane of polylactic acid 
blended with a citric acid ester.  For this investigation 15 mm x 20 mm membranes will 
be utilized. 
 
Comparator, dosage, and mode of administration 
Bio-Gide® membrane is a porcine type I/type III non-cross-linked collagen bilayer 
membrane.  The membranes are resorbed via collagenase over a 24 week period.  The 
dense outer surface faces soft the overlying soft tissues, preventing epithelial or fibrous 
tissue ingrowth.  The porous inner surface faces the bone and/or bone graft material 
and permits osteoblast ingrowth. 
 
Mineralized freeze-dried cortical bone allograft (LifeNet Health) is a particulate bone 
graft material.  It has a particle size of 250-1000 μm and is sterilized via Allowash XG® 
technology. 
 
Duration of treatment 
The study follow-up will be approximately 6-7 months.  The treatment period includes 
guided bone regeneration in anticipation of future dental implant care.  Follow-up visits 
following the guided bone regeneration will occur at 7 days, 14 days, 28 days, 6 
months. 
 
Outcome variables 
Efficacy 
Primary outcome variable:  
- 
Horizontal and vertical bone changes at 6 months 
Secondary outcome variables:  
- 
Inflammation (refer to 4.2.2.1) or infection (refer to 4.2.2.2) 
- 
Membrane exposure 
- 
Soft tissue complications (refer to 4.2.2.3) 
Patient reported outcomes 
- 
Not applicable 
Health economics 
- 
Not applicable 
Pharmacokinetics 
- 
Not applicable 

 
 
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Safety 
- 
Summarize all adverse events 
Genetics 
- 
Not applicable 
 
Statistical methods 
The primary outcome variables of dimensional horizontal and vertical bone changes will 
be analyzed by Wilcoxon rank sum test.   
 
The secondary outcome variables assessing the presence or absence of inflammation, 
infection, and soft tissue complications (wound dehiscence, membrane exposure) will 
be analyzed by chi-square test.   
 
 
 

 
 
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1 INTRODUCTION 
1.1 Background 
Guided bone regeneration refers to the use of occlusive membranes to permit access of 
selective cell populations to an osseous defect (1).  It is based on the principle that 
fibroblast migration occurs at a rate faster than cells with osteogenic potential.  As such 
placement of occlusive membranes creates a secluded space to allow for bone 
regeneration without disruption by fibroblast infiltration (1, 2).  The principles of guided 
bone regeneration have been used for localized alveolar ridge augmentation to increase 
bone dimensions prior to dental implant treatment. 
 
Functional requirements of barrier membranes include biocompatibility, cell 
occlusiveness, space maintenance, integration with the host tissues, and good clinical 
handling (3).  Two types of barrier membranes are commonly used in alveolar ridge 
augmentation: non-resorbable and resorbable barrier membranes.  Non-resorbable 
membranes necessitate a second surgical procedure for membrane removal and are 
associated with increased complications and infection in cases of membrane exposure 
during the healing period.  Resorbable barrier membranes offer the advantages of 
increased biocompatibility and integration.  However, their resorption rate must be 
controlled so that they are able to maintain space for a prerequisite period of time to 
permit bone regeneration.  Resorbable barrier membranes must also be associated with 
minimal inflammatory reactions that do not negatively affect the degree of bone 
regeneration achieved (3-5). 
 
Bone replacement grafts are commonly used in conjunction with barrier membranes to 
aid in space maintenance while providing a scaffold for bone regeneration.  A variety of 
bone graft options are available, including autogenic, allogenic, xenogenic, and 
alloplastic options.  Mineralized allografts have the benefit of providing an 
osteoconductive scaffold with a potential for osteoinductive properties following 
demineralization of the graft particles by osteoclasts (6).  Their use is commonplace in 
clinical practice due to their osteoconductive, scaffolding properties. 
 
Following guided bone regeneration, mean horizontal ridge width gains of 4.2 mm may 
be anticipated with use of a resorbable barrier membrane (7).  Implant survival rates of 
97-100% have been reported using a staged guided bone regeneration technique (7, 8). 
 
1.2 Rationale 
This study is intended to provide statistically robust evidence that guided bone 
regeneration outcomes using a GUIDOR® membrane with allograft is similar or better to 
outcomes obtained using other commercially available barrier membranes with allograft.  
It is intended to define in objective and subjective terms the response of the bone and 
overlying soft tissues to localized ridge augmentation.  To fulfill the goals of this project, 

 
 
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the clinical study will seek to enroll patients with a single bound edentulous space that 
requires ridge augmentation prior to dental implant treatment. 
 
It has been shown that the undisturbed, healed socket will lead to a loss of alveolar 
bone with a mean width reduction of 3.8 mm and height reduction of 1.24 mm within 6 
months (9).  Schropp et. al (2003), found, according to subtraction radiography, that by 
12 months, the alveolar bone present after tooth extraction decreased by up to 50% of 
its original width (10).  Buser, et. al (1990), reported a mean gain of 1.5-5.5mm of new 
bone formation 6-10 months post-GBR (11).  Based on these studies, a significant 
difference should be observed, especially between the bone grafting group and the 
control group. 
 
The goal of guided bone augmentation is to provide an alveolar ridge of sufficient 
dimension to permit dental implant placement.  The healing of these sites should occur 
with an absence of inflammation and other complications. 
 
 
This prospective clinical evaluation will enroll sufficient participants to perform statistical 
analyses of primary objectives.  Additional information regarding the presence or 
absence of inflammation, infection, or other wound healing complications will also be 
obtained through the projected enrollment. 
 
 
 

 
 
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2 STUDY OBJECTIVES 
2.1 Primary objective 
The primary objective is to compare the horizontal and vertical changes in osseous 
dimension of a single bound edentulous zone following guided bone regeneration.  
Three different bone augmentation techniques will be used.  Data will be obtained from 
DICOM images acquired by CBCT imaging.  The dimensional location of the facial bone 
plate in the Z-axis and Y-axis will be reported in terms of a reference point (the mid-
alveolar point positioned on a tangent drawn from the cementoenamel junctions of the 
mesial and distal adjacent teeth.  The changes from baseline to six months will be 
compared. 
 
Hypothesis: The treatment group with GUIDOR membrane with allograft is superior to 
comparative treatment groups (GUIDOR membrane alone or Bio-Gide® membrane with 
allograft). 
2.2 Secondary objectives 
Secondary objectives of the study are to evaluate and compare: 
• Presence or absence of soft tissue inflammation within 3mm from the incision line 
• Presence or absence of infection 
• Membrane exposure 
• Soft tissue complications, including wound dehiscence 
 
 

 
 
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3 STUDY PLAN AND PROCEDURES 
3.1 Overall study design and flow chart 
The study is designed as a randomized control prospective study with multiple study 
centers and is a physician initiated study. 
 
The study population will consist of individuals requiring guided bone regeneration prior 
to dental implant therapy in a single, bound edentulous zone.  Sites within zone 14-24 
or 34-44 (maxillary and mandibular first premolars and anterior teeth) will be included.  
 
60 subjects will be included at two centers. Each subject will be randomized into one of 
three groups: group A (GUIDOR® membrane and FDBA), group B (GUIDOR® 
membrane alone) and group C (Bio-Gide® membrane and FDBA). Each center will 
enroll 30 subjects, 10 per group. 
 
The study will be a 6 month follow-up with 7 main clinic visits. 
 
 
 

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Individuals meeting all inclusion and none of the exclusion criteria and that have signed 
all appropriate consent forms will be further evaluated.  Screening will entail evaluation 
of general dental and systemic health.  It will also include a clinical and radiographic 
assessment of the edentulous site and the adjacent teeth.  Pre-existing radiographs 
(e.g. panoramic and intraoral) can be used but must not be older than 6 months.  
Subjects with adequate alveolar ridges will immediately be scheduled for Visit 2 
provided that they fulfill all inclusion and none of the exclusion criterion. 
 
The following items will be completed during the screening visit: 
• Medical, Social, and Dental History 
• Oral examination 
• Concomitant Medications Use:  Concomitant medications which will be 
collected during this study consist of prescription and OTC drugs except for 
dietary supplements. 
• Confirm radiographic assessment for inclusion and exclusion criteria  
Visit 2:  Cone Beam Computed Tomography Imaging (2 weeks ± 4 days 
from Visit 1) 
Small field-of-view cone beam computed tomography (CBCT) imaging will be obtained 
for all patients at baseline and 6 months following the guided bone regeneration surgical 
procedure using the Carestream CS9300 System or equivalent system.  Images will 
provide baseline data for horizontal and vertical bone locations.  CBCT imaging will be 
conducted in accordance to institutional standards and technique.   
Visit 3:  Guided Bone Regeneration Surgery (8 weeks ± 7 days from Visit 1)  
Prior to randomization, confirmation and verification of all inclusion and exclusion 
criteria must be completed. 
 
The time of enrollment for this study is defined at the time the patient signs the informed 
consent form, meets all inclusion criteria and no exclusion criteria, is randomized and 
receives study treatment.   
 
 
Randomization and Stratification 
Subjects meeting all inclusion and none of the exclusion criteria will be randomly 
allocated to group A, B or C. The randomization will be per center and based on 
smoking status.  
 

 
 
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Figure 2 Randomization and stratification 
 
 
 
Pre-Surgical Procedures 
Buccal and crestal photographs of the planned surgical site will be obtained using a 
Canon 50D digital camera body with a Canon 100mm f/2.8 macro lens and a Canon 
MR-14EX macro ring flash or equivalent device.  The films must be stored in the 
subject’s medical chart. 
 
Pre-surgical antibiotic prophylaxis will be provided for patients at risk for infective 
endocarditis or with total joint replacement according to current guidelines provided by 
the American Dental Association, American Heart Association, and the American 
Academy of Orthopaedic Surgeons (9, 10). 
 
Surgical Procedure 
 
Sedation options will be discussed with the patient and a decision will be made to have: 
• No sedation 
• Oral conscious sedation 
 
Anesthesia: 
20% benzocaine topical anesthesia will be maintained for 1 minute.  Infiltration 
anesthesia using 2% lidocaine with 1:100,000 and 2% lidocaine with 1:50,000 
epinephrine will be provided.  It is anticipated that 3.6 to 5.4cc will be used. 
 
The product will be implanted according to the Instruction for Use. A crestal incision will 
be placed in the bound edentulous site with sulcular incisions extending to the distal line 
angles of the adjacent teeth.  Vertical releasing incisions using a papilla sparing design 
will be extending to or beyond the mucogingival junction.   
 
A full-thickness mucoperiostal flap will be elevated and extended to permit access to the 
edentulous site requiring bone augmentation.  Periosteal release with a new #15 blade 
and bone decortication of the edentulous site with a 1/4 round bur will be completed. 
 
Bone graft material and barrier membranes will be placed within the confines of the 
adjacent osseous architecture accordingly: 

 
 
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• Group A:  FDBA reconstituted in saline will be used to augment the edentulous 
site and will be covered by a GUIDOR® membrane. 
• Group B:  A GUIDOR® membrane will be placed over the edentulous site. 
• Group C:  FDBA reconstituted in saline will be used to augment the edentulous 
site and will be covered by a Bio-Gide® membrane. 
 
Following completion of bone augmentation, the flaps will be reapproximated and 
primary closure will be achieved using 5-0 (CV-6) ePTFE suture in the areas of the 
crestal and sulcular incisions and 5-0 chromic gut suture in the areas of the vertical 
releases.  It is anticipated that horizontal mattress, vertical mattress, continuous 
interlocking, and/or simple loop sutures will be employed. 
 
Post-Surgical Procedures 
Post-surgery, infiltration anesthesia with 0.5% bupivacaine with 1:200,000 will be 
provided.  It is anticipated that 1.8cc will be used. 
 
Post-surgical antibiotic coverage will be provided to patients.  It is recommended that a 
7-day course of 500mg Amoxicillin every 8 hours or 300mg Clindamycin every 6 hours 
will be provided. 
 
Post-surgical analgesics will be provided, it is recommended that 800mg Ibuprofen 
every 6-8 hours and 5/325mg Acetaminophen/Hydrocodone every 4-6 hours. 
 
The following will be completed and documented post-surgery:  
• Buccal and crestal photographs of the surgical site will be obtained using a 
Canon 50D digital camera body with a Canon 100mm f/2.8 macro lens and a 
Canon MR-14EX macro ring flash or a similar product.  The photographs will be 
stored in the subject’s medical history and chart.    
• Concomitant medication changes 
• Adverse event assessment 
• Subject instructions on post-surgical care per institutional standard of care 
 
Visit 4:  Post-Operative Visit (7 days ± 2 days post guided bone 
regeneration procedure) 
The following will be completed and documented: 
• Surgical site examination:  The surgical site will be examined for inflammation 
within 3mm of the incision line.  The site will also be assessed for membrane 
exposure, wound dehiscence, and infection.   
• Buccal and crestal photographs of the surgical site will be obtained using a 
Canon 50D digital camera body with a Canon 100mm f/2.8 macro lens and a 
Canon MR-14EX macro ring flash or a similar product.  The photographs will be 
stored in the subject’s medical history and chart.    
• Concomitant medication changes 
• Adverse event assessment 

 
 
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Visit 5:  Post-Operative Visit (14 days ± 2 days post guided bone 
regeneration procedure) 
The following will be completed and documented: 
• Surgical site examination:  The surgical site will be examined for inflammation 
within 3mm of the incision line.  The site will also be assessed for membrane 
exposure, wound dehiscence, and infection.   
• Suture material removal  
• Buccal and crestal photographs of the surgical site will be obtained using a 
Canon 50D digital camera body with a Canon 100mm f/2.8 macro lens and a 
Canon MR-14EX macro ring flash or a similar product.  The photographs will be 
stored in the subject’s medical history and chart.    
• Concomitant medication changes 
• Adverse event assessment 
 
Visit 6:  Post-Operative Visit (28 days ± 2 days post guided bone 
regeneration procedure) 
The following will be completed and documented: 
• Surgical site examination:  The surgical site will be examined for inflammation 
within 3mm of the incision line.  The site will also be assessed for membrane 
exposure, wound dehiscence, and infection.   
• Buccal and crestal photographs of the surgical site will be obtained using a 
Canon 50D digital camera body with a Canon 100mm f/2.8 macro lens and a 
Canon MR-14EX macro ring flash or a similar product.  The photographs will be 
stored in the subject’s medical history and chart.    
• Concomitant medication changes 
• Adverse event assessment 
. 
Visit 7:  Post-Operative Visit: Cone Beam Computed Tomography Imaging 
(24 weeks ± 7 days post guided bone regeneration procedure) 
The following will be completed and documented during this visit: 
• CBCT:  Small field-of-view cone beam computed tomography (CBCT) imaging 
will be obtained for all patients using the Carestream CS9300 System.  Images 
will provide post-augmentation data for horizontal and vertical bone locations. 
• Surgical site examination:  The surgical site will be examined for inflammation 
within 3mm of the incision line.  The site will also be assessed for membrane 
exposure, wound dehiscence, and infection.   
• Buccal and crestal photographs of the surgical site will be obtained using a 
Canon 50D digital camera body with a Canon 100mm f/2.8 macro lens and a 
Canon MR-14EX macro ring flash or a similar product.  The photographs will be 
stored in the subject’s medical history and chart.    
• Concomitant medication changes 
• Adverse event assessment 

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16(36) 
Table 1  Study plan 
 
 
 
 
 
 
 
 
 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
Visit Description 
Screening 
CBCT 
GBR 
 1 w post 
GBR 
2 w post 
GBR 
4w post 
GBR 
CBCT- 6 
m post 
GBR  
Patient Information 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
Patient demographics 
X 
 
 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
 
 
Oral examination 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
Radiographic examination 
X 
 
 
 
 
 
 
CBCT 
 
X 
 
 
 
 
X 
Clinical photography 
 
 
X 
X 
X 
X 
X 
Randomization 
 
 
X 
 
 
 
 
Guided bone regeneration 
 
 
X 
 
 
 
 
Suture removal 
 
 
 
 
X 
 
 
CBCT 
measurements 
Bone dimensions 
 
X 
 
 
 
 
X 
BMD 
 
X 
 
 
 
 
X 
Inflammation 
 
 
 
X 
X 
X 
X 
Wound dehiscence, membrane exposure, and 
infection 
 
 
 
X 
X 
X 
X 
Post-surgical care instructions 
 
 
X 
 
 
 
 
Adverse events/Adverse device effects 
 
 
X 
X 
X 
X 
X 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
Subject exit 
 
 
 
 
 
 
X 

 
 
 
 
 
3.2 Rationale and risk/benefit assessment  
Possible complications following any oral surgery include thermal sensitivity, flap 
sloughing, some loss of crestal bone height, abscess formation, infection, pain, 
swelling, and complications associated with the use of anesthesia.  As with any type 
of surgical therapy, the patient may experience discomfort for a few days. 
 
It is necessary to further define the effects of different grafting materials on clinical 
outcomes following localized alveolar bone augmentation.  This study will employ 
gold standard methods of evaluation efficacy and safety conforming to that stipulated 
of the medical, clinical research, and regulatory communities to demonstrate clinical 
benefit of GUIDOR® barrier membranes with and without bone replacement grafts.  
The study has been designed to treat a clinical scenario commonly encountered in 
clinical practice.  
 
There are no additional risks to the patient for participating in the study which he/she 
would not otherwise encounter with standard guided bone regeneration procedure.  
The subject would be receiving tests and CBCT if he/she was not participating in this 
study.    
 
Patients who receive standard guided bone regeneration whether or not participating 
in this study benefit from an increased alveolar ridge dimension to permit dental 
implant placement.  The public will benefit from the study results which will help to 
refine the knowledge of bone healing following augmentation with different grafting 
material.  This will help aid clinicians in the selection of materials to optimize their 
clinical outcomes of treatment.  It will also further characterize the effects of 
GUIDOR® membrane on soft tissue healing while comparing its outcomes to other 
commonly used barrier membranes.  Data acquisition includes minimally invasive 
collection methods, both before and after the surgical augmentation procedure.   
Study selection record 
Investigator(s) will keep a record of subjects who were considered for enrollment but 
were never enrolled (e.g., subject screening log).  This information is necessary to 
establish that the subject population was selected without bias. 
Inclusion criteria 
For inclusion in the study subjects must fulfill all of the following criteria: 
 
1. 
Provide written informed consent 
2. 
≥ 21 years and ≤ 75 years 
3. 
In need of one or more implants replacing missing or non-restorable teeth in the 
maxilla within region 14 to 24 or the mandible within region 34 to 44 
4. 
Edentulous for at least 6 months at study site 
5. 
A buccal-lingual ridge width at study site of ≤ 4 mm 

 
 
REV 02 2014-04-01                                                              CONFIDENTIAL 
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6. 
A mesial-distal distance between adjacent teeth at study site at bone level of at 
least 5 mm 
7. 
A keratinized mid-buccal mucosal thickness of at least 2 mm at study site 
(measured buccaly at MD midline from the mucogingival junction to the 
projected alveoalr ridge crest) 
8. 
Teeth adjacent (mesial and distal) to study site must consist of two stable, 
natural teeth without signs of periodontal bone loss (> 3 mm) and/or significant 
soft tissue loss 
9. 
A minimum of twenty teeth in good repair 
 
Exclusion criteria 
Any of the following is regarded as a criterion for exclusion from the study: 
 
1. 
Insufficient interocclusal distance for future dental implant placement and 
restoration  
2. 
More than 3 mm vertical bone loss at study site as measured from the mid-
buccal crest of bone on the adjacent teeth  
3. 
Previous site development (soft and/or bone tissue) performed at the study site 
4. 
Untreated rampant caries and uncontrolled periodontal disease 
5. 
 A history within the last 6 months of the daily use of any tobacco products 
besides cigarettes (smokeless chewing tobacco, e-cigarette, pipe or cigar 
smoking), or of smoking more than 10 cigarettes per day. 
6. 
Current alcohol dependency, alcohol abuse or chemical dependency based on 
DSM-IV Criteria or drug abuse 
7. 
Subjects having uncontrolled endocrine-induced diseases (e.g. uncontrolled 
diabetes mellitus and hyperparathyroidism) 
8. 
Systemic or local disease or condition that would compromise post-operative 
healing and/or osseointegration 
9. 
Use of any substance or medication that will influence bone metabolism (e.g. 
intravenous bisphosphonates) 
10. Need for systemic corticosteroids or any other medication that would influence 
post-operative healing and/or osseointegration 
11. History of radiation in the head and neck region > 30 Gy 
12. Subject reports pregnancy or is nursing at the time of enrollment  

 
 
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13. Unable or unwilling to return for follow-up visits for a period of 6 months 
14. Unlikely to be able to comply with study procedures according to Investigators 
judgement 
15. Previous enrollment or randomization of treatment in the present study 
16. Participation in another clinical trial within 30 days of enrollment 
Restrictions 
Subjects will be advised of the following restrictions during the study period: 
• To avoid disruption of wound healing during the initial study period the subject 
should have a restricted diet for at least 14 days (printed instructions will be 
distributed to the subjects at Visit 3 per institutional standard of care) 
• For current smokers, no more than 10 cigarettes per day are allowed 
Discontinuation of subjects from treatment or assessment 
3.2.1.1 Criteria for discontinuation 
Subjects may be discontinued from study treatment and assessments at any time. 
Specific reasons for discontinuing a subject from this study are: 
 
• Voluntary discontinuation by the subject who is at any time free to discontinue 
his/her participation in the study, without prejudice to further treatment 
• Safety reasons as judged by the investigator 
• Severe non-compliance to protocol as judged by the investigator 
• Subject received further dental therapy on study site or adjacent teeth without 
consent of investigator (e.g. new crown, periodontal surgery, or orthodontics 
on adjacent teeth) 
• Subject lost to follow-up 
3.2.1.2 Procedures for discontinuation 
Subjects who discontinue should always be asked about the reason(s) for their 
discontinuation and the presence of any AEs or ADEs.  If possible, they should be 
seen and assessed by an investigator(s).  Ongoing AEs and ADEs should be 
followed up. 
 
A subject will be classified as lost to follow up only if, he/she has failed to return to 
the required study visits and his/her dental status remains unknown, despite 3 
documented attempts to contact the subject via telephone, fax, email, and certified 
letter.  
3.2.1.3 Procedures for handling incorrect enrolled subjects 
Subjects not meeting the inclusion/exclusion criteria for a study should not be 
enrolled into the study. If a subject is enrolled who does not meet inclusion/exclusion 
criteria, a protocol deviation will be completed.   

 
 
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3.3 Treatments 
Identity of investigational product and comparators 
All components are commercially available. 
 
GUIDOR® barrier membranes are made of polylactic acid with a citric acid ester.  It is 
double-layered; the external layer has large rectangular perforations which face the 
overlying soft tissues and permit connective tissue infiltration, while the inner layer 
has small circular perforations which face bone and inhibit fibrous tissue ingrowth.   It 
maintains its barrier function for 6 weeks, with complete resorption occurring by 6 
months.  Available membrane dimensions include 15 mm x 20 mm, 20 mm x 28 mm, 
and 30 mm x 40 mm.  The membrane is provided in a transparent plastic tray in a 
sealed aluminium pouch.  It comes sterilized via e-beam. 
 
Bio-Gide® barrier membranes are made from non-cross-linked type I/type III porcine 
collagen.  It consists of a dense outer layer that inhibits fibrous tissue ingrowth and a 
rough, fibrous side that helps with clot stabilization and permits osteoblast cell 
attachment.  Resorption occurs over a period of 24 weeks.  Available membrane 
dimensions include 13 mm x 25 mm, 25 mm x 25 mm, and 40 mm x 50 mm.  The 
membrane is provided in transparent plastic tray in a double blister pack.  It comes 
sterilized via gamma irradiation. 
 
Lifenet Health® mineralized cortical freeze-dried particulate bone allograft has a 
particle size of 250-1000 μm.  Available quantities include 0.25 cc, 0.50 cc, 0.70 cc, 
1.20 cc, 2.50 cc.  It is sterilized via Allowash XG® technology, consisting of rigorous 
screening and assessment of donor tissues; cleaning with hypotonic solutions and 
antimicrobial reagents; decontamination, disinfection, and cleaning regimens with 
hydrogen peroxide and isopropanol alcohol solutions; and terminal sterilization with 
gamma irradiation.  The particulate material comes packaged in a sterile vial in a 
blister pack. 
 
GORE-TEX® sutures are expanded polytetrafluoroethylene nonabsorbable 
monofilament sutures.  They are available in suture sizes ranging from CV-0 to CV-
8.  They are an inert material that elicits minimal tissue reaction. 
Labeling 
All grafting materials will be labeled as follows: 
• “Reference number” 
• “Lot number” 
• “Expiration date” 
 
The reference number and lot numbers will be recorded in clinical records (source 
data) and eCRF. 
 

 
 
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Storage 
All study products must be kept in a secure place under appropriate storage 
conditions.  A description of the appropriate storage and shipment conditions are 
specified on the study product label and product information. 
3.4 Method of assigning subjects to treatment groups 
Subject numbers (subject ID) will be consecutively allocated in series at day of 
inclusion (Visit 1).  Subjects at center 1 will receive numbers starting at 101 and 
subjects at center 2 will receive numbers starting at 201.  Enrollment will continue 
until 30 subjects at each center have been allocated a subject ID.  If a subject 
discontinues, the subject number will not be reused. 
Subjects will be randomized at day of alveolar bone regeneration (Visit 3).  At Visit 2 
all study sites in all subjects are considered equivalent.  The randomization schedule 
will be generated using a validated computerized randomization system under the 
responsibility of the investigatory team.  The randomization assignment will be 
concealed via envelope until the surgical date.  Randomization will be stratified by 
center and smoking habit, i.e. each center will have 10 subjects in each group A, B 
and C, respectively with an equal number of subjects with current tobacco 
consumption per group.  Each subject will be treated according to the treatment code 
in the envelope.  The allocation will be revealed to the clinician only following flap 
elevation for the alveolar regeneration procedure. 
The randomization code envelopes will be stored at each center by designated 
research staff. 
Pre-study, concomitant and post-study treatment(s) 
Systemic corticosteroids or any other medication that would compromise post-
operative healing and/or bone healing are not allowed. 
 
After surgery, mouth rinsing with 0.12% non-alcohol chlorhexidine rinse will be 
subscribed according to local routines.  
 
Subjects will be given post-surgical instructions with regards to diet and oral hygiene. 
Oral hygiene instructions will be given to the subjects at all study visits. 
 
Other medication, which is considered necessary for the subject’s safety and well-
being, may be given at the discretion of the investigator(s). The administration of all 
medication (excluding dietary supplements) must be recorded in the appropriate 
sections of the CRF.  
 
 

 
 
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4 MEASUREMENTS OF STUDY VARIABLES AND 
DEFINITIONS OF OUTCOME VARIABLES 
4.1 Screening and demographic measurements 
The following data will be recorded via a standard CRF: 
• Date of birth 
• Height and weight (Body Mass Index) 
• Sex 
• Race 
• Relevant medical and surgical history 
• Medication 
• Oral examination  
• Local condition of alveolus and adjacent teeth 
o Periodontal disease 
o Bone loss 
o Caries 
o Mobility 
o Crown 
o Post/core 
o Endodontic treatment 
o Existing periapical radiolucency 
• Tobacco use 
• Reason for tooth extraction (if known) 
• Duration of edentulous period (if known) 
• Previous bone graft, soft tissue graft, or apical surgery 
• Opposing tooth contact in maximum intercuspation 
4.2 Efficacy 
Primary outcome variable 
4.2.1.1 Dimensional osseous changes 
The amount of horizontal and vertical bone changes will be calculated using data 
from DICOM images acquired by CBCT using 3D software. 
4.2.1.1.1 Methods of assessment 
CBCT images will be obtained at baseline (Visit 2) and 6 months 
following alveolar ridge augmentation (Visit 7).  Using ITK-Snap 3D 
analysis software, the CBCT images will be aligned via superimposition 
of adjacent tooth structures to permit evaluation of bone changes within 
the bound edentulous space.  One masked analyst will complete the 
evaluations. 
 

 
 
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4.2.1.1.2 Derivation or calculation of variable 
The mid-alveolar point positioned on a tangent drawn from the mesial 
and distal adjacent tooth CEJs will be used as a reference point for 
assessment of dimensional bone changes in the Z-axis (bone width) 
and Y-axis (bone height).  The changes in the bone dimensions 
between baseline (Visit 2) and 6 months (Visit 7) will be measured.  
The change for each study site will be compared longitudinally and the 
average for each treatment group will be calculated and compared 
among treatment groups. 
Secondary outcome variables 
4.2.1.2 Inflammation 
The presence or absence of soft tissue inflammation in the area of ridge 
augmentation will be visually assessed. 
4.2.1.2.1 Methods of assessment 
Soft tissue erythema within 3 mm from the crestal incision in the 
edentulous site will be visually assessed at post-operative evaluations 
(Visits 4-6). 
4.2.1.2.2 Derivation or calculation of variable 
Erythema will be marked as either present or absent according to the 
clinician’s judgment.  The percentage of sites with or without 
inflammation will be calculated for each treatment group and compared 
longitudinally.   
4.2.1.3 Infection 
The presence or absence of infection in the area of ridge augmentation will be 
assessed through visual evaluation and palpation. 
4.2.1.3.1 Methods of assessment 
Infection will be assessed at post-operative evaluations (Visits 4-6).  
The presence of suppuration from the crestal incision or soft tissues 
adjacent to the localized ridge augmentation will be assessed through 
visual evaluation.  Fluctuance in the area of the augmentation will be 
assessed through gentle palpation of the surgical site.  (Visits 4-6). 
4.2.1.3.2 Derivation or calculation of variable 
Infection will be marked as either present or absent according to the 
clinician’s judgment.  The percentage of sites with or without infection 
will be calculated for each treatment group and compared 
longitudinally.   
4.2.1.4 Soft tissue complications 
The presence of soft tissue complications, including wound exposure or soft tissue 
dehiscence, will be visually assessed. 
 
 

 
 
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4.2.1.4.1 Methods of assessment 
At each post-operative evaluation (Visits 4-6), the presence of 
membrane exposure or soft tissue dehiscence will be visually 
assessed. 
4.2.1.4.2 Derivation or calculation of variable 
Membrane exposure or soft tissue dehiscence will be marked as either 
present or absent according to the clinician’s judgment.   
4.3 Patient reported outcomes 
Not applicable 
4.4 Health economic measurements and variables 
Not applicable 
4.5 Pharmacokinetics 
Not applicable 
4.6 Safety measurements and variables 
The methods for collecting safety data are described below. 
Adverse Events 
4.6.1.1 Definitions 
The definitions of AEs, ADEs and Serious Adverse Events (SAEs) are given below.  
It is of the utmost importance that all staff involved in the study are familiar with the 
content of this section.  The principal investigator is responsible for ensuring this. 
Adverse Event 
An AE includes any unfavorable and unintended sign, symptom, syndrome or illness 
that develops or worsens during the period of observation in the clinical study.  For 
the purposes of this study, adverse events which are considered related to the GBR 
procedure or related to the GUIDOR membrane will be reported.  Adverse events 
which are not related (temporal relationship of the onset of the event, relative to the 
use/administration of the medical device, is not reasonable or another cause can 
itself explain the occurrence of the event) will not be required to be reported.   
 
For the purposes of this protocol, the following occurrences are considered to be 
expected observations following guided bone regeneration procedure and will not be 
captured as additional complications or device related adverse events: 
• Post-operative nausea determined to be procedure related or due to 
reactions to pain medication 
• Post-operative transient headache or pain responding to standard 
medications 
• Post-operative pain related to procedure within 7 days  
• Post-operative swelling related to the procedure and determined not to be 

 
 
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associated with infection within 7 days of procedure.   
 
Adverse Device Effect 
An ADE is any untoward and unintended response to a medical device.  This 
definition includes any event resulting from insufficiencies or inadequacies in the 
instructions for use of the medical device or any event that is a result of a user error.  
This definition also includes treatment- or procedure-related events. ADEs can only 
occur from the time of medical device use/administration.  Here the event is related 
to the use of the medical device where there is a probable/definite relationship that 
the event may have been caused by the medical device, or treatment.  
• Probably related: temporal relationship of the onset of the event, relative to 
the use/administration of the medical device, is reasonable and the event is 
more likely explained by the medical device/treatment than by any other 
cause.  
• Definitely related: temporal relationship of the onset of the event, relative to 
the use/administration of the medical device, is reasonable and there is no 
other cause to explain the event. 
Serious Adverse Event 
A SAE is an AE/ADE occurring during any study phase of the medical device that 
fulfills one or more of the following criteria: 
• Results in death 
• Is immediately life-threatening 
• Requires in-subject hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Is a congenital abnormality or birth defect 
• Is an important medical event that may jeopardize the subject or may require 
medical intervention to prevent one of the outcomes listed above 
 
For the purposes of this study, all Serious Adverse Events will be reported.   
 
4.6.1.2 Recording of Adverse Events and Adverse Device Effects 
At each visit, the subject will be asked an open question; "Have you had any health 
problems since the previous visit?"  
 
All health problems, reported by the subject or found at the clinic visit, where the 
investigator believes the event to be related to the investigational medical device or 
treatment, must be recorded in the CRF as AEs, specifying time of onset, action 
taken, outcome and whether it constitutes a SAE or not.   
 
Should a pregnancy occur, it must be reported in accordance with the procedures 
described in Section 9.2, Pregnancy.  Pregnancy in itself is not regarded as an AE 
unless there is a suspicion that a medical device under study may have interfered 
with the effectiveness of a contraceptive medication. 

 
 
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4.6.1.3 Reporting of Serious Adverse Events 
Timelines for reporting of SAEs 
Investigators and other study site personnel should inform the IRB of serious 
adverse events per the IRB reporting requirements.  It is recommended that serious 
adverse event be entered into the eCRF within 24 hours upon awareness of the 
event.    
 
4.7 Protocol Deviations 
The investigator should avoid deviating from the protocol.  All deviations related to 
clinical investigation inclusion or exclusion criteria, conduct of the investigation, 
patient management, or patient assessment are to be documented on the eCRF 
provided for that purpose.  Notification to the IRB should be documented and 
maintained in the clinical investigation file (as required). 
 
4.8 Genetics 
Not applicable 
 
 

 
 
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5 DATA MANAGEMENT 
5.1 Data handling 
Paper case report forms will be utilized for the study. The CRF will be completed for 
each included patient.  The completed CRFs will not be made available in any form 
to third parties. The data will be reviewed by the monitor or designee and queries will 
be issued.   The study site personnel are required to resolve any such queries.   
 
At the end of the study, the monitor will perform final validation checks, after which 
Clean File will be declared.  
5.2 Record retention 
To enable evaluations and/or audits the investigator agrees to keep records in the 
Investigator’s Study File (ISF), including the identification list of the participating 
patients, all original signed Informed Consent forms, and detailed records of medical 
device disposition.  The investigator will maintain complete, accurate and current 
study records during the study and for 10 years after the later of the date on which 
the study is terminated or completed, or the date the records are no longer required. 

 
 
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6 STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE 
6.1 Statistical evaluation – general aspects 
A comprehensive Statistical Analysis Plan (SAP) may be prepared before database 
lock. When using the terminology descriptive statistics it means that number of 
patients, mean, median, standard deviation, minimum and maximum values will be 
presented for continuous data and frequencies and percentages for categorical data. 
 
If nothing else is stated, descriptive statistics will be given for each variable in the 
study and p-values may be complemented by confidence intervals as appropriate. 
All p-values presented will be two-sided. A p-value less than 5% will be called 
“statistically significant” but all conclusions will be based on the primary objective and 
hence multiplicity is accounted for even though careful interpretations are necessary 
as multiple tests are performed. 
 
Analysis populations are defined as follows: 
• The Intent-to-Treat (ITT) population includes all enrolled subjects who 
underwent guided bone regeneration procedure. 
• The Per-Protocol (PP) population includes all enrolled subjects who had 
successful guided bone regeneration procedure and no major protocol 
deviations (defined as inclusion/exclusion or informed consent violations.) 
The ITT population will be the primary analysis population for all endpoints. Analyses 
on the PP population will be supportive of the ITT analyses. 
 
Demographics and other baseline characteristics 
Demographics and other baseline characteristics will be presented by means of 
descriptive statistics (by group and in total).  Continuous variables will be presented 
by means of number of observations (N), minimum (min), median, maximum (max), 
mean, and standard deviation (std).  Discrete variables will be presented by 
frequency and percentage. 
Covariates and prognostic variables 
No covariates are judged to influence the outcome of the primary or any of the 
secondary variables. 
Handling of dropouts and missing data 
Patients dropping out from the trial prior to study end will not be replaced.  Data 
totally missing will not be estimated. 
Multicenter 
This study is a multicenter study. However, there is not a priori reason to suspect 
that there will be any qualitative differences between the centers regarding any of the 
efficacy variables nor regarding the safety variables. Therefore, the primary 
statistical analyses will not include center in the model. 

 
 
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In order to harmonize the use and handling of the graft materials, training will be 
conducted prior to study start at each center. 
Subgroup analyses 
No subgroup analyses are planned. 
6.2  Method of statistical analysis 
Primary objective 
The primary objective is to compare dimensional bone changes from baseline (Visit 
2) to six months (Visit 7) occurring in a single bound edentulous space following 
alveolar bone regeneration using three different techniques.  
 
Assume the change (in the mid-buccal horizontal bone dimensions from baseline to 
six months) is denoted CA, CB and CC, for group A, B and C, respectively. The null-
hypotheses (two) is then to test if: 
H0 CA = Ci (i = B and C, respectively)  
can be rejected and hence 
H1 CA ≠ Ci (i = B and C, respectively)  
accepted. 
  
H0 will be tested by means of the Wilcoxon rank sum test. A p-value less than 5% 
will be regarded statistically significant. 
Secondary objectives 
Secondary objectives of the study are to evaluate and compare clinical healing 
parameters between different grafting techniques (i.e. to compare between groups A, 
B, and C): 
• Inflammation by assessing the presence or absence of soft tissue erythema 
within 3 mm from the crestal incision at 1 week, 2 weeks, 4 weeks, and 6 
months following bone augmentation.  The chi-squared analysis will be used. 
• Infection by determining the presence or absence of suppuration or soft tissue 
fluctuance at 1 week, 2 weeks, 4 weeks, and 6 months following bone 
augmentation.  The chi-squared analysis will be used. 
• Soft tissue complications by determining the presence or absence of 
membrane exposure or soft tissue dehiscence at 1 week, 2 weeks, 4 weeks, 
and 6 months following bone augmentation.  The chi-squared analysis will be 
used. 
6.3 Determination of sample size 
A sample size of 20 participants per treatment group was selected following power 
calculations and allowing for 10% patient dropout.  A sample size of 18 patients was 
calculated for the primary outcome variable (horizontal bone changes) with the 
assumption that the detectable difference would amount to 0.5 mm with a standard 
deviation of 0.5.  The type I error probability was set at 0.05 and the statistical power 
was set at 80%. 

 
 
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6.4 Statistical analyses during the course of the study 
The primary and secondary objectives will be analyzed when all data from the 6 
month follow-up visit has been collected, entered, verified, and validated (partial 
clean file).  
 
 

 
 
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7 STUDY MANAGEMENT 
7.1 Monitoring 
A monitoring plan will be developed prior to the initiation of the investigation which 
outlines the extent and nature of monitoring appropriate for the clinical study, 
including the frequency of visits, the strategy for source data verification, based on 
considerations such as the objective, design, complexity, size, critical data points 
and endpoints of the clinical study.   
 
Data will be verified to source during the monitoring process.  The Contract 
Research Organization (CRO), NAMSA will be responsible for monitoring this clinical 
investigation.   
 
Before first subject into the study, a representative from the CRO will visit the 
investigational study site to: 
• Determine the adequacy of the facilities 
• Discuss with the investigator(s) (and other personnel involved with the study) 
their responsibilities with regard to protocol adherence, and the 
responsibilities of the CRO.   
 
During the study, a monitor from the CRO will have regular contact with the study 
site, including visits to: 
• Provide information and support to the investigator(s) 
• Confirm that facilities remain acceptable 
• Confirm the study team is adhering to the protocol and that data are being 
accurately recorded in the eCRFs. 
• Perform source data verification (a comparison of the data in the eCRFs with 
the subject’s medical records at the hospital or practice, and other records 
relevant to the study).  This will require direct access to all original records for 
each subject (e.g., clinic charts). 
 
The monitor will be available between visits if the investigator(s) or other staff at the 
center need information and advice.   
7.2 Audits and inspections 
Authorized representatives of the CRO or IRB may visit the center to perform audits 
or inspections, including source data verification.  The purpose of a CRO audit or 
inspection is to systematically and independently examine all study-related activities 
and documents to determine whether these activities were conducted, and data were 
recorded, analyzed, and accurately reported according to the protocol, applicable 
Good Clinical Practice (GCP), and 21 CFR Part 50.    
 

 
 
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7.3 Training of staff 
The principal investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff).  He or she will ensure that appropriate training 
relevant to the study is given to all of these staff, and that any new information of 
relevance to the performance of this study is forwarded to the staff involved.  New 
study staff will not perform any study related activities until formal approval from the 
Principal investigator.  
7.4 Changes to the protocol 
If it is necessary for the study protocol to be amended, the amendment and/or a new 
version of the study protocol (Amended Protocol) must be notified to or approved by 
each IRB. 
 
If a protocol amendment requires a change to a particular center’s Informed Consent 
Form, the center’s IRB must be notified. Approval of the revised Informed Consent 
Form by the IRB is required before the revised form is used.   
 
The sponsor will distribute administrative changes, amendments and new versions of 
the protocol to each principal investigator. 
7.5 Study timetable 
Before a subject's enrollment in the study and any study-related procedures are 
undertaken the following should be fulfilled: 
• Signed Clinical Study Protocol and other agreements  
• Approval of the study, investigator, Informed Consent and HIPAA form by the 
IRB as required 
• Collection of study required documents  
 
8 ETHICS 
8.1 Ethics review 
The final study protocol, including the final version of the Informed Consent Form, 
must be approved or given a favorable opinion in writing by the IRB as appropriate.  
The investigator must not enroll any subjects into the study until formal written 
approval is given by the CRO. 
 
The Principal Investigator is responsible for informing the IRB of any amendment to 
the protocol in accordance with local requirements.  In addition, the IRB must 
approve all advertising used to recruit subjects for the study. 
 
Progress reports and notifications of SAEs (and ADEs) will be provided to the IRB 
according to local regulations and guidelines. 

 
 
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8.2 Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their 
origin in the Declaration of Helsinki 2008, Good Clinical Practice (GCP), 21 CFR Part 
50 and local IRB requirements.     
8.3 Informed consent 
The investigator(s) at each center will ensure that the subject is given full and 
adequate oral and written information about the nature, purpose, possible risk and 
benefit of the study.  Informed consent process will be conducted in accordance with 
Declaration of Helsinki 2008 and 21 CFR Part 50.  Subjects must also be notified 
that they are free to discontinue from the study at any time.  The subject should be 
given the opportunity to ask questions and allowed time to consider the information 
provided. 
 
The subject’s signed and dated informed consent must be obtained before 
conducting any procedure specifically for the study.  The investigator(s) must store 
the original, signed Informed Consent Form in the subject’s medical record.  A copy 
of the signed Informed Consent Form must be given to the subject. 
8.4 Subject data protection 
The Informed Consent Form will incorporate (or, in some cases, be accompanied by 
a separate document incorporating) wording that complies with relevant data 
protection and privacy legislation.  Pursuant to this wording, subjects will authorize 
the collection, use and disclosure of their study data by the Investigator and by those 
persons who need that information for the purposes of the study. 
 
The Informed Consent Form will explain that study data will be stored in a computer 
database, maintaining confidentiality in accordance with national data legislation. All 
data will be identified by subject ID, study code and initials. 
 
The Informed Consent Form will also explain that for data verification purposes, the 
CRO may require direct access to parts of the hospital or practice records relevant to 
the study, including subjects’ medical history. 
 
 

 
 
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9 PROCEDURES IN CASE OF EMERGENCY 
9.1 Medical emergency 
In the case of a medical emergency you may contact a representative from the study 
team.   
 
Role in the study 
Name 
Address & telephone number 
Principal Investigators 
Lyndon Cooper, DDS, 
PhD 
 
 
 
 
 
Homayoun H. Zadeh, 
D.D.S., Ph.D.  
 
UNC School of Dentistry 
4610 Koury Oral Health Sciences 
Buildling 
CB #7450 
Chapel Hill, NC  27599-7450 
Tel: (919) 537-3175 
 
University of Southern California  
Ostrow School of Dentistry  
925 34th Street Room 4278  
Los Angeles, CA 90089-0641  
Tel: (213)-740-1415 
  
NAMSA- Medical Research 
Organization monitoring 
Nicole Feist, Sr. Medical 
Research Manager  
NAMSA 
4050 Olson Memorial Hwy, Suite 
450, Minneapolis, MN 55422 
Tel: (612) 787-5386 
Fax: (763) 287-3836 
9.2 Pregnancy 
Many physiologic changes can be observed in the pregnant patient and should be 
considered when planning dental treatment. It has been suggested to avoid elective 
dental procedures in the 1st and 3rd trimesters due to risk of spontaneous abortions, 
pre-term births, increased patient discomfort, and increased likelihood of 
intraoperative complications (14).  The ultimate goal in dental therapy during 
pregnancy should be to educate the patient on the importance of oral hygiene and 
plaque control, perform periodontal maintenance therapy and treat emergency 
situations.   
 
Pregnancy itself is not regarded as an AE/ADE unless there is a suspicion that the 
medical device under study may have interfered with the effectiveness of a 
contraceptive medication.  
 
Congenital abnormalities/birth defects and spontaneous miscarriages should be 
reported as SAEs.  Elective abortions without complications should not be handled 
as AEs/ADEs. 
 
 

 
 
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4.  Gottlow J. Guided tissue regeneration using bioresorbable and non-resorbable 
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Ability of commercial demineralized freeze-dried bone allograft to induce new 
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7.  Jensen SS, Terheyden H. Bone augmentation procedures in localized defects in 
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8.  Donos N, Mardas N, Chadha V. Clinical outcomes of implants following lateral 
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9.  Hammerle CHF, Araujo MG, Simion M. (2012). Evidence-based knowledge on 
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10.Schropp, L., Wenzel, A., Kostopoulos, L. & Karring, T. (2003). Bone healing and 
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