A Prospective Study of Bone Augmentation Techniques in Extraction Sockets and Implant Surface Textures
Phase: NA
Conditions: Unrestorable Dentition, Post-Extraction Sockets
Sponsor: University of Alabama at Birmingham

A Prospective Study of Bone Augmentation in Extraction Sockets 
and Implant Surface Textures. 
 
 
Study Protocol & Statistical Analysis Plan 
 
 
NCT00641316 
 
September 17, 2021 
 
 
Nicolaas C. Geurs, DDS, MS, Principal Investigator 
 
University of Alabama at Birmingham 
Birmingham, Al 35294 
 

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Study Synopsis 
 
Study Title 
 
A Prospective Study of Bone Augmentation in Extraction Sockets and Implant 
Surface Textures. 
 
 
 
Rationale 
 
 
Tooth extraction is often associated with resorption of alveolar ridge height and width and 
with compromised soft tissue contours. An increasingly common periodontal practice 
combines skilled surgical technique with extraction site grafting. These procedures are 
thought to retard resorption of the socket volume while lending some control over bone-fill 
– thereby preserving the integrity of the alveolar ridge for future reconstruction with dental 
implants. 
 
While limited evidence-based data exist to support this premise, conflicting data suggest 
that the grafting materials may, in fact, impede natural post-extraction healing.  
 
In addition, the prevailing recommendation to allow grafted bone to heal for four to six 
months before contemplating reconstruction with dental implants is also under scrutiny and 
is cause for debate. Clearly, additional investigation is warranted. 
 
In an effort to establish clinical evidence this randomized-controlled clinical trial will 
assess and compare the efficacy of three different bone grafting applications After two 
months results will be compared to a control group where sites that have been allowed to 
heal without grafting intervention. 
 
The study will then assess the efficacy of early reconstruction with two-piece dental 
implants. We will evaluate the effects of two implant collar surface topographies on the 
longitudinal maintenance of peri-implant osseous and soft-tissue health. Follow-up 
evaluations will be completed at 12 and 24 months after placement of the implants. 
 
 
 
Objectives 
 
 
To evaluate hard and soft tissue healing of grafted and non-grafted extraction sockets in the 
aesthetic zone.  
 
To evaluate longitudinal clinical outcome of dental implants with differing collar surfaces 
implanted in sites 8 weeks after tooth extraction. 
 
 
 
Hypotheses 
 
 
Hypothesis I 
Bone grafted sites preserve alveolar ridge dimensions of extraction sockets more 
effectively than extraction sites that have healed without grafting. 
 
Hypothesis II 
The addition of growth factors to bone grafting materials will enhance osseous and soft-
tissue healing. 
 
Hypothesis III 
Laser Thread Textured (LTT) dental implant will preserve longitudinal peri-implant crestal 
bone more effectively that implants with a Resorbable Blast Textured (RBT) surface.  
 

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Randomization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participants will be stratified for smoking status and randomized to one of four extraction 
protocol groups and one of two implant groups:  
 
Extraction Groups: 
             Group 1. Atraumatic extractions followed by saline irrigation and natural healing 
             [Control] 
          
  
Group 2. Atraumatic extractions followed by Freeze-Dried Bone Allograft (FDBA) 
 
Tri-Calcium Phospate (TCP) + collaplug 
  
           Group 3. Atraumatic extractions followed by FDBA/TCP/Platelet-Rich Plasma 
 
(PRP) +collaplug 
  
 
            Group 4. Atraumatic extractions followed by FDBA/TCP/Platelet-Derived Growth 
 
Factors (PDGF) + collaplug 
 
A secondary randomization will be conducted to select one tooth site per subject to receive 
trephine sampling for histology evaluation. 
 
Implant Groups: 
                      Group-A. LTT collar surface topography 
 
                      Group-B. RBT collar surface topography 
 
 
Procedures 
 
Extractions 
Atraumatic extractions and graft/no-graft procedures will be completed following the 
randomization table and standardized surgical procedures. Three-dimensional images, 
acquired through Cone-Beam CAT-Scan (CBCT), will be captured immediately post-
extraction. Prophylactic antibiotics will be dispensed, prescriptions for post-surgery 
antibiotics and analgesics (prn) will be written. Antibacterial mouth wash will be 
dispensed; written and verbal patient home-care instructions will be provided 
 
To preserve anterior aesthetics, during the healing phase, an Essix retainer will be made for 
each participant and inserted immediately after the extractions/grafting procedures. 
 
Follow-up evaluations 
Performed at week-1, week-2 and week-4, will include: 
Assessment of adverse experiences 
Measurement of clinical parameters 
             Clinical photographs  
             Suture removal at week 2 
 
Implant Placement 
A clinical evaluation and surgical  placement of implants completed at week-8 – to include:  
 
CBCT scan  
 
Prophylactic antibiotics dispensed 
             Pre-surgical oral rinse  
             Measurement of clinical parameters 
 

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Clinical photographs               
             One bone-fill specimen per patient, harvested by trephine (placed in fixative for    
 
later histological analysis)  
 
             Surgeon’s subjective observation of osseous fill quality (D-1-D-4) 
             Randomized insertion of one, two-piece, dental implant per study site 
 
Immediate post-surgical intra-oral radiographs 
             Prescriptions for post-surgery antibiotics and analgesics (prn) 
             Antibacterial mouth wash and ice-packs dispensed 
             Written and verbal home-care instructions  
 
Post- Insertion Follow-up 
Implant surgical follow-up assessment and suture removal will be performed after two-
weeks. 
 
Implants Uncovered 
Mandibular implants will be uncovered after approximately 4 months; maxillary implants 
will be uncovered after approximately 6 months. 
 
Implant Restoration 
Implants will be restored in the conventional manner with aesthetically pleasing cemented 
single crown restorations. 
  
Longitudinal Follow-up 
Two annual follow-up evaluations will be completed at 12 months and 24 months after 
surgical implant placement. Each assessment will include: 
             
             Standardized intra-oral periapical dental radiographs  
  
Clinical photographs  
             Measurement of clinical parameters  
             Assessment of soft-tissue contours 
 
Assessment of overall aesthetics 
  
Assessment of implant/restoration interface 
 
Patient satisfaction survey 
 
 
 
Population 
 
 
 
 
Eighty healthy adult patients (20 in each extraction group) of any ethnicity or gender 
whose treatment plan includes extraction of mandibular and/or maxillary pre-molars and/or 
maxillary anterior teeth and their replacement with root-form dental implants will be 
consecutively recruited for enrollment in the study.  
 
Only treatment of non-adjacent sites will be included in the database. Each participant may 
have up to four non-adjacent sites selected for inclusion as study treatment sites. 
 
Participants must be 19 years old or older with demonstrated ability to understand the 
proposed treatment recommendations and prognosis and be able to provide informed 
consent, in English, without the aid of ad hoc translation.  
 
 
 

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Participants with a reported history of a previous malignant neoplasm, a known 
hypersensitivity to β-TCP or rhPDGF-BB, a Titanium metal allergy, or any other health 
condition or medication regimen that, in the opinion of the investigators, may adversely 
affect bone healing will be excluded.  
Women who are pregnant or nursing at the time of recruiting will be excluded. 
 
 
Outcomes 
 
Radiographic image analysis of osseous architecture changes at study sites over time 
 
Soft-Tissue aesthetic assessments 
 
Patient Satisfaction assessments 
 
Data analysis – results and conclusions 
 
Final report  
 
 
Statistical 
Analyses 
 
 
 
The general approach to statistical analysis of the study aims will be based on mixed-
model analysis of variance (ANOVA). This approach will accommodate the inclusion of 
correlated observations due to study subjects potentially contributing measurements of 
more than one single tooth site to the analysis. 
 
The sample distributions will be examined for each outcome variable. If these distributions 
depart substantially from normality, transformations of the data will be evaluated. If 
normality cannot be established by transformation, rank-based analyses will be used. 
 
Subjects will be included as a random effect on the analyses that include multiple 
observations per subject. For analysis of histological data, only one tooth site per subject 
will be evaluated and the model will not include a random effect.  
 
Smoking status will be included in all models so that the analysis will correspond to the 
study’s randomization strategy.   
   
For the aims in which interaction terms are of interest, significant interaction terms will be 
investigated using plots of least-square means and separate post-hoc analyses for individual 
time points. 
 
 
 

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Table of Contents 
 
Section 
      Title 
Page 
 
1: 
 
Background and Significance 
 
6 
 
2: 
 
Investigational  Design 
 
9 
 
3: 
 
Study Population 
 
10 
 
4: 
 
Study Procedures 
 
11 
 
5: 
 
Tissue Biopsy & Surgical Implant Placement 
 
15 
 
6: 
 
Restoration of Implants 
 
17 
 
7: 
 
Longitudinal Follow-up Protocol 
 
17 
 
8: 
 
Radiographic & Photographic Surveys 
 
18 
 
9: 
 
Adverse Event Reporting  
 
19 
 
10: 
 
Criteria for Success  
 
19 
 
11: 
 
Costs to Participants 
 
20 
 
12: 
 
Outcomes and Analyses  
 
21 
 
13: 
 
Confidentiality 
 
25 
 
14: 
 
Regulatory Issues 
 
26 
 
15: 
 
Ethical Issues 
 
27 
 
16: 
 
Literature Cited 
 
28 
 
17 
 
Study Personnel 
 
31 
 
18 
 
Signature Page 
 
32 
Appendices 
A: 
FDA 510(k) Device Approval  
 
B 
Safety and Effectiveness – GEM-21S™ 
 
C: 
Informed Consent    
 
D: 
The Belmont Report 
 
E: 
Manual of Procedures 
 
 
 
 

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1.0 BACKGROUND AND SIGNIFICANCE 
 
1.1 Tooth Extraction Socket Preservation  
Tooth extraction is often associated with resorption of alveolar ridge height and width and with 
compromised soft tissue contours1-8. An increasingly common periodontal practice combines skilled 
surgical technique with extraction site grafting. These procedures are thought to retard resorption of 
the socket volume while lending some control over bone-fill – thereby preserving the integrity of the 
alveolar ridge for future reconstruction with dental implants. 
.   
Limited evidence-based data exists to support a variety of bone grafting materials used to prevent the 
resorption of bone in the extraction socket. Autografts, allografts, xenografts and alloplasts are all 
considered viable options to maintain and regenerate the site1- 6, 8.  
 
Artzi et al.4 evaluated the histology and histomorphometric analyses of 15 extraction sockets in 15 
patients treated with cancellous porous bovine bone mineral. All procedures involved extraction 
sockets of anterior teeth and premolars; primary closure of the extraction sockets was achieved with a 
pediculated split palatal flap. The bone fill of the extraction sockets was 82.3% lamellar type bone, 
located in the apical portion of the sockets, and the woven type of bone found in the coronal part of the 
sockets. The investigators concluded that the cancellous porous bovine bone mineral was present 9 
months after the procedure and that resorbability of the bone graft material needed further assessment. 
In a second phase of the same study, Artzi et al.5, investigated the grafted extraction sockets by means 
of histochemical analysis and demonstrated the biocompatibility of the cancellous bovine bone 
mineral. 
 
In another study, Froum et al.6 grafted 30 extraction sockets and divided them into three different 
groups. Bioactive glass and demineralized freeze-dried bone allograft (DFDBA) were used in the two 
test groups;the control group received no material at all. Flaps were coronally positioned to achieve 
closure of the site by primary intention. The bioactive glass group exhibited 59.5% of vital bone 
outperforming the DFDBA and non-grafted extraction socket groups that presented 34.7% vital bone 
formation 6 to 8 months following the surgical procedure. The difference in vital bone was not 
considered statistically significant among the three groups. 
  
Data from these studies support the potential of different bone grafting materials to preserve the 
alveolar ridge after extraction. Concomitant investigations, however have reported that grafting 
materials may, in fact, impede natural post-extraction healing7. Thus the most efficacious intervention 
remains clouded by uncertainty. 
 
1.2 Platelet Rich Plasma 
The addition of platelet rich plasma (PRP) to graft materials is gaining clinical acceptance as an added 
stimulus to wound healing in both osseous and soft tissues. PRP, an autologous concentration of 
human platelets in a small volume of plasma, consists of growth factors derived from platelets 
degranulation and cell adhesion proteins such as fibronectin, vitronectin and fibrin. The mechanism of 
action is based on the activation of transmembrane receptors of adult mesenchymal stem cells, 
osteoblasts, fibroblasts, endothelial cells, and epidermal cell lines by the growth factors. 
 
 

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The results from twenty patients who underwent tooth extractions because of root fracture of 
periodontitis are reported by Anitua et al.9 One group received PRP; in five of the ten patients in this 
group PRP was mixed with autologous bone to prevent tissue collapse. The remaining ten patients 
were left untreated and served as controls. The epithelialization in all of the cases treated with PRP was 
complete and significantly better than in areas treated without PRP. Osseous regeneration of mature 
bone was greater in quantity and quality in the PRP sites. Some limitations of this study include the 
absence of statistical analysis and the utilization of bone grafts in five out of ten experimental PRP 
sites that might have contributed to the favorable results as well as the subjective evaluation of soft-
tissue healing. More recent evidence to support supplementing bone grafts with PRP was published by 
Marx in 2004 10. 
 
Despite its clinical acceptance, the scientific evidence for the use of PRP is based on promising case 
series and case reports. There is little data available to indicate an evidence-based advantage of 
grafting plus PRP compared to grafting alone. 
 
1.3 Recombinant Human Platelet Derived Growth Factors 
Recently, a combination of purified recombinant human platelet derived growth factors (rhPDGF-BB) 
with a beta tricalcium phosphate bone substitute [β-tcp] has been approved to aid periodontal wound 
healing. PDGF stimulates the mitosis of alveolar and periodontal ligament cells and β-tcp acts as the 
delivery vehicle that releases the growth factors over time to promote periodontal regeneration11. 
 
As one of 11 centers, our group12 studied PDGF versus a β-tcp control in a prospective, randomized, 
double-blind, controlled human clinical trial conducted in 180 subjects. All subjects exhibited existing 
periodontal defects and were treated with the same surgical method. The two different experimental 
groups included TCP with 0.3 mg/ml of rhPDGF-BB, TCP with 1.0mg/ml; TCP carrier alone served as 
the control. Radiographic evaluation was performed 6 months after the surgical procedure and 
involved measurement of the linear bone growth in mm. The two test groups presented superior linear 
growth reaching to 57% and 34% bone fill compared to the control bone fill of 18%. Soft tissue 
healing was better in the rhPDGF-BB groups and particularly the low dose rhPDGF-BB group. We 
concluded that “the efficacy observed in an infected and inflamed site may indicate the potential of this 
regenerative modality in other bony/soft tissue wound healing applications”. 
 
1.4 Reconstruction with Dental Implants 
Dental implants have been used in dentistry for decades in an attempt to reestablish function and 
aesthetics to areas of the mouth where natural dentition is lost 13, 14. Materials and designs of dental 
implants 15, 16, 17 have evolved over the years to arrive at the optimal combination of materials, shape 
and surface texture that would induce permanence to the restoration.  
 
1.5  Innovative Implant Design Features  
Among the many innovations, implant surface topography has materialized as the focus of recent 
investigations, resulting in a body of evidence lending support to the premise that surface texturing 
influences osseointegration and has a positive affect on soft tissue adaptation to the implants. 
  
Microtextured implant surfaces are thought to increase bone formation via the enhancement of 
osteogenesis, osteoconduction and osteoinduction processes18. Investigators, Buser et al19, in a mini-
pig model, demonstrated that a modified titanium implant surface resulted in similar bone-to-implant 

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contact to hydroxyapatite surface and Wennerberg et al 20 ,21, 22, 23, utilizing different particle size TiO2 
or Al2O3, enhanced the bone formation at the implant surface in the rabbit model. 
 
Further investigations of implant surface characteristics by Hanson and Norton24 showed the 
development of pits on the implant surface. These investigators described hemispheric pits of 1 to 5μm 
in diameter and 1 to 5 μm in depth. The establishment of these pits is believed to increase the 
biomechanical interlock of implants with bone and make implant-bone interface more resistant to the 
forces of shear. 
 
Other studies have shown that the modified implant surface topography alters the soft tissue- implant 
interface on the cellular level. The implant roughness inhibited the attachment and growth of epithelial 
cells while enhancing the growth of fibroblasts 25, 26, 27. Implant microtextured surfaces increased 
bacterial colonization around implants without compromising the surrounding soft tissue health 28.   
 
Based on this evidence, innovative microtexturing of the implant surface appears to enhance tissue 
integration and to promote epithelial attachment to the implant. 
 
1.6 Resorbable Blast Texturing 
The bone response to resorbable blast textured (RBT) implant surfaces have been studied in New 
Zealand male rabbits29. Twenty-four RBT implants were tested against a control group of twenty-four 
machined commercially pure titanium implants. All the implants were inserted into the femoral knee 
joint of the rabbits. The RBT implants were characterized by the plethora of osteoblastic cells residing 
in direct contact with the implant surface. Osteoid matrix was directly deposited on the RBT implant 
surface. 
 
Another investigation by Novaes’ group 30 evaluated the bone-implant interface of four different types 
of implant surfaces, including machined titanium, plasma spraying, hydroxyapatite coating and 
resorbable blast texturing. The RBT implant surfaces exhibited a statistically significant more bone-
implant contact over the machined titanium implant surfaces. 
 
 1.7 Laser MicroTextured Surface 
The laser thread-textured implant surface (LTT) has been recently introduced to dentistry.  Little 
evidence-based data is currently available; one report suggests that the LTT surface developed a 
stronger bond and demonstrated more resistance to tensile forces 31. Another study, utilizing a canine 
model, showed evidence that the laser modified surface was associated with extensive osseointegration 
via a high strength biomechanical interlock, less formation of fibrous tissue32.  
 
1.8 A Rigorous Test 
Innovative implant design features coupled with novel surgical technique are challenging prevailing 
concepts of therapy. The dual issues: adequate, healthy, osseous tissue and the design (surface 
texturing) of implant devices thus remain central to the long-term success of dental implant therapy.  
 
 In an effort to establish further clinical evidence the current study will assess and compare the efficacy 
of three randomly assigned different bone grafting applications, including a PRP enriched material, in 
non-adjacent aesthetic zone extraction sockets. Sites that have healed without augmentation will serve 
as controls.  

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The study will also assess and compare the efficacy of early reconstruction with two-stage dental 
implant restorations and evaluate the effects of an innovative implant collar surface topography on the 
longitudinal maintenance of peri-implant osseous and soft-tissue. 
 
Early reconstruction with implants placed in newly formed regenerated bone may be more prone to 
crestal resorption regardless of implant design. Placing implants with differing surface topographies 
into augmented bone may therefore, represent the most rigorous test of potential bone-preserving 
implant design. 
 
2.0 INVESTIGATIONAL DESIGN 
 
2.1 Study Design 
This prospective, randomized-controlled clinical trial will test three hypotheses. One, bone grafting is 
an efficacious method of enhancing the development of new bone fill in extraction sockets; two, 
adding growth factors to grafting materials will aid osseous healing and help to preserve aesthetically 
pleasing soft tissue contours; and three, surface topography at the collar of implants will influence 
longitudinal preservation of peri-implant bone at the alveolar crest.   
 
2.2 Objectives of the Investigation 
The overall objective of this investigation is two-fold:  
1. To evaluate outcomes with respect to osseous and soft tissue healing of grafted and non-
 
grafted extraction sockets.  
 
 
2. To evaluate longitudinal stability of dental implants with differing surface topographies at 
 
the collar after placement into grafted extraction sockets and sockets that have healed naturally. 
 
2.3 Hypotheses and Specific Aims 
 
Hypothesis I 
Bone grafted sites preserve alveolar ridge dimensions of extraction sockets more effectively than 
extraction sites that have healed without grafting. 
 
Specific Aims 
1: Compare alveolar ridge dimensions in grafted extraction sockets to that of sites healed 
without grafts after 8 weeks of post-extraction healing. 
 
Hypothesis II 
The addition of growth factors to bone grafting materials will enhance osseous and soft-tissue healing. 
 
Specific Aims 
2: Assess the efficacy of bone grafting with and without enrichment with growth factors to 
preserve the volume of bone in extraction sockets. 
 
3: Compare soft tissue healing between groups at week-1, week-2, week-4 and after 8 weeks of 
post-extraction healing 
 

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4:  Assess quantitative bone fill across groups after 2 months of post-extraction healing 
 
5: Compare qualitative bone fill across groups after 2 months of post-extraction healing. 
 
6: Assess and compare the relationship of osseous healing and implant stability at insertion 
across groups after 2 months of post-extraction healing. 
 
Hypothesis III 
Laser Thread Textured (LTT) dental implant will help preserve longitudinal peri-implant crestal bone more 
effectively than implants with Resorbable Blast Texturing (RBT).  
 
Specific Aims  
7: Assess the efficacy of LTT and RBT surface topographies when surgically implanted into 
extraction sockets.  
 
8: Assess peri-implant soft-tissue healing adjacent to LTT and RBT surfaced implants. 
 
9: Assess changes in longitudinal crestal bone level across extraction groups and between 
implant groups at 12 and 24 months after surgical implant placement.  
 
3.0 STUDY POPULATION 
 
3.1 Entrance Criteria 
Eighty healthy adult patients (20 in each group) of any ethnicity or gender whose treatment plan 
includes extraction of maxillary anterior teeth and/or mandibular and/or maxillary pre-molars and their 
replacement with root-form dental implants will be consecutively recruited for enrollment in the study.  
 
The study will include an initial minimum of six time-sensitive, clinic visits over eight consecutive 
weeks.  Implants will be placed 8 weeks after extractions. Following implant placement, additional 
visits, necessary for health maintenance and implant restoration, will be scheduled at the study 
dentist’s discretion. Participants will return for two follow-up visits at 12 and 24 months after implant 
placement. 
 
Only treatment of non-adjacent sites will be included in the database. Each participant may have up to 
four non-adjacent sites selected for inclusion as study treatment sites. 
 
Participants must be at last 19 years old with demonstrated ability to understand the proposed 
treatment recommendations and prognosis and be able to provide informed consent, in English, 
without the aid of ad-hoc translation from another language. Decisionally-impaired adults and/or 
minors, who cannot consent for themselves, will not be enrolled; women who are pregnant or lactating 
at the time of enrollment will be excluded. Women will be tested for current pregnancy status. 
 
Prior to enrollment, prospective participants must agree to be available for the entire duration of the 
study, be compliant with needed study-related evaluations and demonstrate a willingness to comply 
with strict time-line requirements.  Certain health and medication exclusions apply (table 1). 
 
 

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Table 1 Entrance Criteria 
Inclusion 
Exclusion 
Existence of one or more non-adjacent teeth in the 
aesthetic zone that are scheduled for extraction  
 
Pregnancy or nursing at the time of enrollment 
 
Healthy enough to undergo the proposed therapy without 
compromise to their existing health status 
 
Previous malignant neoplasm 
Demonstrated willingness to comply fully with protocol 
time-line and procedural requirements 
 
A known hypersensitivity to β-TCP or rhPDGF-BB 
 
At least nineteen years old  
 
A known hypersensitivity to Titanium metal 
 
Able to read and understand written English without the 
aid of ad hoc interpretation 
 
Any health condition that in the opinion of the clinical 
investigators may adversely affect bone healing 
 
Able to cognitively understand the proposed study 
therapy and possible prognosis 
 
Any medication that in the opinion of the clinical 
investigators may adversely affect bone healing 
 
Able to consent for their own inclusion in the study 
 
Any indication of an inability to make autonomous 
decisions  
 
3.2 Visit Sequence 
The study will include a minimum of six time-sensitive clinic visits over eight consecutive weeks. 
Implants will be placed 8 weeks after extractions. Following implant placement, additional visits, 
necessary for health maintenance and implant restoration, will be scheduled at the study dentist’s 
discretion. Participants will return for two follow-up visits at 12 and 24 months after implant 
placement. 
 
4.0 STUDY PROCEDURES 
 
4.1 Enrollment and Treatment Planning 
After completing an individualized, private consent discussion and obtaining informed consent, a pre-
surgical assessment will be completed. Each enrolled participant will be seen for an initial evaluation 
to include assessments of medical and dental conditions that will verify compliance with entrance 
criteria and for collection of demographic data.  
 
Participants will be assigned a unique identification number. Information will be recorded on baseline 
case report forms (CRFs) developed specifically for this study. 
 
Through consultations with prosthodontic clinicians, the documented treatment plan will be reviewed 
and revised if necessary to develop a therapy that will be of most benefit to the participant.  
 
4.2  Randomization 
Participants will be stratified for smoking status and randomized to one of four extraction groups; three 
experimental groups utilizing three different bone grafting applications and a control group where 
extraction sockets will be allowed to heal naturally. A secondary randomization will be conducted to 
select one tooth site per subject to receive trephine sampling for histology evaluation. At the time of 
enrollment, each participant in groups 1-4 will be further randomized into one of two implant strata. 

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4.3 Randomized Extraction Groups 
 
           Group 1. Atraumatic extractions followed by saline irrigation and natural healing [CONTROL] 
 
                
 
 
 
Group 2. Atraumatic extractions followed by Freeze-Dried Bone Allograft (FDBA)/Tri-
 
Calcium Phosphate (TCP) + collaplug 
  
           Group 3. Atraumatic extractions followed by FDBA/TCP/Platelet-Rich Plasma (PRP) 
 
+collaplug 
  
 
            Group 4. Atraumatic extractions followed by FDBA/TCP/Platelet-Derived Growth Factors 
 
(PDGF) + collaplug 
 
4.4 Randomized Implant Groups 
Each subject will receive two-stage dental implants with the same overall design features with two 
different surface treatments at the implant collar. Subjects with multiple sites will receive the same 
implant design in all study sites.              
             
 Group-A:   Laser Thread Texturing (LTT) collar surface topography 
  Group-B:   Resorbable Blast Texturing (RBT) collar surface topography 
 
 4.5 Pre-surgical Procedures 
Oral impressions will be made and if a temporary replacement for the teeth to be extracted is required, 
a temporary Essix retainer will be fabricated. The Essix retainer, a removable prosthesis, will protect 
the healing tissue in an aesthetically pleasing manner but will not impede the clinical observation of 
study sites. Study casts may also be used to fabricate a surgical guide prior to implant surgery.   
 
4.6 Surgical Extractions 
All surgeries will be performed by qualified clinicians in an appropriately equipped surgical operatory 
located in the Periodontal Clinic at UAB School of Dentistry.  
 
Prior to extraction surgery, participants will be given a loading dose of antibiotics based on their 
medical history and concomitant medications. A suggested prophylactic regimen follows: 
 
 
2 gm of Amoxicillin 1 hour prior to the procedure followed by 500mg (TID) for 7 days 
 
Patients with reported allergy to Amoxicillin: 
 
600mg Clindamycin 1 hour prior to the procedure followed by 300mg (TID) for 7 days 
 
The facial area will be scrubbed and the oral cavity disinfected by rinsing for 1 minute with a (0.12% 
chlorhexidine gluconate) antimicrobial oral rinse. Prior to extractions clinical photographs will be 
taken from the buccal and occlusal aspects. Photographs will be taken in a 1:1 ratio using a Nikon D-
70 camera with a sunpack ringflash. 
 
After preparation and isolation of the surgical area, anesthesia will be achieved in the region by 
regional block or local infiltration. Conscious sedation may be added at the surgeon’s discretion to help 
manage patient anxiety.   
 

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The teeth will be extracted as atraumatically as possible, without raising a flap, utilizing periotomes 
and the Easy Extrac system. Grafting procedures will include the use of FDBA and collagen plugs in 
all experimental groups. In all groups, the integrity of the remaining socket walls will be assessed and 
measurements recorded on the surgical CRF.  The sockets will be debrided and a bleeding surface 
created by decorticating the socket walls with either a curette or a surgical round burr. 
 
4.7 Grafting Extraction Sockets 
After extractions, sockets will be grafted according to each participant’s assigned randomization group. 
 
Group-1: Each socket will be irrigated with sterile saline and allowed to heal naturally [control group]. 
 
 
Group-2: Each socket will be grafted with freeze dried bone allograft (FDBA) mixed with Tri-calcium 
phosphate (TCP) 8:2 ratio; reconstituted with sterile saline.  
 
4.7-2a Irrigate sockets with sterile saline 
 
4.7-2b Pack the graft into each of the study sites using mild pressure achieving complete fill of 
the sockets.   
 
4.7-2cTrim a 3mm section of collaplug and secure it over the grafted areas with 4.0 Vicryl 
crossing mattress sutures. 
 
Group 3: Each socket will be grafted with an 8:2 ratio FDBA/TCP graft reconstituted with Platelet 
Rich Plasma (PRP). 
 
4.7-3a Collect 9-18cc blood sample from the patient via venipuncture prepare the PRP 
following the Cascade Fibrinet System (Appendix A) 
 
 
4.7-3b Mix PRP in the FDBA.TCP graft. 
 
4.7-3c Irrigate sockets with sterile saline. 
 
4.7-3d Pack the graft into each of the study sites using mild pressure achieving complete fill of 
the sockets  
 
4.7-3e Trim a 3mm section of collaplug and secured it over the grafted areas with 4.0 Vicryl 
crossing mattress sutures. 
 
4.7-3f Once secured in place, the soak the collaplug with PRP. 
 
Group 4: Each socket will be grafted with an 8:2 ratio FDBA/TCP graft reconstituted with 
recombinant platelet derived growth factor (PDGF). 
 
4.7-4a Irrigate sockets with sterile saline. 
 
4.7-4b Apply PDGF into the sockets completely wetting all socket walls. 

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4.7-4c Mix PDGF with GEM-21S (product insert Appendix B) 
 
4.7-4d Pack the graft into each of the study sites using mild pressure achieving complete fill of 
 
the sockets 
 
4.7-4e Trim a 3mm section of collaplug and secure it over the grafted areas with 4.0 Vicryl 
 
crossing mattress sutures. 
 
4.7-4f  Once secured in place, soak the collaplug with PDGF. 
 
After completion of procedures the Essix retainer (if used) will be fitted and placed.  
 
A CBCT scan will be made to include images of each study site. Prescriptions for anti-bacterial mouth 
wash, antibiotics, and pain relief will be provided based on individual patient needs. An ice-pack will 
be dispensed. Verbal and written home care instructions will be given and the patient will be scheduled 
for a follow-up appointment. 
 
4.8 Surgical Extraction Data Collection 
The following data points will be collected and recorded on the surgical CRF: A description of the 
integrity of each of the socket walls will be recorded as follows.  
 
4.8-1   Measurements of the Mesio-distal distance and the buco-lingual distance of the socket 
walls 
 
4.8-2   Measurements of dehiscence and fenestration defects made with a UNC-15 periodontal 
probe in relation to the adjacent socket crest and rounded up to the nearest millimeter. 
 
4.8-3 Wound Measurements – Mesio-distal distance and bucco-lingual distance of the soft 
tissue wound margins after suturing made with a UNC-15 periodontal probe and rounded to the 
nearest millimeter. 
 
4.9 Post-Extraction Evaluations 
Participants will return to clinic for oral evaluations as close to 7-days after the extraction/grafting 
procedure as possible and again at 14 days; sutures will be removed at the 14-day visit. An additional 
follow-up visit will be scheduled approximately 1-month following extractions. Healing will be closely 
monitored and appropriate data recorded on follow-up CRFs. 
 
At each visit, medical history will be reviewed and any changes documented. Information regarding 
adverse events will be captured and recorded following IRB and Federal reporting guidelines. Eight 
weeks after the extractions, each study subject will be appointed for a second CBCT scan, a bone-fill 
biopsy and surgical placement of implants. 

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Table 2 – Study  Procedures Visits -1 — 8 
Procedures 
V- (-1) 
Screening 
V-1 
Pre-Tx 
V-2 
EXT/
G 
V-3 
Week 
1 
V-4 
Week 
2 
 
V-5 
Week 
4 
V-6 
Week 8 
implant
s 
V-7 
Week 
10 
V-8 
Expose 
Implant 
Consent Discussion/Obtained 
X 
 
 
 
 
 
 
 
 
Medical History Review 
 
X 
X 
X 
X 
X 
X 
X 
X 
Tx Plan Review 
 
X 
 
 
 
 
 
 
 
Impressions 
 
X 
 
 
 
 
 
 
 
Essix Retainer 
 
X 
 
 
 
 
 
 
 
Randomized to Tx Groups 
 
X 
 
 
 
 
 
 
 
Biopsy site selection 
 
X 
 
 
 
 
 
 
 
Pre-Surg Antibiotics 
 
 
X 
 
 
 
X 
 
 
Pre-Surg Oral Rinse 
 
 
X 
 
 
 
X 
 
 
Tooth Extraction 
 
 
X 
 
 
 
 
 
 
Tx Group Procedure 
 
 
X 
 
 
 
 
 
 
Venipuncture (group 3 only) 
 
 
X 
 
 
 
 
 
 
Clinical Photographs 
 
 
X 
X 
X 
X 
X 
 
X 
CBCT Scan 
 
 
X 
 
 
 
X 
 
 
Periapical Radiographs 
 
 
 
 
 
 
X 
 
X 
Post-Surg 
Instructions/Prescriptions 
 
 
X 
 
 
 
X 
 
X 
Suture Removal 
 
 
 
X 
 
 
 
X 
 
AE’s recorded 
 
 
X 
X 
X 
X 
X 
X 
X 
Bone Biopsy 
 
 
 
 
 
 
X 
 
 
Implant Placement 
 
 
 
 
 
 
X 
 
 
Implant Exposure 
 
 
 
 
 
 
 
 
X 
 
Table 3 Study Procedures Visits 9 —12 
 
Procedures 
 
V-9 
Impressions 
 
V-10 
Final 
Restoration 
 
V-11 
12 month 
 
V-12 
24 month 
 
Medical History Review 
X 
X 
X 
X 
Impressions 
X 
 
 
 
Clinical Photographs 
X 
X 
X 
X 
Final Restoration Attached 
 
X 
 
 
Periapical Radiographs 
 
X 
X 
X 
AE’s recorded 
X 
X 
X 
X 
Soft-tissue assessments 
 
 
X 
X 
Pocket Depth Measurements 
 
 
X 
X 
Patient Satisfaction 
 
 
X 
X 
 
5.0 TISSUE BIOPSY AND SURGICAL PLACEMENT OF IMPLANTS 
 
5.1  Cone Beam CT Imagery 
A Cone Beam Computed Tomography (CBCT) scan will be made eight weeks after the extractions, 
prior to any manipulation of tissue at the study sites. The images will be used to obtain a 3-dimensional 
database of the participant’s anatomy from the volumetric tomography. Axial, sagital, and cross-
images will be reconstructed to measure tooth socket volume.   
 

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5.2 Surgical Implant Placement 
The implants utilized are identical with the exception of the collar surface characteristics (Table 4).  
Each patient will receive either implants with an LTT or an RBT surface according the study 
randomization schedule. 
 
5.3 Patient Preparation 
Prior to implant surgery the subjects will be given a loading dose of antibiotics based on their medical 
history and concomitant medications.  Local anesthesia will be achieved in the region by regional 
block or local infiltration.  Conscious sedation may be added at the surgeon’s discretion to help 
manage a patient’s anxiety.  The facial area will be scrubbed and the oral cavity disinfected by rinsing 
for 1 minute with a (0.12% chlorhexidine gluconate) antimicrobial oral rinse prior to the procedure.    
 
Once the treatment areas are sufficiently anesthetized a crestal incision will be made and full-thickness 
flaps will be raised. With the aid of a surgical guide, the proposed implant sites will be identified; 
measurements of the alveolar ridge will be captured, using a UNC-15 periodontal probe and recorded 
on the implant surgery CRF.   
 
5.4 Implant Selection 
The diameter and length of the implant will be determined by the surgeon based on the tooth location, 
anatomy, and bone volume determined from the CT scan prior to placement.  The collar surface will be 
determined by the randomization scheme.   
 
Table 4  Implant characteristics 
Implant Material: 
Titanium Alloy - Ti-6Al-4V 
Collar Surfaces: 
Resorbable Blast Texturing (RBT) or Laser Thread Texturing (LTT) 
Connection: 
1.5mm deep internal hexagon 
Diameters: 
Ø3.5mm    Ø4.0mm    Ø5.0mm    Ø6.0mm 
Lengths: 
9mm, 10.5mm, 12mm and 15mm 
 
5.5 Drilling & Biopsy Technique 
A standard drilling technique will be utilized except for a modification in the depth of the osteotomy 
and biopsy obtained from study sites described below. Copious amounts of sterile irrigant will be used 
in the osseous drilling procedure to prevent heating and thermal necrosis of the bone and surrounding 
tissue. The drill speed may be adjusted up to a maximum of 2500 rpm during the procedure. Thread 
forming or taping may be indicated in very dense bone and should be at a maximum of 30 rpm.   
 
The surgeon will start with the 2mm diameter trephine drill for study sites and then proceed to increase 
the width with progressive depth drill depending on the implant diameter to be used at the site.  The 
trephine with bone contained within will be harvested from the center core of one study site, per 
patient and will be immediately placed in fixative for later histological analysis. Vials will be labeled 
with the participant’s ID and the date of biopsy; laboratory technicians will be blinded to knowledge of 
participant group assignment. 
 
In this protocol the implant collars are to be positioned 1mm above the level of the crestal bone.  This 
is accomplished by adjusting the depth of the osteotomy for each implant by 1mm.  For example the 

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osteotomy depth for a 15 mm length implant should be 14mm.  Since the collars of the implants are 1 
mm above the bone crestal bone drills will not used in this protocol. 
 
 
5.6 Implant Placement 
The sterile blister pack containing the implant will drop onto a sterile field 
and after thorough irrigation of the site the implant will be inserted directly 
into the prepared bone site.  After placement with the collar 1mm above the 
bone the insertion torque will be measured with a torque wrench and 
recorded on the case report forms.  A cover cap will be placed on the 
implant and the surgical wound sutured.  
 
5.7 ImmediatePost-Operative Procedures 
Standardized intra-oral periapical dental radiographs will be made of each 
study site. Written and verbal post-operative instruction will be provided to 
each participant. An antimicrobial mouth rinse and ice packs will be dispensed. Antibiotics will be 
prescribed for 7 days; analgesics will be prescribed on an as needed basis at the discretion on the 
surgeon. 
 
6.0 RESTORATION OF IMPLANTS 
 
6.1 Implants Uncovered  
Implants will be uncovered upon the investigator’s determination that the implants are sufficiently 
integrated to withstand the forces of loading. In general, mandibular implants will be uncovered and 
restoration initiated approximately 4 months after placement; maxillary implants will be uncovered and 
restoration initiated approximately 6 months after placement. When the implants are uncovered, 
clinical photographs will be taken before, during and after the procedure; following the procedure, 
standardized intra-oral radiographs of each implant site will be made.  
 
6.2  Placement of the final restoration 
Each implant will be restored in the conventional manner with an aesthetically pleasing single crown 
restoration. Restoring materials will be selected by the restoring dentist based on discretion of the 
dentist and individual patient needs. Prosthetic restoration of the implants will require numerous visits 
to the restorative dentist over a period of one to two-months. The restoring dentist will advise when 
additional visits are necessary. Photographs will document each step in the restoration process and of 
radiographs be taken of each area when the final restoration is cemented.  
 
7.0 LONGITUDINAL FOLLOW-UP  
 
 7.1 Post-Restoration Follow-up Evaluations (12-months and 24-months after implant placement) 
Participants will return to the clinic at 12 and 24 months following implant placement. Evaluation of 
implant function and surrounding tissue health will be determined based on an interview with the 
participant, clinical examination of the study sites and an analysis of radiographic and photographic 
data. 
 
__________ Bone level 

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At each visit, study personnel will review and update the participant’s health history and record any 
adverse experiences; a study dentist will complete a thorough periodontal evaluation of the implant 
area and provide an assessment of the prosthetic attachment interface. A set of standardized periapical 
radiographs and clinical photographs will be made.  
 
Case report forms will be used to record the following observations for each implant site:  
Overall soft tissue health 
Plaque and gingivitis scores (modified Löe and Sillness) 
Pocket depth and clinical attachment level 
Implant Stability 
Retention and stability of prosthetic attachment 
Overall aesthetics (soft tissue contours) 
Assessment of reported pain  
Implant survival 
 
Each participant will complete a patient satisfaction questionnaire. Participants will be asked to report 
their own assessments for the following criteria: 
Comfort 
Speech 
Appearance 
Ability to taste food 
Ability to chew food 
Pain on mastication 
General satisfaction 
 
8.0 RADIOGRAPHIC AND PHOTOGRAPHIC SURVEYS 
  
8.1 Cone Beam Computed Tomography 
Cone beam computed tomography (CBCT) images will be used to obtain a 3-dimensional database of 
the patient’s anatomy from the volumetric tomography. Axial, sagital, and cross-images will be 
reconstructed to measure the tooth socket volume. Hounsfield units will be calculated to assess the 
relative tissue density for each study site. CBCT scans will be obtained after the completion of the 
extraction and grafting procedures and again at 8 weeks after the extractions. 
 
8.2 Intra-oral radiographs 
Standardized intra-oral periapical radiographs will be obtained of each site when the implants are 
placed and uncovered, at final implant restoration and at twelve and twenty-four months after the 
implants are placed. A minimum of five radiographs per study site over the duration of the study will 
be obtained. Additional radiographs may be obtained based on the study dentist’s determination of 
need. 
 
 Radiographs will be used to monitor osseous health at the bone-implant interface, to verify implant 
position, to assess the quality of implant-attachment interface and to capture measurements of 
longitudinal osseous support to the implants.   
 
 

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8.3 Radiographic Image Acquisitions  
Longitudinal measurement of osseous support to the implant sites is reliant upon serial radiographs of 
consistently similar quality that accurately image existing anatomy with minimal distortion over time.  
Ideal images for this study will center the targeted sites with at least 2mm of adjacent anatomy visible 
on each side of the implant.  
 
Irregular projection geometry, variations in film positioning and mA/kVp of the X-ray beam and 
exposure time, coupled with poorly controlled film processing at the source (when film-based imagery 
is used) can influence image quality and thus can limit the accuracy of the analysis.  
  
Taking radiographs from the same exact position at each designated interval reduces the possibility of 
geometric inaccuracy. Ensuring parallelism and standardization of periapical radiographs for 
measurement of osseous support is made possible by consistent use of a Rinn bite-block and aiming 
ring and careful positioning of film holding apparatus. This, coupled with fixed exposure time and 
standardized beam settings [milliamperage (mA) and kilovoltage (kVp)], will yield images with 
similar geometry and with constant density leading to a valid and dependable analysis. 
 
8.4 Clinical Photography  
Each study site will be monitored with digital photography to assess the soft tissue healing. 
Photographic assessment will be based on images taken at 1:1 ratio with a Nikon D-70 digital camera 
with a sunpack ringflash. Buccal and occlusal views will be obtained at the initial visit (prior to 
extraction), after completion of the grafting procedures, at 2 and  4 weeks, immediately prior to biopsy 
at 8-weeks, after implant insertion, at each prosthetic restorative visit, when the final restoration is 
attached and at four semi-annual follow-up visits.  
 
9.0 ADVERSE EVENT REPORTING 
 
9.1 Adverse Event Reporting 
Participants will be interviewed at each visit and prompted to discuss any adverse events; such events 
will be recorded. In the event of a serious adverse event, the IRB will be notified per posted 
requirements and in full compliance with federal guidelines for research in human subjects. An event, 
whether study-related or not, will be assessed based on description of the event/pathology, onset, 
duration, severity, analgesics or other medication taken, and possible causality.  
 
10. 0 CRITERIA FOR SUCCESS 
 
10.1 Grafts 
The success criteria for this investigation are determined as follows: Grafts will be deemed successful 
if there are no reported symptoms or clinical signs or of post-application allergy, toxic reactions or 
evidence of gross local or systemic infections.  
 
Histological and histomorphometric analyses will provide evidence of the relative success or failure of 
graft materials to enhance formation of new osseous tissue in extraction sockets. Results will be 
compared across experimental groups and between experimental groups and controls. 
 

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A site that fails to meet the stated criteria for success, or where the width of the ridge remains too 
narrow for implant insertion will be re-grafted (an offer that patients may decline). The site may 
receive an implant at a later date but the site will be exited from the study results. 
 
10.2  Implant Survival  
At each follow-up evaluation participants will be interviewed to determine if any pain or numbness has 
been experienced since implant placement or has developed since the previous interview. The implant 
sites will be examined for any evidence of implant failure including implant suppuration and erythema.  
 
If signs or symptoms of implant failure are observed at any time during the course of the study, a 
periapical radiograph will be obtained and inspected for signs of radiolucency. The investigator will 
make assessment of implant status and if a failure is determined, will be reported on the appropriate 
CRF. At the investigator’s discretion a medical and/or surgical attempt to rescue the implant may be 
made.  
 
10.3 Implant Success 
An implant will be considered successful as long as it remains immobile when tested with instrument 
pressure at follow-up evaluations and offers stable anchorage to a functional prosthetic attachment. A 
successful implant shows no evidence of fracture or signs of peri-implant radiolucency on an intraoral 
radiograph (using a paralleling technique strictly perpendicular to the implant bone-interface), or 
persistent or irreversible signs and/or symptoms of pain, infection, neuropathies or parathesia. 
 
11.0 COSTS TO PARTICIPANTS 
 
11.1 Procedure Fees 
No fees will be charged to participants for the, teeth extraction, socket grafting materials, implant 
devices, implant surgery, CBCTT scans, radiographs, photographs, bone biopsy analysis, or clinical 
evaluations for the entire study.  
 
Participants will be expected to pay a $1,000.00 restoration fee for each study site. This one-time-
only fee will cover costs related to laboratory and materials for the fabrication of the implant 
restoration prosthesis. This fee is to be billed to participants prior to the initiation of any surgical 
procedures.  
 
Study visits are not designed to take the place of routine dental care. Over the course of the study 
participants will be expected to continue with regular dental check-ups with a dentist of their choice. 
Should the need arise patients who do not have a regular dentist of record will be referred in the 
appropriate manner for any non-study related dental treatment. Costs for non-study related treatment 
will be charged to the participant’s account or to their insurance provider in the usual manner per 
dental school policy and will not be paid for from the study account 
 
11.2 Payment to Participants 
Participants will be paid $50.00 after completing the 12-month visit and $50.00 after completing the 
final study visit at 24 months following implant insertion.  
 
 

FMD-007 
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12.0 OUTCOMES AND ANALYSES  
 
The study is structured to provide both subjective and objective data; study sites will be followed data 
will be captured at placement and at 12 and 24 months after implants are placed.  
 
12.1 Objective Data 
Bone biopsies preserved in the trephines and stored in formalin will be submitted to UAB’s CMBD 
(Name of facility) Core Laboratory. Trephine core 2x6mm will be stained with hematoxylin and eosin 
and processed for histologic and histomorphometric analysis. Amount of bone fill and remaining bone 
graft (% of new bone fill, % of residual graft and % of soft tissue) material will be determined and 
compared across groups. 
 
Cone Beam Computed Technology (CBCT) will be used to capture quantitative natural bone fill and 
bone fill following grafting applications at each extraction site.  
 
Image analysis software will be used to capture images from the standardized radiographs taken at 12 
and 24 months following implant placement. Analysis procedures will assess the implant/bone 
interface and measure changes in adjacent crestal alveolar bone levels over time. 
 
12.2 Subjective data  
 
 
Observations of bone quality (D1-D-4) recorded by surgeons at implant placement.  
 
Clinical observations of post-extraction soft-tissue healing 
 
Clinical observations of soft-tissue and osseous response to dental implants  
 
Clinical observations of overall aesthetic appearance  
 
12.3 Outcome Endpoints 
The primary efficacy parameter for implant success will be the duration of implant survival from 
surgical placement to 24 months post-placement across all groups. Measurement of bone height along 
the implant mesial and distal surfaces at 12 and 24 month follow-up evaluations will be captured from 
radiographic images and compared to same measurements at insertion. These measurements will be 
used to derive changes from baseline values.  
 
Efficacy endpoints will include implant and prosthesis function as assessed by gingival health, bone 
levels and participant subjective satisfaction with the study therapy. Differences between groups will 
be calculated and used to determine if osseous changes and implant function are different across 
extraction groups and between implant groups.  
 
Safety will be evaluated by clinical signs and symptoms of dental and medical events. 
 
12.4  Statistical Analysis 
The general approach to statistical analysis of the study aims will be based on mixed-model analysis of 
variance (ANOVA). This approach will accommodate the inclusion of correlated observations due to 
study subjects potentially contributing measurements of more than one single tooth site to the analysis. 
 

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The sample distributions will be examined for each outcome variable. If these distributions depart 
substantially from normality, transformations of the data will be evaluated. If normality cannot be 
established by transformation, rank-based analyses will be used. 
 
Subjects will be included as a random effect on the analyses that include multiple observations per 
subject. For analysis of histological data, only one tooth site per subject will be evaluated and the 
model will not include a random effect.  
 
Smoking status will be included in all models in order to account for differences in response between 
smokers and non-smokers, and so that the analysis will correspond to the study’s randomization 
strategy.  Comparisons between smokers and non-smokers are not a primary interest in the study. 
 
For aims in which interaction terms are of interest, significant interaction terms will be investigated 
using plots of least square means and separate post-hoc analyses for individual time points. 
 
Hypothesis 1 
Differences among the four groups will be evaluated by the overall F-test for the ANOVA. Pairwise 
comparisons among group means will be conducted using Tukey’s test. Contrasts will be constructed 
to address each specific aim (SA). 
 
SA-1: Compare alveolar ridge dimensions in grafted extraction sockets to that of sites healed 
without grafts after 8 weeks of post-extraction healing. 
 
This SA will be addressed by comparing the combined mean of the three graft groups (FDBA/TCP, 
DDBA/TCP/PRP, FDBA/TCP/PDGF) with that of the CONTROL group by calculating a contrast and 
the corresponding F-test. Pairwise comparisons among means will be conducted using Tukey’s test.. 
 
Hypothesis II 
The addition of growth factors to bone grafting materials will enhance osseous and soft tissue healing. 
 
SA-2: Assess the efficacy of bone grafting with and without enrichment with growth factors to 
preserve the volume of bone in extraction sockets. 
 
This SA will be addressed using mixed-model ANOVA to compare mean bone volume among the four 
groups. Post-hoc pairwise comparisons will use Tukey’s test. The effect of growth factors enrichment 
will be addressed using contrasts and F-tests to compare the mean of Group-4 with those of each of the 
other groups. If there is not a significant difference among the group means of Groups 1-3, the 
combined mean of these three groups will be compared with that of Group-4. 
 
SA-3: Compare soft tissue healing between groups at week-1, week-2, week-4 and after 8 
weeks of healing. 
 
The analysis of SA-3 will be mixed-model ANOVA including measurements of healing made at each 
time points. Time will be included in the model in order to account for unequal spacing of the 
observational times. The statistical test that will be of primary interest will be the F-test for Group by 
time interaction. 

FMD-007 
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SA-4: Assess quantitative bone fill across groups after 8 weeks post-extraction healing. 
 
Qualitative bone fill will be compared among four groups using mixed-model ANOVA and the 8 week 
measurement only. Post-hoc pairwise comparisons will use Tukey’s test. 
 
SA-5: Compare qualitative bone fill across groups after 8 weeks post-extraction healing. 
 
Percent new bone, percent residual graft, and percent soft-tissue will be compared among the four 
groups using ANOVA. For this analysis, there will be a single measurement of each of the variables 
per participant, so correlated observations will not be an issue in the analysis. Post-hoc pairwise 
comparisons will use Tukey’s test. 
 
SA-6: Assess the relationship of osseous healing and implant stability at insertion across groups 
after 8 weeks post-extraction healing. 
 
This SA will be addressed by including the implant stability measure as a predictor variable in the 
analysis of osseous healing. The statistical test that will be of primary interest for this analysis will be 
the two-factor interaction of stability and group. 
 
Hypothesis III 
Laser thread-textured (LTT) dental implant will preserve longitudinal peri-implant crestal bone more 
effectively than implants with Resorbable blast texturing (RBT). 
 
SA-7: Assess the efficacy of LTT and RBT surface topographies when surgically implanted 
into extraction sockets. 
 
This SA will be addressed using a survival analysis approach. The primary outcome measure will be 
presence of signs and symptoms of infection at the implant site, since implant failure is expected to be 
rare to non-existent. Frequencies of occurrence of infection will be tabulated for each implant type.  
 
Cox proportional hazards regression will be used to evaluate the rates of infection for LLT and RBT 
implants, allowing for adjustment for potential confounding variables and covariates. A blocking 
variable representing the individual subject will be included in order to reflect multiple implants per 
study subject. 
 
SA-8: Assess peri-implant soft tissue healing adjacent to LTT and RBT surfaced implants 
 
The JEMPT index will be evaluated at the time of final restoration and at 12 and 24 months follow-up 
evaluations. Mixed model ANOVA will be used to compare changes over time between implant types. 
The statistical test that will be of primary interest is the implant type by time interaction. 
 
SA-9: Assess changes in the longitudinal crestal bone levels across extraction groups and 
between implant groups at 12 and 24 months after surgical placement. 

FMD-007 
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The analysis for the SA will be mixed-model ANOVA, accounting for multiple observations per 
subject. The statistical test that will be of primary interest is the F-test for surface type by time 
interaction. 
 
12.5 Power and Sample Size Considerations 
Due to correlation among multiple measurements made on the same participants, the information 
provided by additional tooth sites within an individual is less than that provided by the initial site. 
For the purposes of power analysis, this may be represented by a variance inflation factor (VIF), which 
depends on the number of observations per cluster (individual in this case) and the intraclass 
correlation (ICC). The VIF is calculated as 1 + (average cluster size) X ICC. The VIF can be used to 
calculate an effective sample size, which is the number of independent observations that would be 
required to provide power equal to the larger number of correlated observations that are available to 
the study. 
 
The actual sample sizes for the analysis of aims other than those based on histology data will not be 
known in advance, since multiple extractions pr participant will be included in the study. Histology 
will be conducted on a single site per participant; so variance inflation is not an issue for these 
measures. 
 
Eighty participants will be recruited, each of which will contribute data on one or more extraction sites. 
If the average number of extractions per participant is small, say 1.5 or 2, the power of the study will 
not be severely reduced relative to a study with independent observations, even if the ICC is as large as 
0.50. Assuming ICC = 0.50 and an average of 1.5 extractions pr participant, the total number of 
observations in the study would be 120, VIF=1.25, and the effective sample size would be 96, or an 
expected effective sample size of 24 extractions in each of the extraction groups. If there were an 
average of 3 extractions per participant the same assumptions would yield a total sample size of 160 
VIF = 1.5, and an effective sample size of 107, or approximately 27 extractions per group. 
 
A conservative approach to power estimation was used, assuming an effective sample size of 25 
observations per extraction-implant group. Power calculations utilized the Power and Precision, release 
2.00, (Borenstein, 2000) and nQuery Advisor 6.0 (Janet D. Elashoff, 1995-2005) software packages. 
Power to detect a “medium” effect size, corresponding to a difference between group means equal to 
0.50 times the within-group standard deviation (sd) was calculated. Also, the effect size detectable 
with 80% power was calculated. All power estimates were based on two-sided testing at the 95% 
confidence level. 
 
The power for SA-1 is largely determined by the size of control group, since the primary comparison is 
equivalent to a t-test of the mean of the controls vs others. Thus, the assumed effective sample sizes of 
25 and 75 would yield approximatey 57% power to detect a medium effect size. The difference 
detectable with 80% power would be approximately 0.65sd. 
 
Power for SA-2, SA-4 and SA-5 was based on a one-way ANOVA model. The proposed sample size 
would provide 52% power to detect a medium effect size or 80% power to detect an effect size 
equivalent to a two-group difference of 0.34sd. These approximations also apply to SA-3, with the 
appropriate sd being the within-group standard deviation of the changes across the observation times. 
 

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The total sample size for SA-5 would be 80, or 20 per group, since this SA is based on histology, with 
a single extraction per participant. Power to detect a medium effect size would be 42%. The effect size 
detectable with 80% power is equivalent to a two-group difference of 0.72sd. 
 
Power for SA-6 was based on linear regression with a four-category dummy variable. If stability and 
group each explain 10% of the observed variance, the proposed sample size would provide 80% power 
to detect an increment of 8.6% in explained variance for the stability*group interaction.  
 
Power for comparison of rates of infection signs for SA-7 was based on the chi-square test for the odds 
ratio. The proportions in the two groups were centered on 0.50, in order to provide a conservative 
estimate of power. The effective sample size of 50 per group would provide 80% power to detect an 
odds ratio of approximately 3.2 for the association between implant type and infection.   
 
Power estimation for the comparison of bone height measurements (SA-7), for comparison of changes 
in JEMT index (SA-8) and of changes in crestal bone levels (SA-9) between the two implant types was 
based on a t-test. The proposed sample size would provide 70% power to detect a medium effect size, 
and 80% power to detect a difference of 0.565sd between the groups. For SA-8 and SA-9, sd refers to 
the within-group standard deviation of changes across time. 
 
13.0 CONFIDENTIALITY 
 
13.1 Protection of Personal Health Information 
Identifiable personal health information will be protected from public dissemination and information 
gathered during this study will be kept confidential to the extent permitted by law. Study staff with 
access privileges, as well as members of the IRB may access study-related records and information that 
will identify participants by name.  
 
13.2 Electronic Files 
Data that link an individual to identifying information (birth date, address, telephone numbers plus 
pregnancy status at enrollment) will be entered into a protected electronic master file created 
specifically for this study. A participant log will be created and used to track each participant’s 
progress through the study.  
 
Each participant will be assigned a unique study-specific identification number; except for screening, 
names will not be written on case report forms. Screening forms that include demographic and 
personal information such as birthdates, address and telephone numbers will be filed in the binder with 
the original consent documents.  
 
All study-related dental data will be captured on paper case report forms crafted specifically for this 
study. These forms will be used to record all data point measurements and assessments for the duration 
of the study.  Data collected on the case report forms will be coded and transcribed to an electronic 
spreadsheet created for this study and will be used by the study statisticians for statistical analyses. 
 
 A study-specific participant file will be created to house completed paper case report forms. These 
forms will not be stored in the patient’s dental file; however, in the interest of maintaining an accurate 

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of record-of-dental-treatment, treatment notes will be transcribed and inserted into each participant’s 
dental record.   
 
The data-collection system will be maintained by the study coordinator and will be secured through 
entry into a password protected computer database in the coordinator’s office. Only members of the 
research team granted access privileges will be able to log-on to the study files. 
 
14.0 REGULATORY ISSUES 
 
14.1  IRB Approval 
This protocol will be evaluated and approved by the responsible Institutional Review Board prior to 
screening/entering the first participant into the study. In accordance with federal, state, and university 
regulations governing research on human subjects, required documents will be submitted for IRB 
review by the study coordinator. Initiation of any study-related procedure (including screening) will 
not commence until receipt of IRB approval.  
 
14.2 Informed Consent 
The study investigators, or designee, will participant in a private English language witnessed consent 
discussion with all potential candidates prior to obtaining their consent to participate in this trial.  
Participants must demonstrate an adequate understanding of the spoken and written English language 
and must be able to complete the consenting process without the aid of an interpreter.  
 
Participant’s consent signature will not be obtained under the influence of strong persuasion or any 
effort that could be perceived as coercion; each participant will be given ample opportunity to have all 
their concerns addressed and all their questions answered prior to obtaining the consent signature. 
 
Each participant must demonstrate an autonomous understanding or what it means to be a participant 
in a research study and must be made fully aware of the risk, benefits and costs of participation. In 
addition, all participants must be made aware that they can withdraw their consent at any time during 
the trial and for any reason without jeopardizing their future treatment at the dental school. Participants 
will be made aware that the consequences of early withdrawal including that the study treatment (teeth 
extraction, bone grafts and implant placement) are irreversible procedures.  
 
Only the most current IRB-approved informed consent document will be used for consent signatures. 
The consenting process will be conducted in full compliance with University/IRB ethical policies and 
will follow departmental standard operating procedures. The consent form must be signed in the 
presence of a reliable witness, who must also sign the consent form, before any study therapy can be 
initiated.  Each participant will be given a copy of their signed consent; the original signed consent 
form will remain with the investigator. 
 
14.3 Regulatory Documents 
All original study-related regulatory documents, associated correspondence and original consent 
documents will be housed in a study-specific regulatory binder. The binder will be secured in the 
coordinator’s office and only study personnel will have access to the binder. 

FMD-007 
v.July, 2008  
Page 27 of 33 
15.0 ETHICAL ISSUES 
 
15.1 Ethical Aspects 
This investigation will be conducted under good clinical practice standards and in accordance with the 
ethical principles and guidelines for the protection of human subjects of research as outlined in the 
Belmont Report and in full compliance with UAB policies and Federal Regulations and Guidelines for 
the conduct of research using humans. 

FMD-007 
v.July, 2008  
Page 28 of 33 
16.0 LITERATURE CITED 
 
1. Sclar AG. Strategies for management of single-tooth extraction sites in aesthetic implant therapy. J 
Oral Maxillofac Surg 2004;62:90-105. 
 
2. Lekovic V, Kenney EB, Weinlaender M. A bone regenerative approach to alveolar ridge 
maintenance following tooth extraction. Report of ten cases. J Periodontol 1997;68:563-570. 
 
3. Lekovic V, Camargo PM, Klokkevold PR, et al. Preservation of alveolar bone in extraction sockets 
using bioabsorbable membranes. J Periodontol 1998;69:1044-1049. 
 
4. Artzi Z, Tal H, Dayan D. Porous bovine bone mineral in healing of human extraction sockets. Part I: 
Histomorphometric evaluations at 9 months. J Periodontol 2000;71:1015-1023. 
 
5. Artzi Z, Tal H, Dayan D. Porous bovine bone mineral in healing of human extraction sockets: 2. 
Histochemical Observations at 9 Months J. Periodontol 2001;72: 152-159  
 
6. Froum S, Cho SC, Rosenberg E Rorher M, Tarnow D. Histological Comparison of Healing 
Extraction Sockets Implanted With Bioactive Glass or Demineralized Freeze-Dried Bone Allograft: A 
Pilot Study J Periodontol 2002;73:94-102 
 
7. Zubillaga G, Von Hagen S, Simon BI, Deasy MJ. Changes in alveolar bone height and width 
following post-extraction ridge augmentation using a fixed bioabsorbable membrane 
and demineralized freeze dried bone osteoinductive graft. J Periodontol 2003;74:965-975. 
 
8. Iasella J M, Greenwell H, Miller RL, et al. Ridge preservationwith freeze-dried bone allograft and a 
collagen membrane compared to extraction alone for implant site development: A clinical and 
histologic study in humans.J Periodontol 2003;74:990-999. 
 
9. Anitua E. Plasma rich in growth factors: Preliminary results of use in the preparation of future sites 
for implants. Int. J Oral Maxillofacial Implants 1999;14:529-535. 
 
10. Marx,R.E.,2004.Platelet-rich plasma:evidence to support its use. J. Oral Maxillofac Surg. 2004; 
62:489 –496 
 
11. Nevins M, Giannobile WV, McGuire MK, Kao RT, Mellonig JT, Hinrichs JE, McAllister BS, 
Murphy KS, McClain PK, Nevins ML, Paquette DW, Han TJ, Reddy MS, Lavin PT, Genco RJ, Lynch 
SE.  Platelet-Derived Growth Factor Stimulates Bone Fill and Rate of Attachment Level Gain Results 
of a Large Multicenter Randomized Controlled Trial. J Periodontol 2005;76:2205-2215 
 
12. Reddy MS, Giannobile WV, Nevins M, McGuire MK, Kao R, Lynch SE.  Multicentered 
Radiographic Analysis of a Regenerative Medicine Approach to Periodontal Bone Destruction. 
Southeast Workshop on Tissue Engineering and Biomaterials 2nd Annual February 11-12, 2005 
 

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13. Adel R, Lejholm U, Rockler B & Brånemark  PI. (1981) A 15 year study of osseointegrated 
implants in the treatment of the edentulous jaw. International J Oral Surgery 10:387-416,. 
 
14. Adell, R., Eriksson, B., Lekholm, U., Brånemark, P.I. & Jemt,T. (1990) A long-term follow-up 
study of osseointegratedimplants in the treatment of totally edentulous jaws. International Journal of 
Oral and Maxillofacial Implants 5: 347–359 
 
15. Wataha JC. Materials for endosseous dental implants. J Oral Rehabil 1996;23:79–90 
 
16. Lacefield WR. Current status of ceramic coatings for dental implants. Implant Dent 1998;7:315–
322 
 
17. Hench LL, Wilson J. Surface-active biomaterials. Science 1984;226:630–636 
 
18. Cooper LF. Biologic determinants of bone formation for osseointegration: 
clues for future clinical improvements. J Prosthet Dent 1998;80:439-49. 
 
19. Buser D, Schenk RK, Steinemann S, Fiorellini JP, Fox CH, Stich H. 
Influence of surface characteristics on bone integration of titanium implants. A histomorphometric 
study in miniature pigs. J Biomed Mater Res 1991;25:889-902. 
 
20. Wennerberg A, Albrektsson T, Andersson B. An animal study of c.p. titanium 
with different surface topographies. J Mat Sci Mat Med 1995;6:302-9. 
 
21. Wennerberg A, Albrektsson T, Lausmaa J. Torque and histomorphometric 
evaluation of c.p. titanium screws blasted with 25- and 75-microns-sized 
particles of Al2O3. J Biomed Mater Res 1996;30:251-60. 
 
22. Wennerberg A, Albrektsson T, Albrektsson B, Krol JJ. Histomorphometric 
and removal torque study of screw-shaped titanium implants with three 
different surface topographies. Clin Oral Implant Res 1996;6:24-30. 
 
23. Wennerberg A, Ektessabi A, Albrektsson T, Johansson C, Andersson B. A 
1-year follow-up of implants of differing surface roughness placed in rabbit 
bone. Int J Oral Maxillofac Implants 1997;12:486-94. 
 
24. Hansson S, Norton M. The relation between surface roughness and interfacial 
shear strength for bone-anchored implants. A mathematical model. J Biomech 1999;32:829-36. 
 
25. Cochran, D., Simpson, J., Weber, H.P. & Buser, D.(1994) Attachment and growth of periodontal 
cellson smooth and rough titanium. The International Journal of Oral & Maxillofacial Implants 9: 289–
297. 
 
26. Meyle, J. (1999) Cell adhesion and spreading ondifferent implant surfaces. In: Lang, N., Karring, 
T. & Lindhe, J., eds. Proceedings of the 3rdEuropean Workshop on Periodontology, 55–72.Berlin: 
Quintessence. 

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27. Mustafa, K., Silva Lopez, B., Hultenby, K., Wennerberg,A. & Arvidson, K. (1998) Attachment and 
proliferation of human oral fibroblasts to titanium surfaces blasted with TiO2 particles. A scanning 
electron microscopic and histomorphometric analysis. Clinical Oral Implants Research 9:195–207. 
 
28. Quirynen M, van der Mei HC, Bollen CM, Schotte A, Marechal M, Doornbusch GI, et al. An in 
vivo study of the influence of the surface roughness of implants on the microbiology of supra- and 
subgingival plaque. J Dent Res 1993;72:1304-9. 
 
29. Piattelli M, Scarano A, Paolantonio M, Iszzi G, Petrone G & Piattelli A J Oral Implantol 
2002;28:2-8 
 
30. Novaes AB, Souza SLS, de Oliveria PT & Souza AMMS Int J Oral and Maxillofac Implants 
2002;17:377-383 
 
31. Carter DR, Giori NJ. Effect of mechanical stress on tissue differentiation in the bony implant bed. 
In Davies JE. The Bone- Biomaterial interface. Toronto, University of Toronto Press, 1991:367-379. 
 
32. Britland S, Clark P, Connolly P, Moores G. Micro patterned substratum adhesiveness: A model for 
morphogenic cues controlling cell behavior. Exp Cell Res 1992; 198:124-129 
 

FMD-007 
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Page 31 of 33 
17.0 STUDY PERSONNEL 
 
Name 
Title 
Primary Role 
 
Michael S. Reddy, DMD, DMSc 
 
 
 
Principal Investigator 
 
Overall responsibility for 
conduct of the study 
 
Philip Vassilopoulos, DMD 
 
 
Sub-Investigator 
 
Screening, dental surgery, 
overall patient care 
 
Nicolaas C. Geurs, DDS, MS 
 
 
 
Sub-Investigator 
 
Screening, dental surgery, 
overall patient care 
 
Sandra Jean O’Neal, DMD, MS 
 
 
Sub-Investigator  
 
Prosthodontist, patient care 
 
Perng-ru Liu, DMD 
 
 
Sub-Investigator 
 
Prosthodontist, patient care 
 
Mark S. Litaker, PhD 
 
 
Sub-Investigator 
 
Statistician/ Data Analysis 
 
Sandra J. Haigh, RDH, MS  
 
 
Coordinator 
 
Regulatory Issues 
 
Sheila Akers 
 
 
Coordinator 
 
Coordinating daily clinic 
activities, patient care, 
appointment scheduling, 
 data collection 
 
Research Fellow 
 
 
 
Research Fellow 
 
 
Screening, dental surgery, 
overall patient care 
 
Student Intern 
 
 
Student Intern 
 
 
Assist with general patient 
care, appointment scheduling 
and data collection 
 
 
Dental Assistant 
 
 
Dental Assistant 
 
 
General dental assisting 
activities 
 
 

FMD-007 
v.July, 2008  
Page 32 of 33 
18.0 PROTOCOL APPROVAL SIGNATURE PAGE 
 
A Prospective Study of Differential Implant Surface Texturing and Socket Augmentation Techniques 
 
Protocol Number FMD-07 
 
 
Authored By: 
     
 
Michael Reddy, DMD, DMSc 
      Printed Name 
 
 
____________________________________ 
Signature 
 
 
_________________________________ 
Date 
 
 
Sandra J. Haigh, RDH, MS 
Printed Name 
 
 
______________________________ 
Signature 
 
 
_______________________________ 
Date 
 
 
Mark S. Litaker, PhD 
Printed Name 
 
______________________________ 
Signature 
 
_______________________________ 
Date 
 
 
 
Phillip J. Vassilopoulos, DMD 
Printed Name 
 
 
_____________________________________ 
Signature 
 
 
______________________________________ 
Date 
 
 
Nicolaas C. Geurs, DDS, MS 
 Printed Name 
 
 
____________________________________ 
Signature 
 
 
____________________________________ 
Date 
 
 
 
 
Approved By: 
 
Michael S. Reddy, DMD, DMSc, Department Chair 
Printed Name 
 
 
________________________________________      __________________________________ 
Signature                                                                      Date