Laser-Assisted Regenerative Surgical Therapy for Peri-implantitis: A Randomized Controlled Clinical Trial
Phase: NA
Conditions: Peri-Implantitis
Sponsor: University of Michigan

 
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Laser-Assisted Regenerative Surgical Therapy for  
Peri-implantitis: A Randomized Controlled Clinical Trial 
 
NCT03127228 
 
Version Date:  02-22-18 
 
 

 
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Laser-Assisted Regenerative Surgical Therapy for  
Peri-implantitis: A Randomized Controlled Clinical Trial 
 
 
Principal Investigator: 
Jeff (Chin-Wei) Wang, DDS, DMSc 
 
Co-Investigators: 
Sajjad Ashnagar, DDS 
Riccardo Di Gianfilippo, DDS 
 
Yu Leo Lei, DDS, PhD 
William V. Giannobile D.D.S., D.Med.Sc 
Hom-Lay Wang, DDS., MSD., Ph D 
 
 
Study Coordinator:Janet Kinney, RDH, MS 
 
 
Study Site: 
Graduate Periodontics 
Department of Periodontics and Oral Medicine 
University of Michigan School of Dentistry 
1011 N. University Ave., Ann Arbor, MI 48109-1078 

 
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Table of Contents 
 
 
Introductory Statement 
General Investigator plan 
Study Protocol 
I. Introduction 
II. Objectives 
III. Materials and methods 
IV. Statistical analysis 
V. Regulatory considerations 
VI. References 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Introductory Statement 
Peri-implantitis is a serious emerging new disease with a prevalence of 22% in patients 
with dental implants. (Derks and Tomasi 2015). Although early stage mucositis may be 
controlled non-surgically, established peri-implantitis lesions are still a challenge to 
manage due to the unpredictable results (Suarez-Lopez Del Amo et al. 2016). Studies 
have evaluated the effectiveness of different methods for implant surface 
decontamination, as well as several bone grafting materials attempting to regenerate 
peri-implant bony defects (Claffey et al. 2008). Among the available approaches for 
decontamination, laser therapy (especially Er:YAG laser) has been proven to reduce 
bacterial load without damaging the implant surface (Goncalves et al. 2010; Yamamoto 
and Tanabe 2013). In animal models, there are several studies showing that with the 
Er:YAG laser treatment in preparation for bone grafting procedure, there is an increased 
regenerated bone-to-implant contact for a better regenerative outcome (Nevins et al. 
2014; Takasaki et al. 2007) . Many studies also have shown the benefits of laser to 
improve wound healing, better hemostasis, and positive biostimulation effects (Aoki et 
al. 2015) . However, there is limited human randomized clinical trials assessing the 
clinical benefits of using Er:YAG laser (Schwarz et al. 2013; Schwarz et al. 2011). It is 
still of great interest to critically evaluate whether laser can assist in traditional 
mechanical debridement to promote regenerative therapy. The purpose of the study is 
to evaluate if Er:YAG laser can assist in mechanical debridement and enhance the 
outcome of a regenerative therapy for resolving peri-implant infection and restoring 
bony defects.  
 
General Investigation Plan 
 
This study involves one center and a double-blinded randomized controlled clinical trial 
is planned. Twenty-four adult patients in the need of surgical treatment due to peri-
implantitis infections will be included. A signed written informed consent will be obtained 
after he or she has been given verbal and written information describing the nature and 
duration of the study. Subjects will not be screened or treated until an informed consent 
has been obtained. Subject information will be protected according to the privacy 

 
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regulations of the federal Health Insurance Portability and Accountability Act of 1996 
(HIPAA). 
 
Study Protocol 
I. 
Introduction 
Peri-implant diseases are similar to periodontal diseases and can be classified into 
two different entities, including peri-implant mucositis and peri-implantitis. Peri-implant 
mucositis corresponds to gingivitis and peri-implantitis corresponds to periodontitis in 
natural teeth. As defined by the American Academy of Periodontology, (Peri-implant 
mucositis and peri-implantitis: A current understanding of their diagnoses and clinical 
implications  2013) mucositis represents a disease in which the presence of 
inflammation is confined to the soft tissue surrounding an implant without signs of bone 
loss following initial bone remodeling during healing; while peri-implantitis is an 
inflammatory reaction around an implant, which includes both soft tissue inflammation 
and loss of supporting bone beyond biological remodeling. Regarding the treatment of 
these arising diseases, it has been proven that mechanical non-surgical therapy could 
be effective for peri-implant mucositis. However, when aiming to treat peri-implantitis, 
non-surgical treatment was found not to be effective (Renvert et al. 2008).  
Dental implants are not immune from mechanical or biological complications 
(Aljateeli et al. 2012) and as implant therapy becomes more widely used, peri-implant 
diseases arise with it. It has been reported that 22-28% of implants patients had at least 
one implant with progressive bone loss and 12.4% had bone loss extend beyond 1/3 of 
the implant thread (Atieh et al. 2012; De Bruyn et al. 2013; Fransson et al. 2005; 
Marrone et al. 2012).  
There are currently different techniques available for the treatment of peri-
implantitis, including but not limited to: citric acid, chlorhexidine, local and systemic 
antibiotics, hydrogen peroxide, air powder abrasive treatment, laser and photodynamic 
therapy, as well as implantoplasty. Nevertheless, even though a great variety of studies 
attempted to evaluate the efficacy of these treatment options, no conclusions could be 
made due to most studies differed markedly in design and the surface debridement 
treatment that was performed in combination of various regenerative techniques 

 
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(Claffey et al. 2008). Nonetheless, one of the key steps to achieve a favorable outcome 
is to properly detoxify the contaminated implant surface. 
Laser therapy in general, specifically Er:YAG laser  has demonstrated to be an 
effective treatment in peri-implantitis, due to the high bactericidal potential without 
causing detrimental alterations of the fixture surface (Kreisler et al. 2002; Quaranta et 
al. 2009). More recently, it has been demonstrated that Er:YAG laser at 100 mJ/mm2  
irradiation power represents a safe and effective setting to remove the contaminated 
surface without alteration or melting the implant surface. In addition, implant 
temperature did not reach harmful levels when water was used during laser irradiation 
and thus osseointegration was proved to occur in an animal model after treatment 
(Yamamoto and Tanabe 2013) . Given its potential benefits from several in-vitro and in-
vivo studies, a well-controlled randomized clinical trial is warranted. 
 
II. 
Objectives 
The primary objective of this study is to evaluate the effectiveness of using Er: YAG 
laser to assist in peri-implant defect debridement and implant surface decontamination 
prior to regenerative procedures in the treatment of peri-implant infections. To test this 
objective, three specific aims were developed and clinical measurements will be used 
as the primary outcome [including probing depths (PD), gingival index (GI), bleeding on 
probing (BOP), clinical attachment level (CAL), plaque-index (PI), radiographic bone fill 
(RBF), and 11 points Numeric Rating Scale (11-NRS), see Appendix A for more details]. 
Bacterial profile (BAC) and peri-implant crevicular fluid (PICF) biomarkers will be 
assessed as a secondary exploratory outcome to determine the dynamic change and 
the stability of the treatment.  
 
Specific Aims/Hypothesis: 
Specific Aim 1:  To compare the clinical benefit of Er:YAG laser-assisted peri-
implant defect debridement and surface detoxification with conventional 
mechanical debridement for regenerative therapy. 

 
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Null Hypothesis (H0): Er:YAG laser-assisted surgical debridement combined with 
regenerative therapy significantly improves clinical outcomes (PD, BOP, CAL, RBF)  
compared to conventional mechanical debridement alone. 
Alternative Hypothesis (H1): Er:YAG laser- assisted surgical debridement combined with 
regenerative therapy does not give additional clinical benefits compared to conventional 
mechanical debridement alone. 
 
Specific Aim 2: To evaluate whether Er:YAG laser-assisted regenerative surgical 
therapy can decrease bacterial load and alter microbial profile. 
Null Hypothesis (H0):  Er:YAG laser-assisted surgical therapy significantly decreases 
bacterial load and alter microbial profile compared to mechanical debridement alone. 
Alternative Hypothesis (H1):  Er:YAG laser-assisted surgical therapy does not 
significantly decrease bacterial load and alter microbial profile compared to mechanical 
debridement alone. 
 
Specific Aim 3: To analyze whether Er:YAG laser-assisted regenerative surgical 
therapy can impact the molecular profile of the peri-implant crevicular fluid (PICF) 
and the stability of the treatment. 
Null Hypothesis (H0):  Er:YAG laser-assisted regenerative surgical therapy significantly 
alter the molecular profile of the PCIF compared to mechanical debridement alone. 
Alternative Hypothesis (H1):  Er:YAG laser-assisted surgical therapy does not alter the 
molecular profile of the PICF compared to mechanical debridement alone. 
 
Specific Aim 4: To analyze whether the granulation tissue within the peri-implant 
defect can provide prognostic immunoscore for regenerative outcome and if 
Er:YAG laser has an impact on the landscape of the immunoscore. 
Hypothesis: Peri-implant defect has a specific immunoscore that can predict the 
outcome and stability of the regenerative therapy 
 
 
 

 
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Significance 
Treatment of peri-implantitis is still unpredictable, and one of the challenges is how we 
can detoxify the contaminated rough dental implant surface and restore osseous defect. 
Implant surface detoxification is of paramount importance in order to achieve re-
osseointegration following bone regeneration. Peri-implant defect debridement could be 
easier with the aid of the laser and it could potentially stimulate better healing. A better 
understanding of the effects using laser therapy over the titanium surface and osseous 
defects, will help to establish an evidence-based protocol to manage peri-implantitis. 
Patients can benefit from reestablishing a healthy condition over a previously 
contaminated implant. This prospective randomized controlled clinical trial will allow us 
to potentially develop an effective new protocol for the treatment of peri-implantitis 
infections.  
 
III. 
Materials and Methods 
A. Trial design 
There will be a total of 24 subjects (power calculation was establish at 10 patients per 
group, however, after considering the expected 20% dropout rate, 12 patients will be 
included in each group with at least one implant presenting peri-implantitis that meets 
the inclusion criteria.  Twelve patients will be randomly allocated for each group.  The 
control group will be treated with flap surgery, including implantoplasty of the implant 
surface above the interproximal bone level, debridement of osseous defect, and the 
implant surface with periodontal curettes; followed by human allograft placed in the 
defect and protected by collagen membrane. This procedure is the current standard of 
care. The test group will be treated the same as the control group with the aid of the 
laser application (Er:YAG), which is also routinely used in such treatment for clinicians 
who have access to dental lasers. 
 
B. Study settings 
This investigation will be conducted in the Department of Periodontics and Oral 
Medicine at the U-M School of Dentistry, Ann Arbor, Michigan, USA.   

 
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C. Eligibility 
1.  Pre-Screening Examination 
In order to identify potentially eligible subjects, the electronic database will be screened 
for the procedure code D6010, which corresponds to surgical placement of endosseous 
dental implants. All electronic records initially retrieved with the automated query, will be 
manually reviewed by study team members for inclusion and exclusion criteria in order 
to confirm eligibility of each subject. If they qualify, the subjects will receive an invitation 
letter requesting that they contact the study coordinator by telephone for information 
regarding participation in the study. In addition, the study coordinator will conduct a 
follow-up telephone call approximately two weeks later to the subjects receiving the 
invitation letter to inquire their potential interest to participate in the study.  The study 
coordinator will perform a brief telephone interview to determine whether or not the 
patient will qualify based on age and basic inclusion and exclusion criteria. Subjects 
indicating they may qualify would be scheduled for a screening examination 
appointment. In addition, a flyer will be posted in all of the clinics at the University of 
Michigan School of Dentistry.  
 
2.  Screening Examination V0 
Study personnel will provide each study candidate with a written informed consent form 
at the initial visit prior to administration of any research related procedures. Prior to 
enrolling a subject, study personnel will explain to each subject, the protocol, 
procedures, and objectives of the study, before obtaining consent.  Subjects will be 
given the opportunity to read the informed consent and ask questions.  Study personnel 
will answer all questions that the subject may have and ensure that the subject 
understands all aspects of the study by utilizing the teach-back method.  When the 
subject understands and is willing to participate in the clinical trial, he/she must sign and 
date the Institutional Review Board (IRB) approved Informed Consent Form. 
 
This screening visit will consist of the following procedures: 
-  Perform Informed consent regarding the study 

 
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- Medical history will be reviewed by system, using the School of Dentistry 
medical history questionnaire.  
- Vitals of blood pressure and heart rate will be taken.  
- Clinical measurements including PD, BOP, CAL, GI, PI will be taken. Also, a 
peri-apical radiographic will be performed on the affected implant if inclusion and 
exclusion criteria cannot be determined by the existing radiograph.  
 
If requested by the subjects, information concerning the study and their participation will 
be shared with their healthcare provider (general dentist or physician). Study personnel 
will obtain consent from the subject to release all pertinent information (Appendix B).  
This study protocol will conform with the ethical guidelines of the 1975 Declaration of 
Helsinki as reflected in obtainment of approval by the University of Michigan’s human 
subjects research review committee.  
 
 
Potential subjects will be carefully screened according to the inclusion and exclusion 
criteria as follows: 
 
Inclusion Criteria  
 
Subjects, aged 18 - 85 years 
 
Physical status according to the American Society of Anesthesiologists (ASA) I or II, which 
includes patients who are systemically healthy or suffer under mild to moderate, but well 
controlled systemic diseases. 
 
Subjects having a minimum of 1 dental implant with peri-implantitis. 
 
Dental implants with peri-implantitis ≥ 2 threads (or ≥ 2mm) exposed (infrabony defect) 
identified on the radiograph and pocket probing depth (PPD) ≥ 5mm, with bleeding on 
probing (BOP) and/or suppuration (pus) 
 
The implants are in function for at least 6 months 
 
Only rough surface implant will be included in this study 
Exclusion Criteria 

 
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 
Long-term use of antibiotics > 2 weeks in the past two months 
 
Obvious malpositioning of the dental implants 
 
Subjects taking medications known to modify bone metabolism (such as bisphophonates, 
corticosteroids, Hormone replacement therapy for menopausal women, parathyroid hormone, 
Denosumab, strontium ranelate) 
 
Pregnant females or those planning to become pregnant 
 
Subjects with a history of major diseases, oral cancer, sepsis or those having adverse outcomes 
to oral procedures in the past, will be excluded 
 
Mobility of dental implants 
 
History of alcoholism or drug abuse 
 
Current smokers 
 
Diseases of the immune system or any medical condition that may influence the outcome 
(uncontrolled diabetes (HbA1c >8) 
 
Uncontrolled systemic disease or condition known to alter bone metabolism, like Osteoporosis, 
Osteopenia, Hyperparathyroidism, Paget’s disease 
 
Premature Exclusion Criteria  
 
The researcher believes that it is not the best interest of the subject to stay in the study 
 
If the subject becomes ineligible to participate based on the exclusion criteria 
 
If the subject’s medical condition requires interventions which preclude involvement in the study 
(radiation therapy, chemotherapy, etc) 
 
If the subject does not follow study related instructions  
 
The study is suspended or canceled. 
 
 
D. Randomization 
Subjects will be randomized into one of the two groups. Twelve subjects will be 
allocated to the test group and another 12 subjects to the control group. The subject will 
not know which group he or she belongs as blinded allocation. Randomization will be 
determined by the last digit of the chart number (odd number goes to Group A and even 
number goes to Group B) but if one group has two subjects more than the other group, 
the next subject will automatically be enrolled in the lesser number group to ensure 
timely even distribution. The assignment of control or experimental group to Group A or 
B will be written by the primary surgeon (Principle Investigator) in a concealed envelop 
before recruiting patients. This ensure the clinical examiner be blinded throughout the 
study. This randomization will prevent any operator bias.  
 

 
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E. Pre-surgical Preparation V1 
Prior to the surgical visit, the subject will be asked if they are still willing to participate in 
the study and their medical history will be reviewed. Clinical measurements of PD, BOP, 
CAL, PI and GI will be recorded and peri-implant bacterial and crevicular fluid samples 
will be collected. A prophylaxis or a periodontal maintenance will be completed based 
on the subject’s prior diagnosis. In addition, a set of intraoral photographs will be taken, 
one standardized peri-apical radiograph, and maxillary and mandibular impressions will 
be taken. Articulating paper will be used to check the occlusal contact of the implant 
crown, if there is obvious heavy contact or lateral interference, occlusal adjustment will 
be made. 
 
F. Surgical procedure V2 
The subject will be asked if they are still willing to participate in the study and their 
medical history will be reviewed. The subject’s vitals of blood pressure and heart rate 
will be taken. During this visit, intraoral photos will be taken and all surgeries will be 
performed under local anesthesia using one or more of the following medications: 
 Lidocaine with epinephrine, (Xylocaine 2%®-Epinephrine 1:100,000 and 
1:50,000, Dentsply Pharmaceutical, York, PA, USA). 
 Articaine (Septanest 4%®-Epinephrine 1:100,000, Dentsply Pharmaceutical, 
York, PA, USA). 
 Mepivacaine (Polocaine 2%®-Levonordefrin 1:20,000, Dentsply Pharmaceutical, 
York, PA, USA). 
After local anesthesia, the width of the keratinized tissue around the implant will be 
measured by periodontal probe and the thickness of the peri-implant mucosa will be 
measured with endo file and stopper. 
1) Test and Control group procedures 
Open flap debridement and regenerative approach will be the treatment of choice for 
both groups. Intrasulcular incisions will be performed with a 15-C scalpel around the 

 
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implant to expose the contaminated surface. All the suprabony implant surface will be 
debrided with implantoplasty procedure as a standard of care and the specific treatment 
and outcome will be focused on the infrabony component of the defect. The 
experimental group will have the same treatment as the control group, but the laser will 
be used as a tool to aid in tissue debridement. In control group, the laser will also be set 
up for a fake application. 
 
(A) Control group: 
After the reflection of the flap, removal of the granulation tissue and mechanical 
debridement of infrabony defect and the implant surface with mechanical scalers will be 
performed. 
(B) Test group:  
The same protocol for the control group will be completed with the addition of the 
Er:YAG laser application to assist in mechanical debridement of the osseous defect and 
detoxify the implant surface.  
 
The granulation tissue within the peri-implant defect will be collected during the surgical 
debridement will be stored for Immunoscore analysis: 
Next-gen RNA sequencing will be performed on the peri-implant granulation tissue. This 
additional protocol serves two important scientific goals. First, we have built a novel 
machine learning tool, characterization of immune cell subsets using RNA-Seq data (Ci-
Seq). We will utilize Ci-Seq to comprehensively annotate the immune landscape of the 
granulation tissue. Specifically, we will resolve the percentages of different immune cell 
subsets and determine the weighted impact of each immune subset on the overall 
regenerative potential. Second, we will perform Gene Set Enrichment Analysis (GSEA) 
and differential genes expression profiling to identify key pathways that modulate 
patients’ response to regenerative treatment. 
 
2) Bone Graft and Membrane Placement (Both groups) 
After detoxification of the implant surface, mineralized bone allograft will be applied to 
both groups to fill the peri-implant defects. After the graft material is properly placed, an 

 
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absorbable cross-link collagen membrane will be trimmed to an appropriate size and 
shape to completely cover the implant site, and extend about 3-5mm beyond on the 
facial aspect. The membrane will be tucked under the sub-periosteal flap. Care will be 
taken to ensure that the membrane is resting on bone. Bone grafting and membrane 
placement for peri-implant infrabony defect is a standard of care procedure. 
 
3) Site closure 
Soft tissue will then be sutured with PTFE sutures (Cytoplast - PTFE suture) using 
either a simple interrupted technique or a criss-cross technique. Primary closure of the 
site will be attempted. The main objective of the sutures will be the stabilization of the 
wound. Sutures will be removed 10-14 days after.  
 
5) Post-Operative Care 
 All subjects will be prescribed 500mg of amoxicillin to take 3 times a day for ten days.  
If the subject is allergic to Amoxicillin, they will be prescribed 250 mg of Zithromax 6 
tablets total /sig. 2 tablets the 1st day and Q.D. (1 x per day) until gone. In addition, the 
subject will be prescribed 600 mg of ibuprofen, taken as needed, for pain control. 
Subjects will be instructed to rinse twice daily with chlorhexidine for 1 minute, 2 times 
per day for the first week. Following the first week, the subject will apply chlorhexidine 
with a Q-tip for another 3 weeks.  They will also avoid brushing or touching the area of 
implant placement for 2 weeks. Subjects will be informed that the sutures will be 
removed 2 weeks following the surgical appointment.   
 
G. Outcomes 
The primary outcome examined in this study will be the clinical results.  Secondary 
measurements will include radiographic assessments and post-op pain assessment. 
Exploratory measures will include biomarker profile and microbiological examination. 
 
2 (± 1) Week Follow-Up (V3) 

 
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The subject will return in 2 weeks (±1 week) for follow up care. The subject will be 
asked if they still are willing to participate in the study and their medical history will be 
reviewed. The removal of the sutures or partial removal will be determined depending 
on the healing..  The intensity and duration of post-operative pain assessment will be 
based on patient-reported days and scores using a 11-point numeric pain rating scale 
(NRS-11) (Jensen et al. 1989; Matys and Dominiak 2016). In addition, a standardized 
radiograph and intraoral photographs will be taken, BAC and PICF will be collected, and 
clinical measurements of GI and PI will be taken. 
 
4 (± 1) Week Follow-Up (V4) 
The subject will return in 4 weeks (±1 week) for follow up care. The subject will be 
asked if they still are willing to participate in the study and their medical history will be 
reviewed. If sutures are present, they will be removed. Intraoral photographs will be 
taken. BAC and PICF will be collected and clinical measurements of GI and PI will be 
taken. The subject will be mailed a  compensation of a $40 check from HSIP at the 
conclusion of this visit.   
 
12 (±1) Week Follow-Up (V5)  
The subject will return in 12 weeks (±2 week) for follow up care. The subject will be 
asked if they still are willing to participate in the study and their medical history will be 
reviewed. Intraoral photographs will be taken. A prophylaxis or a perio maintenance will 
be completed. In addition, BAC and PICF will be collected and clinical measurements 
including PD, BOP, CAL, PI, and GI will be taken. The subject will be mailed a  
compensation of a $40 check from HSIP at the conclusion of this visit.   
 
Re-evaluation (±2) 24 Week Follow-Up (V6) 
The subject will return in 24 weeks (±2 week) for follow up care. The subject will be 
asked if they still are willing to participate in the study and their medical history will be 

 
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reviewed. A standardized radiograph and intraoral photographs will be taken. A 
prophylaxis or a periodontal maintenance will be completed. In addition, BAC and PICF 
will be collected and clinical measurements including PD, BOP, CAL, PI, and GI will be 
taken. Peri-implant mucosal thickness and the width of the keratinized tissue will be 
measured. A final impression will also be taken. The subject will be mailed a  
compensation of a $40 check from HSIP at the conclusion of this visit.   
  
 
 
Radiographic assessment of the alterations in alveolar bone fill and crestal level will be 
done through the use of standardize peri-apical x-rays. One peri-apical x-ray may be 
taken at the screening visit (V0), if there is no current x-ray to reference or if inclusion 
and exclusion criteria cannot be determined. Standardized peri-apical x-rays will be 
obtained at three different time points (before surgery (V1), two weeks post-surgery 
(V3), and at the re-evaluation 24 week visit (V6). The ridge dimensions obtained from 
these x-rays will then be compared to the baseline measurements to identify changes. 
 
II) Microbial profile (BAC) and Peri-implant crevicular fluid (PICF) analysis 
PICF samples will be obtained at Pre-surgical Preparation (V1), 2 week (V3), 4 week 
(V4), 12 week (V5) and re-evaluation-24 week (V6). These samples will be used for 
bacterial DNA and biomarker analysis. Samples will be collected with sterile paper point 
and strips. The sites sampled will be isolated with cotton rolls to keep the area dry and 
free of salivary contamination. A gentle air blow will be applied perpendicularly before 
sampling. For biomarker analysis, a perio strip will be inserted into the crevice until mild 
resistance is felt and left for 30 seconds. For microbial profile, a paper point will be 
inserted for 10 seconds. Two sampling per assays will be collected with 90-second 
intervals. The paper point and paper strip will be carefully removed to avoid 
contamination from contact with other tissues and to avoid trauma to the site. The 
samples will then be transferred to sterile micro centrifuge tubes containing protease 
inhibitors and stored at – 80 °C until further processing of the biomarkers analysis. All 

 
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the sampling procedures are established and published by our group (Kinney et al. 
2014; Wang et al. 2016). 
 
 
Examiners calibration 
Calibration of the examiner will be performed through a training exercise with a 
calibrated examiner prior to the beginning of the study.  The calibrated examiner will 
observe and confirm the accuracy of the clinical measurements of PI, GI, and PD of the 
study examiner (>0.8 agreement between examiners will be considered calibrated). 
 
 
IV. 
Statistical Analysis:  
Sample Size 
This study will have a sample size of 24 subjects, 12 in each of the groups.    
The study power was calculated using the software nQuery Advisor v7.0 (Statistical 
Solutions, Saugus MA, USA).  A difference of 2.0mm between groups was considered 
as clinically significant.  The power value was evaluated for probing depths at 6 months 
after the surgery.  A “p” value of less than 0.05 will be considered statistically significant.  
 
Data Analysis 
Mean values, standard deviations, and medians will be calculated for clinical and 
radiographic measurements.  We will examine the univariate association of the probing 
depths with the detoxification method used. We will also attempt to examine the 
association of bacterial load with various combinations of clinical and radiographic 
parameters using multiple logistic regression, but acknowledge that we will be restricted 
by our sample size to at most two or three predictors in any model. Changes of the 
parameters over time within each group as well as differences between groups will be 
analyzed using the repeated measure of analysis of variance. 
 
 
 
 

 
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V. 
Regulatory Considerations  
 
Surgeries and related procedures would be performed at no cost for the patients 
included in the study. Three free dental cleaning and $120 compensation will be given 
to the patients. 
 
 
Study reporting  
1. Adverse events  
Any adverse event, including both observed or volunteered problems, complaints, or 
symptoms, are to be recorded on the Adverse Event Case Report Form.  The intensity 
of the adverse event will be characterized as mild, moderate or severe as follows:  
 
MILD events are usual transient, requiring no special treatment, and do not interfere 
with the subjects daily activities.  
 
MODERATE events traditionally introduce a low level of inconvenience of concern 
to the subject and may interfere with daily activities, but are usually ameliorated by 
simple therapeutic measures.  
 
SEVERE events interrupt a subject’s usual daily activity and traditionally require 
systemic drug therapy or other treatment.  
When intensity changes occur more frequently than once a day, the maximum intensity 
for the event should be listed.  If the intensity category changes over a number of days, 
then these mini-events or changes should be recorded separately (i.e. having distinct 
onset days).  
The investigator will determine the relationship of the adverse event to the study test 
material.  

 
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One of the following determinations will then be used to document the relationship of 
the adverse event to the study test material:  
 NOT RELATED 
 POSSIBLE 
 PROBABLE  
ANY SERIOUS AND UNEXPECTED ADVERSE EVENT INCLUDING 
HOSPITALIZATON OR DEATH DUE TO ANY CASE, WHICH OCCURS DURING 
THIS INVESTIGATION, WHETHER OR NOT RELATED TO THE STUDY, MUST BE 
REPORTED IMMEDIATELY (WITHIN 24 HOURS) TO THE PRINCIPAL 
INVESTIGATOR.  
Reports of serious or unexpected adverse events will be made immediately by 
telephone or fax to:  Dr. Jeff Wang (734)-647-6175 
This telephone report or fax must be followed within 5 days by a written summary fully 
documenting the event in order to permit the Principal Investigator to file a report which 
satisfied regulatory guidelines.  
All serious and unexpected adverse events associated with the use of the study test 
material will be immediately reported to appropriate regulatory agencies by the Principal 
Investigator.  
Adverse events reporting will proceed according to the University of Michigan guidelines 
for standard AE reporting. 
  
2. Discontinuation and replacement of subjects  
 Any subject found to have entered the study in violation of this protocol will be 
withdrawn from the study after discussion with the Principal Investigator  

 
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 An effort will be made to determine why any subject discontinues the study 
prematurely.  This information should be recorded on the appropriate case report 
form.  
 As stated in the informed consent, all subjects reserve the right to withdraw from the 
study at any time.  
 Any female subject that becomes pregnant during the study will be withdrawn from 
the study.  
 Any subject whose condition changes after entering the study, so that he or she no 
longer meets the inclusion or exclusion criteria, will be withdrawn from the study.  
 Any subject who requires the use of an unacceptable concomitant medication will be 
withdrawn from the study.  
 The investigator will discontinue any subject from the study if, in the investigator’s 
opinion, it is not in the subject’s best interest to continue.  
 The date the subject is withdrawn from the study and the reason for discontinuation 
will be recorded on the case report form.  
 When a participant is lost to follow-up, that is, fails to return for study visits, a 
reasonable effort should be made to contact the participant in order to determine 
why the subject failed to return.  This information will be documented on the case 
reporting form (CRF).  When a participant is withdrawn from the study, regardless of 
the cause, all evaluations required at the scheduled end of study day should be 
performed.  
 Subjects discontinued for adverse events will not be replaced. 
3. Data reporting and case report forms (CRFs)  
Data reflecting participant experience with the protocol under investigation will be 
reported to the Principal Investigator and the data recorded on CRFs 
CRFs will be signed and dated by the investigator or a designated representative and 
filled out in black ink.  If an entry on a CRF requires change, the correction will be made 
as follows:   

 
Version 9 Page 21 
 
a. A single line will be drawn through the incorrect entry. 
b. The date will be entered and the change initialed. White-out or erasure on CRFs will 
not be permitted under any circumstance.  
All fields and blanks must be completed.  The following abbreviations will be used when 
values or answers cannot be provided:  NA=not applicable; ND=not done, UNK=not 
known  
Completed original CRFs will be collected by the Principal Investigator. CRF must be 
submitted for each subject.  
Data entry will proceed directly from the case report form.  The data, as well as 
group/subject identification, will be made available to the investigator at the conclusion 
of the study.  
4. Study monitoring  
The investigator will periodically audit all CRFs and corresponding portions of U-M 
School of Dentistry records of each study participant and has a monitoring plan with the 
U-M Institutional Review Board.  The monitoring will provide the Principal Investigator 
the opportunity to evaluate the progress of the study and to verify the accuracy and 
completeness of the CRFs; assure that all protocol requirements, applicable FDA 
regulations and investigator’s obligations are being fulfilled, and to resolve any 
inconsistencies in the study records.  The Principal Investigator may stop the study if it 
is observed that the protocol or sound clinical practices are not being followed.  The 
Principal Investigator may exclude subjects from the study if review of their records 
indicates violations of the protocol or if there are other reasons to believe that their 
inclusion would jeopardize the validity of the study.  
B. 
Regulatory Considerations  
1. Institutional Review Board (IRB) 

 
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The protocol and informed consent for this study must be reviewed and approved by an 
appropriate IRB before enrollment of participants into the study.  
It is the responsibility of the investigator to assure that all aspects of the institutional 
review are conducted in accordance with current Federal Regulations.  A letter with IRB 
approval for the protocol must be received by the Principal Investigator before the 
initiation of the study. Amendments to the protocol will be subject to the same 
requirements as the original protocol.  At each annual protocol renewal, an updated 
report of the numbers of participants and any adverse events will be provided to the 
IRB.  
After completion or termination of the study, the investigator will submit a final report to 
the IRB.  This report should include any deviations from the protocol, the number and 
types or participants evaluated, the number of participants who discontinued, including 
reasons, results of the study, adverse events, and a conclusion summarizing the 
results.  
2. Informed Consent  
A signed, written informed consent must be obtained from each subject before he or 
she enters the study after he or she has been given verbal and written information 
describing the nature and duration of the study.  Subjects are not to be screened or 
treated until an informed consent has been obtained.  The signed informed consent will 
be retained with the study records.  Each subject will also be given a copy of his/her 
informed consent.  
As long as patient information is kept within the University of Michigan, it will be 
protected by the Health System’s privacy policies.  Information about these policies, are 
available at http://www.med.umich.edu/hipaa/npp.htm.  Patient information will be 
protected according to the privacy regulations of the federal Health Insurance Portability 
and Accountability Act of 1996 (HIPAA). 
3. Access of Records  

 
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The investigator understands that the office and hospital records of subjects entered in 
this study will be required to be available under the supervision of the investigator or a 
designated representative for inspection by the FDA.  All subject related information 
provided to the FDA will be done so without subject names or other identifying 
information.  
4. Retention of Data  
The investigator will maintain adequate records for the study including participant’s 
CRF, medical records, informed consent forms, safety reports, information regarding 
participants who discontinued, and any other pertinent data.  All records will be 
maintained in a locked fireproof storage room to which only study investigators have 
access.  
These records will be available to copying and inspection if requested by a properly 
authorized employee of the Department of Health and Human Services, under the 
supervision of the investigator or a designated representative and in accordance with 
federal regulations.  
5. Deviation from the Protocol  
The investigator will not deviate from the protocol without obtaining written approval 
from the IRB.  In medical emergencies, the investigator will use medical judgment and 
will remove the participant from immediate hazard, then notify the IRB regarding the 
type of emergency and course of action taken.  Any other changes or deviation in the 
protocol will be made as an amendment to the protocol and must be approved by the 
IRB before being implemented.  
6. Reports  
The investigator will make an accurate and adequate written progress reports to the IRB 
at appropriate intervals not exceeding one year.  

 
Version 9 Page 24 
 
The investigator will make an accurate and adequate special report to the IRB on any 
serious unexpected or life-threatening adverse event or death occurring in relationship 
to the study whether regarded as study-related or not.  
On completion of the study, the investigators will prepare a final report of the study 
results.  
 
APPENDIX A 
 
Clinical Measurements and Outcomes 
 
A periodontal probe will be used for all clinical measurements.  PD will be measured 
from the gingival margin to the base of the pocket in millimeters.  All PD measurements 
will be rounded to the nearest millimeter. Bleeding on probing will be recorded 
dichotomously as 0 or 1 (0=no, 1=yes). Patient –reported outcome will also be 
assessed using the 11 points Numeric Rating Scale (NRS-11) for the post-operative 
pain assessment. 
 
PD and BOP will be recorded at six sites per implant (mesio-buccal, buccal, disto-
buccal, mesio-lingual, lingual, disto-lingual).  A bleeding index for each patient will be 
determined by dividing the total BOP score of each individual by the number of sites 
examined  
 
The PI (O’Leary et al 1972) will be measured at six surfaces of each tooth. A PI for each 
patient will be determined by dividing the total plaque score of each individual by the 
number of teeth examined  
 
The GI will at midfacial mucosa tissue will be assessed according to Löe (Löe 1967) 
with the following scores: 
 Score 0: Normal gingiva. 
 Score 1: Mild inflammation, slight change in color, slight edema, no bleeding on 
probing. 

 
Version 9 Page 25 
 
 Score 2: Moderate inflammation, redness, edema, glazing, bleeding on probing. 
 Score 3: Severe inflammation, marked redness, edema, ulceration and tendency to 
spontaneous bleeding. 
 
 
 
 
 
 
APPENDIX B 
 
Consent to Release Information To The Subject’s Dentist 
Patient’s Initials/Number:_________________________ 
Date:________________ 
Title of Study:  Laser-Assisted Regenerative Surgical Therapy for Peri-implantitis: 
A Randomized Controlled Clinical Trial 
University of Michigan School of Dentistry 
Department of Periodontics and Oral Medicine 
Principal Investigators: Jeff Wang, DDS, DMSc 
Study Coordinator:  Michelle Arnett, RDH, MS 
 
 
 
 
 
 
CONSENT OF THE SUBJECT 
By signing this document, you are agreeing that we inform your general dentist that you 
are participating in this study.  Information regarding the surgical treatment and other 
pertinent information will be given.  This information will be given by mail or by phone.  
You will be given a copy of this document for your records and one copy will be kept 
with the study records.  Be sure that all your questions concerning the study have been 
answered and understood. 
 
I have read of the information of the information given above.  I understand the meaning 
of this information. I hereby voluntarily consent to release my information to my general 
dentist.   
 
 
___________________________________________ 
Name of Adult Subject of Research (Print) 
 
 
 
 
 
 
 
 
__________________________________________ ___________________ 
Signature of Adult Subject of Research 
 
 
 
Date 
 

 
Version 9 Page 26 
 
____________________________________________ 
____________________ 
Study Investigator/Coordinator Signature 
 
 
 
Date 
 
 
Name of dentist: ______________________________ 
 
Address:             ______________________________ 
 
 
 
       ______________________________ 
 
Phone number:  ______________________________

 
Version 9 Page 27 
 
TABLE I 
Schedule of events 
VISIT 
Screening & 
Enrollment 
Pre-Surgical 
Preparation 
Surgery  
Day 
Post-op 
Re-evaluation 
24wk 
2wk 
4wk 
12wk 
Visit no. 
V0 
V1 
V2 
V3 
V4 
V5 
V6 
Timeline 
Prior to V1 
 before BL 
Baseline (BL) 
2±1wks 
from BL 
4±1wks from 
BL 
12±2wks 
from BL 
24±2wks from BL 
Informed consent  
Sign 
 
X 
X 
X 
X 
X 
X 
Medical history 
X 
X 
X 
X 
X 
X 
X 
Blood pressure and 
heart rate 
X 
 
X 
 
 
 
 
X-ray 
*S(standardized) 
X  
(If needed) 
X(S) 
 
X(S) 
 
 
X(S) 
Suture removal 
 
 
 
X 
X 
*If present 
 
 
Pain assessment 
(NRS-11) 
 
 
 
X 
 
 
 
Prophylaxis/Perio 
Maintenance 
 
X 
 
 
 
X 
X 
Impressions 
 
X 
 
 
 
 
X 
Photograph 
 
X 
X 
X 
X 
X 
X 
Granulation tissue 
sampling 
 
 
X 
 
 
 
 
BAC + PICF 
 
X 
 
X 
X 
X 
X 
Clinical measures 
(PD, BOP, PI, CAL, 
GI) 
X 
 
X 
 
 
X 
*Only GI 
& PI 
X 
*Only  
GI & PI 
X 
 
X 
Peri-implant mucosal 
thickness 
 
 
X 
 
 
 
X 

 
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Subject 
compensation  
 
 
 
 
X 
X 
X 

 
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FIGURE 1 
 
Study outline and sequence of events 
 
 
 
 
 
 
 
≥
≥
β
α
 
 

 
Version 9 Page 30 
 
BIBLIOGRAPHY 
VI. 
References 
 
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Jensen MP, Karoly P, O'Riordan EF, Bland F, Jr., Burns RS. 1989. The subjective experience 
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