Citation
Orthodontic Tooth Movement with Aligners Using AcceleDent(R) Aura Device versus a Sham Device in Adults

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Title:
Orthodontic Tooth Movement with Aligners Using AcceleDent(R) Aura Device versus a Sham Device in Adults a Single- Center, Randomized Controlled Clinical Trial
Creator:
Sedeno, Melissa Alfonso
Place of Publication:
[Gainesville, Fla.]
Florida
Publisher:
University of Florida
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Language:
english
Physical Description:
1 online resource (36 p.)

Thesis/Dissertation Information

Degree:
Master's ( M.S.)
Degree Grantor:
University of Florida
Degree Disciplines:
Dental Sciences
Dentistry
Committee Chair:
WHEELER,TIMOTHY T
Committee Co-Chair:
MCGORRAY,SUSAN P
Committee Members:
RODY,WELLINGTON JOSE,JR
Graduation Date:
4/30/2016

Subjects

Subjects / Keywords:
ATMs ( jstor )
Bones ( jstor )
Dental models ( jstor )
Orthodontics ( jstor )
Orthods ( jstor )
Pain perception ( jstor )
Rats ( jstor )
Teeth ( jstor )
Tooth movement ( jstor )
Vibration ( jstor )
Dentistry -- Dissertations, Academic -- UF
acceledent -- aligners -- orthodontics -- vibration
Genre:
bibliography ( marcgt )
theses ( marcgt )
government publication (state, provincial, terriorial, dependent) ( marcgt )
born-digital ( sobekcm )
Electronic Thesis or Dissertation
Dental Sciences thesis, M.S.

Notes

Abstract:
The AcceleDent(R) Aura device was devised to accelerate tooth movement based on the premise that vibration can accelerate wound healing via angiogenesis and increase bone remodeling rates. The purpose of this study was to investigate the effect of the AcceleDent(R) Aura device over time on total tooth movement and pain perception using a human tooth movement model with aligners. This was a prospective, single-center, randomized controlled crossover study. One maxillary central incisor was moved anteriorly 1.98mm using 6 Zendura(R) plastic aligners. Subjects were randomly assigned to the active or sham device. Crossover occurred halfway through the study. 16M, 23F completed the protocol. A mean of 0.81mm (SD= 0.23) actual tooth movement occurred with the active device, and 0.90mm (SD= 0.22) with the sham device, with no significant difference between them. No significant difference in pain reduction was found between devices. The conclusions of this study are that the AcceleDent(R) Aura device was not found to accelerate the rate of tooth movement or alter pain perception using this human tooth movement model with Zendura(R) plastic aligners. ( en )
General Note:
In the series University of Florida Digital Collections.
General Note:
Includes vita.
Bibliography:
Includes bibliographical references.
Source of Description:
Description based on online resource; title from PDF title page.
Source of Description:
This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Thesis:
Thesis (M.S.)--University of Florida, 2016.
Local:
Adviser: WHEELER,TIMOTHY T.
Local:
Co-adviser: MCGORRAY,SUSAN P.
Electronic Access:
RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2017-05-31
Statement of Responsibility:
by Melissa Alfonso Sedeno.

Record Information

Source Institution:
UFRGP
Rights Management:
Copyright Melissa Alfonso Sedeno. Permission granted to the University of Florida to digitize, archive and distribute this item for non-profit research and educational purposes. Any reuse of this item in excess of fair use or other copyright exemptions requires permission of the copyright holder.
Embargo Date:
5/31/2017
Classification:
LD1780 2016 ( lcc )

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ORTHODONTIC TOOTH MOVEMENT WITH ALIGNERS USING ACCELEDENT AURA DEVICE VERSUS A SHAM DEVICE IN ADULTS: A SINGLE CENTER, RANDO MIZED CONTROLLED CLINICAL TRIAL By MELISSA ALFONSO SEDE O A THESIS PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE UNIVERSITY OF FLORIDA 2016

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2016 Melissa Alfonso Sedeo

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To my family for always encouraging and believing in me and to my husband Eddy, for his never ending patience and support

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4 ACKNOWLEDGMENTS I thank my mentors Dr. Timothy Wheeler, Dr. Wellington Rody, Dr. Calogero Dolce, and Dr. Susan McGorray for their support throughout the residency and resea rch process. I would also like to thank Marie Taylor for serving as the project manager and Kyle Houston for all of his computer engineering work. I thank my parents for constantly encouraging me to reach to new heights and for always believing in me I thank my husband for supporting me day in and day out. I also thank God for giving me the strength and perseverance to follow my dreams.

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5 TABLE OF CONTENTS page ACKNOWLEDGMENTS ................................ ................................ ................................ .. 4 LIST OF TABLES ................................ ................................ ................................ ............ 6 LIST OF FIGURES ................................ ................................ ................................ .......... 7 ABSTRACT ................................ ................................ ................................ ..................... 8 CHAPTER 1 INTRODUCTI ON ................................ ................................ ................................ ...... 9 Background ................................ ................................ ................................ ............... 9 Specific Objectives or Hypotheses ................................ ................................ ......... 11 2 MATERIAL AND METHODS ................................ ................................ .................. 12 Trial Design ................................ ................................ ................................ ............. 12 Participants, Eligibilit y Criteria, and Setting ................................ ............................. 12 Interventions ................................ ................................ ................................ ........... 13 Outcomes ................................ ................................ ................................ ............... 14 Sample Size Calculation ................................ ................................ ......................... 16 Rand omization ................................ ................................ ................................ ........ 16 Blinding ................................ ................................ ................................ ................... 16 Statistical Analysis (Primary and Secondary Outcomes, Subgroup Analyses) ....... 17 Error of the Method ................................ ................................ ................................ 17 3 RESULTS ................................ ................................ ................................ ............... 20 Participant Flow and Recruitment ................................ ................................ ........... 20 Baseline Data ................................ ................................ ................................ ......... 20 Numbers Analyzed, O utcomes, and Estimation ................................ ...................... 20 Harms ................................ ................................ ................................ ..................... 22 4 DISCUSSION ................................ ................................ ................................ ......... 26 Interpretation C onsistent with Results and Other Relevant Evidence ..................... 26 Limitations ................................ ................................ ................................ ............... 29 Generalizability ................................ ................................ ................................ ....... 30 5 CONCLUSIONS ................................ ................................ ................................ ..... 31 LIST OF REFERENCES ................................ ................................ ............................... 32 BIOGRAPH ICAL SKETCH ................................ ................................ ............................ 36

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6 LIST OF TABLES Table page 3 1 Demographics of Subject Population, n=39. Mean age 30.6 years old (SD: 5.8; Range 20.2 40.9). ................................ ................................ ....................... 23 3 2 Actual tooth movement (ATM) in mm. ................................ ................................ 23 3 3 Overall ATM based on device type. ................................ ................................ .... 24 3 4 Device and aligner compliance rates. ................................ ................................ 24 3 5 Range of individual averaged VAS pain ratings before and after device use by week. ................................ ................................ ................................ ............. 25 3 6 Differences in pain perception calculated as change while using the active device minus the change while using the sham device. Positive value indicates more reduction using the Active device. ................................ .............. 25

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7 LIST OF FIGURES Figure page 2 1 Visit overview. ................................ ................................ ................................ ..... 18 2 2 Images from OrthoAnalyzer A. Models post processing. B. Separation of the teeth and long axes indicators. C. Selection of the target tooth in preparation for movement. D. Example of anterior movement of target tooth 0.33mm. Photos courtesy of Kyle Houston. ................................ ....................... 18 2 3 Images from Ortho Insight 3D Orthogonal planes constructed using stable reference points on posterior teeth and used to measure target tooth movement. Photos courtesy of Kyle Houston. ................................ ................... 19 3 1 Flow chart of study sample. ................................ ................................ ................ 22 3 2 ATM over time. ................................ ................................ ................................ ... 23 3 3 Medians of individual averaged VAS pain ratings before and after device use by week. ................................ ................................ ................................ ............. 24

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8 Abstract of Thesis Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Master of Science ORTHODONTIC TOOTH MOVEMENT WITH ALIGNERS USING ACCELEDENT AURA DEVICE VERSUS A SHAM DEVICE IN ADULTS: A SINGLE CENTER, RANDO MIZED CONTROLLED CLINICAL TRIAL By Melissa Alfonso Sedeo May 2016 Chair: Timothy T. Wheeler Major: Dental Sciences Orthodontics The AcceleDent Aura device was devised to accelerate tooth movement based on the premise that vibration can accelerate wound healing via angiogenesis and increase bone remodeling rates. T he purpose of this study was t o investigate the effect of the AcceleDent Aura device over time on total toot h movement and pain perception using a human tooth movement model with aligners. This was a p rospective, single center, randomized controlled crossover study. One maxillary central incisor was moved anteriorly 1.98mm using 6 Zendura plastic aligners. Sub jects were randomly assigned to the active or sham device. Crossover occurred halfway through the study. 16M, 23F completed the protocol. A mean of 0. 81 mm (SD= 0.23) actual tooth movement occurred with the active device, and 0.90mm (SD= 0.22) with the sha m device, with no significant difference between them. No significant difference in pain reduction was found between devices. The conclusions of this study a re that the AcceleDent Aura device was not found to accelerate the rate of tooth movement or alter pain perception using this human tooth movement model with Zendura plastic aligners.

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9 CHAPTER 1 INTRODUCTION Background Orthodontic treatment has the potential to result in a number of commonly known sequelae such as white spot lesions, broken brackets, root resorption and poor oral hygiene E xtended treatment times can lead to these problems in addition to non compliance and patient burnout. Shortening the length of treatment time may reduce these risks in orthodontic treatment and improve a patient overall orthodontic experience. The three stages of orthodontic tooth movement (OTM) consist of initial tooth displacement hyalinization within the PDL and a period of bone resorption and linear tooth movement. 1 3 Several factors affect osteoblast formation and osteoclast differentiation each play ing important roles in bone remodeling. Each stage and factor provide s an opportunit y to modify tooth movement. Pharmacologic versions of these factors such as parathyroid hormone 4 prostaglandin E 1 5 and E 2 6 macrophage colony stimulating factor, 7 and RANKL 8 have been shown to accelerate OTM. Other proposed methods to accelerate OTM include use of optimal forces, 2 low level l aser therapy, 9 11 l ight e mitting diodes, 12 corticotomies, 13 and micro osteoperforations 14 None of these methods ha s been found to be ideal, with several of them having drawbac ks such as systemic side effects or perceived invasivenes s. Skeletal bones constantly undergo a physiologic cycle of deposition and resorption 15,16 similar to bone remodeling during OTM. Low molecular high frequency (LMHF) v ibration has been found to increase the rate of angiogenesis 17 enh ance bone density 18 21 and improve fracture 18,22,23 and bone wound healing Increas es in

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10 osteoblasts and decreases in ost eoclasts were found when applied to craniofacial sutures. 24 Th e use of 60Hz intermit tent vibration applied to maxillary first molars being moved with a spring in rats resulted in s ignificantly greater OTM, increased osteoclasts, increased R ANKL expression, and a faster onset compared to controls. No increased risk of root resorption was noted resulting in the conclu sion that vibration may be a potential method to accelerate OTM with minimal negative side effects. 25 AcceleDent Aura (OrthoAccel Technologies, Inc Bellaire, TX) is a new device marketed to accelerate the rate of OTM and is FDA approved for use in fixed orthodontic treatment The device consists of a mouthpiece that the patient bite s on attached to an extraoral activator. The device vibrates at 30Hz, 2 5 g (0.2 5 N) and is intended to be used for 20 minutes daily. 26,27 The first trial s using this device in humans showed no increased root resorption 26 6 7% compliance and improved satisfaction and discomfort over time. 27 P avlin et al. showed 0.37mm more OTM per month an increase of 48.1% compared to controls using the AcceleDent Aura device during the retraction of upper canines into upper first premolar extraction sites 28 Conversely, Woodhouse et al. found no difference in initial alignment rates when using the device. 29 Th e effect of vibration on OTM and the biological basis for potential effects remain unclear to the orthodontic community. The emphasis of esthetics in dentistry has led to the evolution of clear aligner orthodontic treatment The use of clear aligners has the benefit s of improved ease in maintaining healthy gingival tissues and good oral hygiene. 30 While this has increased adult electivity for orthodo ntic treatment, many challenges are faced when compared to orthodontic treatment with fixed appliances Overall accuracy of OTM using Invisalign

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11 has been found to be 41% of ClinCheck predictions 31 resulting in the need for mid course corrections. An OTM model using clear aligners has been developed and utilized in a number of studies at the University of Florida College of Dentistry Department of Orthodontics The model consists of prescribing a specifie d amount of bodily anterior movement to one maxillary central incisor. 32 36 The conclusion drawn from these studies is that several factors can affect the amount of OTM achieved using Invisalign clear aligner s includ ing sex, age amount of presc ribed movement (0.25 to 0.5mm per aligner), frequency of changing the aligner, and the plastic material used to fabricate the trays. Based on these studies, t he amount of OTM that can be expected while moving one maxillary incisor facially using Invisalig n aligners ranges from 41.5% to 77.4 % of the amount prescribed The use of LMHF vibration has not been evaluated in conjunction with clear aligner therapy Specific O bjectives or H ypotheses The purpose of this study was to determine the effect of the Acc eleDent Aura device on total tooth movement in humans using clear aligners for orthodontic treatment. We also aimed to determine if any differences could be detected when applying this device to a tooth that had already been moving for 6 weeks or to a tooth that continued to move for 6 weeks without vibration after 6 weeks of device use and tooth movement. The null hypothesis was that there would be no difference in amount of OTM between the active and sham devices. Our secondary aim was to determine the effect of the AcceleDent Aura device on perceived pain among patients with clear aligner orthodontic therapy.

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12 CHAPTER 2 MATERIAL AND METHODS Trial D esign This study was designed as a single center randomized, control led cross over, clinical tria l with an allocation ratio of 1:1 No changes to trial design were made after the study began. A pilot study was previously conducted by the same research group and reported by Mazzuoccolo 37 The pilot study consisted of 6 subjects with similar proc edures as the current trial to ca librat e study personnel. Data from the pilot study was not included in the results for this larger study. Participants, E ligibility C riteria, and S etting This trial was approved by the Western Institutional Review Board (Olympia, Washington, IRB # 20131856) and was listed on ClinicalTrials.gov. Participants were recruited from the University of Florida All of the study procedures were completed at the Un iversity of Florida College of Dentistry Orthodontic Research Clinic and monitored by Juno Clinical Research Services, LLP (San Antonio, TX) The following inclusion criteria were used: (1) 18 to 40 years old seeking orthodontic treatment that could be co mpleted within 2 years with fixed appliances or aligners; (2) adult dentition with all anterior maxillary teeth and two posterior teeth bilaterally consisting of any combination of one premolar and one molar per side ; (3) a t least one maxillary central inc isor positioned to allow antero posterior movement of 1.98mm of crown tipping ; (4) n ormal pulp vitality and healthy periodontal tissues based on an intraoral exam ; (5) g ood health based on a medical history ; (6) w illingness and ability to comply with study procedures, attend study visits, and complete the study ; and (7) t he ability to understand and sign a written informed consent The following comprised the exclusion criteria: (1) s evere

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13 malocclusion requiring more than 2 years of orthodontic treatment or surgical intervention to correct ; (2) m ore than 3mm pocket depth or more than 1mm of recession on upper anterior teeth, indicating significant periodontal disease ; (3) a ctive caries not under ca re of a dentist or periodontist; (4) c hronic daily use of a ny non steroidal anti inflammatory medication, estrogen, calcito nin, or corticosteroids; (5) current smoker or having smoked in the last 6 months ; (6) p regnant women determined by a positive urine pregnancy test, taken prior to radiographic exposure ; and (7) a ny condition which could result in increased risk to the subject as determined by the investigator. Interventions Subjects were seen for biweekly visits from day 0 to 84. On day 0, the first aligner was provided to subjects with 0.33mm anterior movem ent of the target tooth prescribed. The subjects were provided with either the sham or active AcceleDent Aura device and were instructed to use the device for 20 minutes daily A full overview of procedures done at each visit is detailed in Figure 2 1 Each subsequent aligner prescrib ed an additional 0.33mm of tooth movement, for a total of 1.98mm over 6 aligners changed biweekly. T he device typ e was s witched on day 42 The active and sham AcceleDent Aura devices looked and operated the same, with the exception that the sham device made a humming noise without the vibrational frequency. After expressing interest in the study, subjects attended Preliminary Visit 1 consisting me dical history, and performing an intraoral exam. I nclusion and exclusion criteria were reviewed and the target maxillary central incisor tooth was chosen. The criteria for choosing the target tooth consisted of the ability to achieve the desired movemen t with

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14 consideration to the initial position of both incisors. If both met this criterion the target tooth was chosen randomly by the p rincipal i nvestigator. Preliminary Visit 2 consisted of a digital intraoral scan using the 3Shape Trios (Copenhagen, D enmark). This scan was used to fabricate the aligners for the study. This visit also included full intraoral and extraoral photos and a full Cone Beam Computed Tomography scan (CBCT) (Imaging Sciences International, iCAT, Hatfield, PA, USA). All women w ere required to test negative for pregnancy prior to the CBCT. Ste re olithograp h ic (.STL) files were generated from the initial digital scan of the maxillary and mandibular arches and imported into OrthoAnalyzer (3Shape, Copenhagen, Denmark). Using the software t he long axis of the target tooth was identified based on crown anatomy. The tooth was moved anteriorly perpendicular to this long axis in increments (Figure 2 2) Stereolithographic files were genera ted for each of the following amounts of movement: 0.33mm, 0.66mm, 0.99mm, 1.32mm, 1.65mm, and 1.98mm. These .STL files were then sent to NorthStar Orthodonti cs, Inc. (Park Rapids MN, USA) for 3D printing and aligner fabrication using Zendura (Bay Mater ia ls, LLC, Fremont, CA) plastic. Outcomes The digital scan taken at Preliminary Visit 2 was used as the baseline to determine amount of OTM from s cans taken on days 14, 28, 42, 56, 70, and 84 For each time point the .STL file from the intraoral scan was imported into OrthoAnalyzer and processed similarly to the Preliminary Visit 2 scan. Once processed, the .STL file was exported and imported into Ortho Insight 3D ( Motion View Software, LLC Chattanooga, TN). Using this software, three orthogonal refer ence planes ( Figure 2 3 ) were generated based on the superimposition of stable reference structures on

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15 posterior teeth OTM was calculated in three dimensions, measured by the di fference in measurements from these three planes to points on the target toot h between time points Amount of OTM was calculated as Projected Tooth Movement (PTM) and Actual Tooth Movement (ATM). PTM was defined as the amount of tooth movement that occurred strictly in the anterior intended direction. ATM was defined and measured as the amount of tooth movement that occurred regardless of the direction including other movements, such as tipping and intrusion. ATM was used to compare groups as it included total movement and outcomes were comparable to PTM A systematic i ntraoral exam was performed at every biweekly visit to monitor the health of the teeth oral soft tissues a nd periodontium Pulp testing of # 7, # 8, # 9, and # 10 was done on days 0, 42, and 84 by air drying the tooth spraying a c otton tip applicator with E ndo Ice Refrigerant Spray and applying it to the center of the crown. On these same days periodontal probing of these teeth was also performed using the Florida Probe and pocket depth and bleeding on probing were recorded using FP32 software (Florida Probe Corporation, Gainesville, FL) P hotos were collected throughout the study to monitor the visual appearance of the intraoral tissues around the target tooth. A full CBCT was taken at Preliminary Visit 2 and a partial CBCT of the maxilla was taken on day 84 This radiograph is often taken as part of the standard orthodontic records at the University of Florida College of Dentistry Department of Orthodontics and served as initial records for treatment after the study A full radiology interpretation and report was completed by the University of Florida Department of Oral and Maxillofacial Rad iology Department and was reviewed by the p rincipal i nvestigator. These

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16 radiographs served to evaluate for potential root resorption by visual inspection by the principal investigator S elf reported compliance was recorded using a diary to record the time s at which the aligner was inserted and removed and was calculated as the percent of 24 hours the subject wore the aligner. AcceleDent Aura compliance was reco rded in a memory chip within the device and d ownloaded at each appointment. Pain perception was recorded using a standardized 100mm Visual Analogue clinic visits the VAS score was recorded before inserting the new aligner, just after insertion and just after using the AcceleDent Aura device for 20 minutes in the clinic. On every other day the VAS score was recorded via the diary before and after device use Sample S ize C alculation The sample size of this study was 40 subjects, based off of previous OTM studies conducted at the University of Florida College of Dentistry Department of Orthodontics using th e same model. 32 35 It was powered to detect a minimum difference of 15% OTM with a standard deviation of 0.25 or less. Analysis of VAS scores was such that larger differences in values would result in greater power. Randomization Enrolled subjects were stratified by sex and randomly assigned in blocks of 4 to a n initial device, active or sham. Blinding Subjects were blinded as to device by being informed that they were participating in a study comparing two different frequencies of vibration using the AcceleDent Aura

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17 device. Dispensed devices had no visual information to indicate what device the subject had, blinding the clinical invest igators The investigator s who performed the tooth movement a nd VAS scores measurements were blinded as well Statistical A nalysis ( P rimary and S econdary O utcomes, S ubgroup A nalyses) A modified intent to treat analysis, including all subjects that received at least one aligner, and a per protocol analysis including subjects who completed more than 90% of the visits including days 0, 42, and 84, were planned for this study. A paired t t est was used to determine if the tooth movement using the active device differed from that while using the sham device. Additionally, a linear mixed model analysis was used to determine if there was a period or sequence effect A p value less than 0.05 w as considered a statistically significant difference SAS and R statistical software were used to perform the statistical analyses. Error of the M ethod In order to determine reliability, tooth movement measurements were re calculated for five randomly cho sen subjects, and a reliability coefficient was calculated for each time point A reliability co efficient can range from 0 to 1, 1 indicating perfect reliability. The reliability co efficient for ATM was 0.892 on day 42 and 0.911 on day 84.

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18 Preliminary Visit 2 Day 0 Days 14, 28, 56, 70 Day 42 Day 84 Intraoral exam X X X X Pulp test X X X Periodontal probing X X X Max occlusal & frontal photos X X X Digital impression scan X X X X AcceleDent Aura 20 minutes X X X Switch active/ sham devices X VAS pain index X X X X Intraoral & extraoral photos X X CBCT & Pregnancy test (women) Full Partial Dispense aligner & diary X X X Collect aligner & diary X X X Figure 2 1 Visit o verview A. B. C. D. Figure 2 2 Images from OrthoAnalyzer A. Models post processing. B. Separation of the t eeth and l ong axe s i ndicators C. S election of the t arget t ooth in p reparation for m ovement D. E xample of a nterior movement of t arget tooth 0.33 mm Photos court esy of Kyle Houston.

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19 Figure 2 3 Images from Ortho Insight 3D Orthogonal p lanes constructed using stable reference points on p osterior t eeth and used to measure target tooth movement Photos courtesy of Kyle Houston.

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20 CHAPTER 3 RESULTS Participant F low and Recruitment Figure 3 1 provides a CONSORT flow chart outlining the subject status through the study Patients were recruited from November 2013 to February 2014. 44 subjects were initially enrolled in the study 3 of which dropped pr ior to assignment. 19 subjects assigned to the sham AcceleDent Aura device first (Group S A ) and 20 subjects assigned to the active AcceleDent Aura d evice first (Group A S ) completed the study. The trial concluded in June 2014 once all data collection was complete Baseline D ata The demographics of the study population are reported in Table 3 1. The average age of subjects was 30.6 years old (Standard deviation: 5.8 ; R ange 20.2 40.9 ) Numbers A nalyzed O utcomes and E stimation The subjects that dropped from the study did so before day 14; thus they were eliminated from the data and per protocol analysi s was used. 39 subjects were included in all of the analyses. From day 0 to 84 Group S A experienced a mean 1.72mm ATM, and Group A S experience d a mean 1. 70 mm ATM (Table 3 2) Figure 3 2 illustrates ATM in both groups using all of the time points. ATM by device, combin ing the data from both groups showed a mean 0.81mm ATM using the active device a nd 0.90mm using the sham device (Table 3 3). A mean difference of 0.09mm more ATM using the sham device was not statistically significant ( t test, p value= 0.10 ). Mean compliance rates of the active and sham devices were 83% and 85% respectively (Table 3 4) The ranges and standard devi ations for devi ce compliance

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21 were large Mean self reported aligner compliance was 83%, regardless of device (Table 3 4) Among those with the active device, ATM had a moderately positive correlation with aligner compliance ( Pearson correlation coefficient= 0.45 ) Th e re was no statistically sig nificant difference within male and female groups when comparing the active and sham devices or between sexes when looking at ATM using either device or overall Due to the small number of subjects identifying as Black, Hispanic, or Asian, these subjects were group ed as Non Whites for statistical comparison. No statistically significant difference in ATM was found within White and Non White groups for the two devices or in ATM between groups with either device or overall When assessing the effect of age on ATM using the devices, a moderate ly negative correlation was found between age and ATM using the sham device ( Spearman Rank correlation coefficient= 0.37 ). To assess the VAS scores, each individual ore and after device use were averaged by week The se means were combined by group and the medians were taken to prevent skewing the data with outliers (Figure 3 3) Overall, pain scores were extremely low throughout the study and were generally higher on odd numbered weeks whe n new aligners were dispensed. A wide variation of pain experience s was noted based on the large range of median VAS scores (Table 3 5). To compare the pain change between devices the change while using the active device minus t he change while using the sham device for paired weeks was calculated A statistically significant difference was found in Weeks 2 and 8 when the Sham device provided a greater mean reduction of pa in of 0.24, on a scale of 100 (Table 3 6) ( Wilcoxon Signed

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22 Rank Test, p value = 0.02) St atistical ly significant differences were not noted at other time points. Harms No adverse side effects were noted in this study as a result of using the Acceledent Aura device. N o significant changes were noted in the oral or dental health of subjects. No significant or unusual root blunting or external root resorption was noted when comparing CBCT radiographs from day s 0 and 84 based on visual inspection Figure 3 1 Flow cha rt of study sample Phone Screenings (n=83) Clinic Screening (n= 57) Enrolled into study (n=44) Group A S Active Device T i to T s (n=20) Group A S Sham Device T s to T f (n=20) Group S A Sham Device T i to T s (n=19) Group S A Active Device T s to T f (n=19) Dropped from study (n=5) Failure to meet enrollment criteria (n=3) Could not comply with study protocol (n=1) Dropped by PI for failure to meet criteria to continue (n=1) Not accepted (n=13) Not Accepted (n=26) Failure to meet enrollment criteria

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23 Table 3 1. Demographics of Subject Population n=39 Mean age 30.6 years old (SD : 5.8; R ange 20.2 40.9). n % Sex Male 16 41 Female 23 59 Race White 29 74 Black 6 15 Asian 1 3 Hispanic 3 8 Table 3 2. Actual tooth movement (ATM) in mm Days Median Mean Standard Deviation Range Group S A (n=19) 0 to 42 (Sham) 0.77 0.77 0.17 0.45 1.06 42 to 84 (Active) 0.93 0.93 0.23 0.47 1.27 0 to 84 1.7 2 1.7 0 0. 35 0.92 2. 32 Group A S (n=20) 0 to 42 (Active) 0.72 0.70 0.17 0.41 1.13 42 to 84 (Sham) 0.97 1.02 0.20 0.78 1.62 0 to 84 1.7 6 1.7 2 0. 25 1.29 2. 10 Figure 3 2 ATM over time. 0 0.5 1 1.5 2 0 14 28 42 56 70 84 ATM (mm) Day Group S-A Group A-S Devices Switched

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24 Table 3 3 Overall ATM based on device type. Median Mean Standard Deviation Range Active (n= 3 9 ) 0.77 0.8 1 0.23 0.41 1.27 Sham (n= 39) 0.90 0.90 0.22 0.45 1.62 Difference (Active minus Sham) 0.07 0.09 0.34 1.14 0.69 P < 0.05 based on Paired t test Table 3 4 Device and aligner compliance rates. Median Mean Standard Deviation Range PCC with ATM Active Device Device Compliance 93 83 24 7 105 0.2 3 Aligner Compliance 85 83 9 54 93 0.4 5 Sham Device Device Compliance 97 85 22 27 111 0.01 Aligner Compliance 85 83 8 60 92 0.03 PCC: Pearson Correlation Coefficient *Statistically significant Figure 3 3 M edian s of individual average d VAS pain ratings before and after device use by week 0 0.5 1 1.5 2 2.5 3 1 2 3 4 5 6 7 8 9 10 11 12 VAS Pain Score Week PreDevice Use PostDevice Use PreDevice Use PostDevice Use Devices Switched Group S A: Group A S :

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25 Table 3 5. Range of individual average d VAS pain ratings before and after device use by week. Table 3 6 D ifferences in pain perception calculated as change while using the active device minus the chang e while using the sham device. P ositive value indicate s more reduction using the Active device Week Median Mean Standard Deviation Range WSR Paired t test 1 / 7 0.29 0.06 3.45 6.14 12.48 0.32 0.91 2 / 8 0.10 0.24 0.83 2.26 3.00 0.02* 0.08 3 / 9 0.00 0.43 2.13 10.17 3.29 0.40 0.22 4 / 10 0.00 0.10 0.91 2.29 3.31 0.70 0.49 5 / 11 0.07 0.17 1.73 2.50 8.05 0.99 0.56 6 / 12 0.00 0.31 1.54 2.43 7.81 0.48 0.21 WSR: Wilcoxon Signed Rank *Statistically significant

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26 CHAPTER 4 DISCUSSION Interpretation Consistent with R esults and O ther R elevant E vidence In this study, the AcceleDent Aura device was found to be safe and easy to use, as shown by the lack of adverse side effects and 83% mean compliance rate of active device use. ATM was used for the results in order to depict overall OTM that occurs in reality when using aligners, as shown by previous studies 33 In this study reasonable reliability of tooth movement measurements was achieve d. Due to the small sample size, reliability results could have been greatly influenced by one or two values. Both groups demonstrated more OTM from day 42 to 84 which can best be attributed to OTM over time as opposed to an effect of device type. Durin g the initial placement of force on a tooth, a period of cell recruitment and hyalinization occurs, resulting in a lag phase and delay of OTM. Once tooth movement has been occurring for some time, the cells are already present in the area and the period o f hyalinization decreases. The increased amount of ATM in the second half of the study in both groups is most likely evidence of this biological process. Comparing overall tooth movement with the active and sham device s no statistically or clinically s i gnificant difference was noted (Table 3 3) In this study 85 % to 86 % of the total prescribed tooth movement was achieved T his amount is greater than the 77.4% OTM reported in the last Invisalign study conducted at the University of Florida 35 It is important to note that in this study the amount per aligner was 0.33mm wh ich is unlike any of those studies, and the plastic material for aligner fabrication differed. Sex and race do not appear to play a factor in ATM while using the device. The negative correlation of ATM using the sham device

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27 with age indicates that older subjects tended to experience less OTM in this group compared to y ounger subjects. These results are similar to those of Chisari et al. who found that OTM decreased with age approaching 40 years old. 32 Mean s elf reported compliance rate for aligner wear was 83%. The use of a diary fo r recording compliance could be biased and its reliability is unknown. Studies have shown that lower aligner compliance rates resul t in less OTM 35 leading to the conclusion that b etter aligner compliance in our study may have resulted in more OTM. The correlation between the aligner compliance with ATM in those with the active devic e further enforces improved OTM outcomes when aligner compliance increases. Device compliance was 83% for the active device and 85% for the sham device. Subjects used the device in the clinic for each of their appointments, ensuring that the device was us ed at least the first day of each aligner but th e actual days missed, either consecutive or sporadic, may influence outcome s In addition to this, device compliance had a very large range and the medians were consistently higher than the means indicatin g that the means may have be en affected by a few individuals with poor compliance. We chose to still use means to describe this data as it provides an actual representation of real clinic situations where some subjects may exhibit poor compliance. Pavlin et. al. 28 reported 48.1% faster canine retraction while using the AcceleDent Aura device with fixed appliances. The group using the active device experience d 0.37mm more tooth movement per month, an amount that may not be clinically significant. This study included subjects age s 12 to 40 years old, unlike the present study which skeletal developmental stage may

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28 have implications for outcomes and a comparison of OTM between adults an d children was not reported. To oth measurements were also made directly in the mouth which may result in more err or than cas t or digital measurements Bowman 38 reported 3 0% faster leveling using the device in a retrospective study which has significantly greater risk for bias than a randomized control trial. The findings in our study are not consistent with the results of these recent studies. The findings in our study are consistent with those by Woodhouse et al. 29 and Yadav et al. 39 who found no effect on OTM ra tes using vibration Additionally, Kalajzic et al. found a decrease in OTM in rats with vibration, as well as a decrease in osteoclasts. 40 Yadav et al. using 30Hz frequency vibration, 41 and Xie et al., using whole body v ibration, also showed a decrease of osteoclastic activity in mice. 42 A possible negati ve correlation was recently found between vibration and sclerostin in the alveolar bone. 39,41 Sclerostin is a regulatory marker for bone formation; its presence results in decreased bone formation. Decreased sclerostin with vibration indicates a potential increase in bone formation In order to alter tooth movement, though, bone resorption also has to increase. Several studies support the anabolic effects of vibration 19 21,24,43 with less evidence to support increased alterations of the cata bolic side of bone remodeling. Conversely, Nishimura et al. found an increas e in osteoclasts in rats subjected to vibration during OTM 25 As suggested by Huang et al., a better understanding of the changes occurring at the molecular level will improve our ability to find ways to accel erate OTM more efficiently. 44 Unfortunately, the effect of vibration on OTM at the molecular level is still unclear at this time. The frequen cy of the vibrat ion and the timing at which i t is applied may also have effects on molecular changes.

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29 Regarding pain perception using the AcceleDent Aura device no statistically significant difference was found between the devices. In general all of the pain ratings tended to be low with some outliers reporting higher levels of pain. As e xpected, higher pain was noted during the weeks when aligners were delivered, consiste nt with typical orthodontic discomfort. Our results are not in agreeme nt with the results of Lobre et al. who found lower pain ratings among subjects with the AcceleDent Aura device compared to controls. 45 That study only collected pain data after device use though, and therefore is unable to assess pain reduction Limitations One of the limitations of our study was the set up procedure which required several manual step s The risk of error was reduced by having all of these procedures completed by one computer technician and by conducting a pilot study for calibration Another limitation was the use of Zendura plastic, which is a rigid polyurethane. The magnitude of the forces placed on teeth using aligners depends on the thickness of the plastic and the thermoplastic forming process. 46,47 It is also dependent on the amo unt that the teeth are moved per aligner. 0.33mm was chosen in this study as an intermediate amount compared to the previous studies using this OTM model which used 0.25mm to 0.5mm per aligner 32 35,37 A study by Simon et al. found the forces using Invisalign to be within the range of typical orthodontic forces. 48 A comparison of the rigidity of Zendura material proprietary Smart Track material used in the most recent study 35 using this OTM model, would help to determine if the forces placed in this study were appropriate. Unfortunately there is a lack of literature

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30 evaluating Zendura plastic and the forces it imposes on teeth, although aligner systems such as Clear Correct use it regularly for OTM with aligner therapy. Generalizability The generalizability of these results may be limited as th is study was conducted at one center by one study group that manually fabricated the aligners and oversaw the orthodontic treatment.

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31 CHAPTER 5 CONCLUSIONS The findings of this study suggest that the AcceleDent Aura device does not alter the amount of orthodontic tooth movement when using aligners for orthodontic treatment. Age, sex, and race w ere not found to be variables related to OTM outcomes when using the AcceleDent Aura device. The device was also not found to alter pain perception during tooth movement using Zendura plastic aligners. Overall pain scores were low regardless of device. More research is indicated to determine the biological effects of low magnitude and high frequency vibration on orthodontic tooth movement. This study was registered on https://clinicaltrials.gov (ClinicalTrials.gov Identifier: NCT01962012). It was app roved by the Western Institutional Review Board (WIRB # 20131856 ). This study was funded by OrthoAccel Technologies.

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32 LIST OF REFERENCES 1. Wise GE, King GJ. Mechanisms of tooth eruption and orthodontic tooth movement. J Dent Res 2008;87:414 434. 2. Storey E. The nature of tooth movement. Am J Orthod 1973;63:292 314. 3. Reitan K. Clinical and histologic observations on tooth movement during and after orthodontic treatment. Am J Orthod 1967;53: 721 745. 4. Soma S, Matsumoto S, Higuchi Y, Takano Yamamoto T, Yamashita K, Kurisu K et al. Local and chronic application of PTH accelerates tooth movement in rats. J Dent Res 2000;79:1717 1724. 5. Yamasaki K, Shibata Y, Imai S, Tani Y, Shibasaki Y, Fukuha ra T. Clinical application of prostaglandin E1 (PGE1) upon orthodontic tooth movement. Am J Orthod 1984;85:508 518. 6. Seifi M, Eslami B, Saffar AS. The effect of prostaglandin E2 and calcium gluconate on orthodontic tooth movement and root resorption in r ats. Eur J Orthod 2003;25:199 204. 7. Brooks PJ, Heckler AF, Wei K, Gong SG. M CSF accelerates orthodontic tooth movement by targeting preosteoclasts in mice. Angle Orthod 2011;81:277 283. 8. Kanzaki H, Chiba M, Arai K, Takahashi I, Haruyama N, Nishimura M et al. Local RANKL gene transfer to the periodontal tissue accelerates orthodontic tooth movement. Gene Ther 2006;13:678 685. 9. Cruz DR, Kohara EK, Ribeiro MS, Wetter NU. Effects of low intensity laser therapy on the orthodontic movement velocity of huma n teeth: a preliminary study. Lasers Surg Med 2004;35:117 120. 10. Genc G, Kocadereli I, Tasar F, Kilinc K, El S, Sarkarati B. Effect of low level laser therapy (LLLT) on orthodontic tooth movement. Lasers Med Sci 2013;28:41 47. 11. Doshi Mehta G, Bhad Pat il WA. Efficacy of low intensity laser therapy in reducing treatment time and orthodontic pain: a clinical investigation. Am J Orthod Dentofacial Orthop 2012;141:289 297. 12. Ekizer A, Uysal T, Guray E, Akkus D. Effect of LED mediated photobiomodulation th erapy on orthodontic tooth movement and root resorption in rats. Lasers Med Sci 2013. 13. Fischer TJ. Orthodontic treatment acceleration with corticotomy assisted exposure of palatally impacted canines. Angle Orthod 2007;77:417 420. 14. Alikhani M, Raptis M, Zoldan B, Sangsuwon C, Lee YB, Alyami B et al. Effect of micro osteoperforations on the rate of tooth movement. Am J Orthod Dentofacial Orthop 2013;144:639 648.

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33 15. Lerner UH. Bone remodeling in post menopausal osteoporosis. J Dent Res 2006;85:584 595. 16. Proff P, Romer P. The molecular mechanism behind bone remodelling: a review. Clin Oral Investig 2009;13:355 362. 17. Young SR, Dyson M. The effect of therapeutic ultrasound on angiogenesis. Ultrasound Med Biol 1990;16:261 269. 18. Kasturi G, Adler RA. Mechanical means to improve bone strength: ultrasound and vibration. Curr Rheumatol Rep 2011;13:251 256. 19. Rubin C, Turner AS, Bain S, Mallinckrodt C, McLeod K. Anabolism. Low mechanical signals strengthen long bones. Nature 2001;412:603 604. 20. Rubin C Turner AS, Muller R, Mittra E, McLeod K, Lin W et al. Quantity and quality of trabecular bone in the femur are enhanced by a strongly anabolic, noninvasive mechanical intervention. J Bone Miner Res 2002;17:349 357. 21. Gilsanz V, Wren TA, Sanchez M, Dore y F, Judex S, Rubin C. Low level, high frequency mechanical signals enhance musculoskeletal development of young women with low BMD. J Bone Miner Res 2006;21:1464 1474. 22. Leung KS, Shi HF, Cheung WH, Qin L, Ng WK, Tam KF et al. Low magnitude high frequen cy vibration accelerates callus formation, mineralization, and fracture healing in rats. J Orthop Res 2009;27:458 465. 23. Shi HF, Cheung WH, Qin L, Leung AH, Leung KS. Low magnitude high frequency vibration treatment augments fracture healing in ovariecto my induced osteoporotic bone. Bone 2010;46:1299 1305. 24. Peptan AI, Lopez A, Kopher RA, Mao JJ. Responses of intramembranous bone and sutures upon in vivo cyclic tensile and compressive loading. Bone 2008;42:432 438. 25. Nishimura M, Chiba M, Ohashi T, Sa to M, Shimizu Y, Igarashi K et al. Periodontal tissue activation by vibration: intermittent stimulation by resonance vibration accelerates experimental tooth movement in rats. Am J Orthod Dentofacial Orthop 2008;133:572 583. 26. Kau CH. A radiographic analysis of tooth morphology following the use of a novel cyclical force device in orthodontics. Head Face Med 2011;7:14. 27. Kau C, Nguyen J, English J. The clinical evaluation of a novel cyclical force generating device in orthodontics. Orthod Pract 2012 ;1:10 15. 28. Pavlin D, Anthony R, Raj V, Gakunga PT. Cyclic loading (vibration) accelerates tooth movement in orthodontic patients: A double blind, randomized controlled trial. Seminars in Orthodontics 2015;21:187 194.

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34 29. Woodhouse NR, DiBiase AT, Johnso n N, Slipper C, Grant J, Alsaleh M et al. Supplemental vibrational force during orthodontic alignment: a randomized trial. J Dent Res 2015;94:682 689. 30. Clements KM, Bollen A M, Huang G, King G, Hujoel P, Ma T. Activation time and material stiffness of s equential removable orthodontic appliances. Part 2: Dental improvements. American Journal of Orthodontics and Dentofacial Orthopedics 2003;124:502 508. 31. Kravitz ND, Kusnoto B, BeGole E, Obrez A, Agran B. How well does Invisalign work? A prospective clin ical study evaluating the efficacy of tooth movement with Invisalign. Am J Orthod Dentofacial Orthop 2009;135:27 35. 32. Chisari JR, McGorray SP, Nair M, Wheeler TT. Variables affecting orthodontic tooth movement with clear aligners. American Journal of Or thodontics and Dentofacial Orthopedics 2014;145:S82 S91. 33. Drake CT, McGorray SP, Dolce C, Nair M, Wheeler TT. Orthodontic tooth movement with clear aligners. ISRN Dent 2012;2012:657973. 34. McGorray SP, Dolce C, Kramer S, Stewart D, Wheeler TT. A random ized, placebo controlled clinical trial on the effects of recombinant human relaxin on tooth movement and short term stability. Am J Orthod Dentofacial Orthop 2012;141:196 203. 35. Patel ND. Effect of Aligner Material, Duration, and Force Level on Tooth Mo vement: University of Florida; 2014. 36. McGorray SP, Chisari JR, Wheeler TT. Variables affecting orthodontic tooth movement with clear aligners Am J Orthod Dentofacial Orthop. 37. Mazzuoccolo AM. Effect of AcceleDent Aura on Orthodontic Tooth Movement wit h Aligners: A Pilot Study Department of Orthodontics: University of Florida; 2015. 38. Bowman SJ. The effect of vibration on the rate of leveling and alignment. J Clin Orthod 2014;48:678 688. 39. Yadav S, Dobie T, Assefnia A, Gupta H, Kalajzic Z, Nanda R. Effect of low frequency mechanical vibration on orthodontic tooth movement. Am J Orthod Dentofacial Orthop 2015;148:440 449. 40. Kalajzic Z, Peluso EB, Utreja A, Dyment N, Nihara J, Xu M et al. Effect of cyclical forces on the periodontal ligament and alve olar bone remodeling during orthodontic tooth movement. Angle Orthod 2014;84:297 303. 41. Yadav S, Assefnia A, Gupta H, Vishwanath M, Kalajzic Z, Allareddy V et al. The effect of low frequency mechanical vibration on retention in an orthodontic relapse mod el. Eur J Orthod 2015.

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35 42. Xie L, Jacobson JM, Choi ES, Busa B, Donahue LR, Miller LM et al. Low level mechanical vibrations can influence bone resorption and bone formation in the growing skeleton. Bone 2006;39:1059 1066. 43. Komrakova M, Sehmisch S, Tezv al M, Ammon J, Lieberwirth P, Sauerhoff C et al. Identification of a vibration regime favorable for bone healing and muscle in estrogen deficient rats. Calcif Tissue Int 2013;92:509 520. 44. Huang H, Williams RC, Kyrkanides S. Accelerated orthodontic tooth movement: molecular mechanisms. Am J Orthod Dentofacial Orthop 2014;146:620 632. 45. Lobre WD, Callegari BJ, Gardner G, Marsh CM, Bush AC, Dunn WJ. Pain control in orthodontics using a micropulse vibration device: A randomized clinical trial. Angle Orthod 2015. 46. Hahn W, Dathe H, Fialka Fricke J, Fricke Zech S, Zapf A, Kubein Meesenburg D et al. Influence of thermoplastic appliance thickness on the magnitude of force delivered to a maxillary central incisor during tipping. Am J Orthod Dentofacial Orthop 2009;136:12 e11 17; discussion 12 13. 47. Kwon JS, Lee YK, Lim BS, Lim YK. Force delivery properties of thermoplastic orthodontic materials. Am J Orthod Dentofacial Orthop 2008;133:228 234; quiz 328 e221. 48. Simon M, Keilig L, Schwarze J, Jung BA, Bouraue l C. Forces and moments generated by removable thermoplastic aligners: incisor torque, premolar derotation, and molar distalization. Am J Orthod Dentofacial Orthop 2014;145:728 736.

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36 BIOGRAPHICAL SKETCH Melissa Alfonso Sedeo was born and raised in Miami, Florida as a first generation Cuba n American She attended the University of Florida for her undergraduate degree where she earned her Bachelor of Arts degree in political science with a minor in chemistry, an d Honors Certificate in 2009. During her u ndergraduate career, Melissa was involved in her sorority Phi Mu Fraternity, where she served as chapter President in 2008. She also conducted research with the University o f Florida College of Dentistry Departm ent of Community Dentistry and Behavioral Science. She presented a poster of her findings at the American Association of Dental Research Meeting in 2009 In 2013 she obtai ned her Doctor of Dental Medicine degree at the University of Florida. Her dental honors include induction into Omicron Kappa Upsilon Xi Omicron chapter; the Al pha Omega Award for Scholarship; Hinman Dental Society Scholar 2012; and the American Associat ion of Orthodontists Award. Currently, Melissa serves as Chief Resident and recently had the honor of speaking at the OrthoVoice 2015 conferen ce about her research project. Upon graduation in May 2016, Melissa plans to return to the South Florida area to practice orthodontics in a private practice setting.