Proposed Pilot Study Clinical Protocol

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Accelerated Invisalign Therapy in Conjunction With OrthodontiCell Bioelectric Stimulator

Mouthpiece

Purpose:

The objective of this study is to investigate the effects of accelerated Invisalign and bioelectric stimulation controlled protein release and stem cell homing therapy on rate of orthodontic tooth movement, activation of inflammation biomarkers as well as pain levels experienced by orthodontic patients during the initial 12 weeks of alignment.
Participants:
Up to 30 orthodontic patients of the Forsyth Institute will be recruited for this study. Patients older than 18 years old will be otherwise healthy subjects previously diagnosed with malocclusion.
Procedures (methods):
Each patient will be randomly allocated into either a control group or one of two intervention groups. Patients within the control group will receive standard Invisalign therapy without vibration. Patients within the intervention groups will receive accelerated Invisalign therapy with or without vibration. Patients receiving OrthodontiCell bioelectric stimulation therapy will utilize a conductive mouthpiece device which provides bioelectric signals at low voltages and at a micro current for twenty minutes daily. Three dimensional images of each subject’s dentition will be recorded five times at 0 days, 4 days, 2 weeks, 6 weeks, and 12 weeks progress visits.
Condition
Intervention
Phase
Malocclusion
Device: OrthodontiCell Bioelectric stimulator Device: Accelerated Invisalign therapy
Phase I/II
Study Type:
Interventional
Study Design:
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single Blind (Investigator)
Primary Purpose: Treatment
Official Title:
Orthodontic Tooth Movement With Accelerated Invisalign Therapy Using OrthodontiCell Bioelectric Stimulator: A Randomized Clinical Trial
Further study details as provided by OrthodontiCell a Leonhardt’s Launchpads co. 
Primary Outcome Measures:
·         Rate of orthodontic tooth movement [Little’s Irregularity Index, mm/day, percent] [ Time Frame: 12 weeks ]
The rate of orthodontic tooth movement (mm/day) as well as a reduction in the irregularity index (percentage) will be evaluated between a control group (2 week aligner wear) and two intervention groups (4 day aligner wear and 4 day aligner wear with vibration)
Secondary Outcome Measures:
·         Activity of Bone Turnover Markers (BTMs) during Orthodontic Tooth Movement [Quantitative Polymerase Chain Reaction (qPCR), Cycle threshold values (Ct)] [ Time Frame: 12 weeks ]
Gingival crevicular fluid will be sampled to determine if vibratory stimulation during orthodontic tooth movement increases the activity of the Receptor Activator of Nuclear Factor-KappaB (RANK), Receptor Activator of Nuclear Factor-KappaB Ligand (RANKL) and Osteoprotegerin (OPG) cell signaling pathway.
·         Patient Discomfort [Visual Analog Scale in conjunction with Faces Pain Scale, 1-10] [ Time Frame: 12 weeks ]
Research subjects will be asked to complete questionaires during each clinical visit in order to determine what effect vibratory stimulation has on patient discomfort during orthodontic treatment
Estimated Enrollment:
30
Study Start Date:
May 2018
Estimated Study Completion Date:
December 2018
Estimated Primary Completion Date:
December 2018 (Final data collection date for primary outcome measure)
Arms
Assigned Interventions
No Intervention: Standard Invisalign Therapy
Patients receiving standard Invisalign therapy will be instructed to wear each aligner 24 hours day. Patients will be permitted to progress to the subsequent aligner after 14 days of compliant aligner wear.
Standard Invisalign Therapy Only
Experimental: Accelerated Invisalign
Patients receiving accelerated Invisalign therapy will be instructed to wear each aligner 24 hours day. Patients will be permitted to progress to the subsequent aligner after 4 days of compliant aligner wear.
Device: Accelerated Invisalign therapy
Patients receiving accelerated Invisalign therapy will be instructed to wear each aligner 24 hours day. Patients will be permitted to progress to the subsequent aligner after 4 days of compliant aligner wear.
Experimental: Accelerated Invisalign and OrthodontiCell Bioelectric Stimulation
In addition to the accelerated Invisalign protocol described in Arm #2, patients will undergo intraoral bioelectric stimulation therapy using an OrthdontiCell bioelectric stimulator for a duration of 20 minutes per day.
Devices: Orthodonticell Bioelectric Stimulation 
Patients receiving vibration should be biolectric therapy will be instructed to bite down on the OrthodontiCell mouthpiece, which releases bioelectric signals for RANKL expression first for accelerated tooth movement and after tooth movement OPG for freezing teeth positions for 20 minute daily.
Device: Accelerated Invisalign therapy
Patients receiving accelerated Invisalign therapy will be instructed to wear each aligner 24 hours day. Patients will be permitted to progress to the subsequent aligner after 4 days of compliant aligner wear.
Detailed Description:
Align Technology©, Inc. developed Invisalign® in 1997 to meet the esthetic demands of orthodontic patients and providers. Invisalign patients receive a series of computer-assisted designed stereolithic clear retainers to incrementally resolve their malocclusion. Invisalign® and other advances in orthodontic technology such as clear aligners, ceramic brackets and lingual braces offer options to address the esthetic demands of most orthodontic patients but duration of treatment continues to be one of the most challenging aspects of practice.
In 2015, Howard Leonhardt an inventor and CEO of Leonhardt Ventures, working with Dr. John Marchetto an Orthodontist and Dr. Jorge Genovese a bioelectric organ regeneration researcher, within the Leonhardt’s Launchpads Utah, Inc. innovation incubator and accelerator, developed the OrthdontiCell device to accelerate tooth movement, reduce orthodontic treatment time, reduce patient pain and freeze teeth stabilization after movement. Patients receiving OrthodontiCell bioelectric therapy are instructed to bite down on the OrthdontiCell mouthpiece, which emits bioelectric signals to provide a 46% increase of RANKL, a known accelerated tooth movement protein, for 20 minutes per day.  After accelerated tooth movement is complete the OrthdontiCell device treatment sessions are switched to an OPG protein expression signal that has been shown in animal studies to increase OPG expression by over 1000% compared to baseline.  The theory underlying OrthdontiCell and the use of specific bioelectric stimulation signals to promote specific targeted proteins expression of RANKL to expedite orthodontic tooth movement started with RANKL injection studies completed in the last decade in Spain in other locations demonstrating > 40% increased expression of RANKL in tissues surrounding teeth accelerates tooth movement by up to 2/3rds   The Leonhardt team published their first stem cell organ regeneration study in 1988 in The Physiologist working with Dr. Race Kao and Dr. George Magovern.  In 1999 they published their first study of bioelectric treatment for limb salvage in the American Heart Association Journal CIRCULATION working with Dr. Shinichi Kanno.  Howard Leonhardt filed in 1999 the first of a series of more than 100 patent claims for bioelectric controlled release of regeneration and healing promoting proteins including stem cell homing, proliferation and controlled differentiation joined by Dr. Jorge Genovese and in some protein expression patents by Dr. Juan Chachques and Dr. Shinichi Kanno. The team has since added a dozen more controlled expressions from its platform bioelectric stimulation technology including controlled expression of SDF-1 (a stem cell homing signal), IGF-1, HGF, EGF, PDGF, VEGF, eNOS, HIF 1 Alpha, IL-6, Activin A=B, Follistatin and Tropoelastin.  The team has completed a number of pre-clinical and clinical studies document bioelectric stimulation and stem cell treatments for organ and wound healing for other applications outside of orthodontics.  The OrthodontiCell team of bioengineers of Utah have conducted a number of rodent studies at BioInnovations Gateway and the University of Utah confirming the precise control of the OrthodontiCell Bioelectric Stimulator in increasing RANKL expression by >46% and OPG > 1000% compared to baseline levels prior to stimulation.  These confirmed results previously obtained by Dr. Jorge Genovese at his lab in Argentina.
Accelerated orthodontic tooth movement may offer many benefits to both, the patient and the orthodontist. Reduced treatment time reduces the burden of orthodontic treatment by decreasing risk for undesired treatment sequelae (e.g., white spot lesion, caries, gingivitis, etc) and potentially reduces the discomfort commonly associated with orthodontic treatment.
There are also potential negative outcomes associated with accelerated orthodontic tooth movement. For the patient, there is a potential increased risk for root resorption, increased treatment fees and pain associated with treatment. At this time, there is no published data regarding the potential for orthodontic relapse following the accelerated orthodontic tooth movement. There are several publications supporting the fact that relapse is a known risk for conventional orthodontic treatment. The investigators can make the safe assumption that accelerated orthodontic treatment would be no different than conventional orthodontic therapy with regard to relapse potential. This study has is the first to follow accelerated tooth movement with controlled release of a known teeth position stabilization protein to attempt to reduce risk of relapse.  At this time orthodontic patients must be compliant with regard to orthodontic retention with the regular wear or retainers or relapse will be expected.  This device may be the first to eliminate or reduce this requirement dreaded by patients.
In this study, the investigators propose a randomized prospective clinical design to investigate effects of OrthodontiCell Bioelectric Stimulation therapy on the efficiency of tooth movement, teeth stabilization and on the activation of gingival crevicular fluid biomarkers and on patient discomfort in conjunction with accelerated Invisalign therapy.

Eligibility
Ages Eligible for Study:
18 Years to 99 Years   (Adult, Senior)
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Criteria
Inclusion Criteria:
  1. Males or females over the age of 18 years old desiring orthodontic treatment.
  2. Adult dentition with all upper and lower front teeth present and any premolar and molar combination in the upper posterior of two teeth on each side.
  3. Normal pulp vitality and healthy periodontal tissues as determined by intraoral exam.
  4. Good health as determined by medical history.
  5. Willingness and ability to comply with study procedures, attend study visits, and complete the study.
  6. The ability to understand and sign a written informed consent form, which must be signed prior to initiation of study procedures.
Exclusion Criteria:
  1. Patient under the age of 18 years old
  2. Women may not be pregnant. Negative urine pregnancy tests prior to exposure to cone beam imaging is required to verify pregnancy status.
  3. Patients diagnosed with systemic diseases such as diabetes, hypertension (high blood pressure), temporomandibular disorders (jaw disorders), or craniofacial syndromes.
  4. Severe malocclusions that would require adjunctive procedures other than Invisalign. These include impacted teeth, closure of extractions spaces.
  5. Significant periodontal disease (> 4mm pocket depth or >2 mm of recession on upper anterior teeth).
  6. Active caries not under care of either a dentist or periodontist.
  7. Chronic daily use of any non-steroidal anti-inflammatory medication, estrogen, calcitonin, or corticosteroids.
  8. History of use or current use of any bisphosphonate medication or other medication for treatment of osteoporosis.
  9. Current smoker (must not have smoked in the last 6 months).
  10. Failing to comply with research protocols

Locations

Sponsors and Collaborators
OrthodontiCell, a Leonhardt’s Launchpads co.

Principal Investigators:

Consultants to Study:

John Marchetto, M.S. Ph.D. Orthodontist, Tufts University, Chief Medical Officer OrthodontiCell

Leslie Miller, M.D. – Chief Medical Officer, Leonhardt’s Launchpads

Jorge Genovese, PhD. Bioelectric Organ Regeneration Research Scientist

Howard Leonhardt, hPhD. Bioemedical Engineering University of Northern California, Inventor

More Information

Contact: OrthodontiCell a Leonhardt’s Lauchpads co. email howard@leonhardtventures.com