Office location Objectives 5/1/2017. Pneumopedics and Craniofacial Epigenetics. Do I snore?

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Pneumopedics and Craniofacial Epigenetics American Sleep and Breathing Academy Office location

Copyright 2017 No part of this presentation may be recorded, reproduced, or distributed

com Tel: (971) 302 2233 or 2234 E mail: drsingh@vivoslife.

disclosure Dr Singh is President of Vivos BioTechnologies, Inc.

FDA All the DNA appliances are FDA registered The mrna appliance is FDA cleared for mild to

United States Patent issued July, 2014 United States Patent issued March, 2011 United States

United States Patent issued Sept, 2009 United States Patent issued April, 2008 United States

adequacy Objectives Guilleminault and Stoohs, 1990 Do I snore?

as well as the concept of epigenetic orthodontics Introduce the principles of Pneumopedics

1 Pneumopedics and Craniofacial Epigenetics American Sleep and Breathing Academy Office location 2017 Dr. G. Dave Singh DDSc PhD DMD 2017 Vivos BioTechnologies, Inc. Professor Dr. G. Dave Singh DMD PhD DDSc Vivos BioTechnologies, Inc. Copyright 2017 No part of this presentation may be recorded, reproduced, or distributed without prior written consent Tel: (971) or 2234 E mail: drsingh@vivoslife.com World Association of Sleep Medicine, Seoul, South Korea March 2015 Conflict of interest disclosure Dr Singh is President of Vivos BioTechnologies, Inc. BMS (a wholly owned subsidiary of Vivos) is registered as a medical device facility with the FDA All the DNA appliances are FDA registered The mrna appliance is FDA cleared for mild to moderate OSA United States Patent issued August, 2015 United States Patent issued May, 2015 United States Patent issued July, 2014 United States Patent issued March, 2011 United States Patent issued Feb, 2011 Canadian Patent issued Jan, 2012 Canadian Patent issued Jan, 2011 United States Patent issued Sept, 2009 United States Patent issued April, 2008 United States Patent issued Jan, 2008 Marked interaction between craniofacial morphology and upper airway adequacy Objectives Guilleminault and Stoohs, 1990 Do I snore? Appreciate the principles of craniofacial epigenetics, which includes epigenetic orthopedics as well as the concept of epigenetic orthodontics Introduce the principles of Pneumopedics Gain knowledge of biomimetic oral appliances Apply these concepts as a potential cure for Obstructive Sleep Apnea in a multi disciplinary, dental setting Do I need mandibular advancement? Can we change these phenotypes non surgically? 1

WHAT IS EPIGENETICS? Epigenetics is the study of phenotypic changes that occur via mechanisms other than DNA sequence alteration.

Types of epigenetic modification include: ADP ribosylation, acetylation, methylation, phosphorylation, sumoylation and ubiquitination. What about teeth? Spivakov M, Fisher AG.

The New York Times (February 19, 2015) reports that 200 scientists working on an ambitious federal project have begun to understand the complicated system of switches that regulates genes, turning

Their findings are published in 24 papers in Nature and other journals. A science that studies natural models and then uses these designs and processes to solve human problems.

2 WHAT IS EPIGENETICS? Epigenetics is the study of phenotypic changes that occur via mechanisms other than DNA sequence alteration. These changes are mediated by covalent attachments of chemical groups to the DNA and its associated proteins, histones and chromatin. Types of epigenetic modification include: ADP ribosylation, acetylation, methylation, phosphorylation, sumoylation and ubiquitination. What about teeth? Spivakov M, Fisher AG. Epigenetic signatures of stem cell identity. Nature Reviews Genetics 8, , Researchers release most complete mapping of the Human Epigenome to date WHAT IS BIOMIMETICS (BIOMIMICRY)? The New York Times (February 19, 2015) reports that 200 scientists working on an ambitious federal project have begun to understand the complicated system of switches that regulates genes, turning some on and others off. The scientists hope these discoveries will eventually lead to a deeper understanding of diseases and new ways to treat or cure them. Their findings are published in 24 papers in Nature and other journals. A science that studies natural models and then uses these designs and processes to solve human problems. WHAT IS CRANIOFACIAL EPIGENETICS? Craniofacial epigenetics uses a person s natural genes to correct and straighten the jaws, teeth, soft tissues and functional spaces, painlessly, using biomimetic appliances Epigenetic orthodontics Cosmetic treatment with health benefits Includes epigenetic orthopedics for bone formation and remodeling WHAT MAKES CRANIOFACIAL EPIGENETICS DIFFERENT FROM TRADITIONAL DENTOALVEOLAR ORTHODONTICS AND FROM RAPID PALATAL EXPANSION? Craniofacial epigenetics is aimed at the overall health of the craniofacial region by providing appropriate treatment protocols that address the underlying etiology of the signs and symptoms of OSA, TMD, malocclusions, etc. PNEUMOPEDICS Non-surgical upper airway remodeling 2

PSGs with and without a MAD were performed at start of treatment and for those that had been continuously treated with MADs

AHI increased from 17 after long term use to 32 without the device and 35 with it WHAT MAKES PNEUMOPEDICS DIFFERENT FROM

Patients treated with oral appliances may experience deteriorations in disease severity and treatment efficacy during

Long-term efficacy of an oral appliance in early treated patients with obstructive sleep apnea. Sleep Breath.

Pre-Distraction osteogenesis Post-Distraction osteogenesis Craniofacial epigenetics is aimed at the overall health of the

symptoms of OSA, TMD, malocclusions, etc.

During growth, spatial and functional alignment of skeletal elements is maintained through remodeling of bony surfaces

3 PSGs with and without a MAD were performed at start of treatment and for those that had been continuously treated with MADs for at least 15 years. AHI increased from 17 after long term use to 32 without the device and 35 with it WHAT MAKES PNEUMOPEDICS DIFFERENT FROM MANDIBULAR ADVANCEMENT DEVICES? Patients treated with oral appliances may experience deteriorations in disease severity and treatment efficacy during continuous long term MAD treatment. Marklund M. Long-term efficacy of an oral appliance in early treated patients with obstructive sleep apnea. Sleep Breath. 2016;20(2): Pre-Distraction osteogenesis Post-Distraction osteogenesis Craniofacial epigenetics is aimed at the overall health of the craniofacial region by providing appropriate treatment protocols that address the underlying etiology of the signs and symptoms of OSA, TMD, malocclusions, etc. Improved facial soft tissue profiles Center of Craniofacial Disorders Pre-Distraction MRI Post-Distraction MRI Results from midfacial distraction osteogenesis alone showed similarity to maxillo mandibular advancement Midfacial bone Facial profile Center for Craniofacial Disorders Upper airway Can we achieve similar results non surgically? During growth, spatial and functional alignment of skeletal elements is maintained through remodeling of bony surfaces (including the periodontium) to permit function Environmentally (or genetically ) induced changes (e.g. tooth extraction, digit sucking etc.) produce changes in early morphologic relationship new solution (phenotypic variation) This new solution represents Departure from the genetically encoded developmental body plan (Temporo Spatial Patterning) Developmental compensation occurs to permit compromised function malocclusion, TMD, OSA, tori, etc Decompensation required through treatment with appropriate spatial signaling to re establish (genomic) pattern formation for optimal form and function Singh, GD. Michigan Craniofacial Growth Series, 2004 Singh, GD. British Dental Journal,

4 What is the dental arch morphology in adults with OSA? Case progress with biomimetic DNA appliance October, 2010 Courtesy: Dr Dennis Alleman October, 2011 N = 108 Mean upper arch OSA configuration 7 11% narrower Mean lower arch OSA configuration 10 11% narrower Banabilh, Singh et al., J Oral Rehabil July, 2015 Courtesy: Dr Gary Sacher August, 2016 Craniofacial effects following DNA appliance treatment: 38 year old adult diagnosed with OSA Change in upper airway after 15 months After 10 months of active treatment the minimum transpalatal width increased from 34mm to 39mm 3D CBCT scan transverse sections Singh, Wendling et al. Dent Today % increase in upper airway volume from 12889mm 3 to 22024mm 3 Change in upper airway after 15 months 4

5 Change in upper airway after 15 months Decrease in AHI from 24/hr to 2.8/hr after 10 months with no device in the patient s mouth 38 year old: 12 months DNA appliance therapy Enhanced craniofacial homeostasis Singh GD et al. Dent Today 2011 Case study: Non surgical cosmetic treatment with health benefits Initial 3 Months Singh and Cress, Dent Today, Months 12 Months 5

6 Upper arch: Orthodontic changes Lower arch: Orthodontic changes Initial 12 Months Initial 12 Months Singh and Cress, Dent Today, 2013 Singh and Cress, Dent Today, 2013 POST = BLUE 3D CBCT SUPERIMPOSITION PRE = GREY UPPER AIRWAY ANALYSIS 17cm 3 28cm 3 Singh and Cress, 2013 Pneumopedic effect with no appliance in mouth Singh and Cress, Dent Today, 2013 Biomimetic effects in adults following epigenetic orthodontic treatment with the DNA appliance Transpalatal bone width (mm) Patient Pre treatment Post treatment ASE FE HF CH KH NN KR Is there an increased transpalatal bone width after DNA appliance therapy in adults? Singh, Heit et al., J Ind Orthod Soc JD Mean P value =

Is there an increased maxillary bone volume after DNA

14cm 3 15cm 3 Biomimetic effects in adults following

treatment Post treatment ASE 14143 15121 FE 15218 19823

Table Clinic 16869 Prize 2013 KR 12389 17287 JD 21536

7 Is there an increased maxillary bone volume after DNA appliance therapy in adults? 14cm 3 15cm 3 Biomimetic effects in adults following epigenetic orthodontic treatment with the DNA appliance Singh, Heit et al., J Ind Orthod Soc Maxillary Bone Volume (mm 3 ) Patient Pre treatment Post treatment ASE FE HF CH KH NN Table Clinic Prize 2013 KR JD Mean 17.3 cm cm 3 P value = 0.02 Singh, Heit et al., J Ind Orthod Soc 2014 Example of Non surgical procedure: Courtesy: Dr. Lihua Zhang DDS Pre treatment conditions Courtesy: Dr. Lihua Zhang DDS Example of Non surgical procedure: Pre treatment and progress comparison Courtesy: Dr. Lihua Zhang DDS Courtesy: Dr. Lihua Zhang DDS 7

Superimposition of 3D CBCT scan mid sagittal section Increase in upper airway (retropalatal/retroglossal) distances 31.5mm 35.5mm 2.2mm 5.0mm 4.7mm 8.

CBCT scan mid sagittal section Increase in upper airway (retropalatal/retroglossal) distances PNEUMOPEDICS PNEUMOPEDICS Total volume 11.

5mm Pseudo colored mid sagittal sections of 3D CBCT scans Courtesy: Dr Tammarie Heit Courtesy: Dr Felix Liao, DDS MAGD WHAT IS PNEUMOPEDICS?

The biomimetic oral appliance system uses the principles of Epigenetics to activate a person's naturally occurring genes to correct deficiencies in the craniofacial region.

It is a pain free, minimally invasive process, which uses no drugs, medication or injections.

8 Superimposition of 3D CBCT scan mid sagittal section Increase in upper airway (retropalatal/retroglossal) distances 31.5mm 35.5mm 2.2mm 5.0mm 4.7mm 8.0mm TRANSPALATAL BONE WIDTHS Courtesy: Dr Tara Griffin PNEUMOPEDICS Singh GD Dental sleep medicine in the 21 st Century Sleep Scholar, 2015 Courtesy: Dr Tara Griffin Superimposition of 3D CBCT scan mid sagittal section Increase in upper airway (retropalatal/retroglossal) distances PNEUMOPEDICS PNEUMOPEDICS Total volume 11.8cm 3 Minimum crosssectional area 141mm 2 Total volume 27.5cm 3 Min. cross sectional area 379mm 2 9.5mm 8.5mm 13.5mm 12.5mm Pseudo colored mid sagittal sections of 3D CBCT scans Courtesy: Dr Tammarie Heit Courtesy: Dr Felix Liao, DDS MAGD WHAT IS PNEUMOPEDICS? Pneumopedics is the process of non surgical, upper airway remodeling that may result from treatment with a biomimetic oral appliance. How does Pneumopedics work? The biomimetic oral appliance system uses the principles of Epigenetics to activate a person's naturally occurring genes to correct deficiencies in the craniofacial region. The tissues in the craniofacial region are slowly redeveloped and remodeled over time, making corrections to the structure of the upper airway, non surgically. It is a pain free, minimally invasive process, which uses no drugs, medication or injections. During the Pneumopedic process, the craniofacial region undergoes structural changes so that the functional space of the upper airway increases volumetrically, allowing for improved function of basic, physiologic processes, such as breathing during sleep. This is the reason that this system of biomimetic oral appliances can be used to treat, reduce and eventually eliminate OSA. Further research questions Is there an increased nasal cavity widths after DNA appliance therapy in children/adults? Is there an increased nasal airway volume after DNA appliance therapy in children/adults? 8

First adult case: One year progress Objective 1.71mm 1.28mm 2.57mm 3.

biomimetic oral appliance therapy Distance between nasal septum and Inferior conchae Methods After obtaining

38 years) prior to and 18 months after biomimetic oral appliance therapy.

Volumetric reconstruction of nasal cavity volume To acquire the nasal cavity volume, volumetric, 3-D

superiorly from the palatine process of the maxilla and the palatine bone to the cribriform plate of the

9 First adult case: One year progress Objective 1.71mm 1.28mm 2.57mm 3.02mm The aim of this study is to evaluate changes in nasal airway volume in adult patients following biomimetic oral appliance therapy Distance between nasal septum and Inferior conchae Methods After obtaining informed consent, we undertook 3D cone-beam (CBCT) scans of 11 consecutive, adult patients (mean age approx. 38 years) prior to and 18 months after biomimetic oral appliance therapy. These cases had all been diagnosed with clinical midfacial hypoplasia without congenital malformation. Volumetric reconstruction of nasal cavity volume To acquire the nasal cavity volume, volumetric, 3-D reconstruction of the nasal cavity was undertaken between the anterior and posterior nasal spines, extending superiorly from the palatine process of the maxilla and the palatine bone to the cribriform plate of the ethmoid bone. Laterally, the maxillary sinuses were trimmed out at their junction with the nasal cavity on the 3D CBCT data. Volumetric reconstruction of the nasal cavity Volumetric reconstruction of the nasal cavity 9

Volumetric reconstruction of the nasal cavity Measurement of nasal airway

The findings were subjected to statistical analysis, using paired t-tests.

adults (cm 3 ) after 18 months Subject Pre Treatment Post Treatment ASE 33.

614 NN 27.505 30.981 KR 35.183 35.785 Table Clinic Prize 2014 JB 16.465 23.

114 Courtesy: Dr Tammarie Heit, DDS Mean 39.8cm 3 42.3cm 3 p value P < 0.

Cranio, 2016 Example of Non surgical procedure: Courtesy: Dr Tammarie Heit,

airway volume after DNA appliance therapy in adults diagnosed with OSA?

10 Volumetric reconstruction of the nasal cavity Measurement of nasal airway volume The nasal cavity volume was calculated in all cases. The findings were subjected to statistical analysis, using paired t-tests. Improved nasal symmetry and functional space Nasal airway volume changes in adults (cm 3 ) after 18 months Subject Pre Treatment Post Treatment ASE FE HF CH KH NN KR Table Clinic Prize 2014 JB JD EA TR AT Courtesy: Dr Tammarie Heit, DDS Mean 39.8cm cm 3 p value P < 0.05 Singh, Heit et al. Cranio, 2016 Example of Non surgical procedure: Courtesy: Dr Tammarie Heit, DDS Further research questions What are the effects of increased nasal airway volume after DNA appliance therapy in adults diagnosed with OSA? The aim of this study is to test the hypothesis that the upper airway can be enhanced in adults diagnosed with OSA so that CPAP therapy might potentially become avoidable 10

Results Methods 11 consecutive adults aged >21yrs. Diagnosed with mild to moderate OSA, following HST interpreted by a Board certified sleep physician.

The mean AHI of the study sample was calculated prior to and after treatment with no appliance in the mouth when both sleep studies were done. Subject Pre AHI Post AHI Months A 5.4 3.1 16 B 18.9 7.

4% Singh, Griffin et al. World Association of Sleep Medicine, 2015 doi:10.1016/j.sleep.2015.02.020 Follow up study with 19 consecutive adults aged >21yrs Singh GD, Griffin TM,Chandrashekhar R.

11 Results Methods 11 consecutive adults aged >21yrs. Diagnosed with mild to moderate OSA, following HST interpreted by a Board certified sleep physician. Each subject was treated using biomimetic oral appliance therapy by a dentist (TG) with advanced training in dental sleep medicine. The mean AHI of the study sample was calculated prior to and after treatment with no appliance in the mouth when both sleep studies were done. Subject Pre AHI Post AHI Months A B C D E F G H I J K Mean Std p value < 0.01 Mean AHI Improvement 68.4% Singh, Griffin et al. World Association of Sleep Medicine, 2015 doi: /j.sleep Follow up study with 19 consecutive adults aged >21yrs Singh GD, Griffin TM,Chandrashekhar R. Biomimetic oral appliance therapy in adults with mild to moderate obstructive sleep spnea. Austin J Sleep Disord. 2014;1(1): 5. Each subject was treated using biomimetic oral appliance therapy (mrna appliance) by a different dentist (SC) with advanced training in dental sleep medicine 51% reduction in AHI with significant improvements in RDI and ODI also. Patient History and Physical Findings Oropharyngeal appearance: Before and after tonsillectomy A 27 year old female reported to our office with TMD symptoms, was screened for OSA and was diagnosed with severe obstructive sleep apnea with an initial AHI of 105/hour Level 1 sleep study showed AHI 118/hr Referred to ENT for tonsillectomy. Reduced AHI 70/hr and controlled on CPAP, which she did not like. Initiated DNA appliance therapy for 9 months (combined with CPAP). Resulted in AHI of 1/hour without CPAP or DNA appliance in situ. Courtesy: Dr Tammarie Heit, DDS 11

Pulmonologist s Report Appliance Pre AHI OSA Dx Post AHI Mths

DNA appliance or mrna appliance therapy DNA 56.5 Severe 18.

8 16 DNA 36.3 Severe 5.1 10 DNA 44.2 Severe 12 11 DNA 39.

7 9 mrna Severe 34.5 11.3 9 mrna Severe 43.3 19.0 9 mrna Severe 50.

1 9 mrna Severe 50.8 26.6 9 Mean 45.9 16.5 9.7 Std 10.5 8.8 1.

001 Change 64% reduction Singh, Griffin and Cress, J Sleep

12 Pulmonologist s Report Appliance Pre AHI OSA Dx Post AHI Mths Follow up study on severe OSA treated by different dentists, using DNA appliance or mrna appliance therapy DNA 56.5 Severe DNA 40 Severe DNA 41 Severe DNA 74.8 Severe DNA 36.3 Severe DNA 44.2 Severe DNA 39.1 Severe 22 7 DNA 40.7 Severe mrna Severe mrna Severe mrna Severe mrna Severe mrna Severe mrna Severe mrna Severe Mean Std p value p < Change 64% reduction Singh, Griffin and Cress, J Sleep Disorders Therapy, 2016 More recent data: Long term (5yr) follow up Pre treatment 4.7cm 3 Post treatment 31.8cm 3 Pediatric Cases 5 years later Singh, Liao, Stevens, ENT

13 Upper DNA appliance Upper DNA appliance only Singh and Lipka, J Amer Acad Courtesy: Gnathol Dr Gabriela Orthop. Lipka, 2009 DDS Singh and Lipka, J Amer Acad Gnathol Orthop Upper DNA appliance only Pediatric Cases August 2012 May 2016 Singh and Lipka, J Amer Acad Gnathol Orthop Courtesy: Dr. Dennis Klemp August 2012 May 2016 November 2012 May 2016 Courtesy: Dr. Dennis Klemp Courtesy: Dr. Dennis Klemp 13

14 November 2012 May 2016 Adult Cosmetic Cases Case study 1: Non surgical cosmetic treatment with health benefits Courtesy: Dr. Dennis Klemp Harris and Singh, J Amer Ortho Soc 2013 Pre treatment Mid treatment Harris and Singh, J Amer Ortho Soc 2013 Harris and Singh, J Amer Ortho Soc 2013 Post treatment Finished Case: 14 months These correlations of form and function support the notion of Craniofacial Homeostasis Harris and Singh, J Amer Ortho Soc 2013 Harris and Singh, J Amer Ortho Soc

15 16yr old Female: 18 months Courtesy: Dr Kwangyeon Kim, South Korea 16yr old Female: 18 months 19yr old Female: 16 months Courtesy: Dr Kwangyeon Kim, South Korea Courtesy: Dr Kwangyeon Kim, South Korea 19yr old Female: 16 months 27yr old Female: 30 months Courtesy: Dr Kwangyeon Kim, South Korea Courtesy: Dr Kwangyeon Kim, South Korea 15

27yr old Female: 30 months Courtesy: Dr Kwangyeon Kim, South Korea SUMMARY Pneumopedics is the process of non surgical, upper airway remodeling that may result from treatment with a biomimetic oral

basic, physiologic processes, such as breathing during sleep. This is the reason that this system of biomimetic oral appliances can be used to treat, reduce and eventually eliminate OSA.

16 27yr old Female: 30 months Courtesy: Dr Kwangyeon Kim, South Korea SUMMARY Pneumopedics is the process of non surgical, upper airway remodeling that may result from treatment with a biomimetic oral appliance. How does Pneumopedics work? The biomimetic oral appliance system uses the principles of Epigenetics to activate a person's naturally occurring genes to correct deficiencies in the craniofacial region. The tissues in the craniofacial region are slowly redeveloped and remodeled over time, making corrections to the structure of the upper airway, non surgically. It is a pain free, minimally invasive process, which uses no drugs, medication or injections. During the Pneumopedic process, the craniofacial region undergoes structural changes so that the functional space of the upper airway increases volumetrically, allowing for improved function of basic, physiologic processes, such as breathing during sleep. This is the reason that this system of biomimetic oral appliances can be used to treat, reduce and eventually eliminate OSA. CONCLUSIONS Non-surgical upper airway remodeling can be obtained in both children and adults, and suggests that genetically-encoded developmental mechanisms may be epigenetically-modulated by biomimetic oral appliances to enhance the upper airway in patients with OSA. These findings may help dentists in the management of adults and children diagnosed with obstructive sleep apnea, using Pneumopedics and craniofacial epigenetics. American Sleep and Breathing Academy info@myasba.com 1745 W Deer Valley Rd, Suite 112 Phoenix, AZ Thanks for your attention! Office location 2017 Dr. G. Dave Singh DDSc PhD DMD 2017 Vivos BioTechnologies, Inc. Tel: (971) or 2234 E mail: drsingh@vivoslife.com 16

Developing Facial Symmetry Using an Intraoral Device: A Case Report

Developing Facial Symmetry Using an Intraoral Device: A Case Report by Theodore R. Belfor, D.D.S.; and G. Dave Singh, D.D.Sc., Ph.D., B.D.S. Dr. Theodore Belfor graduated from New York University College