university of manitoba faculty of dentistry
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University of Manitoba Faculty of Dentistry
Anthony M. Iacopino DMD PhD
DeanProfessor, Restorative DentistryDirector,
Centre for Oral-Systemic Health
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Bugs, Biofilm, and Magic Bullets:
Implications for Clinical Practice
Special Event
Thunder Bay
February 12, 2010
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Why should we think more broadly?
EmergingTechnologies
Changing
HealthcareEnvironment
New Science
InterprofessionalAwareness
ImprovedPublic Health
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Periodontal Disease: Gingivitis and Periodontitis
Chronic inflammatory disease one of the most prevalent microbial diseases of mankind
and primarily a gram negative anaerobic oral infection
gingival inflammation
destruction of periodontal supporting tissues
exfoliation of teeth in severe cases
organisms within microbial flora of dental plaque biofilmare the major etiologic agents (Porphyromonas gingivalis,
Tannerella forsythia, and Campylobacter rectus)
microorganisms and endotoxins generate localized host-mediated tissue destructive immune response (cellular,inflammatory cytokines)
(Moritz and Mealey, Grand Rounds Oral-Sys Med 2:13-20, 2006)
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Progression of Poor Oral Health
Scottsdale Report, 2007
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Title (32 Myriad Web Pro)
Periodontal Disease: Gingivitis and Periodontitis
75% of North American population has some formof periodontal disease (~ 15% have severe disease)
recent data indicates gingivitis may be as damaging as
periodontitis (systemic inflammatory burden)
(Moritz and Mealey, Grand Rounds Oral-Sys Med 2:13-20, 2006)
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Periodontal Disease: Gingivitis and Periodontitis
Traditional Clinical Indices and Diagnostics
plaque index
gingival index (bleeding on probing)
pocket depth
loss of attachment risk factors (i.e., smoking, genetics, systemic disease, age)
Individualized medicine/consideration of biofilm
persistence of orange/red complex
importance of bleeding regardless of pocket depth
epigenetic effects (alteration of host DNA)
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Periodontal Disease: Importance of the Biofilm
Biofilm maturation and characteristics
early colonizers, intermediate (orange), and late (red)
early colonizers create environment for late colonizers(top of the food chain)
biofilm communicates, resists host defense/antibiotics
orange and red (P gingivalis, C rectus) able to evade hostdefenses and have ability for invasion/dissemination
P gingivalisand C rectusare erosive/ulcerative, havetoxins that kill immune cells, and avoid lymphatic system
gingival tissue is highly vascular and total blood volumecirculates through serving as systemic entry portal
(Marsh PD, J Clin Periodontol 6:7-15, 2005)
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Periodontal Disease: Systemic Effects
Transient bacteremia/endotoxemia
linked to disease severity and periods of
progression/exacerbation
organisms invade deep connective tissues and have
been found in vascular endothelium
during progression of gingivitis to periodontitis
pockets gradually deepen and ulcerate
cumulative surface area of ulcerated pockets increases in size
to the palm of a hand creates systemic exposure
tissue destructive responses not limited to oral cavity
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Periodontal Disease: Systemic Effects
Effects ofsystemic exposure
similar to acute/chronic infection in any other location
of the body
elevation of serum pro-inflammatory cytokines (IL-1,Il-6, TNF-) and acute phase reactants (CRP) hasmany effects on systemic biochemistry/physiology
leads to elevations of serum lipid levels (FFA, LDL/TRG)
destructive influences on cells and tissues
systemic inflammatory state may adversely effect manyorgan systems leading to initiation or exacerbation of systemicdiseases/conditions associated with chronic inflammation
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Periodontal Disease: Systemic Effects
Effects ofsystemic exposure
epigenetic changes in target tissues (not mutations)
part of environmental stressor category of host alteration
methylation of DNA changes three dimensional conformation
specific effects in each tissue and disease state
decreases transcription and shuts down local defenses andhealing response to allow colonization/dissemination, altershost metabolism to feed bacteria (carbohydrates)
DNA changes are conserved during cell division and the hostis permanently changed
(Barros and Offenbacher, J Dent Res 88:400-408, 2009)
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Periodontal Disease: Systemic Effects
Adverse pregnancy outcomes
epigenetic changes in target tissues
C rectus causes changes in the developing placenta that impairperfusion causing inflammation and rise in PGE2(contraction of uterine smooth muscle, membrane rupture,
neonatal inflammatory syndrome)
C rectus is abortive bug in veterinary medicine and equineindustry, new data links exposure to 3-fold risk in humans
C rectus shown to reduce IGF-2 growth factor expression in
utero and may be major player in fetal growth restriction
C rectus acts like syphilis and gets into nerve and brain tissueof fetus possibly causing neurologic impairments
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The Oral-Systemic Mechanism: Chronic Inflammation
Untreated oral infection has effects on organ systems
primary inflammatory response enters the system and isprocessed in circulation and liver
secondary and tertiary mediators of chronic inflammation
contributes to overall systemic inflammatory burden
years of elevated systemic inflammation lead todestructive effects on target tissues
Scottsdale Report, 2007
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Relationship Between Periodontitis andSystemic Diseases/Conditions
respiratory disease osteoporosis
arthritis Alzheimers disease
stroke adverse pregnancy outcomes
cardiovascular disease diabetes
gastrointestinal disease
end stage renal disease
Grand Rounds in Oral-Systemic MedicineGapski and Cobb 1(1):14-23, 2006;
Moritz and Mealy 1(2):13-21, 2006;Iacopino 1(3):25-37, 2006;Paquette 1(4):14-25, 2006;
Tae-Ju Oh et al., 2(1):10-21, 2007
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PeriodontitisElevated Serum
Pro-InflammatoryCytokines
Hyperlipidemia
Diabetes
BacteremiaEndotoxemia
InsulinResistance
-CellDestruction
Cardiovascular/Cerebrovascular
Disease
Arthritis
RespiratoryInfection
Aspiration
Dementia
MicrogliaActivation
SynovialInflammation Atherosclerosis
Altered LipidMetabolism
Rheumatoid
Factor
Atherosclerosis
HSP Mimicry and Seeding (Vascular Endothelium)
Linkage Between Periodontitis and Systemic Diseases/ConditionsAdverse
PregnancyOutcome
Seeding (Gut) Gastrointestinal Disease
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Reversibility of Periodontitis-InducedSystemic Inflammation
Periodontitis linked to systemic inflammation andtreatment of periodontitis reduces systemicinflammation
65 healthy subjects (severe generalized periodontitis) blinded randomized control clinical trial
measured CRP, IL-6, LDL cholesterol at baseline andtwo months after treatment (standard therapy) at baseline, inflammatory markers were significantly elevated
after treatment, significant reductions in CRP (p=0.03),IL-6 (p=0.006), and LDL (p=0.002)
reductions independent of age, gender, BMI, ethnicity
(DAiuto et al., J Clin Perio 34:124-129, 2007)
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Reversibility of Periodontitis-InducedEndothelial Dysfunction
Periodontitis linked to endothelial dysfunction (arterial
stiffness/elasticity) and treatment of periodontitisimproves endothelial function
flow-mediated dilatation decreased with severeperiodontitis and corresponding elevations of CRP(Mercanoglu et al., J Periodontol 75:1694-1700, 2004)
treatment of periodontitis and improved periodontalhealth increases flow-mediated dilatation(Tonetti et al., N Engl J Med 356:911-920, 2007)
pulse-wave velocity higher with periodontitis and
corresponding elevations of CRP, IL-6, and TNF-;treatment of periodontitis decreases pulse-wavevelocity and levels of inflammatory biomarkers(Seymour et al., Clin Microbiol Infect 13:3-10, 2007)
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Gastrointestinal
Systemic Inflammation
Genitourinary Respiratory
Diabetes
Smoking
StressObesityDiet
Autoimmune DiseaseGenetics
Environment
Total Burden of Infection
Atherosclerosis
Oral
Linkage Between Infection and Inflammation in CVD and Diabetes
Direct Infection
Molecular Mimicry
- Responsibility of all health professionals to reduce oral infection- Effective health policy must focus on reduction of risk factors- Modest changes in risk can produce significant changes in disease burden
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Periodontal Disease: Treatment Phase I therapy
oral hygiene instruction to reduce microbial burden brushing/flossing mechanical disruption of biofilm
scaling/root planning to remove etiology removes plaque/calculus, polishes tooth surfaces
follow-up care (8 weeks duration, 6-month recall)
adjunctive antimicriobials (antiseptics/antibiotics; i.e., Atridox,Arestin, Periochip, Listerine, Perioguard, Viadent)
modulation of host response (antiinflammatories; i.e., Periostat)
Phase II therapy surgical intervention to restore original architecture
corrects bony defects and establishes cleansible architecture
bone augmentation/grafting and tissue regeneration to restoreadequate tooth support
increased justification to remove epigenetically modified tissue
Prevention is the best treatment available!
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Title (32 Myriad Web Pro)Reduce Oral Inflammation: Good Enough?
Antimicrobials/Host Modulators rinses, toothpastes, chips
adjunctive antibiotics
PERIOSTAT20mg
DoxycyclineHyclate
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Targeted Antibodies: The Holy Grail?
Core Philosophy:
Produce large quantities at pharmacological purity
Rapid and low-cost manufacturing process
Highly specific and effective
No microbial resistance or side effects
Multiple points of intervention (systemic potential)
Perform relevant and convincing clinical trials
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Title (32 Myriad Web Pro)
MaternalDental Plaque
Maternal AntibodyResponse to Flora
Low Maternal Antibody
Response Maternal PeriodontitisProgression
Fetal Exposure to
Periodontitis PathogensFetal IgM Response to
Periodontitis Pathogens
Elevated Fetal Inflammatory CytokinesCellular Damage
PTB
(Madianos et al., Ann Periodontol 6:175-182, 2001)
Current Thinking: Individual Responses
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Title (32 Myriad Web Pro)
PatientDental Plaque
Patient AntibodyResponse to Flora
Low Patient Immune
Response
Local Inflammation Progression to
Systemic Inflammation;
Periodontal Pathogen Invasion
Chronic End Organ
Exposure to
Inflammatory Burden
Can Begin at8 Years of Age
10-40 YearsIncubation Time
Exacerbation orInitiation of Systemic
Inflammatory Disease
(International Association of Dental Research, Miami 2009)
Current Thinking: Individual Responses
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International Centre for Oral-Systemic Health
ParticipatingFaculties &
Centres
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Comprehensive Patient Care
Hospitals
Long-Term Care Facilities Community Health Settings Urban and Rural Clinics
Interprofessional Teams
Dentist Hygienist
Physician Nurse Pharmacist Dietician Physical Therapist Social Worker Behavioral Psychologist
Interprofessional Education and Research Approaches
Content in oral-systemic science revolving around themes
(inflammation, overall health and wellness)
Biomedical and clinical investigators establish oral-systemicresearch areas in basic biomedical investigation, clinicalintervention/practice models, or epidemiology/public healthleading to systems improvements
Oral-Systemic
Health
HumanEcology
Nursing
Dentistry
Medicine
Pharmacy
Social Work
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ICOSH-IGY Partnership: New Frontier?
Key Assets:
IGY technology to produce antibodies
Broad scope of IGY patents
ICOSH expertise in oral-systemic science
ICOSH infrastructure for clinical trials
ICOSH oral microbial repository
University of Manitoba Technology Transfer Office
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Chicken Egg Yolk Antibody (IgY) Production
inject pathogenic bacteria or specific antigeniccomponents of bacteria into chickens (selected bugsfor caries, periodontal disease, etc.)
chicken makes IgY against the pathogenic bacteriathat is contained in egg yolks
harvest IgY from egg yolks using unique technology
Applications Igy is specific and essentially inert (no cross-reactivity
with human cells/tissues, no side effects)
local use for oral diseases (toothpastes, rinses, gels,microspheres for slow release and substantivity)
systemic use (delivery routes to circulation similar toanti-TNF drugs) to target oral-systemic connections
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Therapeutic Antibodies: State of the Science
Caries most work has involved host protective response fromvaccination (host produces its own antibody)
vaccination approach expensive and difficult
caries vaccine (S mutans) can be effective through
prevention of accumulation ofS mutans in biofilm viacontinuous secretion of salivary IgM but lingeringissues prevent widespread use (mainly hesitancyassociated with vaccines and potential side effects)
IgY approach to S mutans against same bacterial
antigenic component has been effective in animalmodels (administration through drinking water) andin human volunteers using rinses and sprays
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Therapeutic Antibodies: State of the Science
Kou and Zhi, J Stomatol 21:339-41, 2003) most convincing study in animal models rat model using S mutans IgY gargle, IgY lyophilized powder,
egg yolk food containing IgY
significant reduction in caries scores
Human studies are encouraging but preliminary in
nature (more work needs to be done)
Caries:
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Therapeutic Antibodies: State of the Science
Periodontal Disease some work done on systemic anti-TNF to reduce
inflammatory tissue damage (arthritis drugs likeInfleximab and Embrel)
plagued by side effects and complications still doesnt address microbial etiology
approach requires reduction of biofilm (oralmicrobial burden), reduction of red/orange complexbacteria, and possibly systemic intervention toaddress bacteremia related to oral-systemicconnections
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IgY Therapy: Major Concerns
IgY is a protein and might be vulnerable to salivary and
digestive enzymes For biofilm formation, early time points are crtical, so
worry of oral digestion of proteins not as great, IgY
interacts with bugs on contact, daily application should
influence biofilm formation and maturation as bacteria
lose biofilm attachment capability
Oral IgY administration already shown to be effective
for GI applications (longer transit time and greater
potential for digestion, high concentration/purity may
preserve IgY effect)
Need to demonstrate ability to establish circulating IgY
for applications in broader oral-systemic realm
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Title (32 Myriad Web Pro)Basic Oral Care and Medical Spending
Preliminary estimates of medical cost savings for
high-risk populations provided with basicpreventive oral health services
four-year period in the US
$50 per person for diabetes, cardiovascular disease,
and cerebrovascular disease
$700 per mother/child pair for pregnancy
(Albert et al, BMC Health Services Res 6:103-109, 2006;
Ide et al, J Periodontol 78:2120-2126, 2007;Quinonez and Stearns, J Periodontol 79:203-206, 2008)
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Title (32 Myriad Web Pro)Canada: Current Numbers
Canada's population is estimated at 33,143,600
Over 2 million Canadians have diabetes and thatnumber is expected to reach 3 million by 2010
About 2 million Canadians currently living with
some form of heart disease or stroke
Current number of annual Canadian births is 341,048
(Statistics Canada 2008; Canadian Diabetes Assoc 2008;
Heart and Stroke Foundation of Canada, 2008)
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Where Are We Going?
ICOSH partnership with ABY provides linkage oftechnology with clinical research and human resources
New collaboration offers significant potential forchanges to approaches for improving oral-systemichealth, healthcare practice, and overall public health
The shape of things to come?
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O i it M f t
University of Manitoba Faculty of Dentistry