University of Manitoba Faculty of Dentistry

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University of Manitoba Faculty of Dentistry Anthony M. Iacopino DMD PhD Dean Professor, Restorative Dentistry Director, Centre for Oral-Systemic Health

One university. Many futures.

Special Event

Bugs, Biofilm, and Magic Bullets: Implications for Clinical Practice Thunder Bay February 12, 2010

One university. Many futures.

Why should we think more broadly? Changing Healthcare Environment Emerging Technologies New Science Interprofessional Awareness Improved Public Health

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Periodontal Disease: Gingivitis and Periodontitis (Moritz and Mealey, Grand Rounds Oral-Sys Med 2:13-20, 2006)

 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 biofilm are the major etiologic agents (Porphyromonas gingivalis, Tannerella forsythia, and Campylobacter rectus) • microorganisms and endotoxins generate localized hostmediated tissue destructive immune response (cellular, inflammatory cytokines) One university. Many futures.

Progression of Poor Oral Health Scottsdale Report, 2007

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Disease: Gingivitis and Periodontitis Title –Periodontal (32 Myriad Web Pro ) (Moritz and Mealey, Grand Rounds Oral-Sys Med 2:13-20, 2006)

75% of North American population has some form of periodontal disease (~ 15% have severe disease) – recent data indicates gingivitis may be as damaging as periodontitis (systemic inflammatory burden)

One university. Many futures.

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) One university. Many futures.

Periodontal Disease: Importance of the Biofilm (Marsh PD, J Clin Periodontol 6:7-15, 2005)

 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 host defenses and have ability for invasion/dissemination • P gingivalis and C rectus are erosive/ulcerative, have toxins that kill immune cells, and avoid lymphatic system • gingival tissue is highly vascular and total blood volume circulates through serving as systemic entry portal One university. Many futures.

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

One university. Many futures.

Periodontal Disease: Systemic Effects  Effects of “systemic exposure” • similar to acute/chronic infection in any other location of the body • elevation of serum pro-inflammatory cytokines (IL-1β, Il-6, TNF-α) and acute phase reactants (CRP) has many 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 many organ systems leading to initiation or exacerbation of systemic diseases/conditions associated with chronic inflammation

One university. Many futures.

Periodontal Disease: Systemic Effects (Barros and Offenbacher, J Dent Res 88:400-408, 2009)

 Effects of “systemic 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 and healing response to allow colonization/dissemination, alters host metabolism to feed bacteria (carbohydrates) • DNA changes are conserved during cell division and the host is permanently changed One university. Many futures.

Periodontal Disease: Systemic Effects  Adverse pregnancy outcomes • epigenetic changes in target tissues • C rectus causes changes in the developing placenta that impair perfusion 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 equine industry, 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 tissue of fetus possibly causing neurologic impairments One university. Many futures.

The Oral-Systemic Mechanism: Chronic Inflammation Scottsdale Report, 2007

Untreated oral infection has effects on organ systems • primary inflammatory response enters the system and is processed in circulation and liver • secondary and tertiary mediators of chronic inflammation • contributes to overall “systemic inflammatory burden” • years of elevated systemic inflammation lead to destructive effects on target tissues One university. Many futures.

Relationship Between Periodontitis and Systemic Diseases/Conditions • respiratory disease

• osteoporosis

• arthritis

• Alzheimer’s disease

• stroke

• adverse pregnancy outcomes

• cardiovascular disease

• diabetes

• gastrointestinal disease

• end stage renal disease

Grand Rounds in Oral-Systemic Medicine Gapski 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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Linkage Between Periodontitis and Systemic Diseases/Conditions Respiratory Infection Aspiration

Adverse Pregnancy Outcome

Dementia Microglia Activation


Elevated Serum Bacteremia Hyperlipidemia Endotoxemia Pro-Inflammatory Altered Lipid Cytokines Metabolism Rheumatoid Factor Synovial β-Cell Atherosclerosis Inflammation Destruction Insulin Arthritis Resistance Diabetes Cardiovascular/ HSP Mimicry and Seeding (Vascular Endothelium) Cerebrovascular Disease Seeding (Gut) Gastrointestinal Disease


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Reversibility of Periodontitis-Induced Systemic Inflammation (D’Aiuto et al., J Clin Perio 34:124-129, 2007)

 Periodontitis linked to systemic inflammation and treatment of periodontitis reduces systemic inflammation • 65 healthy subjects (severe generalized periodontitis) • blinded randomized control clinical trial • measured CRP, IL-6, LDL cholesterol at baseline and two 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

One university. Many futures.

Reversibility of Periodontitis-Induced Endothelial Dysfunction

 Periodontitis linked to endothelial dysfunction (arterial stiffness/elasticity) and treatment of periodontitis improves endothelial function • flow-mediated dilatation decreased with severe periodontitis and corresponding elevations of CRP (Mercanoglu et al., J Periodontol 75:1694-1700, 2004) • treatment of periodontitis and improved periodontal health 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-α; treatment of periodontitis decreases pulse-wave velocity and levels of inflammatory biomarkers (Seymour et al., Clin Microbiol Infect 13:3-10, 2007) One university. Many futures.

Linkage Between Infection and Inflammation in CVD and Diabetes Total Burden of Infection Gastrointestinal

Molecular Mimicry Direct Infection

Genitourinary Respiratory

Systemic Inflammation




Smoking Stress Obesity Diet Autoimmune Disease Genetics Environment

- 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 One university. Many futures.

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 restore adequate tooth support – increased justification to remove epigenetically modified tissue

Prevention is the best treatment available! One university. Many futures.

Reduce OralWeb Inflammation: Good Enough? Title – (32 Myriad Pro)  Antimicrobials/Host Modulators • rinses, toothpastes, chips • adjunctive antibiotics

PERIOSTAT® 20mg Doxycycline Hyclate

One university. Many futures.

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 One university. Many futures.

Current Thinking: Individual Responses Title – (32 Myriad Web Pro ) (Madianos et al., Ann Periodontol 6:175-182, 2001)

Maternal Dental Plaque

Maternal Antibody Response to Flora

Low Maternal Antibody Response

Fetal Exposure to Periodontitis Pathogens

Maternal Periodontitis Progression

Fetal IgM Response to Periodontitis Pathogens


Elevated Fetal Inflammatory Cytokines Cellular Damage One university. Many futures.

Current Thinking: Individual Responses Title – (32 Myriad Web Pro ) (International Association of Dental Research, Miami 2009)

Patient Dental Plaque

Patient Antibody Response to Flora

Low Patient Immune Response

Local Inflammation Progression to Systemic Inflammation; Periodontal Pathogen Invasion

Chronic End Organ Can Begin at 8 Years of Age Exposure to Inflammatory Burden

Exacerbation or Initiation of Systemic 10-40 Years Incubation Time Inflammatory Disease

One university. Many futures.

International Centre for Oral-Systemic Health

Participating Faculties & Centres

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International Centre for Oral-Systemic Health

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Human Ecology

Pharmacy Dentistry Social Work

Nursing Oral-Systemic Health Medicine

Comprehensive Patient Care • Hospitals • Long-Term Care Facilities • Community Health Settings • Urban and Rural Clinics

Interprofessional Teams Interprofessional Education and Research Approaches • Content in oral-systemic science revolving around themes (inflammation, overall health and wellness) • Biomedical and clinical investigators establish oral-systemic research areas in basic biomedical investigation, clinical intervention/practice models, or epidemiology/public health leading to systems improvements

One university. Many futures.

• Dentist • Hygienist • Physician • Nurse • Pharmacist • Dietician • Physical Therapist • Social Worker • Behavioral Psychologist

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 One university. Many futures.

Chicken Egg Yolk Antibody (IgY)  Production • inject pathogenic bacteria or specific antigenic components of bacteria into chickens (selected bugs for caries, periodontal disease, etc.) • chicken makes IgY against the pathogenic bacteria that 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 to anti-TNF drugs) to target oral-systemic connections One university. Many futures.

Therapeutic Antibodies: State of the Science

 Caries • most work has involved host protective response from vaccination (host produces its own antibody) • vaccination approach expensive and difficult • caries vaccine (S mutans) can be effective through prevention of accumulation of S mutans in biofilm via continuous secretion of salivary IgM but lingering issues prevent widespread use (mainly hesitancy associated with vaccines and potential side effects) • IgY approach to S mutans against same bacterial antigenic component has been effective in animal models (administration through drinking water) and in human volunteers using rinses and sprays

One university. Many futures.

Therapeutic Antibodies: State of the Science Caries:  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)

One university. Many futures.

Therapeutic Antibodies: State of the Science

 Periodontal Disease • some work done on “systemic” anti-TNF to reduce inflammatory tissue damage (arthritis drugs like Infleximab and Embrel) • plagued by side effects and complications • still doesn’t address microbial etiology • approach requires reduction of biofilm (oral microbial burden), reduction of red/orange complex bacteria, and possibly systemic intervention to address bacteremia related to oral-systemic connections

One university. Many futures.

Therapeutic Antibodies: State of the Science Periodontal Disease:  Yokoyama et al, J Oral Sci 49:201-206, 2007 • • • • • • •

most convincing study thus far preliminary human study applied subgingival gel containing P gingivalis IgY significant reduction in probing depth and bleeding on probing significantly reduction in P gingivalis impaired ability of P ginigivalis to colonize bacterial plaque first indication that P gingivalis IgY may be an effective immunotherapeutic agent in the treatment of periodontitis • additional human studies are next logical step

One university. Many futures.

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 One university. Many futures.

Oral Care and) Medical Spending Title – Basic (32 Myriad Web Pro (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)

• Preliminary estimates of medical cost savings for high-risk populations provided with basic preventive 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

One university. Many futures.

Canada: Title – (32 Myriad WebCurrent Pro) Numbers (Statistics Canada 2008; Canadian Diabetes Assoc 2008; Heart and Stroke Foundation of Canada, 2008) • Canada's population is estimated at 33,143,600 • Over 2 million Canadians have diabetes and that number 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 One university. Many futures.

Healthcare Cost Savings Title –Canadian (32 Myriad Web ProSystem ) • Conservative estimates of cost savings

over four years in Canada • 60% of Canadians with some form of periodontal disease; $40 per person for diabetes, cardiovascular disease, and cerebrovascular disease; $500 per mother/child pair for pregnancy • provision of basic preventive oral health services as part of comprehensive healthcare for these high-risk populations results in $200 million reduction in overall healthcare spending ($50 million per year) One university. Many futures.

Where Are We Going?  ICOSH partnership with ABY provides linkage of technology with clinical research and human resources  New collaboration offers significant potential for changes to approaches for improving oral-systemic health, healthcare practice, and overall public health

The shape of things to come? One university. Many futures.

University of Manitoba Faculty of Dentistry [email protected]

One university. Many futures.

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