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Translational Research

Mission:

Originally, we were interested in the 3-linked arenas of clinical/translational research and their impact upon diagnostic microbiology, specifically, and healthcare, generally, with three branches: Biofilms, Antibiotic Resistance, and Clinical and Financial Outcomes.

Recently, we added the 4th topic of oral drivien systemic infectious diseases, focusing on the oral-lung (VAP) connection specifically and oral health, generally, with an international focus (Asia-Pacific and the UK).

Translational research Model
International University Biofilm Research Consortium IUBRC Model

Overview:

Oral Biofilms: Architects of Disease, Head to Toe
Tooth to Lung
John G. Thomas, Ph.D.

In the oral cavity, there are greater than 700 different microbial species; it is the most diverse microbial population in the host and diversity equals survival. However, a select proportion will up-regulate from planktonic phenotype (PP) to a biofilm phenotype (PBF), attach to the gingival surface, periodontal pocket, or endodonic surface based on their stress response genes and 'Quorum Sensing.' Microorganisms actually have three phenotypes or potential Life Cycles (Figure 1). Eight key environmental/cultural characteristics magnify the selection/composition of multi-species biofilm inhabitants during a 4 Stage life-cycle (I-IV) in clinical disease: gingivitis (microaerophilic microbes), periodontitics and endodontics (anaerobic microbes).

The unifying concept is the Ecological or Plaque Hypothesis, which recognizes that ecological pressure (including antibiotics) is necessary for low number "Professional Pathogens" to out-compete resident flora ("Beneficial Species") and achieve numerical dominance (ratio) associated with biofilm pathogenicity (PBF:PP); antibiotics may be contraindicated. Ten serious human diseases are linked to poor oral hygiene at a cost of more than 40 billion dollars/year.

Systemic Consequences and links of oral biofilm architecture (Attached, Stages II and III) and Dispersal (Stage IV) is now focusing on ventilator associated pneumonia (VAP) and concomitant increased antibiotic resistance. Further, there is evidence from our Ventilator-Endotracheal-Lung (V-E-L) model that a co-biofilm of, first, oral dental flora and second, traditional pneumonia flora, are responsible for a robust multi-species biofilm that is a reservoir for dispersal of up-regulated fragments to the alveoli spaces with loss of susceptibility.

In fact, the potential mechanism, the link connecting oral-lung infections may be that poor oral hygiene predisposes high-risk patients to dental plaque colonization by traditional respiratory pathogens and that for ICU patients; recent antibiotic exposure increases this colonization significantly. We have turned this into the "Double-Hit" Hypothesis and expanded it to include secondary colonization of the ETT lumen with an up-regulated Phase II co-biofilm (Figure 2). This co-biofilm is emerged by 3-synergistic isolates, colonizing the surface in preferred order: Strep. mutans, Candida albicans, and Pseudomonas aeruginosa. Their 3-D structure resembles plaque and we call it "Bio-Plaque" (Figure 3).

Therapeutics modalities are refocusing on multiple interventions, recognizing that the properties of biofilms are similar to hydrated organic polymers acting as tumors (multi-cell communities). Antibiotics may be counter-indicated as Minimal Intervention (MI) is an emerging strategy and none works alone.

We have evaluated in our two biofilm engineered, clinical models, 1) a hydroxyapitate tooth and 2) a three part ventilator-endotrach-lung, with various intervention strategies: 1) mechanical disruption/removal (sonication), 2) anti-infectives (silver ions/tobromycin), and 3) immune modulation (azithromycin/low dose doxycline) and a CMT (Chemically Modified Tetracycline) working at different Stages of the biofilm phenotype (Stages I-IV) and planktonic phenotype (Stage 0) (Figure 4).

One cannot eliminate the preformed attached biofilm, but by reducing the 1) bioburden both planktonic and biofilm phenotype and 2) effectively maintaining a normal flora (Beneficial Species) that favors a ratio of oral planktonic over the biofilm phenotype with non-carcinogenic and non-periopathogen inhabitants (Plaque Hypothesis), one can decrease oral biofilm associated diseases and linked systemic consequences, particularly lung (VAP).

Figure 1Figure 1
 
Figure 2
Figure 2
 
Figure 3
Figure 3
Figure 4
Figure 4

Milestones:

  • 1996: Support from CollaGenex Pharmaceuticals
    The development and implementation of an IRB approved protocol for the use of Doxycycline as an anti-periodontal treatment.
  • 1998: Support from CollaGenex Pharmaceuticals
    The submission to and approval from the FDA for Periostat® as an adjunctive therapy for periodontal disease management (recognized in US Today).
  • 2000: The design, evaluation, and implementation of a 3 component Ventilator-Endotrach-Lung (VEL) Model to study biofilms in endotracheal tubes.
  • 2003: Support from Tyco Healthcare, Nellcor Division
    The expansion of the VEL Model to an Intensive Care Unit simulated environment with 6 VEL Model Stations to evaluate the efficacy of silver containing endotracheal tubes.
  • 2004:The utilization of quantitative imaging and COMSTAT to stage biofilm formation, similar to tumor growth classification.
  • 2005: Support from Tyco Healthcare, United States Surgical Division
    The development, implementation, and analysis of a broth biofilm model to study biofilm adherence on anti-infective polymer sutures.
  • 2006: Support from Tyco Healthcare, Nellcor Division
    The successful Pre-IDE submission to the FDA for Clinical Trials of silver-containing endotracheal tubes.