Drug – bio-affecting and body treating compositions – Dentifrices
Reexamination Certificate
2000-06-06
2004-12-14
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Dentifrices
C424S050000, C514S002600, C514S023000
Reexamination Certificate
active
06830745
ABSTRACT:
FIELD AND BACKGROUND OF THE INVENTION
Standard chemical analyses, traditional microscopic methods as well as digital imaging techniques such as confocal scanning laser microscopy, have transformed the structural and functional understanding of biofilms. Investigators, with these techniques have a clearer understanding of biofilm-associated microorganism cell morphology and cellular functions. The heightened awareness of metabolic biochemistry and the events associated with them have led to a better understanding, not only of individual cells and their varying environments, but also collections of cells that form colonies. Further, certain relationships of colonies to each other are under the direct influence of the biofilm in which they reside.
Concurrent with the increased understanding of cellular activity and inter-colony relationships, there has been an awareness developed about the biofilm in which the cells reside. While there has been an increased understanding of the architecture and composition of the biofilm matrix, the most significant advances have occurred in the inter-relationships among cells, colonies and biofilm matrices. Indeed, the basis of one aspect of this invention is founded in the integration of the enlightened understanding of microorganism activity within the influence of the biofilm in which they reside.
Biofilms are matrix-enclosed accumulations of microorganisms such as bacteria (with their associated bacteriophages), fungi, protozoa and viruses that may be associated with these elements. While biofilms are rarely composed of a single cell type, there are common circumstances where a particular cellular type predominates. The non-cellular components are diverse and may include carbohydrates, both simple and complex, proteins, including polypeptides, lipids and lipid complexes of sugars and proteins (lipopolysaccharides and lipoproteins).
For the most part, the unifying theme of non-cellular components of biofilms is its backbone. In virtually all known biofilms, the backbone structure is carbohydrate or polysaccharide-based. The polysaccharide backbone of biofilms serves as the primary structural component to which cells and debris attach. As the biofilm grows, expands and ages along biologic and non-biologic surfaces in well-orchestrated enzymatic synthetic steps, cells (planktonic) and non-cellular materials attach and become incorporated into the biofilm. The growing biofilm not only attracts living cells; it also captures debris, food particles, cell fragments, insoluble macromolecules and other materials that add to the layer upon the polysaccharide backbone. In this fashion, layering continues and is repeated so that the initial layers i.e., those closest to the original polysaccharide backbone, become buried or embedded in the biofilm. As the biofilm ages, there are layers upon layers of polysaccharide backbone with the attendant cells, debris and insoluble macromolecular structures.
Biofilms are the most important primitive structure in nature. In a medical sense, biofilms are important because the majority of infections that occur in animals are biofilm-based. Infections from planktonic bacteria, for example, are only a minor cause of infectious disease. In industrial settings, biofilms inhibit flow-through of fluids in pipes, clog water and other fluid systems and serve as reservoirs for pathogenic bacteria and fungi. Industrial biofilms are an important cause of economic inefficiency in industrial processing systems.
Biofilms are prophetic indicators of life-sustaining systems in higher life forms. The nutrient-rich, highly hydrated biofilms are not just layers of plankontic cells on a surface; rather, the cells that are part of a biofilm are a highly integrated “community” made up of colonies. The colonies, and the cells within them, express exchange of genetic material, distribute labor and have various levels of metabolic activity that benefits the biofilm as a whole.
Planktonic bacteria, which are metabolically active, are adsorbed onto a surface which has copious amounts of nutrients available for the initial colonization process. Once adsorbed onto a surface, the initial colonizing cells undergo phenotypic changes that alter many of their functional activities and metabolic paths. For example, at the time of adhesion,
Pseudomonas aeruginosa
(
P. aeruginosa
) shows upregulated algC, algD, algU etc. genes which control the production of phosphomanomutase and other pathway enzymes that are involved in alginate synthesis which is the exopolysaccharide that serves as the polysaccharide backbone for
P. aeruginosa's
biofilm. As a consequence of this phenotypic transformation, as many as 30 percent of the intracellular proteins are different between planktonic and sessile cells of the same species.
In summary, planktonic cells adsorb onto a surface, experience phenotypic transformations and form colonies. Once the colonizing cells become established, they secrete exopolysaccharides that serves as the backbone for the growing biofilm. While the core or backbone of the biofilm is derived from the cells themselves, other components e.g., lipids, proteins etc, over time, become part of the biofilm. Thus a biofilm is heterogeneous in its total composition, homogenous with respect to its backbone and heterogeneous with respect it its depth, creating diffusion gradients for materials and molecules that attempt to penetrate the biofilm structure.
Biofilm-associated or sessile cells predominate over their planktonic counterparts. Not only are sessile cells physiologically different from planktonic members of the same species, there is phenotypic variation within the sessile subsets or colonies. This variation is related to the distance a particular member is from the surface onto which the biofilm is attached. The more deeply a cell is embedded within a biofilm i.e., the closer a cell is to the solid surface to which the biofilm is attached or the more shielded or protected a cell is by the bulk of the biofilm matrix, the more metabolically inactive the cells are. The consequences of this variation and gradient create a true collection of communities where there is a distribution of labor, creating an efficient system with diverse functional traits.
Biofilm structures cause the reduced response of bacteria to antibiotics and the bactericidal consequences of antimicrobial and sanitizing agents. Antibiotic resistance and persistent infections that are refractory to treatments are a major problem in bacteriological transmissions, resistance to eradication and ultimately pathogenesis. While the consequences of bacterial resistance and bacterial recalcitrance are the same, there are two different mechanisms that explain the two processes.
The use of enzymes in degrading biofilms is not new. Compositional patents as well as published scientific literature support the concept of using enzymes to degrade, remove and destroy biofilms. However, the lack of consistency in results and the inability to retain the enzymes at the site where their action is required has prohibited their widespread use.
As an alternative to enzymes, harsh chemicals, elevated temperatures and vigorous abrasion procedures are preferentially used over enzymes. There are conditions, however, where these non-enzymatic approaches cannot be used e.g., caustic- and acidic-sensitive environments, temperature or abrasion sensitive components that are associated with the biofilm and dynamic fluid action. When a biofilm is growing in an area where there is a constant fluid flow, the agents that remove biofilms are flushed away before they can carry our their desired function. This is particularly true for medical situations where aggressive sterilization procedures cannot be carried out and there is a desired fluid flow.
Removing and controlling biofilm growth in biologic media are specifically sensitive to harsh treatments. Biofilms in the oral cavity, on implanted devices and infections that occur in the alimentary and vaginal tracts or in eyes, ears etc. are particularly suited f
Budny John A.
Budny Matthew J.
Abrahams Colin P.
Pharmacal Biotechnologies, LLC
Weddington Kevin E.
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