Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M31/00—Devices for introducing or retaining media, e.g. remedies, in cavities of the body
  • A61M31/002—Devices for releasing a drug at a continuous and controlled rate for a prolonged period of time
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
  • A61M2037/0007—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin having means for enhancing the permeation of substances through the epidermis, e.g. using suction or depression, electric or magnetic fields, sound waves or chemical agents

Definitions

• This invention relates to methods of permeabilizing biofilms, e.g., to deliver compounds such as antibiotics, antiseptics or photosensitizing agents into or through biofilms using stress or pressure waves.
• Biofilms are typically matrix-enclosed microbial aggregates associated with each other and a solid surface. Bacteria within biofilms have an increased resistance to antimicrobial agents relative to that of planktonic cells of the same species. The relative impermeability of biofilms to compounds such as antimicrobial agents may be one reason why microbial infections associated with biofilms are difficult to treat.
• the invention is based on the discovery that stress or pressure waves can be used to permeabilize biofilms, and thus can be used to transport compounds into or through biofilms.
• the new methods can be used to deliver compounds of a wide range of sizes and net charges into and through biofilms.
• the invention features a method of delivering a compound into or through a biofilm.
• the method includes contacting the biofilm with the compound and propagating a sufficient number of stress waves into the biofilm to increase the permeability of the biofilm, thereby enabling the compound to pass into the biofilm. Because the permeability is enhanced for up to several minutes, the stress wave can be applied in a first step, and the compound can be applied to the permeabilized biofilm in a later step. The later step can be separated by several seconds or minutes from the first step. Alternatively, the stress waves can be used to help drive the compound into the biofilm.
• Stress or pressure waves are broad-band compressive waves having a rise time of at least 500 ps to 100 ⁇ s, e.g., 1 ns to 1 ⁇ s, 10 ns to 100 ns, 10 ns to 10 ⁇ s, or 100 to 300 ns. Stress waves have no measurable tensile component.
• the stress waves have a peak pressure of at least 50 bar, e.g., 200-700, 300-500, or 550-650 bar. Preferably, the stress waves have a peak pressure of no more than 800, 1000, or 2000 bar.
• the stress waves have a quick rise time of 10 ⁇ s or less, and have a duration of 100 ns to 1 ⁇ s, e.g., 200- 600 ns. Between 1 and 50 or more pulses (i.e., individual stress waves) can be applied in one treatment, e.g., 1, 2, 3, 4, or 5-10 pulses.
• the stress waves are generated by directing a pulsed laser beam to a target material that is coupled to the biofilm.
• the laser beam typically has a wavelength of between 140 nm and about 12 ⁇ m, e.g., 250, 400, 450, 500, 550, 625, 675, 725, 800, 900, 1000, or 1 100 nm.
• the target material includes a material that absorbs laser energy, and laser-induced rapid heating of the absorbing material generates the stress wave.
• the target material can be, e.g., a polymer, such as polystyrene.
• the target material can also be a metal foil. Metals suitable for use in the metal foil include, e.g., aluminum or copper.
• a material that is transparent to light e.g., a quartz or glass plate, is bonded to a surface of the target material to confine the plasma generated by a laser beam, thereby increasing the efficiency of conversion of laser energy into the mechanical energy of the stress wave.
• the compound is provided in a reservoir containing a coupling medium suitable for mixing with the compound.
• the reservoir is arranged to enable the coupling medium to directly contact a surface of the biofilm.
• the coupling medium may also contain a surfactant, such as sodium lauryl sulfate.
• the biofilm can be associated with an enamel surface of a mammal, e.g., on a tooth surface.
• the biofilm can also be associated with a periodontal pocket in a mammal.
• the biofilm is associated with a tracheal or lung surface.
• the compound can be a bioactive agent, e.g., a therapeutic agent such as an antimicrobial agent.
• antimicrobial agents include antibiotics, e.g., metronidazole and minocycline; antiseptics, e.g., chlorhexidine and triclosan; photosensitizing agents, e.g., the benzoporpherene derivative monoacid ring A (BPD-MA).
• Biofilms that can be permeabilized with the methods of the invention include those produced by a bacteria or a product of a bacteria, e.g., a capsular polysaccharide produced by a bacteria.
• the biofilm may contain one or several different bacterial species. In some applications the bacterial species will include P. gingivalis or Actinomycete spp., e.g., A. viscosus.
• the biofilms may also include one or more fungal or protozoan species, or products thereof.
• the invention also includes a method of delivering a compound, such as an antimicrobial agent, into or through a biofilm.
• the method includes contacting the biofilm with the antimicrobial agent and exposing a target material coupled to the biofilm to a pulsed laser beam.
• One or more stress waves are then propagated through the biofilm contacting the antimicrobial agent, thereby causing the antimicrobial agent to pass into or through the biofilm.
• Also included in the invention is a method of permeabilizing a biofilm by exposing the biofilm to stress waves, thereby permeabilizing the biofilm. Thereafter, compounds can pass through the biofilm, e.g., by diffusion or an applied force.
• the invention further includes a method of treating disorders associated with a biofilm by exposing the biofilm to a stress wave.
• the stress waves permeabilize the biofilm to allow entry by a therapeutic agent.
• the stress waves can also permeabilize the biofilm to enable entry of other agents, e.g., atmospheric oxygen.
• the methods described herein can be applied to biofilms in any animal or human subject, e.g., a mammal such as a human, dog, horse, cow, or cat.
• the methods are particularly suitable for permeabilizing biofilms associated with diseases of the oral cavity, e.g., chronic destructive periodontitis.
• the methods can also used to permeabilize biofilms adhering to other solid surfaces not found in an animal, e.g., solid surfaces on instrumentalities used in food processing and in medical applications.
• Permeabilizing a biofilm with stress waves allows compounds, such as bioactive agents and therapeutic agents, to be administered with highly localized effects to areas of diseased cells, thus sparing other tissues of the body. In this way, healthy tissues and organs are spared from adverse effects of a systemically administered drug.
• compounds such as bioactive agents and therapeutic agents
• all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present document, including definitions, will control. Unless otherwise indicated, materials, methods, and examples described herein are illustrative only and not intended to be limiting. Various features and advantages of the invention will be apparent from the following detailed description and from the claims.
• Fig. 1 is a schematic drawing of a device for generating a stress wave by laser ablation of a target coupled to a biofilm.
• Fig. 2 is a graph illustrating the waveform of a stress wave generated by the ablation of a black polystyrene target material with a single 23 ns Q- switched ruby laser pulse.
• Fig. 3 is a graph illustrating the phototoxicity of A. viscosus in biofilms after incubation with 50 ⁇ g/ml methylene blue (MB) for 1 minute (white bar) and 5 minutes (hatched bar) followed by the application of a single pressure wave and red light (L+MB+PW) or light only (L+MB).
• MB methylene blue
• the invention provides new methods of delivering compounds, e.g., antimicrobial agents such as antibiotics, antiseptics, and photosensitizers, into or through biofilms using stress or pressure waves.
• the stress waves induce a transient increase in the permeability of the biofilm, thereby allowing delivery of the compound into the biofilm at the time the stress waves are applied, or shortly thereafter.
• the method is thus useful for delivering compounds to treat conditions associated with the presence of biofilms.
• Biofilms are matrix-enclosed microbial aggregates associated with each other and a solid surface. While a biofilm may contain microbial cells, it may also contain extracellular substances, such as proteins or polysaccharides, e.g., capsular polysaccharides expressed by the microbe.
• Biofilms can be found in association with both low and high nutrient sources. Examples of biofilms are disclosed in Table 1 of Wimpenny, Adv. Dent. Res., 1_1 : 150-159, 1997, which is incorporated by reference herein in its entirety. Biofilms include those found in association with high nutrient sources such as plant surfaces, e.g., rhizospheres, but also on inert surfaces such as contact lenses, prostheses, catheters, metal plates, joints, heart valves, and stents.
• high nutrient sources such as plant surfaces, e.g., rhizospheres, but also on inert surfaces such as contact lenses, prostheses, catheters, metal plates, joints, heart valves, and stents.
• biofilms include animal surfaces, e.g., oral surfaces, including, e.g., the cheek, tongue, palate, epithelium, tooth surfaces, epithelia, such as the gut, rumen and vagina, and the surfaces of internal organs such as the lung and heart, and on heart valves.
• oral surfaces including, e.g., the cheek, tongue, palate, epithelium, tooth surfaces, epithelia, such as the gut, rumen and vagina, and the surfaces of internal organs such as the lung and heart, and on heart valves.
• dental plaque When present in the oral cavity as subgingival biofilms, they are referred to as dental plaque. Dental plaque is involved in the development of conditions such as caries, periodontitis, dental implant failures, denture stomatitis, and oral yeast infections such as candidiasis.
• biofilms associated with specific microbial infections include those formed in supragingival deposits by gram positive Actinomycete spp., especially A. viscosus.
• Gram-negative bacteria can also be found in association with supragingival biofilms. These bacteria include P. gingivalis, F. nucleatum, as well as coccobacilli and Capnocytophage spp.
• Pathogens associated with non-oral biofilms include P. aeroginosa, which is found in the trachea of patients suffering from cystic fibrosis disease; E. coli biofilms found in infections associated with urinary tract and intestinal infections, and biofilms formed by Staphylococcus spp. in eye infections. The latter infections are frequently associated with contact lenses.
• Biofilms can also be found in association with eukaryotic cells, e.g., cells specialized for secretion of extracellular matrix such as those described in Alberts et al., Molecular Biology of the Cell, 3rd Ed., 1994, at p. 1189.
• eukaryotic cells e.g., cells specialized for secretion of extracellular matrix such as those described in Alberts et al., Molecular Biology of the Cell, 3rd Ed., 1994, at p. 1189.
• These cells include epithelial cells, e.g., ameloblasts, which secrete tooth enamel, the proteoglycan-secreting planum semilunatum cells of the vestibular apparatus of the ear, and the interdental cell of the organ of Corti, which secretes the tectorial membrane-covering hair cells of the organ of Corti.
• Other cells include nonepithelial cells such as fibroblasts, pericytes, nucleus pulposus cells of invertebral disc, cementoblast/odontocytes, chondrocytes of hyaline cartilage, fibrocartilage, or elastic cartilage, osteoblasts/osteocytes, and osteoprogenitor cells, which are the stem cells of osteoblasts.
• Other extracellular matrix-secreting cells include the hyalocytes of the vitreous body of the eye, and the stellate cell of the perilymphatic space of the ear.
• the methods of the invention can be used to increase the permeability of these naturally occurring biofilms to allow compounds to pass into the biofilms and into the underlying cells and tissues.
• Stress waves can be generated by various energy sources.
• stress waves can be generated by ablation or thermoelastic expansion of an appropriate target material by a high energy optical source such as a laser (Doukas et al., Physical Characteristics and Biological Effects of Laser- Induced Stress Waves, Ultrasound in Med. & Biol., 22:151-164, 1996).
• a high energy optical source such as a laser
• stress waves When stress waves are generated by laser, they can be referred to as laser stress waves.
• the laser beam can be generated by standard optical modulation techniques known in the art, e.g., Q-switched or mode-locked lasers using, for example, electro or acousto-optic devices.
• Standard commercially available lasers that can operate in a pulsed mode in the infrared, visible, and/or near infrared spectrum include Nd:YAG, Nd:YLF, C0 2 , excimer, dye, Ti:sapphire, diode, holmium (and other rare-earth materials), and metal-vapor lasers.
• the pulse widths of these light sources are adjustable, and can vary from several tens of femtoseconds (fs) to several hundred microseconds.
• the optical pulse width can vary from 100 fs to about 10 ⁇ s and is preferably between about 500 ps and 40 ns.
• Stress waves can also be generated by extracorporeal Hthotripters (one example is described in Coleman et al., Ultrasound Med. Biol., 15:213-227, 1989). These stress waves have rise times of 30 to 450 ns, which is longer than laser-generated stress waves.
• lithotripter used is not critical, as long as it is capable of generating stress waves.
• electrohydraulic, electromagnetic, or piezoelectric Hthotripters can be used.
• Stress waves can also be generated using transducers, such as piezoelectric transducers.
• the transducer is in direct contact with the coupling medium, and undergoes rapid displacement following application of an optical, thermal, or electric field to generate the stress wave.
• dielectric breakdown can be used, and is typically induced by a high-voltage spark (similar to those used in certain extracorporeal Hthotripters; see e.g., Coleman et al, Ultrasound Med. Biol., 15:213-227, 1989).
• a piezoelectric transducer the transducer undergoes rapid expansion following application of an electrical field to cause a rapid displacement in the coupling medium.
• Stress waves can alternatively be generated by inducing explosive reactions in energetic materials such as those described in Kodama et al., Ultrasound Med. Biol. 24: 1459 (1998).
• Useful energetic materials include nitrocellulose (NC), glacidy azide polymer (GAP), bis-azidomethyloxetane polymer (BAMO), azidomethyl methyloxetane polymer (AMMO), and silver azide.
• NC nitrocellulose
• GAP glacidy azide polymer
• BAMO bis-azidomethyloxetane polymer
• AMMO azidomethyl methyloxetane polymer
• Fiber optic delivery systems are particularly maneuverable and can be used to irradiate target materials located adjacent to biofilms to generate stress waves in remote, otherwise inaccessible locations.
• optical delivery systems when optically coupled to lasers, for example, are preferred as they can be integrated into catheters and related flexible devices, and used to irradiate most organs in the human body.
• the wavelength of the optical source can be easily tailored to generate the appropriate absorption in a particular target material, which then emits the stress waves.
• the absorbing target material acts as an optically triggered transducer. Following absorption of light, the target material undergoes rapid thermal expansion, or is ablated, to launch a stress wave.
• metal and polymer films have high absorption coefficients in the visible and ultraviolet spectral regions.
• the target material may be present as part of a container and can be composed of a metal such as aluminum or copper; a plastic, such as polystyrene, e.g., black polystyrene; a ceramic; or a highly concentrated dye solution.
• the target material must have dimensions larger than the cross-sectional area of the applied laser energy.
• the target material must be thicker than the optical penetration depth of the laser into the target so that no light passes through to strike the surface of the biofilm or underlying tissue. When the target material is present as part of a container, it must also be sufficiently thick to provide mechanical support.
• the typical thickness will be 1/32 to 1/16 inch, i.e., a metal foil.
• the thickness will be generally 1/16 to 1/8 inch.
• a coupling medium is a liquid, gel, or cream medium in which the stress waves are propagated.
• the coupling medium enables a direct contact of the stress wave to the surface of the biofilm layer and minimizes acoustic reflections.
• the solution or gel in which the compound to be delivered is dissolved or suspended may itself act as the coupling medium.
• a coupling medium can be used during application of the stress waves, and then, if desired, removed to apply the compound to the now permeabilized biofilm.
• a solution containing the compound to be delivered e.g., water, oil, such as castor oil, an isotonic medium such as phosphate buffered saline (PBS), or a gel such as a collagenous gel, can all be used as the coupling medium.
• PBS phosphate buffered saline
• a gel such as a collagenous gel
• a stress wave of the appropriate rise time can be generated by propagating in a non-linear coupling medium (e.g., water) for a distance determined as described in W098/23325.
• the compound to be delivered is thoroughly dispersed in, and is preferably dissolved in, the coupling medium.
• hydrophilic compounds can be mixed with an aqueous coupling medium (e.g., water, solutions of surfactants, such as sodium lauryl sulfate (SLS), benzalkonium chloride (BAC), cocoamidopropyl betaine (CAPB)), and hydrophobic compounds can be mixed with an oil-based coupling medium (such as castor oil). These agents also enhance the coupling ability of the medium.
• the coupling medium can in addition include a surfactant that enhances transport of the compound to be delivered, e.g., by prolonging the period of time in which the biofilm remains permeable to the compound following the generation of a stress wave.
• the surfactant can be, e.g., an ionic or nonionic detergent and thus can include, e.g., sodium lauryl sulfate, cetyl trimethyl ammonium bromide, and lauryl dimethyl amine oxide.
• Stress wave characteristics can be measured using methods standard in the art. For example, peak stress or pressure, and rise time can be measured using a polyvinylidene fluoride (PVDF) transducer method as described in Doukas et al., Ultrasound Med. Biol., 21 :961 (1995).
• PVDF polyvinylidene fluoride
• a useful parameter by which to assess the efficiency of generation of the stress wave is the coupling coefficient (C m ), which is defined as the total momentum transfer to the target material during ablation divided by the pulse energy.
• C m the coupling coefficient
• the permeabilizing effects of stress waves can be enhanced using confined ablation.
• a laser beam-transparent material such as a quartz optical window, or glass
• Confinement of the plasma created by ablating the target material by using the transparent material increases the coupling coefficient by an order of magnitude (Fabro et al., J. Appl. Phys., 68:775, 1990).
• the transparent material can be quartz, glass, or transparent plastic. Since voids between the target material and the confining transparent material allow the plasma to expand, thereby decreasing the momentum imparted to the target, the transparent material is preferably bonded to the target material using an initially liquid adhesive, such as carbon-containing epoxies, to prevent such voids.
• the transport rate of a drug diffusing passively through the biofilm along its concentration gradient can be increased by applying hydrostatic pressure on the surface of the biofilm following application of the stress wave.
• the hydrostatic medium can be any liquid, such as water or phosphate buffered saline.
• the compounds can be bioacHve agents such as photosensitizing agents, e.g., benzoporpherene derivative monoacid ring A (BPD-MA); antibiotics, such as metronidazole and minocycline, and antiseptics, such as chlorhexidine and triclosan.
• photosensitizing agents e.g., benzoporpherene derivative monoacid ring A (BPD-MA)
• antibiotics such as metronidazole and minocycline
• antiseptics such as chlorhexidine and triclosan.
• bioactive compounds which can be used include therapeutic agents such as chemotherapeutics, e.g., cisplatin, polypeptides, including growth factors and antibodies, and nucleic acids, such as oligonucleotides, DNA, RNA, and plasmids, local anesthetics, such as lidocaine and benzocaine.
• therapeutic agents such as chemotherapeutics, e.g., cisplatin, polypeptides, including growth factors and antibodies, and nucleic acids, such as oligonucleotides, DNA, RNA, and plasmids, local anesthetics, such as lidocaine and benzocaine.
• the compounds may optionally be heated prior to generation of the stress wave to facilitate their transport into the biofilms.
• differential drug localization can be achieved using guidelines for administration determined using standard techniques known in the field of pharmacology.
• the compound dosage and time course are such that a 2:1 or greater concentration ratio is achieved in the treated tissues, cells, or other treated sites, compared to the surrounding, untreated tissues or sites. Determining the appropriate dosage for a specific compound, and for a particular subject or patient (human or animal) is a routine matter for one skilled in the art of pharmaceutical administration. Two approaches are commonly used to assay directly the quantity of drug in the diseased (treated) and surrounding sites. First, tissue samples are obtained from animals (e.g., pigs) or patients who have been treated with different dosage and timing protocols.
• the quantity of drug in each sample is then measured either chemically, or if there is a unique optical signal such as fluorescence, then by quantitative microscopy or laser- induced fluorescence.
• the results are tabulated to determine a scale of optimum drug dosages and types of stress waves for a given biofilm, the structure attached to the biofilm, and the compound.
• Compounds which have a toxic effect at higher dosages can be administered to a patient using guidelines for administration that will produce greater concentrations of the drugs in the treated tissues or cells compared to the surrounding tissues, while maintaining adequate levels of the drug in these treated tissues or cells.
• Topical application and delivery of compounds by the new methods allow the compounds to be localized to a site of interest.
• the compound e.g., a drug
• the compound is more concentrated at the site of action and has a minimal, if any, systemic concentration. This enhances the therapeutic effect of the drug and simultaneously minimizes systemic side effects.
• Another advantage compared to systemic administration is that compounds transported through biofilms bypass systemic deactivation or degradation (e.g., hepatic "first-pass" effects). Gastrointestinal incompatibility and potential toxicological risks are also minimized relative to systemic administration.
• drugs developed for topical application can be designed so that they are deactivated systematically (i.e., the "soft drug” concept), using standard techniques. Topical administration may also be desired when the compound is rare or expensive.
• the biofilm was generated by culturing A. viscous on an enamel surface. Enamel surfaces measuring 5 x 5 x 2 mm were sterilized and suspended in trypticase soy agar with 5% sheep blood in wells of 24-well plates with cultures of A. viscosus. Plates containing the suspended enamel surfaces were incubated in an anaerobic chamber at 35°C. Fresh medium containing A. viscosus cultures was added twice per week until a 1.0-1.5 mm thick biofilm was formed.
• Specimens were incubated with methylene blue (Sigma, St. Louis, MO), followed by exposure to a laser pulse, or incubated with methylene blue only for 5 minutes in the absence of light.
• methylene blue Sigma, St. Louis, MO
• Specimens to be exposed to a laser pulse were placed in a reservoir as shown in Fig. 1.
• a reservoir 10 contained the enamel surface 12, to which the A. viscosus biofilm 14 was adhered.
• the biofilm 14 was bathed in a solution 16 containing 50 ⁇ g/ml methylene blue for 5 minutes, after which a sterile black plastic (unexpanded polystyrene) target 18 (1 cm in diameter and 1 mm thick) was placed over the top of the reservoir 10 in contact with the solution 14.
• Biofilms were exposed to a single laser pulse 20, which, after ablating the target 16 generated a stress wave 22 through the solution 16.
• the laser pulse was generated with a Q-switched ruby laser (not shown).
• the operating parameters of the laser were 694 nm, 2.1 J, and 23 ns pulse duration.
• the temporal waveform of a stress wave generated by ablation of the polystyrene target by 694 nm radiation from the Q-switched laser is shown Fig. 2.
• the stress wave was measured by a calibrated piezoelectric transducer and had a rise time of 50 nsec, 110 nsec duration, and peak pressure of 600 bar.
• the beam size was about 6 mm in diameter and provided a fluence of about 7.0 J/cm 2 .
• the specimens were then placed in petri dishes, covered with PBS, after which biofilms were viewed with a Leica TCS NTTM fluorescence scanning confocal microscope.
• the microscope was equipped with a lOx water immersion objective lens.
• An argon laser (476 nm) was used as the excitation source for methylene blue. Sections were collected at 100 ⁇ m intervals and analyzed by image-processing to assess the distribution of methylene blue within the biofilm matrices.
• biofilms were grown on enamel surfaces as described in Example 1. Biofilms were incubated with methylene blue for 1 or 5 minutes and exposed to stress waves (one pulse), after which they were exposed to 666 nm red light with a fluence of 15 J/cm at an irradiance of 50 mW/cm . In control samples, biofilms were treated only with methylene blue, or were treated with methylene blue and exposed to red light, but without stress waves. An argon ion laser with an emission of 514.5. nm was used to pump a dye laser. The laser light was coupled into a 1.0 mm quartz fiber and appropriate spot sizes were created with an objective lens.
• Example 3 Delivery of Bioactive Agents into Biofilms in Periodontal Pockets A solution of metronidazole is applied to a periodontal pocket of a patient with chronic destructive periodontitis. Stress waves generated by ablation of a polystyrene target material with a Q-switched ruby laser are used to permeabilize biofilms (dental plaque) attached to the tooth root.
• a stainless steel needle (0.8 mm inner diameter by 1.3 mm outer diameter) is used as a hollow waveguide.
• the blunt end of the needle is sealed with the target that absorbs the laser pulse.
• the target is chosen so that it absorbs the laser pulse completely.
• the target Upon delivery of the laser pulse, the target emits a stress wave that temporarily increases the permeability of the biofilm. As a result, the metronidazole passes into the biofilm, thereby facilitating metronidazole-mediated destruction of cells in the biofilm.

Landscapes

• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Engineering & Computer Science (AREA)
• Veterinary Medicine (AREA)
• Chemical & Material Sciences (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Organic Chemistry (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Pharmacology & Pharmacy (AREA)
• Biomedical Technology (AREA)
• Communicable Diseases (AREA)
• Anesthesiology (AREA)
• Oncology (AREA)
• Heart & Thoracic Surgery (AREA)
• Hematology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Radiation-Therapy Devices (AREA)
• Cosmetics (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Dental Preparations (AREA)
• Physical Or Chemical Processes And Apparatus (AREA)
• Medicinal Preparation (AREA)

Applications Claiming Priority (3)

Publications (1)

Family

ID=22460051

Family Applications (1)

Country Status (4)

Families Citing this family (12)

Family Cites Families (7)

• 2000
  • 2000-05-12 CA CA002373447A patent/CA2373447A1/en not_active Abandoned
  • 2000-05-12 WO PCT/US2000/013231 patent/WO2000067917A1/en active Search and Examination
  • 2000-05-12 EP EP00946762A patent/EP1210182A1/de not_active Withdrawn
  • 2000-05-12 JP JP2000616934A patent/JP2003534235A/ja not_active Withdrawn

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events