WO2012177807A1 - Electrochemical disinfection of implanted catheters - Google Patents
Electrochemical disinfection of implanted catheters Download PDFInfo
- Publication number
- WO2012177807A1 WO2012177807A1 PCT/US2012/043409 US2012043409W WO2012177807A1 WO 2012177807 A1 WO2012177807 A1 WO 2012177807A1 US 2012043409 W US2012043409 W US 2012043409W WO 2012177807 A1 WO2012177807 A1 WO 2012177807A1
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- WO
- WIPO (PCT)
- Prior art keywords
- catheter
- electrodes
- voltage
- biofilm
- implantable
- Prior art date
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Classifications
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- A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
- A61L29/12—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
- A61L29/126—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
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- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
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- A61M25/0043—Catheters; Hollow probes characterised by structural features
- A61M2025/0056—Catheters; Hollow probes characterised by structural features provided with an antibacterial agent, e.g. by coating, residing in the polymer matrix or releasing an agent out of a reservoir
Definitions
- the invention relates generally to implantable, "indwelling" catheters. More particularly, the invention relates to systems and methods for detecting the presence of a biofilm on a catheter surface and killing microorganisms in the biofilm, without removal of the catheter from a patient's body.
- Microbial biofilms are formed when microorganisms adhere to a biotic or abiotic surface and produce extracellular macromolecules that facilitate adhesion to the surface and form a structural matrix that supports and protects the microorganisms.
- a biofilm is thus an accumulation of microorganisms such as bacteria embedded in an extracellular hydrated matrix primarily composed of exopolymers and other filamentous macromolecules, typically glycopeptid.es.
- a biofilm is generally described as a layer of bacteria (or other microorganisms), or as a plurality of layers and/or regions on a surface wherein bacteria are encased in a matrix of extracellular polymeric substances, or "EPS."
- EPS extracellular polymeric substances
- a substantial fraction of the biofilm is actually composed of this matrix; see, e.g., Donian (2001) Emerging Infectious Diseases 7(2):277-281.
- Microorganisms in biofilms in many cases exhibit characteristics that are different from those seen with planktonic (freely suspended) microorganisms, particularly with respect to phenotypic traits like growth rate and resistance to antimicrobial treatment.
- biofilms can and do form on a variety of surfaces in a virtually unlimited number of contexts, biofilm formation in the medical arena is particularly concerning.
- biofilm- related infections are extraordinarily tolerant to treatment with antimicrobial agents, and biofilm formation on medical implants is therefore extremely problematic.
- Microorganisms can attach to and develop biofilms on any type of medical implant, whether temporarily or permanently inserted or implanted in a patient's body, and can be a source of chronic bacterial infections.
- Chronic infections that are caused by biofilms on a medical implant e.g., otitis media and osteomyelitis
- biofilms accounted for about 65% of infections treated in the developed world. See Costerton et al. (1999) Science 284: 1318-1322.
- Medical devices are critical in modern-day medical practice. At the same time, they are major contributors to morbidity and mortality.
- the use of a medical device, particularly an implanted medical device or medical "implant,” is the greatest exogenous predictor of healthcare-associated infection; Manangan et al. (2002) Emerg. Infect. Dis. 8:233-236. Most infections that arise in the hospital setting, or "nosocomial” infections, occur primarily at four sites within the body: the urinary tract; the respiratory tract; the bloodstream; and surgical wound sites. According to Ryder et al.
- nosocomial urinary tract infections 95% of nosocomial urinary tract infections are caused by an infected urinary catheter, 86% of nosocomial pneumonias are caused by an infected mechanical ventilator, and 87% of nosocomial bloodstream infections are associated with an infected intravascular device.
- nosocomial bloodstream infections associated with an implanted catheter are the most life threatening of the aforementioned nosocomial infections and associated with the most significant medical costs.
- the medical implants must be removed in order to remove the biofilm and then re-inserted into a patient's body. Examples of implantable medical devices on which biofilms may form include, without limitation:
- Catheters e.g., arterial catheters, central venous catheters, dialysis tubing, endotracheal tubes, enteral feeding tubes, gastrostomy tubes, hemodialysis catheters, nasogastric tubes, nephrostomy tubing, pulmonary artery catheters, tracheostomy tubes, umbilical catheters, and urinary catheters;
- Implants e.g., arteriovenous shunts, breast implants, cardiac and other monitors, cochlear implants, defibrillators, dental implants, maxillofacial implants, middle ear implants,
- neurostimulators orthopedic devices, pacemaker and leads, penile implants, prosthetic devices, replacement joints, spinal implants, and voice prostheses;
- Implanted devices such as artificial hearts, contact lenses, fracture fixation devices, infusion pumps, insulin pumps, intracranial pressure devices, intraocular lenses, intrauterine devices, joint prostheses, mechanical heart valves, ommaya reservoirs, suture materials, urinary stents, vascular assist devices, vascular grafts, vascular shunts, and vascular stents.
- a central venous catheter (also referred to as a "central line” or "CVC”) is a widely used catheter that is placed in a large vein in the neck, chest, or groin and serves as a conduit for delivering medications, parenteral nutrition, and fluids.
- CVC central venous pressure
- a CVC is commonly used in plasmapheresis, dialysis, and chemotherapy, and is also relied upon to obtain critically important measurements, such as central venous pressure ("CVP").
- CABSIs catheter-associated bloodstream infections
- CRBSIs catheter-related bloodstream infections
- the intensive care environment accounts for 80,000 of these infections, with an attributable mortality as high as 35% and a cost to treat at $56,000 per episode. See Department of Health & Human Services, USA: Guidelines for the Prevention of Intravascular Catheter-Related Infections, 2011.
- the approaches that have been taken to counteract the widespread problem have not succeeded in either preventing biofilm formation or eliminating a biofilm that has formed without removal of the catheter from a patient's body.
- CVC biofilm formation is generally problematic with implantable medical devices, it will be appreciated that the risk of infection is that much higher with catheters such as the CVC that remain in place for an extended time period.
- the most common bacteria found in CVC biofilms are Staphylococcus aureas, Staphylococcus epidermis sepsis, Candida albicans, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Enterococcus faecalis. These bacteria may originate from patient's skin microflora, exogenous microflora from health care personnel, or contaminated infusions, and can migrate from the skin along the exterior surface or internally from the catheter hub or port.
- Biofilms form not only on the outer surface of the catheter, but also on the inner lumen of the catheter, particularly with long-term catheterization; see Raad et al. (1998) Lancet 351 :893-98.
- the problem of infection is not limited to venous catheters, but also affects other types of catheters and medical devices as indicated above, such as urinary catheters, ventriculoperitoneal shunts, in-dwelling catheter-like prostheses (vascular conduits), dialysis tubing, endotracheal tubes, Foley catheters, and the like.
- urinary catheters ventriculoperitoneal shunts, in-dwelling catheter-like prostheses (vascular conduits), dialysis tubing, endotracheal tubes, Foley catheters, and the like.
- an implantable catheter is provided that can be
- the implantable catheter comprises: an elongate catheter body having a proximal end, a distal end, at least one lumen extending through the catheter body and adapted to transport fluid from the proximal region to the distal region, an outer surface on the exterior of the catheter body, and an inner surface on the interior of the lumen; at least two exterior electrodes on and integral with the outer surface of the catheter, the exterior electrodes being elongate and extending longitudinally along the outer surface of the catheter body from the proximal end to the distal end; optionally, at least two interior electrodes on and integral with the inner surface of the catheter, the interior electrodes being elongate and extending longitudinally along the outer surface of the catheter body from the proximal end to the distal end; and a means for receiving an applied voltage from a voltage source so that an electric field is generated across the at
- an implantable catheter system in another aspect of the invention, includes the implantable catheter and a voltage source, where the voltage source may be a direct current source, an alternating current source, and a pulsed voltage source.
- the invention provides a method for inhibiting a biofilm surface of the implantable catheter described above, where biofilm "inhibition” encompasses killing
- the method comprises applying a voltage across at least the exterior electrodes of a magnitude that is effective to create a biofilm-inhibiting concentration of oxidizing agents from endogenous compounds present in the body without causing significant damage to cells and tissues that are not associated with the biofilm. Voltage may be applied intermittently at regular intervals or continuously, for a time period of at least 72 hours. In contrast to prior methods proposed for biofilm destruction, it is important to note that in the present method, the voltage is applied and the electric field thus generated in the absence of an added biocidal agent and in a noninvasive manner, without removing the catheter from a patient's body.
- the aforementioned method further includes the step of detecting or confirming the presence or formation of a biofilm on at least the outer surface of the catheter prior to applying a voltage across at least the external electrodes on the catheter surface.
- the method can involve impedance measurement across the electrodes using Electrical Impedance Spectroscopy (EIS) or an alternative technique to measure impedance, as statistically significant increases in impedance across the electrodes are indicative of the formation of a biofilm.
- EIS Electrical Impedance Spectroscopy
- Other methods e.g., oxygen determination at the catheter surface, can also be used.
- the invention provides a method for preventing formation of a biofilm on an implantable catheter, again without need for an added biocidal agent and without removal of the catheter from the patient's body.
- the method involves applying a voltage across at least the exterior electrodes of a magnitude that is effective to create a concentration of oxidizing agents from endogenous compounds present in the body that is sufficient to prevent formation of a biofilm on the catheter surface.
- FIG. 1 is a perspective view of a segment of a catheter of the invention with two exterior electrodes.
- FIG. 2 is a perspective view of a segment of a catheter of the invention with two exterior electrodes and a third point electrode.
- FIG. 3 is a perspective view of a segment of a catheter of the invention with a plurality of exterior electrodes embedded in the outer surface in interdigitated fashion.
- FIG. 4 is a perspective view of a segment of a catheter of the invention with two exterior electrodes embedded in the outer surface and two interior electrodes embedded in the inner surface.
- FIG. 5 is a cross-sectional view of an implantable catheter of the invention wherein two electrodes extend from the outer catheter surface through the catheter wall to the inner catheter surface.
- FIG. 6 illustrates the use of an interior mask in electrode fabrication via electroless plating, to create the interior gaps seen in the embodiment of FIG. 5.
- FIG. 7 shows images obtained using confocal microscopy of a P. aeruginosa bio film grown for 6 h in minimal static media on a graphite electrode (4 cm in length) and exposed to
- FIG. 7A shows the anode before electrochemical treatment
- FIG. 7B shows the anode 40 min after electrochemical treatment was initiated
- FIG. 7C shows the anode after 2 h treatment. The images were obtained 4 cm from the electrode connection to the power supply.
- FIG. 8 shows images obtained using confocal microscopy of a P. aeruginosa bio film grown for 6 h in minimal static media on a graphite electrode (4 cm in length) and exposed to
- FIG. 8 A shows the anode control without
- FIG. 8B shows the anode-associated biofilm 6 h after prophylactic treatment was initiated
- FIG. 8C shows the cathode 6 h after prophylactic treatment was initiated. The images were obtained 4 cm from the electrode connection to the power supply.
- FIG. 9 shows images obtained using confocal microscopy of a P. aeruginosa biofilm grown for 6 h in minimal static media on a graphite electrode (4 cm in length) and exposed to
- FIG. 9 A shows the anode control without
- FIG. 9B shows the anode-associated biofilm lh after initiation of electrochemical treatment.
- the images were obtained 4 cm from the electrode connection to the power supply.
- FIG. 10 shows images obtained using confocal microscopy of a P. aeruginosa biofilm grown for 6 h in minimal static media on a graphite electrode (16 cm in length) and exposed to
- FIG. 10A shows the anode control without treatment 6h after attachment of cells to the electrode
- FIG. 10B shows the anode-associated biofilm after 60 min treatment
- FIG. IOC shows the anode after 90 min treatment
- FIG. 10D shows the cathode after 60 min treatment
- FIG. 10E shows the cathode of FIG. 10D 30 min after reversing polarity and thereby switching the electrode to an anode.
- the images were obtained 12 cm from the electrode connection to the power supply.
- FIG. 11 shows images obtained using confocal microscopy of a P. aeruginosa biofilm grown for 6 h in minimal static media on a graphite electrode (4 cm in length) and exposed to
- FIG. 11 A shows the anode control without treatment 6h after attachment of cells to the electrode
- FIG. 1 IB shows the anode-associated bio film 6h after prophylactic treatment was initiated
- FIG. 11C shows the cathode 6h after prophylactic treatment was initiated. The images were obtained 4 cm from the electrode connection to the power supply.
- FIG. 12 shows images obtained using confocal microscopy of a P. aeruginosa bio film grown in glucose minimal media for 24 h in flow chambers on a glass surface supported with a gold electrode grid (grid squares are 400x400 ⁇ ), and exposed to electrochemistry using -1.2 V at 20 ⁇ /cm 2 .
- FIG. 13A shows the anode before electrochemical treatment
- FIG. 12B shows the anode 10 min after treatment was initiated
- FIG. 12C shows the anode after 1 h treatment.
- FIG. 13 shows images obtained using confocal microscopy of a P. aeruginosa biofilm grown in glucose minimal media for 72 h in flow chambers on a glass surface supported with a gold electrode grid (grid squares are 400x400 ⁇ ), and exposed to electrochemistry using -1.2 V at 20 ⁇ /cm 2 .
- FIG. 13A shows the anode before electrochemical treatment
- FIG. 13B shows the anode 20 min after treatment was initiated
- FIG. 13C shows the anode after 1 h treatment
- FIG. 13D shows the anode-associated biofilm after 3 h treatment.
- FIG. 14 shows images obtained using confocal microscopy of a P. aeruginosa biofilm grown in glucose minimal media for 72 h in flow chambers on a 20 cm long graphite electrode, and exposed to electrochemistry using 2 ⁇ /cm 2 .
- FIG. 14A shows a control sample after 72 h growth
- FIG. 14B shows the anode after 72 h treatment
- FIG. 14C shows the cathode after 72 h treatment
- the inset images in FIGS. 14A, 14B, and 14C show dead cells in the inspected area.
- FIG. 15 shows images obtained using confocal microscopy of a P. aeruginosa biofilm grown in glucose minimal media for 72 h in flow chambers on a 20 cm long graphite electrode, and exposed to electrochemistry using 20 ⁇ /cm 2 .
- FIG. 15A shows a control sample after 72 h growth
- FIG. 15B shows the anode after 72 h treatment
- FIG. 15C shows the cathode after 72 h treatment.
- FIG. 16 is a column diagram showing CFU/ml of isolated cells from Gfp tagged P.
- FIG. 17 shows images obtained using confocal microscopy of an E. coli biofilm grown for 6 h in minimal static media on a graphite electrode (4 cm in length) and exposed to electrochemistry using -0.8 V at 25 ⁇ /cm 2 .
- FIG. 17 shows images obtained using confocal microscopy of an E. coli biofilm grown for 6 h in minimal static media on a graphite electrode (4 cm in length) and exposed to electrochemistry using -0.8 V at 25 ⁇ /cm 2 .
- FIG. 17A shows the anode control without electrochemical treatment 6 h after initial attachment of cells
- FIG. 17B shows the anode-associated biofilm after 1 h treatment
- FIG. 17C shows the cathode biofilm after lh treatment. The images were obtained 4 cm from the electrode connection to the power supply.
- FIG. 18 is a column diagram showing CFU/ml of isolated cells from E. coli biofilm grown in glucose minimal media on graphite electrode. Biofilm was exposed to electrochemistry using 10-25 ⁇ /cm 2 . Biofilm cells were isolated from graphite electrode before (Control) and after treatment (Anode and Cathode) followed by plating for determination of CFU/ml on selective plates.
- the X- axis shows Control, Anode and Cathode, respectively, and the units on the Y-axis show CFU/ml.
- FIG. 19 shows a biofilm of Staphylococcus aurous [R 8325-4] (having a mutation in RsbU, which makes this strain sigma B negative; sigma B regulates many virulence factors in S.aureus) (A, B, C) and Staphylococcus aurous [15981] (expressing virulence) (D, E, F) cells grown for 6 h in TSB media on a 4 cm long graphite electrode. Images were obtained 4 cm from the electrode connection to the power supply. The biofilm was exposed to electrochemistry using -0.8V (25 ⁇ / ⁇ 2 ). A and D show the biofilm on the graphite electrode without treatment, while B and E show the anode- associated biofilm after 1 h treatment and C and F show the cathode after 1 h treatment.
- FIG. 20 is a column diagram showing CFU/ml of isolated cells from Staphylococcus aurous [R 8325-4] (A) biofilm and Staphylococcus aurous [15981] (B) biofilm grown for 6 h in TSB media on a 4 cm long graphite electrode. Cells were isolated from the graphite electrode before (Control) and after treatment (Anode and Cathode with -0.8V (25 ⁇ A/cm 2 )) followed by plating for
- the X-axis shows Control, Anode and Cathode, respectively, and the units on the Y-axis are CFU/ml.
- thermosetting polymer can refer to a single thermosetting polymer or to two or more thermosetting polymers in combination
- flexible elastomer can refer to a single such elastomer or to a composite of two or more such elastomers in combination.
- implantable catheter refers to a catheter that is implanted or inserted in the human body either temporarily or permanently.
- inhibiting refers to the process of killing microorganisms in a biofilm that is present or forming on a surface, and thus includes all of the following: elimination or destruction of a biofilm; disruption of a biofilm; reduction in the thickness of a biofilm; the killing of some or all of the microorganisms within a biofilm; and prevention of biofilm growth.
- fection refers to biofilm inhibition as defined above, typically referring to the killing of microorganisms within a biofilm on a catheter surface.
- biofilm refers to a matrix-enclosed microbial accretion on and anchored to the surface of an implanted medical device.
- biofilm formation is intended to include the formation, growth, and modification of the bacterial or other colonies contained with biofilm structures, as well as the synthesis and maintenance of the polysaccharide matrix of the biofilm structures.
- the implantable catheter of the invention is thus one that can be electrochemically activated to kill infecting microorganisms in a biofilm present on its exterior and/or interior surfaces and/or prevent biofilm growth thereon.
- the infecting microorganisms in the biofilm are typically bacterial cells, but there may also be colonies of yeast, fungi, mold, or other colonizing microorganisms in the biofilm.
- FIG. 1 illustrates one such catheter, shown generally at 10.
- the catheter is composed of an elongate catheter body 12 having a continuous, substantially cylindrical annular wall 14 defining an outer catheter surface 16 and an inner catheter surface 18.
- the wall 14 of catheter body 12 also defines a central hollow lumen or passageway 20, through which fluid can flow from proximal region 22 to distal region 24 in connection with any of a variety of diverse medical applications.
- Proximal region 22 terminates in an inflow tip at the proximal end of the catheter, while distal region 24 terminates in an outflow tip at the distal end of the catheter.
- the wall thickness is generally about 0.5 mm, while the catheter length can vary a great deal depending on the application, anywhere from several centimeters to several meters, averaging about 1 m to 2 m in most contexts.
- the implantable catheter 10 contains at least two exterior electrodes 26 and 28 integral with the outer surface 16, with one electrode serving as an anode and the other electrode serving as a cathode, as determined by the polarity of the applied voltage.
- the electrodes may each be in the form of a very thin film layer on the outer surface, or they may be impressed into the outer surface such that the electrode surface and the catheter surface surrounding the electrode are co-planar.
- the electrodes can be composed of a metallic or nonmetallic element, composition, alloy, or composite that is inert in vivo, including, by way of example: a metal per se, such as gold, platinum, silver, palladium, or the like; an alloy of two or more metals, e.g., a platinum-iridium alloy; a metal-coated substrate, such as a platinum-plated titanium or titanium dioxide substrate, or a platinum- and/or ruthenium-coated nickel substrate; a metal oxide, e.g., ruthenium oxide (i.e., ruthenium (IV) oxide, or Ru0 2 ), rhenium oxide (generally rhenium (IV) oxide [Re0 2 ] or a composition of mixed-valence rhenium oxides), iridium oxide, or the like; a metal carbide such as tungsten carbide,
- Electrodes of graphite, carbon-polymer composites, and noble metals are generally preferred.
- Noble metal electrodes include, for example, electrodes fabricated from gold, palladium, platinum, silver, iridium, platinum-iridium alloys, platinum-plated titanium, osmium, rhodium, ruthenium, and oxides and carbides thereof.
- Carbon-polymer composite electrodes are fabricated from pastes of particulate carbon, e.g., carbon powder, carbon nanoparticles, carbon fibers, or the like, and a thermosetting polymer.
- Carbon-polymer composite electrodes are particularly desirable, for economic as well as practical reasons. Aside from the relatively low cost of such electrodes, use of a precursor composed of a paste of particulate carbon and a thermosetting or thermoplastic polymer or prepolymer thereof enables manufacture of the implantable catheter via extrusion, with the electrodes extruded along with the polymeric catheter body.
- Illustrative polymers for this purpose include, without limitation, polyurethanes, polyvinyl chloride, silicones, poly(styrene-butadiene-styrene), polyether-amide block copolymers, and the like.
- Carbon-polymer pastes for this purpose are readily available commercially, e.g., from ECM, LLC, in Delaware, Ohio.
- Preferred polymers are thermoplastic.
- a polymerization initiator and cross-linking agent may be included in the fabrication mixture.
- Electrochemical activation is carried out by creating an electric field across the area of the outer surface 12 so as to generate species that kill microorganisms in any biofilm present or forming on the outer surface. These species, or “biocides,” are created upon application of the aforementioned electric field from endogenous compounds present in the body, in the region of the outer surface.
- the electric field is generated by application of a voltage across electrodes 26 and 28 using a voltage source, which may be a direct current (DC) source, such as a battery, e.g., in the form of a
- DC direct current
- the catheter thus includes a means for receiving voltage from the voltage source to generate the electric field, e.g., conductive wires in electrical communication with the voltage source and the electrodes.
- the voltage source e.g., a battery
- the particular type of device used to generate the electric field is not critical to the practice of the invention, and a wide variety of devices that are capable of generating an electric field of appropriate voltage and amperage may be used. Representative such devices are described in U.S. Patent Nos. 5,312,813 and 5,462,644.
- the applied voltage must be sufficient to generate current flow from electrode to electrode, across the gap 30 that separates the electrodes, which comprises the dielectric material of the catheter body.
- the gap between the electrodes will be in the range of about 1000 A to about 2 ⁇ for plated metallic electrodes, and in the range of about 10 ⁇ to about 200 ⁇ for extruded composite electrodes.
- an important advantage of the invention is that the biocidal agents, i.e., the chemical species that kill
- microorganisms in the biofilm present or forming on a surface of the catheter and prevent biofilm growth thereon are created from materials endogenous to the cells and tissue of the human body in the vicinity of the catheter surface. That is, application of a voltage across the electrodes results in the oxidation of chloride ions at the anode (chloride ions are ubiquitous within the body in the form of dissolved chloride salts), and in the reduction of oxygen at the cathode.
- the resulting species include the oxidizing agents hydrogen peroxide, superoxide ion, hypochlorous acid, and hypochlorite ion.
- the biocidal potential of these species is well documented, e.g., in the electrochemical sterilization of salt water.
- the material used to form the body 12 of the implantable catheter 10 is necessarily
- the catheter body 12 is preferably made of a strong yet flexible polymeric material, such as silicone, polyurethane, polyvinyl chloride (PVC), polyamide, polyethylene, polybutylene terephthalate, polyetherimide, polyethylene, polyethylene terephthalate, polyethylene naphthalate, or any combinations thereof.
- a flexible silicone elastomer is particularly preferred as the material for the catheter body.
- the implantable catheter shown generally at 32 is provided with two thin film exterior electrodes 34 and 36 and a third electrode that may be a point electrode 38 present on the catheter surface 40 within gap 42, as illustrated.
- a third electrode that may be a point electrode 38 present on the catheter surface 40 within gap 42, as illustrated.
- the third electrode serves as a reference electrode, while electrodes 34 and 36 serve as the working electrode and counter electrode. When the polarity of the applied voltage is reversed, electrodes 34 and 36 will alternate functions. It will be appreciated that the third electrode is not necessarily a point electrode or present on the surface of the catheter.
- the reference electrode can be a third elongate electrode on the outer surface 16, or it may be located on the inner surface 44 of the catheter or anywhere in a solution that is in contact with the other two electrodes.
- the reference electrode can be a simple wire electrode, e.g., a silver wire electrode, placed in the perfusion fluid, in the catheter hub.
- a potentiostat can be employed to maintain the potential of the working electrode versus the reference electrode by adjusting the current at the counter electrode, as is known in the art.
- a voltage source as described with respect to the two- electrode embodiment of FIG. 1 can also be used.
- the implantable catheter shown generally at 46 is provided with a plurality of interdigitated electrodes 48 on outer surface 50.
- the interdigitated electrodes may be metallic or they may be composed of any of the electrode materials enumerated as candidates for the embodiment of FIG. 1. This configuration can increase the efficiency of the system and may in some cases represent the preferred embodiment.
- two or more flexible mesh electrodes can be used as well, e.g., fabricated from silver or other metallic nanowire, or woven from metal wire and polymer fibers. They may be pressed into the outer surface of the catheter during device manufactured or otherwise incorporated in or attached to the catheter's outer surface. Voltage sources as described for the embodiment of FIG. 1 may be employed here as well.
- an implantable catheter 48 of the invention is provided with two thin film exterior electrodes 52 and 54 on the outer catheter surface 56 and two additional thin film interior electrodes 58 and 60 on the inner catheter surface 62.
- the advantage added by employing interior electrodes is the capability of killing microorganisms within a biofilm present or forming on the inner surface of the catheter as well as on the outer surface.
- use of the interior electrodes reduces the likelihood of occlusions that may occur as a result of biofilm buildup on the inner catheter surface.
- This system may include an additional electrode (not shown) to serve as a reference electrode for both the interior and exterior electrodes, as described above with respect to the embodiment of FIG. 2, or may include two additional electrodes, one serving as a reference electrode for the interior electrodes, and the other serving as a reference electrode for the exterior electrodes.
- an implantable catheter 64 is provided with two electrodes 66 and 68, each which extends from the outer catheter surface 70 through the catheter wall 72 to the inner catheter surface 74, thus serving as and providing the benefit of a system having interior and exterior electrodes but using a simpler and more economically advantageous design. Because the electrodes extend through the catheter body all the way to the distal terminus of the catheter, this embodiment is advantageous in providing an active catheter tip, ensuring that the present methodology is fully effective to inhibit biofilm at the distal region of the catheter.
- Radioopacity is required in numerous imaging techniques involving catheter placement and maneuvering, including, by way of example, X-ray, MRI, CT technology, fluoroscopy, or the like. For instance, with a gold electrode, the gold itself will add some radioopacity, but the levels may not be sufficient for the surgeon to visualize under fluoroscopy. If a gold or silver electrode is used, it will generally be desirable for an additional means for imparting radioopacity.
- radioopaque material into the polymeric insulator alone and /or into the polymer electrode matrix.
- suitable radioopaque materials for use in the present context include, without limitation, barium sulfate, barium titanite, zirconium oxide, and bismuth. Titanium, tungsten, or tantalum are also possibilities, providing that the amount incorporated is not so high as to limit conductivity.
- the radioopaque material can be incorporated into the implantable catheter as (1) strips down the length of the catheter or (2) markers in the form of rings or bands along the catheter.
- the radioopaque material can also be present as (3) an outer layer completely surrounding the catheter radially as well as continuously along the entire length of the catheter.
- radioopaque strips can be co-extruded or painted on via powder mixed in with a polymer in another line or in the form of a polymer / radioopaque maste introduced into another line.
- the markers can simply be painted on.
- the radioopaque material can be added in powder or paste form to an extrusion mixture.
- the interior of the catheter may be longitudinally segmented into two or more lumens as necessary for implementation in a particular medical procedure.
- one lumen may be sized to receive a guidewire to facilitate proper and exact positioning of the catheter and particularly the distal tip within the patient's body, as may be confirmed during insertion using fluoroscopy (alternatively, the guidewire can be contained in a single-lumen catheter as illustrated in the figures described above).
- a second lumen may be used to contain an optical fiber used in any of a variety of contexts, including as a means to measure oxygen concentration in the blood.
- the catheter electrodes and catheter body may be coated with a biocompatible hydrophilic material that reduces surface roughness and decreases the risk of thrombogenicity.
- a biocompatible hydrophilic material that reduces surface roughness and decreases the risk of thrombogenicity.
- Such materials will be known to those of ordinary skill in the art and/or are described in the pertinent texts and literature; see, e.g., LaPorte, Hydrophilic Polymer Coatings for Medical Devices (CRC Press, 1997).
- PHEMA poly(hydroxyethyl methacrylate)
- PHEEMA poly(hydroxyethoxyethyl methacrylate)
- PHEEMA poly(hydroxydiethoxyethyl methacrylate)
- PMEMA poly(methoxyethyl methacrylate)
- PMEEMA poly(methoxydiethoxyethyl methacrylate)
- PMEEMA poly(methoxydiethoxyethyl methacrylate)
- PMDEEMA poly(methoxydiethoxyethyl methacrylate)
- PEGDMA poly(ethylene glycol dimethacrylate)
- PEGDMA poly( vinyl alcohol)
- PVA poly(carboxylic acids) such as poly(acrylic acid) (PAA) and poly(methacrylic acid) (PMAA); poly(N-vinyl-2-pyrrolidone); and cellulose ethers such as hydroxypropyl methylcellulose (HPMC)
- one electrode in the implantable catheter system serves as an anode and another electrode serves as a cathode, as determined by the polarity of the applied voltage.
- ROS reactive oxygen species
- i.e., chemically reactive molecules containing oxygen that are destructive to biofilm cells are formed at both anode and cathode.
- the reactions taking place at the anode involve the oxidation of anions, particularly chloride ions, which, as noted above, are present throughout the body in the form of dissolved chloride salts.
- the resulting oxidation products include hypochlorous acid (HOC1) and hypochlorite ion (CIO ), both of which serve as reactive oxidizing agents for purposes of biofilm destruction and growth inhibition.
- the reactions taking place at the cathode that give rise to oxidizing species include the reduction of endogenous oxygen to give superoxide ion (0 2 ), an oxidizing agent, which in turn reacts with water to yield hydrogen peroxide and the peroxide anion.
- the methods herein involve periodically reversing the polarity of the applied voltage such that each electrode is alternately an anode or a cathode. In this way, the rate and extent of bio film destruction is approximately the same at each electrode.
- Polarity reversal can be manual or automatic, using any effective means for accomplishing the reversal, e.g., using a simple manual switch on the voltage source/power supply or using a programmable automated system in which an automatic controller operates a switch at regularly programmed intervals.
- Polarity reversals can be of any frequency, e.g., a frequency in the range of about 1 cycle every 30 seconds to about 1 cycle every hour, preferably in the range of about 1 cycle every minute to about 1 cycle every 45 minutes, and more preferably in the range of about 1 cycle every 5 minutes to about 1 cycle every 30 minutes, with "cycle” referring to the interval between polarity reversals in which the direction of current remains constant.
- the means for reversing polarity comprises a control circuit that connects the voltage source to the electrodes on the catheter, and not only controls polarity reversal but can also modulate the voltage level, frequency, time of voltage application, current density, and the like, and ideally can be programmed with a predetermined operating profile such as the prevention, destruction, and sensing profiles discussed in Section IV.
- Suitable manufacturing techniques include electroless plating (also known as chemical plating or auto-catalytic plating), extrusion, chemical vapor deposition (CVD), and printing. All of the aforementioned techniques may be used to provide external electrodes, while electroless plating and extrusion are the methods of choice for manufacture of implantable catheters having both inner and outer electrodes.
- electroless plating is a widely used non-galvanic plating method for providing an electrically conductive material on substrates, including insulating substrates, which, in the context of the present invention, involves the creation of thin- film electrodes on the catheter surface or surfaces. Electroless plating involves several simultaneous reactions in aqueous solution, which occur without the use of electrical power as in electroplating. Accordingly, fabrication of electrodes in the present method using the electroless plating technique involves first activating the exterior and interior surfaces of the catheter by treating the surfaces with an activating agent that will covalently or electrostatically bind the metal to be deposited.
- this activation layer is readily provided using a silanizing agent that reacts with surface silanol groups and results in free reactive moieties on the catheter surface.
- the reactive surface moieties may be, for instance, sulfhydryl, cyano, or amino, depending on the silanizing agent selected.
- Representative silanizing agents include, without limitation, (3-aminopropyl)-trimethoxysilane (APTMS) and (3-mercaptopropyl)-trimethoxysilane (MPTMS).
- a metallic compound or composition generally composed of a noble metal that is inert but provides an electrochemically active surface, which serves as the substrate for plating.
- noble metals include gold, silver, palladium, and platinum.
- An exemplary process is as follows. Prior to surface activation, the regions of the catheter surfaces that will not be plated, i.e., the regions that will serve as the gaps between electrodes, are masked. This can be done by using any material that is impermeable as well as inert to the electroless plating solutions, with the interior gap provided by physically introducing an elongate rigid mask material (e.g., a rigid piece of plastic) into the catheter and the exterior gap provided using exterior masking segments. As illustrated in FIG. 6, the interior masking segment 76 extends across the inner diameter of the inner catheter surface 78 from one interior section 80 to the diametrically opposed interior section 82.
- an elongate rigid mask material e.g., a rigid piece of plastic
- the catheter is immersed in an aqueous solution of palladium chloride and then coated with a solution containing a stannous salt (e.g., stannous chloride), generally by immersion in that solution.
- a stannous salt e.g., stannous chloride
- This process results in deposition of Pd°, palladium metal, on the catheter surface.
- the interior masking segment 76 is then extracted from the catheter interior, while exterior masking segments are simply physically removed from the exterior catheter surface.
- gold or an alternative metallic electrode material onto the palladium-coated regions of the catheter surfaces using any plating technique, to provide a thin film electrode layer in the range of about 50 nm to about 100 nm in thickness.
- the metal precursor solution may be a solution of a palladium compound and a Lewis base ligand in a solvent, e.g., palladium propionate, propionate acetate, etc., and a nucleophilic nitrogenous ligand such as aniline, pyridine, cyclopentyl amine, or the like.
- a solvent e.g., palladium propionate, propionate acetate, etc.
- a nucleophilic nitrogenous ligand such as aniline, pyridine, cyclopentyl amine, or the like.
- the coating is then treated in a manner that chemically facilitates separation of the ligand from palladium, leaving a layer of elemental palladium on the catheter surface.
- Such processes are described in detail in U.S. Patent No. 7,981,508 to Sharma et al. (assigned to SRI International, Menlo Park, CA), the disclosure of which is incorporated by reference herein.
- electroless plating The advantages of electroless plating are that the reactions involved are very simple electrochemical reactions that take place on a surface and proceed at ambient temperature with aqueous solutions. There is no need for elevated temperature or pressure, organic solvents, or complex equipment. It should also be noted that in the present context, fabrication of the implantable catheter using electroless plating is a versatile manufacturing technique, insofar as the process can be used for providing exterior electrodes only, interior electrodes only, or both interior and exterior electrodes.
- a paste is prepared using a precursor or prepolymer to the flexible elastomer that will serve as the catheter body, and, on the exterior and optionally the interior of the paste as it is fed into the extruder, at least two strips of a conductive electrode composition.
- the precursor or prepolymer to the flexible elastomer is cross- linkable with heat, ultraviolet radiation, or chemically, using a cross-linking agent.
- the conductive electrode composition comprises a mixture of conductive particles, e.g., carbon particles, and a thermosetting or thermoplastic, preferably thermosetting polymer that is curable photochemically, thermally, or chemically, e.g., in the presence of moisture.
- the paste would contain a crosslinkable siloxane polymer or prepolymer that is readily curable, to form the catheter body.
- an added crosslinking agent might be necessary.
- crosslinkable refers to a polysiloxane having reactive or functional groups that enable thermal, photochemical, or chemical crosslinking. Silicone polymers of this description are generally known and commercially available. By way of illustration, mention may be made of dimethyl polysiloxane, methylphenyl polysiloxane, cyanoalkylmethyl polysiloxane, and fluoroalkylmethyl siloxane.
- crosslinkable polysiloxane is dimethyl polysiloxane, which is characterized as possessing high strength and elasticity.
- the conductive electrode composition is preferably composed of a mixture of particulate carbon, e.g., carbon powder, carbon nanoparticles, carbon fibers, or the like, and a thermosetting polymer, e.g., a thermally or photochemically curable polymer typically selected from polyurethanes, polyvinyl chloride, silicones, poly(styrene-butadiene-styrene), and polyether-amide block copolymers, with carbon representing in the range of about 5 wt.% to about 25 wt.% of the mixture.
- the extruded catheter is then treated as necessary, e.g., with light and/or heat and/or moisture, to cure the polysiloxane and thereby form the catheter body and to harden the thermosetting polymer of the conductive electrode composition to form the carbon-polymer composite electrodes.
- a similar manufacturing process would be used.
- the material to be extruded can be heated prior to and/or during the extrusion process.
- Electrode structures having a first conductive material, a second conductive material, and a dielectric material can be coextruded in this manner to provide an electrode structure having the first conductive material and the second conductive material electrically isolated by the dielectric material.
- extrusion is a simple and straightforward technique, and makes it possible to carefully control the position, width, and thickness of the electrodes, it is a preferred technique for fabrication of the implantable catheter.
- the implantable catheter can also be fabricated by depositing electrode material on the exterior surface of a catheter using CVD, or by using a printing technique that essentially involves pressing pre-formed electrode strips into the exterior surface of a softened catheter body.
- the operating parameters suitable for implementation of the present invention will vary, depending on the intended method of use and the voltage application regimen. That is, the method of the invention may be used to kill microorganisms in an existing biofilm on an implantable catheter surface, to prevent growth of a biofilm on an implantable catheter surface, or to sense the formation of a biofilm on an implantable catheter surface.
- the electric field generated on the catheter surface(s) may be applied by the voltage source either intermittently or continuously.
- a duration of voltage application in the range of about 15 minutes to about 6 hours, typically in the range of about 30 minutes to about 3 hours; application frequency in the range of about once or twice daily to about once or twice weekly; an applied voltage in the range of about 0.5 V to about 1.5 V, preferably in the range of about 0.6 V to about 1.2 V, most typically in the range of about 0.8 V to about 1.2 V; and a current density in the range of about 5 ⁇ /cm 2 to about 200 ⁇ /cm 2 , typically in the range of about 10 ⁇ /cm 2 to about 200 ⁇ /cm 2 , and most typically in the range of about 20 ⁇ /cm 2 to about 100 ⁇ /cm 2 .
- the applied voltage is in the range of about 0.3 V to about 1.3 V, typically in the range of about 0.3 V to about 0.7 V, and the current density is in the range of about 5 ⁇ /cm 2 to about 50 ⁇ /cm 2 .
- application of voltage to generate an electric field across the catheter surface(s) is preferably an ongoing, continuous, low voltage process, with applied voltage in the range of about 0.2 V to about 1.0 V, preferably in the range of about 0.3 V to about 0.6 V.
- the resulting current density at the catheter surface is typically in the range of about 5 ⁇ /cm 2 to about 30 ⁇ /cm 2 .
- the invention also encompasses a method and system for sensing the formation of or confirming the presence of a biofilm on an implantable catheter surface, and the application of voltage to generate an electric field across the catheter surface may be intermittent or continuous. Very low voltage is required here, on the order of about 10 mV to about 30 mV.
- the system includes a means for detecting an increase in impedance across the external electrodes on the outer surface and/or inner surface of the catheter, i.e., an increase relative to the measured impedance across the electrodes in the absence of a biofilm.
- the detection means e.g., Electrical Impedance Spectroscopy (EIS) or an alternative technique, is operatively connected to a means for communicating the measurement to an external device for a user to view.
- the communication means comprises electric circuitry for providing an output signal, e.g., an electronic, optical, or
- an increase in impedance of more than 50% noted in at least two consecutive measurements is indicative of the presence of or formation of a biofilm on the catheter surface.
- the electrodes used for biofilm destruction i.e., for killing microorganisms in the biofilm
- the sensing process can be employed initially to detect changes in impedance associated with the growth of a pathogenic biofilm, and as noted above, the same system, without modification or adaptation of any sort, may then be activated at a higher voltage, as described earlier herein, to kill microorganisms in the biofilm and thereby disinfect the catheter surface.
- an electrochemical or other type of oxygen rather than use impedance measurement to detect the presence or formation of a biofilm on the catheter surface, an electrochemical or other type of oxygen
- the microorganisms in the biofilm can be killed using the method described earlier herein.
- Any electrochemical oxygen sensor and oxygen determination method may be used, including, by way of example, a galvanic oxygen sensor, a polarographic oxygen sensor, a coulometric sensor, or the like.
- the information pertaining to actual use of a single implantable catheter system in a patient can be stored and tracked.
- Such information includes, for example, the installation date of the catheter, the access dates of the catheter, the activation dates and times, voltage levels, duration of use, and the like.
- Information on the activation pattern of a catheter e.g., prophylactic at a low voltage level versus activation at a high level once a biofilm has been detected, can yield critical information relevant to a determination of what therapies work best for which patients.
- the implantable catheter system should include an internal clock that can store date and time, a sensor (e.g., a capacitive or resistive sensor) in the catheter to determine when its fluid connector is accessed, a means for monitoring activation patterns and power used, and a means to communicate with a data output device and optionally through a wired or wireless communication channel with a hospital network.
- a sensor e.g., a capacitive or resistive sensor
- the pertinent information can thereby be made known to medical personnel through a dashboard, the patient's electronic medical record (EMR) or a parallel system or application.
- EMR electronic medical record
- the information provided will serve as a quality control for the use of the catheter and a source of new knowledge to optimize the clinical use of the catheter and reduce the morbidity and mortality due to bio film infections.
- the information system will provide the following benefits: provide control over the number of times the implantable catheter is accessed and the length of time it is used; produce new knowledge to determine what pattern of use results in better outcomes for a patient; avoid unnecessary and costly removal of catheters when catheter infection is suspected; and over time, optimize the use of activation patterns of the catheter so as to result in optimal patient outcomes.
- the implantable catheter of the invention finds utility in a diverse plurality of contexts in which a catheter is implanted in a patient.
- the method and implantable catheter of the invention find utility in connection with a wide variety of catheter types, e.g., with arterial catheters, central venous catheters, dialysis tubing, endotracheal tubes, enteral feeding tubes, Foley catheters, gastrostomy tubes, hemodialysis catheters, nasogastric tubes, nephrostomy tubing, pulmonary artery catheters, tracheostomy tubes, tympanostomy tubes, shunts, umbilical catheters, urinary catheters, and the like.
- catheter types are short-term and long-term indwelling catheters, with short-term catheters remaining in place for less than 30 days, and long-term catheterization defined as requiring implantation for more than 30 days.
- Particularly important areas of use are medical procedures that require repeated and prolonged access to a patient's vascular system, for example, to carry out transfusions, administer antibiotics, drugs, nutrition, or chemotherapy agents to the bloodstream, or to purify a patient's blood.
- central venous catheters normally remain implanted for a longer period of time than other venous catheters, especially when there is an extended and ongoing need for their use, such as the administration of total parenteral nutrition in a chronically ill patient.
- blood is removed for filtering and purification externally to the body; typically, access is obtained through a vein or artery.
- the implantable catheter is inserted through the patient's skin so that the distal end remains under the skin, within the patient's body, while the proximal end extends outside the body for connection to an external line.
- the distal end generally enters a patient's vein, and the proximal end is connected through an external line to a device used to receive, supply, and/or process medical fluids, such as blood.
- the outer surface of the catheter body is exposed to the environment surrounding the catheter. For example, the outer surface may be in contact with the contents of a body lumen into which the catheter has been inserted.
- a device is implanted in the body of a patient, in which case the implant surfaces are at risk for infection with biofilm microorganisms.
- implants include, without limitation, stents, including biliary, hepatic, and esophageal stents, orthopedic prostheses, pins, joints, and other implants, dental implants, intracardiac prostheses, vascular prostheses including prosthetic heart valves, artificial hearts, and pacemakers.
- TLB Staphylococcus aureus trypticase soy broth
- antibiotics were added at final concentrations of 100 ⁇ g/ml Ampicillin and 20 ⁇ / ⁇ 1 Gentamycin.
- Visualization of live and dead cells was carried out by staining with Baclight live dead stain from Molecular Probes, Inc. (Eugene, OR, USA) showing live cells by green fluorescence and dead cells by red fluorescence.
- Gfp was constitutively expressed in cells (e.g., for PAOl), live cells are represented by green fluorescence from Gfp.
- Pseudomonas aeruginosa (PAOl) Tn7::Gfp tagged, Amp r , Km 1
- Flow cells were inoculated with the strain of interest grown for 18h in LB medium and diluted to OD 0.01 prior to inoculation. After having stopped the media flow the flow channels were inverted and 250 ⁇ of the diluted mixture was carefully injected into each flow channel using a small syringe. After 1 h the flow channel was inverted and the flow was resumed using a Watson Marlow 205S peristaltic pump (Watson Marlow Inc., Wilmington, Mass.). The mean flow velocity in the flow cells was 0.2 mm/s. A scaled up flow cell was developed and used for monitoring growth and killing efficiencies on typical catheter-length electrodes. This flow cell had the dimensions of 4 x 30 x 160 mm and was mounted with graphite electrodes.
- Multichannel simulated fluorescence projection (SFP, a shadow projection) images and vertical cross sections through the biofilm were generated by using the IMARIS software package (Bitplane AG, Zurich, Switzerland). Images were further processed for display by using Photoshop software (Adobe, Mountain View, Calif).
- Image acquisition for quantification using COMSTAT For quantification of biomass and calculation of % of dead cells, independent biofilm experiments were performed acquiring image stacks randomly of the respective biofilm samples. Images were further treated using COMSTAT (Heydorn et al. (Oct. 2000) Microbiology 146 (Pt 10):23950407. By viewing the images from the confocal microscope and quantifying the relative amounts of green cells and red cells at regular intervals, one can calculate biomass and monitor biofilm growth. The fraction of dead cells can thereby be deduced throughout the electrochemical process.
- FIGS. 7-15 and 17 confirm the efficacy of the electrochemical method and system of the invention in inhibiting biofilm growth, in terms of both killing microorganisms and preventing biofilm growth.
- FIGS. 7-11 show images of P. aeruginosa biofilms grown in the static system, in glucose minimal media, on a 4 cm long graphite electrode (FIGS. 7-9 and 11) or on a 16 cm long graphite electrode (FIG. 10). These images were taken 4 cm and 12 cm from the electrode connection to the power supply respectively, and varying electrochemical treatments were used, as follows: FIG. 7, - 1.2 V at 20 ⁇ /cm 2 ; FIG. 8, -0.6 V at 10 ⁇ /cm 2 ; FIG. 9, -0.6 V at 10 ⁇ /cm 2 ; FIG. 10, -1.2 V at 25 ⁇ /cm 2 ; and FIG. 11, -0.8 V at 25 ⁇ /cm 2 .
- FIG. 12-15 show images of P. aeruginosa biofilms grown in a dynamic, flow-through system using the flow chambers described earlier herein. Again, the images confirm the efficacy of the invention in a variety of contexts: duration of biofilm growth (FIG. 12, 24 h; FIGS. 13-15, 72 h); type of electrode (FIGS. 12 and 13, gold on glass; FIGS. 14 and 15, a 20 cm graphite electrode); and electrochemical parameters (FIGS. 12 and 13, -1.2 V at 20 ⁇ /cm 2 ; FIG. 14, 2 ⁇ /cm 2 ; FIG. 15, 20 ⁇ /cm 2 ).
- FIG. 16 show killing efficacy of P. aeruginosa biofilms evaluated by colony forming units (CFU/mL) after electrochemical treatment according to the invention.
- CFU/mL colony forming units
- FIGS. 17, 18, 19 and 20 illustrate efficacy with additional microorganisms, E. coli (images shown in FIG. 17 and a CFU/ml diagram shown in FIG 18) and Staphylococcus aurous strains (images shown in FIG. 19 and a CFU/ml diagram shown in FIG. 20).
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Priority Applications (4)
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AU2012272993A AU2012272993B2 (en) | 2011-06-20 | 2012-06-20 | Electrochemical disinfection of implanted catheters |
JP2014517132A JP6555885B2 (ja) | 2011-06-20 | 2012-06-20 | 埋込型カテーテルの電気化学的殺菌 |
CA2837726A CA2837726C (en) | 2011-06-20 | 2012-06-20 | Electrochemical disinfection of implanted catheters |
EP12733312.8A EP2720727B1 (en) | 2011-06-20 | 2012-06-20 | Electrochemical disinfection of implanted catheters |
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CN109717841B (zh) * | 2019-03-12 | 2022-02-22 | 西南医科大学 | 一种皮肤病变内源性电场测量装置及方法 |
US20210121683A1 (en) * | 2019-10-23 | 2021-04-29 | Cardiac Pacemakers, Inc. | Implantable devices and methods for control of bacterial infections |
US11666749B2 (en) * | 2019-10-23 | 2023-06-06 | Cardiac Pacemakers, Inc. | Implantable devices and methods for control of bacterial infections |
US20220124465A1 (en) * | 2020-07-11 | 2022-04-21 | Gregory J. Hummer | Method and devices for detecting viruses and bacterial pathogens |
US11832152B2 (en) * | 2020-07-11 | 2023-11-28 | Gregory J. Hummer | Method and devices for detecting viruses and bacterial pathogens |
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JP6555885B2 (ja) | 2019-08-07 |
JP2015507481A (ja) | 2015-03-12 |
US9320832B2 (en) | 2016-04-26 |
CA2837726A1 (en) | 2012-12-27 |
EP2720727B1 (en) | 2019-06-19 |
AU2012272993B2 (en) | 2016-02-04 |
US20130041238A1 (en) | 2013-02-14 |
US9381276B1 (en) | 2016-07-05 |
US20160193388A1 (en) | 2016-07-07 |
CA2837726C (en) | 2016-09-20 |
AU2012272993A1 (en) | 2013-12-19 |
EP2720727A1 (en) | 2014-04-23 |
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