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WO1997025917A9 - Structures multifonctionnelles d'electrodes destinees a l'analyse et au chauffage electriques de tissus corporels - Google Patents

Structures multifonctionnelles d'electrodes destinees a l'analyse et au chauffage electriques de tissus corporels

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Publication number
WO1997025917A9
WO1997025917A9 PCT/US1997/000896 US9700896W WO9725917A9 WO 1997025917 A9 WO1997025917 A9 WO 1997025917A9 US 9700896 W US9700896 W US 9700896W WO 9725917 A9 WO9725917 A9 WO 9725917A9
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WO
WIPO (PCT)
Prior art keywords
electrically
network
electrode segments
exterior wall
controller
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Ceased
Application number
PCT/US1997/000896
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English (en)
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WO1997025917A1 (fr
Filing date
Publication date
Priority claimed from US08/629,014 external-priority patent/US5836874A/en
Application filed filed Critical
Priority to JP9526268A priority Critical patent/JP2000504242A/ja
Priority to EP97903022A priority patent/EP0879015A4/fr
Publication of WO1997025917A1 publication Critical patent/WO1997025917A1/fr
Publication of WO1997025917A9 publication Critical patent/WO1997025917A9/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Definitions

  • the invention generally relates to electrode structures deployed in interior regions of the body. In a more specific sense, the invention relates to electrode structures deployable into the heart for diagnosis and treatment of cardiac conditions.
  • Physicians examine the propagation of electrical impulses in heart tissue to locate aberrant conductive pathways.
  • the aberrant conductive pathways constitute peculiar and life threatening patterns, called dysrhythmias.
  • the techniques used to analyze these pathways commonly called “mapping," identify regions in the heart tissue, called foci, which are ablated to treat the dysrhythmia.
  • Conventional cardiac tissue mapping techniques use multiple electrodes positioned in contact with epicardial heart tissue to obtain multiple electrogra s.
  • Digital signal processing algorithms convert the electrogram morphologies into isochronal displays, which depict the propagation of electrical impulses in heart tissue over time.
  • These conventional mapping techniques require invasive open heart surgical techniques to position the electrodes on the epicardial surface of the heart.
  • ischemic tissue occupying the border zone between infarcted tissue and healthy tissue has an electrical resistivity that is about two-thirds that of healthy heart tissue. See, e.g., Fallert et al., "Myocardial Electrical Impedance Mapping of Ischemic Sheep Hearts and Healing Aneurysms," Circulation, Vol. 87, No. 1, January 1993, 199-207.
  • Panescu U.S. Patent 5,487,391 and Panescu et al U.S. Patent 5,485,849 demonstrate that this observed physiological phenomenon, when coupled with effective, non-intrusive measurement techniques, can lead to cardiac mapping systems and procedures with a CIR better than conventional mapping technologies.
  • the Panescu '391 and , 849 Patents use a multiple electrode structure and signal processing methodologies to examine heart tissue morphology quickly, accurately, and in a relatively non-invasive manner.
  • the systems and methods disclosed in the Panescu '391 and '849 Patents transmit electrical current through a region of heart tissue lying between selected pairs of the electrodes, at least one of the electrodes in each pair being located within the heart.
  • E-Characteristic the electrical characteristic of tissue lying between the electrode pairs. This electrical characteristic (called the "E-Characteristic") can be directly correlated to tissue morphology. A low relative E-Characteristic indicates infarcted heart tissue, while a high relative E-Characteristic indicates healthy heart tissue. Intermediate E-Characteristic values indicate the border of ischemic tissue between infarcted and healthy tissue.
  • the treatment of cardiac arrhythmias also requires electrodes capable of creating tissue lesions having a diversity of different geometries and characteristics, depending upon the particular physiology of the arrhythmia to be treated.
  • a conventional 8F diameter/4mm long cardiac ablation electrode can transmit radio frequency energy to create lesions in myocardial tissue with a depth of about 0.5 cm and a width of about 10 mm, with a lesion volume of up to 0.2 cm 3 .
  • These small and shallow lesions are desired in the sinus node for sinus node modifications, or along the A-V groove for various accessory pathway ablations, or along the slow zone of the tricuspid isthmus for atrial flutter (AFL) or AV node slow pathways ablations.
  • VT ventricular tachycardia
  • Multi-purpose cardiac ablation electrodes that can both examine the propagation of electrical impulses in heart tissue and also create lesions of different geometries and characteristics.
  • Multi-purpose electrodes would possess the requisite flexibility and maneuverability permitting safe and easy introduction into the heart. Once deployed inside the heart, these electrodes would possess the capability to map cardiac tissue and to emit energy sufficient to create, in a controlled fashion, either large and deep lesions, or small and shallow lesions, or large and shallow lesions, depending upon the therapy required.
  • One aspect of the invention provides multi-function systems and methods for use in association with body tissue.
  • the systems and methods employ a structure including an exterior wall adapted to contact tissue, which carries an array of electrically conducting electrode segments.
  • An electrically conductive network is coupled to the electrode segments, including at least one electrically conductive path individually coupled to each electrode segment.
  • a controller is coupled to the electrically conductive network. The controller operates in a first mode during which the network is electrically conditioned to individually sense at each electrode segment local electrical events in tissue, such as electrical potentials, resistivity, or impedance.
  • the controller further operates in a second mode during which the network is electrically conditioned, based at least in part upon local electrical events sensed by the electrode segments, to couple at least two electrode segments together to simultaneously transmit electrical energy to create a physiological effect upon a region of body tissue, such as heating or ablating the tissue region.
  • the controller operates in conjunction with the array of electrode segments in a first mode during which the network is electrically conditioned to individually transmit through each electrode segment electrical energy creating a local physiological effect upon body tissue, such as electrically stimulating localized tissue.
  • the controller further operates in a second mode during which the network is electrically conditioned to couple at least two electrode segments together to simultaneously transmit electrical energy creating a regional physiological effect upon body tissue, such as heating or ablating the tissue region.
  • Another aspect of the invention provides systems and methods for pacing heart tissue.
  • the systems and methods make use of a structure including an exterior wall adapted to contact heart tissue.
  • the exterior wall is adapted to selectively assume an expanded geometry having a first maximum diameter and a collapsed geometry having a second maximum diameter less than the first maximum diameter.
  • the exterior wall carries electrically conducting electrodes.
  • An electrically conductive network is coupled to the electrodes, including at least one electrically conductive path individually coupled to each electrode.
  • a controller is coupled to the electrically conductive network.
  • the controller operates in a first mode during which the network is electrically conditioned to transmit electrical energy through the electrodes to pace heart tissue.
  • the controller further operates in a second mode during which the network is electrically conditioned to sense electrical events through the electrodes.
  • FIG. 1 is a view of a system for analyzing the morphology of heart tissue that embodies the features of the invention
  • Fig. 2 is an enlarged side view of an expandable-collapsible electrode structure associated with the system shown in Fig. 1, shown in the expanded geometry;
  • Fig. 3 is an enlarged side view of the expandable-collapsible electrode structure shown in Fig. 2, shown in the collapsed geometry;
  • Fig. 4 is an enlarged and somewhat diagrammatic view of the surface of the electrode structure shown in Figs. 2 and 3, showing the high density pattern of electrode segments;
  • Fig. 5 is a side elevation view of an expandable-collapsible electrode structure associated with the system shown in Fig. 1, with an interior spline support structure shown in its expanded geometry;
  • Fig. 6 is a side elevation view of the expandable-collapsible electrode structure shown in Fig. 5, with its interior spline support structure shown in its collapsed geometry;
  • Fig. 7 is a side elevation view of an expandable-collapsible electrode structure associated with the system shown in Fig. 1, with an interior mesh support structure shown in its expanded geometry;
  • Fig. 8 is a side elevation view of an expandable-collapsible electrode structure associated with the system shown in Fig. l, the structure having an electrically conductive body;
  • Fig. 9 is a side elevation view of an expandable-collapsible electrode structure with a bull's eye pattern of electrode zones;
  • Fig. 10 an expandable-collapsible electrode structure with a circumferentially spaced pattern of electrode zones;
  • Fig. 11 is an expandable-collapsible electrode structure suitable for noncontact mapping of the interior of the heart.
  • the system 10 includes a flexible catheter tube 12 with a proximal end 14 and a distal end 16.
  • the proximal end 14 carries a handle 18.
  • the distal end 16 carries an electrode structure 20, which embodies features of the invention.
  • the physician uses the electrode structure 20 in association with a process controller 40 to take multiple, sequential measurements of the transmission of electrical current through heart tissue. Based upon these current transmissions, the controller 40 derives the electrical characteristic of tissue lying between the electrode pairs, called the
  • E-Characteristic The E-Characteristic can be directly correlated to tissue morphology.
  • the electrode structure 20 can be also used to ablate tissue in the system 10.
  • the electrode structure 20 includes an expandable-collapsible body 22.
  • the geometry of the body 22 can be altered between a collapsed geometry (Fig. 3) and an enlarged, or expanded, geometry (Fig. 2).
  • fluid pressure is used to inflate and maintain the expandable-collapsible body 22 in the expanded geometry.
  • the catheter tube 12 carries an interior lumen 34 along its length.
  • the distal end of the lumen 34 opens into the hollow interior of the expandable- collapsible body 22.
  • the proximal end of the lumen 34 communicates with a port 36 (see Fig. 1) on the handle 18.
  • the expandable- collapsible body 22 can be urged into a significantly expanded geometry of, for example, approximately 7 to 20 mm.
  • the structure 20 can include, if desired, a normally open, yet collapsible, interior support structure 43 to apply internal force to augment or replace the force of fluid medium pressure to maintain the body 22 in the expanded geometry.
  • the form of the interior support structure 43 can vary. It can, for example, comprise an assemblage of flexible spline elements 25, as shown in Fig. 5, or an interior porous, interwoven mesh or open cell foam structure 26, as shown in Fig. 7.
  • the internally supported expandable-collapsible body 22 is brought to a collapsed geometry, after the removal of the inflation medium, by outside compression applied by an outer sheath 28 (see Fig. 6), which slides along the catheter tube 12.
  • an outer sheath 28 see Fig. 6
  • forward movement of the sheath 28 advances it over the expanded expandable- collapsible body 22.
  • the expandable-collapsible body 22 collapses into its low profile geometry within the sheath 28.
  • Rearward movement of the sheath 28 retracts it away from the expandable-collapsible body 22.
  • the expandable-collapsible body 22 can be formed about the exterior of a glass mold. In this arrangement, the external dimensions of the mold match the desired expanded geometry of the expandable-collapsible body 22.
  • the mold is dipped in a desired sequence into a solution of the body material until the desired wall thickness is achieved. The mold is then etched away, leaving the formed expandable-collapsible body 22.
  • the expandable-collapsible body 22 may also be blow molded from extruded tube.
  • the body 22 is sealed at one end using adhesive or thermal fusion.
  • the opposite open end of the body 22 is left open.
  • the sealed expandable-collapsible body 22 is placed inside the mold.
  • An inflation medium, such as high pressure gas or liquid, is introduced through the open tube end.
  • the mold is exposed to heat as the tube body 22 is inflated to assume the mold geometry.
  • the formed expandable-collapsible body 22 is then pulled from the mold.
  • Various specific geometries can be selected.
  • the preferred geometry is essentially spherical and symmetric, with a distal spherical contour, as Fig. 2 shows.
  • the body 22 when used in the ventricle, the body 22 should have a generally spherical contour. When used in the atrium, the body 22 should have a generally elongated contour. When used epicardially, the body 22 should have a generally concave contour.
  • the structure 20 includes an array of small electrode segments 44 overlying all or a portion of the expandable-collapsible body 22. The array orients the small electrode segments 44 in a high density, closely spaced relationship. The resistivity of each electrode segment 44 is low relative to the resistivity of the body 22 spacing the segments 44 apart.
  • the electrode segments 44 comprise metal, such as gold, platinum, platinum/iridium, among others, deposited upon the expandable-collapsible body 22 by sputtering, vapor deposition, ion beam deposition, electroplating over a deposited seed layer, photo-etching, multi-layer processes, or a combination of these processes.
  • the signal paths 32 are deposited on the body using conventional photo- etching or multi-layer processes.
  • the signal paths 32 communicate with wires 33, which extend through catheter tube 12 for coupling to connectors 38 carried by the handle 18.
  • a distal steering mechanism 52 (see Fig. 1) enhances the manipulation of the electrode structure 20 both during and after deployment.
  • the steering mechanism 52 can vary.
  • the steering mechanism 52 includes a rotating cam wheel 56 coupled to an external steering lever 58 carried by the handle 18.
  • the cam wheel 56 holds the proximal ends of right and left steering wires 60.
  • the wires 60 pass with the signal wires 33 through the catheter tube 12 and connect to the left and right sides of a resilient bendable wire or leaf spring (not shown) adjacent the distal tube end 16. Further details of this and other types of steering mechanisms are shown in Lundguist and Thompson U.S. Patent 5,254,088, which is incorporated into this Specification by reference.
  • the array of electrode segments 44 functions in both a diagnostic mode and a therapeutic mode.
  • each segment 44 is conditioned by the controller 40 to transmit electrical current through tissue.
  • the electrode segments 44 can transmit electrical current in either a unipolar mode or a bipolar mode. When operated in a unipolar mode, the current return path is provided by an exterior indifferent electrode attached to the patient. When operated in a bipolar mode, the current return path is provided by an electrode segment located immediately next to or spaced away from the selected transmitting electrode segment 44.
  • the controller 40 acquires impedance information about the heart tissue region that the electrode segments 44 contact.
  • the impedance information is processed by the controller 40 to derive the E-Characteristic, which assists the physician in identifying regions of infarcted tissue where ablation therapy may be appropriate.
  • the coupled electrode segments 44 being held by the body in intimate contact with tissue and thereby shielded from contact with the blood pool, direct essentially all current flow into tissue, thereby obtaining tissue characteristic information free of artifacts.
  • the high density of electrode segments 44 carried by the expandable-collapsible body 22 also provides superior signal resolution for more accurate identification of the potential ablation region.
  • the controller 40 electrically couples a grid of adjacent electrode segments 44 together overlying the identified region to a source 42 of ablation energy.
  • the coupled electrode segments simultaneously receive ablation energy from the source 42 (see Fig. 1) , thereby serving as a large-surface area transmitter of the energy.
  • the type of ablation energy used can vary, in the illustrated and preferred embodiment, the coupled electrode segments 44 transmit radio frequency (RF) electromagnetic energy.
  • RF radio frequency
  • the ablation energy from the coupled electrode segments pass through tissue, typically to an external patch electrode (forming a unipolar arrangement) .
  • the transmitted energy can pass through tissue to a separate adjacent electrode in the heart chamber (forming a bipolar arrangement) .
  • the radio frequency energy heats the tissue, mostly ohmically, forming a lesion.
  • a controller 43 preferably governs the conveyance of radio frequency ablation energy from the generator 42 to the selected coupled electrode segments 44.
  • the array of electrode segments 44 carries one or more temperature sensing elements 104, which are coupled to the controller 43. Temperatures sensed by the temperature sensing elements 104 are processed by the controller 43. Based upon temperature input, the controller 43 adjusts the time and power level of radio frequency energy transmissions by the coupled electrode segments 44, to achieve the desired lesion patterns and other ablation objectives.
  • the temperature sensing elements 104 can take the form of thermistors, thermocouples, or the equivalent.
  • the body 22 can itself be electrically conductive, having a resistivity similar to the tissue it contacts (i.e., about 500 ohm «cm) , or greater or more than this amount.
  • the body can be made conductive by the inclusion by coextrusion of an electrically conductive material, like carbon black or chopped carbon fiber.
  • the electrically conductive body 22 is used in association with an interior electrode 200, like that shown in Fig. 8.
  • a hypertonic saline solution 204 also fills the interior of the electrically conductive body 22 (as also shown in Fig. 8) , to serve as an electrically conductive path to convey radio frequency energy from the electrode 200 to the body 22.
  • the electrically conductive body 22 functions as a "leaky” capacitor in transmitting radio frequency energy from the interior electrode 200 to tissue.
  • the amount of electrically conductive material coextruded into the body 22 affects the electrical conductivity, and thus the electrical resistivity of the body 22, which varies inversely with conductivity. Addition of more electrically conductive material increases electrical conductivity of the body 22, thereby reducing electrical resistivity of the body 22, and vice versa.
  • the user selects a body 22 with a given resistivity according to a function that correlates desired lesion characteristics with the electrical resistivity values of the associated body 22. According to this function, resistivities equal to or greater that about 500 ohm*cm result in more shallow lesions, while resistivities less than about 500 ohm*cm result in deeper lesions, and vice versa.
  • the body 22 can be made electrically conductive by being made porous. Used in association with the interior electrode 200 and hypertonic solution 204 within the body 22, the pores of the porous body 22 establishes ionic transport of ablation energy from the electrode 200, through the electrically conductive medium 204, to tissue outside the body.
  • the electrode segments 44 can be used in tandem with the electrically conductive body to convey radio frequency energy to ablate tissue.
  • the controller 40 electrically couples a grid of adjacent electrode segments 44 together to a source 42 of ablation energy
  • the interior electrode 200 also receives radio frequency energy for transmission by the medium 204 through the electrically conductive body 22.
  • the conductive body 22 extends the effective surface area of the coupled segments 44, thereby enhancing the ablation effect. If the body 22 is porous enough to actually perfuse liquid, an interior electrode 200 is not required to increase the effective electrode surface area of the segments 44. The perfusion of hypertonic liquid through the pores at the time the regions transmit radio frequency energy is itself sufficient to increase the effective transmission surface area of the segments 44.
  • the segments 44 can themselves be made from a porous, electrically conducting material. In this way, ionic transport can occur by mass transfer or perfusion through the segment 44 themselves.
  • the expandable-collapsible electrode structure 20 shown in Fig. 2 can also be used in association with conventional pacing apparatus (not shown) for pacing the heart to acquire electrograms in a conventional fashion.
  • the pacing apparatus is electrically coupled to the connectors 38 to provide a pacing signal to a selected one electrode segment 44, generating depolarization foci at selected sites within the heart.
  • the electrode segments 44 also serve to sense the resulting electrical events for the creation of electrograms. Used in this fashion, the structure 20 can accommodate both pace mapping and entrainment pacing techniques.
  • the expanded structure 20 can also be used to convey pacing signals to confirm contact between tissue and the segments 44. The ability to carry out pacing to sense tissue contact is unexpected, given that the expanded structure 20 presents a surface area significantly greater than that presented by a conventional 4mm/8F electrode.
  • Fig. 9 shows an expandable- collapsible body 22, as previously described, which carries an electrically conductive shell 300 that has been segmented into separate electrode zones 302 arranged in a concentric "bulls eye" pattern about the distal tip of the body 22.
  • the shell 300 can be segmented into axially elongated, circumferentially spaced electrode zones 302.
  • the electrode zones 302 are formed by masking regions on the body 22 which are to be free of the shell 300.
  • a metal material having a relatively high electrical conductivity, as well as a relative high thermal conductivity, such as gold, platinum, platinum/iridium, among others, is deposited upon the unmasked regions on the body 22 by sputtering, vapor deposition, ion beam deposition, electroplating over a deposited seed layer, or a combination of these processes.
  • preformed foil shells can be applied in axially spaced bands on the distal region to form the segmented zones.
  • the segmented zones can comprise signal wire snaked through the wall with noninsulated signal wire portions exposed on the exterior wall.
  • each zone 302 is coupled to a dedicated signal wire or a dedicated set of signal wires (not shown) .
  • the controller 43 can direct ablation energy differently to each zone according to prescribed criteria.
  • a pacing signal can be conveyed to a selected one electrode zone.
  • the electrode zones 302 can also serve to sense the resulting electrical events for the creation of electrograms.
  • bipolar electrode segments 304 are placed in the regions between the zones 304.
  • These bipolar electrode segments 304 like the zones 302 themselves, comprise metal materials, such as gold, platinum, platinum/iridium, among others, deposited upon the body 22 by sputtering, vapor deposition, ion beam deposition, electroplating over a deposited seed layer, or a combination of these processes.
  • preformed foil patches can be applied to form the bipolar segments.
  • the bipolar segments 304 are electrically coupled to signal wires (not shown) to allow bipolar electrogram acquisition, pacing, or E-Characteristic measurements.
  • signal wires not shown
  • the interior surface of the body 22 can also carry electrodes 306 suitable for unipolar or bipolar sensing or pacing or sensing of E-Characteristics.
  • Different electrode placements can be used for unipolar or bipolar sensing or pacing.
  • pairs of 2-mm length and 1-mm width electrodes 306 can be deposited on the interior surface of the body 22.
  • Connection wires (not shown) can be attached to these electrodes 306.
  • the interelectrode distance is about 1 mm to insure good quality bipolar electrograms.
  • Preferred placements of these interior electrodes 306 are at the distal tip and center of the structure 22. Also, when multiple zones 302 are used, it is desired to have the electrodes 306 placed in between the zones 302.
  • Fig. 10 it is preferred to deposit opaque markers 308 on the interior surface of the body 22 so that the physician can guide the device under fluoroscopy to the targeted site.
  • Any high-atomic weight material is suitable for this purpose.
  • platinum, platinum-iridium. can be used to build the markers 106. Preferred placements of these markers 308 are at the distal tip and center of the structure 22.
  • Fig. 11 shows a structure 310 for mapping electrical activity within the heart without physical contact between the structure and endocardial tissue.
  • the structure 310 comprises an expandable-collapsible body that takes the form of a mesh 312 made from interwoven resilient, inert wire or plastic filaments preformed to the desired expanded geometry.
  • a sliding sheath (as previously shown and described in conjunction with Fig. 6) advanced along the catheter tube 12 compresses the mesh structure 312 to collapse it. Likewise, retraction of the sheath removes the compression force, and the freed mesh structure 312 springs open.
  • the mesh structure 312 serves as the support for the electrode segments 44, which can be deposited on the filaments as on a shell supported by the filaments.
  • all or a portion of the mesh filaments could be made electrically conductive.
  • the network of the filaments makes it possible to form electrodes whose spacial location can be determined.
  • the mesh structure 312 can be made to normally assume the collapsed geometry.
  • one or more interior bladders 314 can accommodate the introduction of an inflation medium to cause the mesh structure 312 to assume the expanded geometry.
  • the interior bladder could be eliminated.
  • a biocompatible liquid such as sterile saline
  • the expandable-collapsible mesh structure 312 can be positioned within the blood pool of a heart chamber.
  • the electrode segments 44 sense electrical potentials in blood. Electrical potentials in myocardial tissue can be inferred from the sensed blood potentials, without actual contact with the endocardium. Further details of this methodology are found in Pilkington, Loftis, Thompson et al.(Ed.), High Performance Computing in Biomedical Research (Part 3) , "Inverse Problems and Computational Methods," CRC Press, Inc.

Abstract

L'invention porte sur des systèmes et procédés de chauffage de tissus corporels à structure multifonctionnelle (22) dont la paroi extérieure est en contact avec lesdits tissus. Ladite structure comporte un réseau de segments d'électrodes électroconducteurs (44) porté par la paroi extérieure. Un réseau électroconducteur est raccordé aux segments d'électrode par au moins une liaison électroconductrice (32) reliant individuellement chaque segment d'électrode. Les systèmes et les procédés peuvent fonctionner dans un premier mode où le système est réglé pour détecter séparément sur chaque segment d'électrode des événements électriques locaux tels que des potentiels électriques, la résistivité ou l'impédance, et dans un second mode où le réseau électrique est réglé, en partie en fonctions des événements détectés par les segments d'électrodes, pour relier au moins deux d'entre eux en vue de la transmission simultanée d'énergie électrique pour le chauffage ou l'ablation d'une zone de tissus corporels.
PCT/US1997/000896 1996-01-19 1997-01-17 Structures multifonctionnelles d'electrodes destinees a l'analyse et au chauffage electriques de tissus corporels Ceased WO1997025917A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP9526268A JP2000504242A (ja) 1996-01-19 1997-01-17 体の組織を電気的に分析し加熱するための多機能電極構造体
EP97903022A EP0879015A4 (fr) 1996-01-19 1997-01-17 Structures multifonctionnelles d'electrodes destinees a l'analyse et au chauffage electriques de tissus corporels

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
US1022596P 1996-01-19 1996-01-19
US1035496P 1996-01-19 1996-01-19
US1022396P 1996-01-19 1996-01-19
US60/010,225 1996-01-19
US60/010,354 1996-01-19
US60/010,223 1996-01-19
US08/629,014 1996-04-08
US08/629,014 US5836874A (en) 1996-04-08 1996-04-08 Multi-function electrode structures for electrically analyzing and heating body tissue

Publications (2)

Publication Number Publication Date
WO1997025917A1 WO1997025917A1 (fr) 1997-07-24
WO1997025917A9 true WO1997025917A9 (fr) 1997-10-09

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JP (1) JP2000504242A (fr)
CA (1) CA2243595A1 (fr)
WO (1) WO1997025917A1 (fr)

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