Apparatuses for remodeling tissue of or adjacent to a body passage

The present invention relates to methods and devices for remodeling tissue in a body passage or tissue adjacent to a body passage.

A wide variety of in-vivo medical devices have been developed for medical applications, such as intravascular applications. Some of these devices include guide wires, catheters and the like. These devices are manufactured by any one of a variety of different manufacturing methods and can be used according to any one of a variety of methods. Of the known medical devices and methods, each has certain advantages and disadvantages.

<p num="0003"> Alternative medical devices, as well as alternative methods of manufacturing and using medical devices, continue to be needed.</p>

<p num="0004"> The present disclosure provides alternatives to the design, materials, manufacturing methods and uses of medical devices. Exemplary methods include methods of treating patients with hypertension. This method involves preparing the device. The device includes a catheter that extends along the longitudinal axis. Balloons with unexpanded and dilated states can be attached to the ends of the catheter. In the expanded state, the balloon may have a plurality of cylindrical treatment zones extending along the longitudinal axis. Multiple electrode pad assemblies can be attached to the balloon. Each electrode pad assembly includes a substrate that supports a first electrode pad and a second electrode pad, and each electrode pad has a pair of elongated bipolar electrodes. The electrode pads of each electrode pad assembly may be offset longitudinally and circumferentially with respect to each other. This method also dilates the balloon within the renal artery to electrically connect the electrodes to the wall of the renal artery and therapeutically alters the nerves surrounding the renal artery to reduce hypertension in the patient. Including driving bipolar energy between each pair of bipolar electrodes.</p><p num="0005"> Each electrode pad may include a temperature sensor located between the pair of electrodes. The expansion of the balloon allows the temperature sensor to be thermally coupled to the wall of the renal artery. In some embodiments, the method may further include inducing energy into the bipolar pair in response to a temperature signal from the temperature sensor so as to heat the wall approximately uniformly.</p><p num="0006"> The electrode pad assembly can be placed on the balloon such that at least some of the electrode pads are longitudinally separated from their circumferentially adjacent electrode pads. In some embodiments, the method may further comprise advancing the balloon into the renal artery by flexing the balloon between electrode pads that are longitudinally separated.</p><p num="0007"> Another exemplary method includes a method of treating the body passage. This method involves preparing the device. The device includes a catheter that extends along the longitudinal axis. Balloons with unexpanded and dilated states can be attached to the ends of the catheter. In the expanded state, the balloon may have a plurality of cylindrical treatment zones extending along the longitudinal axis. Multiple electrode assemblies can be coupled to the balloon. Each electrode assembly includes a distal electrode pad and a proximal electrode pad. The distal electrode pad may be longitudinally separated from the proximal electrode pad by an intermediate tail. Each electrode pad may include a pair of bipolar electrodes. The distal electrode pad and the proximal electrode pad may be offset in the circumferential direction with respect to each other in the expanded state of the balloon. The plurality of electrode pads are arranged longitudinally so that each cylindrical treatment zone contains at least one of the distal electrode pads and the proximal electrode pads of the plurality of electrode pad assemblies. can do. The intermediate tail of each electrode assembly may extend longitudinally such that the distal and proximal electrode pads of any particular electrode pad assembly occupy a non-adjacent therapeutic zone of the balloon. The method also involves expanding the balloon in the section of the body passage. This section can be elongated along the axis. This method also activates the electrode pads while the balloon expands to deliver energy to the section of the body passage so that the section of the body passage receives multiple discontinuous treatments along the longitudinal axis. Including that.</p><p num="0008"> By activating the electrode pads, at least one injured site can be formed in the section of the body passage for each treatment zone of the balloon. The damaged sites can be non-contact with each other. For example, at least one injured site in each treatment zone may not axially overlap with at least one injured site in an adjacent treatment zone.</p><p num="0009"> This method involves monitoring the temperature at each of the electrode assemblies. Monitoring temperature can include monitoring the temperature of one of its bipolar electrode pairs using a heat sensing device using at least one of the electrode assemblies and / or. Monitoring the temperature involves using at least one of the electrode assemblies to monitor the temperature of one of the pair of bipolar electrodes using a heat sensing device of the pair of the other bipolar electrode.</p><p num="0010"> Each pair of bipolar electrodes may include a plurality of ground electrodes and a plurality of active electrodes. Each of the plurality of ground electrodes and the active electrode may be elongated along the axis, and / or each of the plurality of ground electrodes and the active electrode shall be elongated in the transverse direction with respect to the axis. Can be done.</p><p num="0011"> The balloon may have four cylindrical treatment zones. The two electrode assemblies can be coupled to the balloon such that each zone contains one distal electrode pad or one proximal electrode pad. In some embodiments, each of the two non-adjacent cylindrical treatment zones comprises two distal electrode pads or two proximal electrode pads, and the other two non-adjacent cylindrical treatment zones. Three electrode assemblies can be coupled to the balloon such that each contains one distal electrode pad or one proximal electrode pad. In some embodiments, one particular cylindrical treatment zone comprises one proximal electrode pad of one electrode assembly and two intermediate tails of the other two electrode assemblies. You may. In some embodiments, one particular cylindrical treatment zone comprises two distal electrode pads of two different electrode assemblies and one intermediate tail of the remaining electrode assembly. May be good.</p><p num="0012"> The balloon may have four cylindrical treatment zones, each of which contains two non-adjacent cylindrical treatment zones, each containing two distal electrode pads or two proximal electrode pads, and the other. Four electrode assemblies can be coupled to the balloon such that each of the two non-adjacent cylindrical treatment zones contains one distal electrode pad or one proximal electrode pad. The two distal electrode pads of the two different electrode assemblies can occupy a particular cylindrical treatment zone, and each of these two distal electrode pads is of the other two other electrode assemblies. It is separated in the circumferential direction by the tail part in the middle of one of them. The two proximal electrode pads of the two different electrode assemblies can occupy a particular cylindrical treatment zone, and each of these two proximal electrode pads is of the other two other electrode assemblies. It is separated in the circumferential direction by the tail part in the middle of one of them.</p><p num="0013"> An exemplary device may include a catheter that extends along the longitudinal axis. The balloon can be attached to the end of the catheter. Multiple electrode assemblies can be attached to the balloon. Each electrode assembly may include a first electrode pad and a second electrode pad that are longitudinally separated. The electrode pads of each electrode assembly may be offset in the circumferential direction with respect to each other in the expanded state of the balloon. The plurality of electrode assemblies can be arranged longitudinally such that one of the electrode pads of one of the plurality of electrode assemblies is disposed longitudinally between the electrode pads of another electrode assembly.</p><p num="0014"> Another exemplary device includes a catheter that extends along the longitudinal axis. The balloon can be attached to the end of the catheter. In the expanded state, the balloon may have a plurality of cylindrical treatment zones extending along the longitudinal axis. Multiple electrode assemblies can be attached to the balloon. Each electrode assembly may include a distal electrode pad and a proximal electrode pad. The distal electrode pad may be longitudinally separated from the proximal electrode pad by an intermediate tail. Each electrode assembly may include a pair of bipolar electrodes. The distal electrode pad and the proximal electrode pad may be offset in the circumferential direction with respect to each other in the expanded state of the balloon. The plurality of electrode pads are arranged longitudinally so that each cylindrical treatment zone contains at least one distal electrode pad and one proximal electrode pad of the plurality of electrode assemblies. be able to. The intermediate tail of each electrode assembly may extend longitudinally such that the distal and proximal electrode pads of any particular electrode assembly occupy a non-adjacent therapeutic zone of the balloon.</p><p num="0015"> The balloon may have four cylindrical treatment zones, and the two electrode assemblies should be coupled to the balloon such that each zone contains one distal electrode pad or one proximal electrode pad. Can be done.</p><p num="0016"> The balloon has four cylindrical treatment zones, each of the two non-adjacent cylindrical treatment zones containing two distal electrode pads or two proximal electrode pads, and the other two non-adjacent cylinders. Three electrode assemblies can be coupled to the balloon such that each of the shaped treatment zones contains one distal electrode pad or one proximal electrode pad.</p><p num="0017"> One particular cylindrical treatment zone may include one proximal electrode pad of one electrode assembly and two intermediate tails of two other electrode assemblies. One particular cylindrical treatment zone may include two distal electrode pads of two different electrode assemblies and one intermediate tail of the remaining electrode assembly.</p><p num="0018"> The balloon may have four cylindrical treatment zones, each of the two non-adjacent cylindrical treatment zones containing two distal electrode pads or two proximal electrode pads and the other two. Four electrode assemblies can be coupled to the balloon such that each of the two non-adjacent cylindrical treatment zones contains one distal electrode pad or one proximal electrode pad.</p><p num="0019"> The two distal electrode pads of the two different electrode assemblies can occupy a particular cylindrical treatment zone, and each of these two proximal electrode pads is of the other two other electrode assemblies. It is separated in the circumferential direction by the tail part in the middle of one of them.</p><p num="0020"> The two proximal electrode pads of the two different electrode assemblies can occupy a particular cylindrical treatment zone, and each of these two proximal electrode pads is of the other two other electrode assemblies. It is separated in the circumferential direction by the tail part in the middle of one of them.</p><p num="0021"> Each electrode pad may include a ground electrode and an active electrode. Each electrode pad may include a heat sensing device. Each electrode assembly may further include a proximal tail extending from the proximal electrode pad.</p><p num="0022"> For each electrode assembly, the intermediate tail contains an intermediate ground line, an intermediate active electrode line and an intermediate thermal sensor line, and the proximal tail includes an intermediate active electrode line, an intermediate thermal sensor line, and near. Includes grounding line, proximal active electrode line and proximal heat sensing line.</p><p num="0023"> The width of the proximal tail may be approximately 150% of the width of the intermediate tail. The intermediate ground line may extend on an axis shared with the proximal ground line. Both the distal ground electrode of the distal electrode pad and the proximal ground electrode of the proximal electrode pad may extend along an axis shared with the intermediate and proximal ground lines. Thereby, the distal ground electrode, the intermediate ground line, the proximal ground electrode and the proximal ground line all extend along their axis.</p><p num="0024"> Another exemplary device includes an expandable balloon that includes an outer surface and a plurality of separate flexible circuits that extend along the outer surface of the expandable balloon. At least some of the flexible circuits may each include more than one energy treatment site. Some at least some parts of the flexible circuit can be shaped so that they are at least roughly keyed to the shape of at least one adjacent flexible circuit.</p><p num="0025"> At least some of the flexible circuits are a distal electrode pad, a proximal electrode pad, an intermediate tail extending between the distal electrode pad and the proximal electrode pad, and a proximal electrode. Each may include a proximal tail that extends proximally away from the pad.</p><p num="0026"> At least some of the distal electrode pads can be positioned close to the intermediate tail and at least some of the proximal electrode pads can be positioned close to the intermediate tail. be able to.</p><p num="0027"> Some at least some parts of the flexible circuit can be shaped so that they are not inserted between the shapes of at least one adjacent flexible circuit. At least some energy treatment sites in the flexible circuit may be offset longitudinally and circumferentially with respect to each other.</p><p num="0028"> The energy treatment site may each include a pair of adjacent bipolar electrodes. The energy treatment site may further include a temperature sensor positioned between a pair of adjacent bipolar electrodes.</p><p num="0029"> Another exemplary device includes an elongated catheter, an expandable balloon associated with the catheter, and a plurality of circumferentially spaced flexible circuits extending longitudinally along the surface of the expandable balloon. Each flexible circuit may include at least one electrode. The electrodes may be axially and circumferentially separated from each other. The flexible circuit can be adhesively secured to the expandable balloon and includes a plurality of openings through the flexible circuit. The openings can be configured to increase the flexibility of the flexible circuit.</p><p num="0030"> The electrode may include a unipolar electrode. Each flexible circuit may include a first unipolar electrode and a second unipolar electrode. The first unipolar electrode and the second unipolar electrode may be offset in the circumferential direction. The unipolar electrode of the first flexible circuit may be offset longitudinally with respect to the unipolar electrode of the adjacent flexible circuit.</p><p num="0031"> The device may further include a common electrode. The common electrode can be positioned on the surface of the expandable balloon. At least some corners of the flexible circuit can be rounded corners.</p><p num="0032"> Each flexible circuit may include at least one conductor trace extending longitudinally along the flexible circuit. Each flexible circuit may include at least two separate conductor traces extending longitudinally along the flexible circuit.</p><p num="0033"> Another exemplary device includes an expandable balloon that includes an outer surface. Multiple separate flexible circuits extend along the outer surface of the expandable balloon. At least some of the flexible circuits may include two or more unipolar electrodes, respectively. Some at least some parts of the flexible circuit can be shaped so that they are at least roughly spaced between the shapes of at least one adjacent flexible circuit.</p><p num="0034"> The flexible circuit can be adhesively coupled to the outer surface of the balloon. Flexible circuits may include openings that are configured to increase the flexibility of the circuit. Another exemplary device includes an expandable balloon that includes an outer surface. At least one flexible circuit can be attached to the outer surface of the expandable balloon. At least one flexible circuit may include a first insulating layer. At least one heat sensitive device can be positioned at least partially within the first insulating layer. The conductive layer can be placed on top of the first insulating layer and at least a portion of the conductive layer can be electrically connected to the heat sensitive device. A second insulating layer can be placed on top of the conductive layer. At least one unipolar electrode can be associated with the conductive layer.</p><p num="0035"> At least one electrode can be positioned on top of the second insulating layer and can be coupled to the conductive layer through the second insulating layer. The heat sensitive device may have a thickness of less than approximately 0.15 mm.</p><p num="0036"> The at least one unipolar electrode may include at least two unipolar electrode pads, and the heat sensitive device can be positioned between a pair of unipolar electrode pads. Upon contact with the tissue, the heat sensitive device can be positioned relative to the unipolar electrode so that it is configured to measure the temperature representing both the unipolar electrode and the tissue.</p><p num="0037"> The heat sensing device may or may not be electrically connected to the unipolar electrode. The device can be configured to expand sufficiently at an expansion pressure of 10 atmospheres (1013 kPa) or less, or an expansion pressure of 6 atmospheres (608 KPa) or less.</p><p num="0038"> Another exemplary device includes an expandable inflexible balloon that includes an outer surface. The expandable balloon can be configured to fully inflate at an expansion pressure of 10 atmospheres (1013 kPa) or less. A plurality of thin film flexible circuits may extend longitudinally along the outer surface of the balloon. At least one of the flexible circuits is a first insulating layer facing the outer surface of the balloon, at least one heat sensing device, a conductive layer on the first insulating layer, a second on the conductive layer. It may include an insulating layer and at least one electrode associated with the conductive layer. The maximum thickness of the flexible circuit can be less than 0.2 mm.</p><p num="0039"> The maximum thickness of the flexible circuit can be equal to the sum of the thicknesses of the first insulating layer, the heat sensing device, the conductive layer, the second insulating layer and the electrodes. At least one electrode can be a unipolar electrode.</p><p num="0040"> The heat sensitive device can be positioned at least partially within the first insulating layer. The thickness of the heat sensing device can be less than 0.15 mm. The balloon can be configured to inflate well at an expansion pressure of 6 atmospheres (608 KPa) or less.</p><p num="0041"> An exemplary electrode pad may include a bottom insulating layer with a bottom opening. The heat sensing component can be positioned within the bottom opening and the heat sensing component may have a first pole and a second pole. The conductive layer may be above the bottom insulating layer. The conductive layer may include a first trace connected to the first pole, a second trace connected to the second pole, and a third trace. The upper insulating layer can be overlaid on top of the conductive layer. The upper insulating layer may have a first plurality of openings over the first trace and a second plurality of openings over the second trace. The first plurality of electrodes can be superposed on top of the upper insulating layer and can be conductively coupled to the first trace through the first plurality of openings in the upper insulating layer. The second plurality of electrodes can be superposed on top of the upper insulating layer and can be conductively coupled to the second trace through the second plurality of openings.</p><p num="0042"> The bottom insulating layer may have a rectangular shape extending in the lateral and longitudinal directions. The rectangular shape may transition to a narrow extension extending in the longitudinal direction. The first trace may include a first elongated electrode trace extending longitudinally.</p><p num="0043"> The first trace may further include a first ground pad that is laterally displaced from the first elongated trace. The ground pad may be electrically connected to the heat sensitive component. The third trace may include a power pad coupled to the heat sensitive component.</p><p num="0044"> The distal portion of each of the first elongated electrode trace and ground pad can be connected by a bridge portion. Each of the first plurality of electrodes may be elongated in the longitudinal direction.</p><p num="0045"> The second trace may include a second elongated electrode trace extending longitudinally. The second elongated electrode trace can be made substantially parallel to the first elongated electrode trace.</p><p num="0046"> The bottom insulating layer and the top insulating layer may each contain a flexible polymer. The flexible polymer may contain polyimide. The polyimide can be approximately 0.0013 mm thick.</p><p num="0047"> The upper insulating layer can be individually shaped with respect to the upper surface of the conductive layer. The shape of the upper insulating layer may substantially match the shape of the lower insulating layer. The heat sensitive component may include a thermistor. The thermistor can be approximately 0.10 mm thick.</p><p num="0048"> The surface area of the first plurality of electrodes can be substantially equal to the surface area of the second plurality of electrodes. The first plurality of electrodes and the second plurality of electrodes may contain gold.</p><p num="0049"> An exemplary electrode assembly may include a bottom insulating layer that includes a distal electrode pad, an intermediate tail, and a proximal electrode pad. The bottom insulating layer may have a thermistor opening. The bottom layer is rectangular and may extend longitudinally and laterally. The thermistor can be positioned within the thermistor opening and may have a grounding electrode and a power supply electrode. The conductive layer can be overlaid on top of the bottom insulating layer. The conductive layer may include a ground trace connected to the first pole, a second trace connected to the second pole, and a third trace. The upper insulating layer can be overlaid on top of the conductive layer. The upper insulating layer may have a first plurality of openings over the first trace and a second plurality of openings over the second trace. The first plurality of electrodes can be superposed on top of the upper insulating layer and can be conductively coupled to the first trace through the first plurality of openings in the upper insulating layer. The second plurality of electrodes can be superposed on top of the upper insulating layer and can be conductively coupled to the second trace through the second plurality of openings.</p><p num="0050"> An exemplary flexible circuit assembly may include a distal electrode pad. The distal electrode pad is positioned within the distal bottom insulating layer with the distal thermista opening, the distal thermista opening and far with the first distal pole and the second distal pole. Distal Thermista, a distal conductive layer overlaid on top of the distal bottom insulating layer, extending linearly along the ground axis and coupled to the first distal sensor pole. A distal conductive layer containing a conductive trace, a distal sensor trace attached to a second distal pole, and a distal active electrode trace, a distal upper part overlaid on top of the distal conductive layer. A distal upper insulating layer that is an insulating layer and has a plurality of first distal openings over a first distal trace and a second distal multiple openings over a second distal trace. A second that extends along the ground axis and is superposed on top of the distal upper insulating layer and is conductively coupled to the distal ground trace through multiple first distal openings in the distal upper insulating layer. Overlaid on top of one distal electrode, as well as a distal upper insulating layer, and laterally displaced from the first distal electrode on the first lateral side of the ground axis. In addition, it may include a plurality of second distal electrodes that are conductively coupled to the distal active electrode trace through the second distal multiple openings. The intermediate tail may extend proximally from the distal electrode pad. The intermediate tail may include an intermediate bottom insulating layer extending from the distal bottom insulating layer and an intermediate conductive layer overlaid on top of the intermediate insulating layer. The intermediate conductive layer is coupled to the intermediate ground line extending along the ground axis from the distal ground trace, the distal active electrode trace, and to the ground axis on the first lateral side of the ground axis. An intermediate active electrode line extending along a parallel first outer axis, and a ground axis and a first outer axis on the first lateral side of the ground axis, as well as being coupled to a distal sensor trace. It may include an intermediate sensor line extending along a first inner axis parallel to the ground axis between them. Overlay the middle top insulating layer on top of the middle conductive layer Can be Proximal electrode pads can be coupled to intermediate extension members. Proximal electrode pads have a proximal bottom insulating layer with a proximal thermista opening, positioned within the proximal thermista opening, and have a first proximal pole and a second proximal pole. It may include a proximal thermista as well as a proximal conductive layer overlaid on top of the distal bottom insulating layer. The proximal conductive layer extends linearly along the ground axis and is coupled to the first proximal sensor electrode, the proximal ground trace, and the distal to the second distal pole. Sensor traces and proximal active electrode traces may be included. The proximal upper insulating layer can be overlaid on top of the proximal conductive layer. Even if the proximal upper insulating layer has multiple first proximal openings over the first proximal trace and second proximal openings over the second proximal trace. Good. Multiple proximal electrodes can extend along the ground axis and superimpose on top of the proximal upper insulating layer, proximal through the first proximal multiple openings of the proximal upper insulating layer. Conductively coupled to the ground trace of. Multiple electrodes of the second proximal can be superposed on top of the proximal upper insulating layer and laterally displaced from the plurality of electrodes of the first proximal on the second lateral side of the ground axis. It is conductively coupled to the proximal active electrode trace through multiple openings in the second proximal. The proximal tail can extend proximally from the proximal electrode pad. The proximal tail may include a proximal insulating layer extending from the proximal bottom insulating layer and a proximal conductive layer overlaid on top of the proximal insulating layer. The proximal conductive layer is coupled to the proximal ground line extending along the ground axis from the proximal ground trace, the distal active electrode trace, and the ground shaft on the second lateral side of the ground shaft. A proximal active electrode line extending along a second outer axis parallel to, coupled to a proximal sensor trace, as well as a ground axis and a second outer axis on the second lateral side of the ground axis. Proximal sensor line, intermediate active electrode line, and intermediate sensor extending along a second inner axis parallel to the ground axis with It may include a line. The proximal upper insulating layer can be overlaid on top of the proximal conductive layer.</p><p num="0051"> Another exemplary device includes an expandable balloon that includes an outer surface and at least one flexible circuit that is attached to the outer surface of the expandable balloon. The at least one flexible circuit is a first insulating layer, at least one heat sensing device that is at least partially positioned within the first insulating layer, and a conductive layer above the first insulating layer. It may include a conductive layer, a second insulating layer above the conductive layer, and at least one electrode associated with the conductive layer, of which at least a portion of the conductive layer is electrically connected to the heat sensitive device. ..</p><p num="0052"> At least one electrode can be positioned on the second insulating layer and can be coupled to the conductive layer through the second insulating layer. The heat sensitive device may have a thickness of less than approximately 0.15 mm. For example, the heat sensing device may have a thickness of approximately 0.1 mm.</p><p num="0053"> At least one electrode may include a pair of bipolar electrodes. The heat sensing device can be positioned between a pair of bipolar electrodes. Upon contact with the tissue, the heat sensitive device can be positioned relative to the bipolar electrode pair so that it is configured to measure the temperature representing both the bipolar electrode and the tissue.</p><p num="0054"> The heat sensing device can be electrically connected to one of a pair of bipolar electrodes. A pair of bipolar electrodes may include a plurality of active electrodes and a plurality of ground electrodes. The plurality of active electrodes can be arranged along the first longitudinal axis, and the plurality of ground electrodes are offset from the first longitudinal axis and are generally parallel to the first longitudinal axis. Arranged along the longitudinal axis of 2.</p><p num="0055"> Upon contact with the tissue, the heat sensitive device can be positioned with respect to at least one electrode and at least one electrode configured to measure the temperature representing both of the tissue.</p><p num="0056"> Another exemplary method comprises a method of treating a patient with hypertension. This method involves preparing the device. The device may include a catheter, an expandable balloon that is attached to the catheter and includes an outer surface, and at least one flexible circuit that is attached to the outer surface of the expandable balloon. The at least one flexible circuit is a first insulating layer, at least one heat sensing device that is at least partially positioned within the first insulating layer, and a conductive layer above the first insulating layer. It may include a conductive layer, a second insulating layer above the conductive layer, and at least one electrode associated with the conductive layer, of which at least a portion of the conductive layer is electrically connected to the heat sensitive device. This method also dilates the balloon within the patient's renal arteries and drives energy through at least one electrode to therapeutically alter at least one nerve close to the renal artery to reduce the patient's hypertension. And may include.</p><p num="0057"> Preparing the device may include preparing a device having at least a pair of bipolar electrodes and a heat sensing device positioned between the pair of bipolar electrodes. The method may also include measuring the temperature representing both the at least one electrode and the wall of the renal artery using a heat sensing device.</p><p num="0058"> Another exemplary device may include a catheter, an expandable balloon that is attached to the catheter and includes an outer surface, and at least one flexible circuit that is attached to the outer surface of the expandable balloon. .. The at least one flexible circuit is a first insulating layer, at least one heat sensing device that is at least partially positioned within the first insulating layer, and a conductive layer above the first insulating layer. It may include a conductive layer, a second insulating layer above the conductive layer, and at least one electrode associated with the conductive layer, of which at least a portion of the conductive layer is electrically connected to the heat sensitive device.</p><p num="0059"> An exemplary catheter includes an elongated flexible catheter body. An expandable structure can include a radially expandable balloon and multiple flexible circuits extending along the outer surface of the balloon, each flexible circuit having at least one electrode. And include at least one temperature sensor. The expandable structure may have an outer diameter of less than 4 mm when in the expanded form.</p><p num="0060"> The outer diameter of the expandable structure can be approximately 1 mm to 3 mm. The balloon does not have to be cannulated. At least a part of the outer surface of the balloon can be a flexible polyimide film. The flexible polyimide film can define the bottom insulating layer of a plurality of flexible circuits.</p><p num="0061"> The top surface of the bottom insulating layer of the balloon may be in direct contact with at least one conductive layer of the flexible circuit. Each flexible circuit may include a bottom insulating layer adjacent to the outer surface of the balloon.</p><p num="0062"> An exemplary system for renal denervation in patients with a major renal artery extending between the aorta and the kidney and an auxiliary renal artery extending between the aorta and the kidney is a first balloon catheter and a second. Balloon catheters, each with a balloon having a small profile form and a large profile form, with multiple flexible circuits extending along the outer surface of each balloon, each flexible circuit having at least one electrode. Including. At least one of the balloons may have a large profile morphology with an outer diameter of less than 4 mm. The power supply can be electrically connected to the electrodes of the first and second balloon catheters and can be configured to excite the electrodes with renal denervation energy.</p><p num="0063"> One of the balloons may have a large profile morphology with an outer diameter of 4 mm or more. The first balloon and the second balloon may have a large profile morphology of various outer diameter sizes.</p><p num="0064"> This system can be used for renal denervation in patients who further have a second renal artery extending between the aorta and the second kidney. The system can further include a third balloon catheter with a small profile form and a large profile form, with multiple flexible circuits extending along the outer surface of the third balloon, each flexible circuit at least. It contains one electrode and the electrode of the third balloon catheter is electrically connected to the power supply.</p><p num="0065"> The first balloon, the second balloon and the third balloon, when in large profile form, can define different outer diameters from each other. The outer diameter of the third balloon can be 4 mm or more in the case of a large profile form.</p><p num="0066"> An exemplary renal denervation method is to position a radially expandable structure of an elongated flexible catheter body in a position within the auxiliary renal artery that connects the aorta to the kidney, the aorta and The kidney is further connected by the main renal artery and the radially expandable structure contains multiple electrodes, positioning and radial so that at least a subset of the electrodes engage the walls of the auxiliary renal arteries. To expand the extensible structure and use a power source that is electrically connected to the electrodes to excite at least a subset of the electrodes to deliver energy to tissues close to the auxiliary renal arteries. And may be included.</p><p num="0067"> This method also positions the radially expandable structure in a position within the main renal artery and the radial structure so that at least some of the electrodes engage the wall of the main renal artery. It may include dilation and exciting at least some of the electrodes to deliver energy to tissues in close proximity to the main renal artery.</p><p num="0068"> This method also positions the second radially expandable structure of the second elongated flexible catheter body in a position within the main renal artery and the second radially expandable structure. Expanding the second radially expandable structure so that at least a subset of the multiple electrodes of the renal artery engages the wall of the main renal artery, and at least a subset of electrodes of the second radially expandable structure. May include exciting and delivering energy to tissues in close proximity to the main renal artery.</p><p num="0069"> Exciting the electrodes may include multiple excitation cycles. The electrodes of the subset of excited electrodes can be changed during at least some of the excitation cycles. The energy output setting of the power supply can be changed during at least some of the excitation cycles.</p><p num="0070"> Another exemplary method of renal denervation may include positioning a radially expandable structure of an elongated flexible catheter body within the renal arteries that connect the aorta to the kidney. The radially expandable structure may include multiple electrodes. The method may also include expanding a radially expandable structure such that a subset of electrodes engage the walls of the renal arteries. Another subset of electrodes can be in the aorta. The method may also involve exciting at least some of the subset of electrodes that engage the walls of the renal arteries with a power source that is electrically connected to the electrodes.</p><p num="0071"> Another exemplary method of renal denervation may include positioning a radially expandable structure of an elongated flexible catheter body within the renal arteries that connect the aorta to the kidney. The radially expandable structure may include multiple electrodes. This method also uses a power source that is electrically connected to the electrodes to extend a radially expandable structure such that at least a subset of the electrodes engage the walls of the renal artery. Exciting at least some of the subset of electrodes that engage the wall, repositioning the radially expandable structure to a second position within the renal artery, and in the second position. Expanding the radially expandable structure so that a subset of the electrodes engages the wall of the renal artery and the different subset of electrodes are within the aorta, and in a second position, engages the wall of the renal artery. It may include exciting at least some of a subset of matching electrodes.</p><p num="0072"> The renal arteries may include ancillary renal arteries. The main renal artery can also connect the aorta to the kidney. An exemplary system for renal denervation in patients who may have a major renal artery extending between the aorta and the kidney and an auxiliary renal artery extending between the aorta and the kidney is a first balloon catheter and Includes a second balloon catheter, each with a balloon having a small profile form and a large profile form, with multiple flexible circuits extending along the outer surface of each balloon, each flexible circuit having at least one. Includes electrodes. At least one of the balloons may have a large profile morphology with an outer diameter of less than 4 mm. The system is also configured to be electrically connected to the flexible circuits of the first and second balloon catheters, as well as the electrodes of the first and second balloon catheters. It may include a power source that is configured to be excited at different time points by renal denervation energy.</p><p num="0073"> One of the balloons may have a large profile morphology with an outer diameter of 4 mm or more. The first balloon and the second balloon may have a large profile morphology of various outer diameter sizes.</p><p num="0074"> This system can be for renal denervation of patients who further have a second renal artery extending between the aorta and the second kidney. The system can further include a third balloon catheter with a small profile form and a large profile form, with multiple flexible circuits extending along the outer surface of the third balloon, each flexible circuit at least. Includes one electrode. The electrodes of the third balloon catheter can be configured to be electrically connected to a power source.</p><p num="0075"> The first balloon, the second balloon and the third balloon, when in large profile form, can define different outer diameters from each other. The outer diameter of the third balloon can be 4 mm or more in the case of a large profile form.</p><p num="0076"> An exemplary catheter may include an elongated flexible catheter body. An expandable structure can be associated with the catheter body and includes a radially expandable balloon and a plurality of flexible circuits extending along the outer surface of the balloon, each flexible circuit having at least one electrode and Includes at least one temperature sensor. The expandable structure may have an outer diameter of less than 4 mm when in the expanded form.</p><p num="0077"> The outer diameter of the expandable structure can be approximately 1 mm to 3 mm. The balloon does not have to be cannulated. At least a part of the outer surface of the balloon can be a flexible polyimide film.</p><p num="0078"> The flexible polyimide film can define the bottom insulating layer of a plurality of flexible circuits. The top surface of the bottom insulating layer of the balloon may be in direct contact with at least one conductive layer of the flexible circuit.</p><p num="0079"> Each flexible circuit may include a bottom insulating layer adjacent to the outer surface of the balloon. Also disclosed is an exemplary system for renal denervation in patients with a major renal artery extending between the aorta and the kidney and an auxiliary renal artery extending between the aorta and the kidney. The system includes a first balloon catheter and a second balloon catheter, each having a small profile form and a large profile form, with multiple flexible circuits extending along the outer surface of each balloon. Each flexible circuit comprises at least one electrode and at least one of the balloons has a large profile morphology with an outer diameter of less than 4 mm. The power supply can be electrically connected to the electrodes of the first and second balloon catheters and can be configured to excite the electrodes with renal denervation energy.</p><p num="0080"> One of the balloons may have a large profile form with an outer diameter of 4 mm or more. The first balloon and the second balloon may have a large profile morphology of various outer diameter sizes.</p><p num="0081"> This system can be intended for renal denervation of patients who further have a second renal artery extending between the aorta and the second kidney. The system can further include a third balloon catheter with a small profile form and a large profile form, with multiple flexible circuits extending along the outer surface of the third balloon, each flexible circuit at least. It contains one electrode and the electrode of the third balloon catheter is electrically connected to the power supply.</p><p num="0082"> The first balloon, the second balloon and the third balloon, when in large profile form, can define different outer diameters from each other. The outer diameter of the third balloon can be 4 mm or more when in the form of a large profile.</p><p num="0083"> An exemplary renal denervation method is to position a radially expandable structure of an elongated flexible catheter body at a location within the auxiliary renal artery that connects the aorta to the kidney, the aorta and The kidney may include positioning, which is further connected by the main renal artery. The radially expandable structure may include multiple electrodes. This method involves extending a radially expandable structure such that at least a subset of the electrodes engage the walls of the auxiliary renal arteries, and using a power source that is electrically connected to the electrodes. It may further include exciting at least a subset of the electrodes of the kidney to deliver energy to tissues in close proximity to the auxiliary renal arteries.</p><p num="0084"> This method also positions the radially expandable structure in a position within the main renal artery and the radial structure so that at least some of the electrodes engage the wall of the main renal artery. It may include dilation and exciting at least some of the electrodes to deliver energy to tissues in close proximity to the main renal artery.</p><p num="0085"> This method also positions the second radially expandable structure of the second elongated flexible catheter body in a position within the main renal artery and the second radially expandable structure. Expanding the second radially expandable structure so that at least a subset of the multiple electrodes of the renal artery engages the wall of the main renal artery, and at least a subset of electrodes of the second radially expandable structure. May include exciting and delivering energy to tissues in close proximity to the main renal artery.</p><p num="0086"> Exciting the electrodes may include multiple excitation cycles. The electrodes of the subset of excited electrodes can be changed during at least some of the excitation cycles.</p><p num="0087"> The energy output setting of the power supply can be changed during at least some of the excitation cycles. Another exemplary method of renal denervation may include positioning a radially expandable structure of an elongated flexible catheter body within the renal arteries that connect the aorta to the kidney. The radially expandable structure may include multiple electrodes. This method is also to dilate a radially expandable structure such that one subset of the electrodes engages the wall of the renal artery, while another subset of the electrodes is in the aorta. It may include exciting at least some of the subset of electrodes that engage the walls of the renal arteries with a power source that is electrically connected to the electrodes.</p><p num="0088"> Another exemplary method of renal denervation may include positioning a radially expandable structure of an elongated flexible catheter body within the renal arteries that connect the aorta to the kidney. The radially expandable structure may include multiple electrodes. This method also uses a power source that is electrically connected to the electrodes to extend a radially expandable structure such that at least a subset of the electrodes engage the walls of the renal artery. Exciting at least some of the subset of electrodes that engage the wall, repositioning the radially expandable structure to a second position within the renal artery, and in the second position. Expanding the radially expandable structure so that a subset of the electrodes engages the wall of the renal artery and the different subset of electrodes are within the aorta, and in a second position, engages the wall of the renal artery. It may include exciting at least some of a subset of matching electrodes.</p><p num="0089"> The renal arteries may include ancillary renal arteries. The main renal artery can connect the aorta to the kidney. Another exemplary system for renal denervation of patients with a major renal artery extending between the aorta and the kidney and an auxiliary renal artery extending between the aorta and the kidney is also disclosed. The system includes a first balloon catheter and a second balloon catheter, each having a small profile form and a large profile form, with multiple flexible circuits extending along the outer surface of each balloon. , Each flexible circuit comprises at least one electrode. At least one of the balloons may have a large profile morphology with an outer diameter of less than 4 mm. The system is also configured to be electrically connected to the flexible circuits of the first and second balloon catheters, as well as the electrodes of the first and second balloon catheters. It may include a power source that is configured to be excited at different time points by renal denervation energy.</p><p num="0090"> One of the balloons may have a large profile morphology with an outer diameter of 4 mm or more. The first balloon and the second balloon may have a large profile morphology of various outer diameter sizes.</p><p num="0091"> This system can be for renal denervation of patients who further have a second renal artery extending between the aorta and the second kidney. The system can further include a third balloon catheter with a small profile form and a large profile form, with multiple flexible circuits extending along the outer surface of the third balloon, each flexible circuit at least. Includes one electrode. The electrodes of the third balloon catheter can be configured to be electrically connected to a power source.</p><p num="0092"> The first balloon, the second balloon and the third balloon, when in large profile form, can define different outer diameters from each other. The outer diameter of the third balloon can be 4 mm or more in the case of a large profile form.</p><p num="0093"> Near the body passage using a device including a catheter with multiple electrodes, a high frequency energy generator, and a controller configured to couple the energy generator to the multiple electrodes and selectively excite the electrodes. An exemplary method of treating tissue is also disclosed. The method may include using the device to subject tissue near the body passage to multiple energy therapy cycles. The treatment cycle is to determine the desired voltage for a subset of electrodes to maintain a given target temperature profile in close proximity to at least a subset of electrodes and to correspond to the desired voltage determined for one of the electrodes. May include setting the output voltage of the energy generator and exciting at least some of the electrodes at the output voltage to deliver the energy to the body passages. The electrodes used to set the output voltage can be changed in subsequent treatment cycles, at least in some cases.</p><p num="0094"> The treatment cycle may further include identifying the first electrode. The first electrode can be used to set the output voltage when the voltage requirement for the first electrode is greater than zero.</p><p num="0095"> The identification of the first electrode can cycle a plurality of electrodes per treatment cycle. The treatment cycle may further include identifying at least one electrode in close proximity to the first electrode to induce an earth leakage. At least one electrode in close proximity to the first electrode to induce an earth leakage can be assumed to be unexcited during the treatment cycle.</p><p num="0096"> Multiple electrodes can include multiple bipolar electrodes, and identifying at least one electrode in close proximity to induce leakage to the first electrode will induce leakage to the anode of the first electrode. It may include identifying at least one electrode having an adjacent cathode.</p><p num="0097"> Determining the desired voltage of an electrode in a subset of electrodes can be based on the previous output voltage applied to that electrode in a subset of electrodes. Determining the desired voltage of an electrode in a subset of electrodes can also be based on the difference between the temperature of the subset of electrodes measured in close proximity to that electrode and the temperature of interest.</p><p num="0098"> Determining the desired voltage of an electrode in a subset of electrodes can be based on the temperature error at that time and the average temperature error over time for that electrode in the subset of electrodes.</p><p num="0099"> The desired voltage is:</p><p num="0100"><maths num="1"><img id="000002" he="7" wi="159" file="JP6130397B2_D0001.tif" img-format="tif" img-content="drawing" /></maths>In the equation, V is the desired voltage and V_LIs the previously calculated output voltage, T_eIs the temperature error of that electrode in a subset of the electrodes, K_L, K_PAnd K_IIs a constant and n is a time value in the range 0 to t seconds.</p><p num="0101"> The desired voltage is:</p><p num="0102"><maths num="2"><img id="000003" he="15" wi="159" file="JP6130397B2_D0001.tif" img-format="tif" img-content="drawing" /></maths>In the equation, V is the desired voltage and V_LIs the previously calculated output voltage, T_eIs the temperature error of that electrode in a subset of the electrodes, K_PAnd K_IIs a constant.</p><p num="0103"> An energy delivery device having multiple separate energy delivery sites, an energy generator, and a controller configured to couple the energy delivery site to the energy generator and selectively excite multiple energy delivery sites. Illustrative methods of treating the body passage with the equipped device are also disclosed. The method may include using the device to provide the body passage for multiple treatment cycles. At least some of the treatment cycles could be determined for multiple possible output levels for at least a subset of energy delivery sites and for one of the energy delivery sites to maintain a given parameter of treatment. Setting the actual power level of the energy generator to correspond to a different power level, and exciting at least some of the energy delivery sites at the actual power level to deliver the energy to the body passage. May include. The energy delivery sites that can be used to set the actual power level will vary from treatment cycle to treatment cycle, at least in some cases.</p><p num="0104"> Finding a plurality of possible power levels may include finding a plurality of possible excitation times. Finding a plurality of possible output levels may include finding a plurality of possible output voltages.</p><p num="0105"> Exciting at least some of the energy delivery sites at the actual power level is greater than or equal to the actual power level set during the treatment cycle. At least some of the energy delivery sites associated with possible power levels. May include exciting.</p><p num="0106"> Determining the possible output level for one of the energy delivery sites can be based on the output level applied to the energy delivery site in the previous treatment cycle.</p><p num="0107"> Determining the possible output level for one of the energy delivery sites can also be based on the characterization of the error between the actual state in close proximity to the energy delivery site and a given parameter.</p><p num="0108"> At least some of the treatment cycles may further include identifying a first energy delivery site from multiple energy delivery sites. The identification of the first energy delivery site can cycle a plurality of energy delivery sites per treatment cycle.</p><p num="0109"> If the possible output level determined for the first energy delivery site is greater than zero, then the actual output level can be set using the available output level determined for the first energy delivery site.</p><p num="0110"> At least some of the energy delivery sites in close proximity to the first energy delivery site can be assumed to be unexcited during the treatment cycle. Illustrative methods of inducing desired therapeutic changes in tissue using an electrosurgical system are also disclosed. The method may include electrically connecting multiple electrodes of the system to multiple tissue zones and heating the tissue in multiple heating cycles. Each heating cycle can have an associated selected zone to determine the desired potential for the selected zone according to the desired properties and to determine the appropriate set of electrodes for the application of the desired potential. It may include pumping a selected set of electrodes at a desired potential. This method also involves monitoring the temperature signals from those zones, exchanging selected zones of the zones, and identifying the desired changes and sets of electrodes in response to the temperature signals. May include simultaneously inducing the desired therapeutic change in the tissue of the zone.</p><p num="0111"> Tissue can be placed near the body passage. The plurality of electrodes can be coupled to the zone by expanding the expandable body in the passage. The electrode may include a bipolar electrode supported by an expandable body. The desired potential may include a bipolar potential.</p><p num="0112"> An exemplary system for treating tissue near the body passages is a catheter with multiple electrodes, a high frequency energy generator, and an energy generator coupled to multiple electrodes and selective electrodes during multiple energy treatment cycles. Includes a controller, which is configured to excite in. During the treatment cycle, the system finds the desired voltage for a subset of electrodes to maintain a given target temperature in close proximity to at least a subset of electrodes and corresponds to the desired voltage found for one of the electrodes. The output voltage of the energy generator can be set so that at least some of the electrodes are excited at the output voltage and the energy is delivered in close proximity to the body passages, and the system can be configured to deliver energy. In this case, the electrodes used to set the output voltage are configured to change for each treatment cycle.</p><p num="0113"> An exemplary energy generator may include a high frequency energy generator and a controller. The controller can be configured to couple the energy generator to a catheter with multiple electrodes. The controller finds the desired voltage for the subset of electrodes so that it maintains a given target temperature in close proximity to at least the subset of electrodes, and the energy generator to correspond to the desired voltage found for one of the electrodes. To selectively excite electrodes during multiple energy treatment cycles, including setting the output voltage of the electrodes and exciting at least some of the electrodes at the set output voltage and delivering energy to the body passages. Can be configured. The controller can be configured to change the electrodes used to set the output voltage for each treatment cycle, at least in some cases.</p><p num="0114"> An energy delivery device having multiple separate energy delivery sites, an energy generator, and a controller configured to couple the energy delivery site to the energy generator and selectively excite multiple energy delivery sites. Illustrative methods of treating the body passage with the equipped device are also disclosed. The method may include using the device to provide the body passage for multiple treatment cycles. At least some of the treatment cycles select one of the energy delivery sites as the main energy delivery site and the energy delivery sites that are not in close proximity to the main energy delivery site to induce energy leakage. It may include identifying at least a subset and exciting at least some of the subset of energy delivery sites. The energy delivery site that can be selected as the primary energy delivery site varies from treatment cycle to treatment cycle, at least in some cases.</p><p num="0115"> Tissues near the body passage are treated with a device having multiple electrodes, an energy generator, and a controller configured to couple the energy generator to the electrodes and selectively excite the electrodes. An exemplary method is also disclosed. The method may include using the device to subject tissue near the body passage to multiple energy therapy cycles. The treatment cycle corresponds to the desired power setting for a subset of electrodes and the desired power setting for one of the electrodes so as to maintain a given temperature profile of interest in close proximity to at least the subset of electrodes. It may include setting the actual power setting of the energy generator to do so, and exciting at least some of the electrodes in the actual power setting to deliver the energy to the body passage. The electrodes that can be used to set the actual power settings will vary in subsequent treatment cycles, at least in some cases.</p><p num="0116"> Illustrative methods of delivering energy-based therapies to tissues close to blood vessels are also disclosed. This method is to position a radially expandable structure of an elongated flexible catheter body at a position within the vessel, in which a plurality of electrodes are positioned in a radially expandable structure. And to extend a radially expandable structure to engage the walls of the blood vessel so that at least a subset of the electrodes establish multiple electrical circuits, each electrical circuit being among the electrodes. Expanding, including one and part of the tissue within the treatment zone, exciting multiple circuits in chronological order with the power supply, and controlling the delivery of energy with the processor coupled to the power supply. Such control is to confirm the presence of the electrical circuit, selectively excite the electrodes during its time series, and the energy delivered to the treatment zone to the internal tissue at the desired temperature. It may include controlling, including adjusting one or more parameters of the electrical circuit to heat to a temperature within the range, thereby inducing a tissue remodeling reaction.</p><p num="0117"> Electrodes can be selectively excited by identifying an appropriate group of electrodes and at the same time exciting the group of electrodes during that time series and by repeatedly cycling through that time series. The group can be determined in response to multiple temperature signals associated with parts of the tissue within the treatment zone, thereby changing the group over the cycle.</p><p num="0118"> The electrodes can include unipolar electrodes that are positioned on the balloon and are included in a plurality of bending circuits, each bending circuit comprising at least one of the unipolar electrodes. The bend circuit may further include a temperature sensitive structure in close proximity to at least one of the unipolar electrodes, the temperature sensitive structure being electrically connected to the processor to provide feedback.</p><p num="0119"> The balloon can be inflated with an expansion pressure of about 5 atmospheres or less. The expanded diameter of the expandable structure can be from about 2 mm to about 10 mm. For example, the expanded diameter of the expandable structure can be about 3 mm or less.</p><p num="0120"> Illustrative methods of delivering energy-based therapies to tissues close to blood vessels are also disclosed. The method is to position the expandable structure of the elongated catheter at a location within the blood vessel, the expandable structure comprising multiple electrodes, at least some of the multiple electrodes being expandable. Longitudinally spaced along, the electrodes are electrically connected to the power supply, extending the positioning and expandable structure so that at least some of the electrodes are in contact with the tissue. To verify which of the multiple electrodes is in contact with the tissue and to select at least one of the electrodes in contact with the tissue using a processor coupled to the power supply. The electricity associated with at least some of the electrodes so that the energy delivered to the treatment zone heats the internal tissue, which is to specifically excite and control the delivery of energy using a processor. It may include adjusting or controlling one or more parameters of energy therapy based on monitoring of feedback from the circuit.</p><p num="0121"> To determine if one of the electrodes is in contact with tissue is to measure the characteristics of the electrical circuit associated with the electrode and to determine if the measured characteristics meet the criteria. May include.</p><p num="0122"> Selective excitation of at least one electrode may include exciting electrodes that meet the criteria and not exciting electrodes that do not meet the criteria. Measuring the characteristics of an electrical circuit may include measuring the resistance associated with the electrical circuit.</p><p num="0123"> Selective excitation of at least one electrode may include exciting only the electrode associated with the measured resistance within a predetermined range. Positioning an expandable structure that includes a plurality of electrodes may include positioning an expandable structure that includes a plurality of unipolar electrodes.</p><p num="0124"> Positioning an expandable structure includes positioning an expandable structure that includes a plurality of unipolar electrodes and common electrodes. Determining whether the measured characteristic meets the criteria is determining whether the measured characteristic associated with the first unipolar electrode meets the first criterion and determining whether the second unipolar electrode meets the criteria. It may include determining whether the measured property associated with meets the second criterion. The first and second criteria can be different.</p><p num="0125"> Determining whether the measured properties meet the criteria is whether the measured properties associated with the first unipolar electrode and the measured properties associated with the second unipolar electrode meet a single criterion. It may include determining whether or not.</p><p num="0126"> Illustrative systems for delivering energy-based therapies to tissues close to blood vessels are also disclosed. The system includes an elongated catheter containing an expandable structure at or near its distal end. The expandable structure can include multiple electrodes, at least some of which are longitudinally spaced along the expandable structure. The system also measures the characteristics of power supplies that are electrically connected to multiple electrodes and the electrical circuits associated with at least some of the electrodes and whether the measured characteristics meet the criteria. By determination, it may include a processor configured to verify whether at least some of the electrodes are in contact with the tissue. The processor can be configured to excite at least one of the electrodes, verifying that at least one of the electrodes is in contact with the tissue. The processor so that the energy delivered to the treatment zone heats the internal tissue to a temperature of about 55 ° C to about 75 ° C, while the tissue lined up in the treatment zone heats to less than about 45 ° C. It can be configured to control the delivery of energy based on the monitoring of feedback from at least some of the electrical circuits and to regulate one or more parameters of energy therapy.</p><p num="0127"> The plurality of electrodes having an expandable structure may be a plurality of unipolar electrodes. The expandable structure may further include at least one common electrode. The elongated catheter may further include at least one common electrode.</p><p num="0128"> The system may further include at least one common electrode pad. Illustrative methods of delivering energy-based therapies to tissues close to blood vessels are also disclosed. The method is to use an elongated catheter to position the expandable structure of the energy-based treatment system into a position within the blood vessel, where the expandable structure is at or to the distal end of the catheter. It may include positioning, which is positioned in the vicinity of the portion and includes a plurality of unipolar electrodes. The energy-based treatment system can further include a common electrode and a power source, the power source being electrically connected to a plurality of unipolar electrodes. This method is also to extend the expandable structure so that at least some of the electrodes are in contact with the tissue and to use a processor to measure the characteristics of the electrical circuit. Each electrical circuit was identified by measuring and identifying a subset of unipolar electrodes for excitation, associated with one of multiple unipolar and common electrodes. A subset of electrodes may include identifying, having measured properties within the desired range, and simultaneously exciting one or more of the identified unipolar electrodes for excitation. Good.</p><p num="0129"> Common electrodes can be associated with expandable structures. Another exemplary method of delivering energy-based treatment to tissues close to the blood vessel is to position the expandable structure of the elongated catheter into a position within the blood vessel, where the expandable structure is far from the catheter. Positioned at or near the distal end, it contains multiple unipolar electrodes, at least some of the unipolar electrodes are longitudinally spaced along an expandable structure and multiple electrodes. Is electrically connected to a power source, positioning and expanding the expandable structure so that at least some of the electrodes are in contact with the tissue, and selectively selecting a subset of the electrodes. At least of the electrodes so that the energy delivered to the treatment zone heats the internal tissue to a temperature within the desired range by exciting to and controlling the delivery of energy using a processor. It may include adjusting or controlling one or more parameters of energy therapy based on the monitoring of feedback from the electrical circuits associated with some.</p><p num="0130"> The method may also involve using a processor to identify a subset of electrodes for excitation prior to selectively exciting a subset of electrodes. Identifying a subset of electrodes may include measuring the characteristics of the electrical circuit associated with each of the plurality of electrodes.</p><p num="0131"> Identifying a subset of electrodes may further include using a processor to compare the measured properties and identify a subset for excitation. Identifying a subset for excitation may include identifying a group of electrodes with substantially similar measured properties.</p><p num="0132"> Identifying a subset of electrodes may further include determining whether the measured properties associated with each of the plurality of electrodes meet certain requirements. Determining whether the measured properties associated with each of the plurality of electrodes meets a predetermined requirement determines whether the measured properties associated with each of the plurality of electrodes fall within a predetermined range. It may include that.</p><p num="0133"> Determining whether the measured properties associated with each of the plurality of electrodes fall within a predetermined range may include using the same predetermined range for each of the electrodes.</p><p num="0134"> Determining whether the measured properties associated with each of the plurality of electrodes fall within a predetermined range may include using different predetermined ranges for at least some of the electrodes.</p><p num="0135"> Using a device that includes a catheter with multiple unipolar electrodes, a high frequency energy generator, and a controller configured to couple the energy generator to the unipolar electrode and selectively excite the unipolar electrode. An exemplary method of treating tissue near the body passage is also disclosed. The method may include using the device to subject tissue near the body passage to multiple energy therapy cycles. The treatment cycle is to determine the desired voltage of a subset of unipolar electrodes so as to obtain a given target temperature profile in close proximity to at least a subset of unipolar electrodes, and the desired voltage determined for one of the unipolar electrodes. It may include setting the output voltage of the energy generator to correspond to the voltage and exciting at least one of the unipolar electrodes at the output voltage to deliver the energy to the body passage. .. The unipolar electrodes that can be used to set the output voltage will vary in subsequent treatment cycles, at least in some cases.</p><p num="0136"> The treatment cycle can further include identifying the first unipolar electrode, where the first unipolar electrode is the output voltage if the voltage requirement for the first unipolar electrode is greater than zero. Is used to set.</p><p num="0137"> The identification of the first unipolar electrode can cycle a plurality of unipolar electrodes per treatment cycle. The treatment cycle may further comprise identifying at least one unipolar electrode associated with electrical circuit characteristics that are substantially different from the electrical circuit characteristics associated with the first unipolar electrode. At least one unipolar electrode associated with substantially different electrical circuit characteristics can be assumed to be unexcited during the treatment cycle.</p><p num="0138"> The characteristic of the electrical circuit used for identification can be an impedance measurement. Energy delivery devices with multiple separate unipolar energy delivery sites, common electrodes, energy generators, and unipolar energy delivery sites are coupled to the energy generator and selectively excite multiple unipolar energy delivery sites. Also disclosed is an exemplary method of treating a body passage using a device comprising a controller, configured as described above. The method may include using the device to provide the body passage for multiple treatment cycles. At least some of the treatment cycles seek multiple possible output levels for at least a subset of unipolar energy delivery sites to maintain a given parameter of treatment and one of the unipolar energy delivery sites. Setting the actual output level of the energy generator to correspond to the possible output level determined with respect to, and exciting at least some of the unipolar energy delivery sites at the actual output level to transfer energy through the body passage. May include delivery to. The unipolar energy delivery site used to set the actual power level can be varied from treatment cycle to treatment cycle, at least in some cases.</p><p num="0139"> Also disclosed are methods of treating patients with congestive heart failure. The method is to position an expandable balloon within the patient's renal artery, where the expandable balloon comprises multiple electrode assemblies, at least some of which are pairs of at least two bipolar electrodes. The two bipolar electrode pairs are offset longitudinally and circumferentially from each other, and at least some of the bipolar electrode pairs are electrically connected to the wall of the renal artery. At least of a pair of bipolar electrodes to dilate the balloon within the renal artery and to therapeutically alter at least one nerve adjacent to the renal artery to treat congestive heart failure in the patient. It may include exciting some.</p><p num="0140"> Exciting at least some of the pairs of bipolar electrodes can include adjusting the energy output of the pairs of bipolar electrodes using multiple temperature sensors, where each sensor is of the pair of bipolar electrodes. Positioned between one.</p><p num="0141"> Positioning the expandable balloon into the patient's renal artery is to position the expandable balloon, with the pair of bipolar electrodes in the electrode assembly offset longitudinally from the pair of bipolar electrodes adjacent in the circumferential direction. It may include positioning.</p><p num="0142"> Another exemplary method of treating a patient with congestive heart failure is to position an expandable device containing an array of energy delivery structures within the patient's renal arteries, and at least some of the energy delivery structures. An energy delivery structure that dilates an expandable device close to the wall of the renal artery and therapeutically alters at least one nerve close to the renal artery to treat a patient's congestive heart failure. It may include exciting at least some of them.</p><p num="0143"> The energy delivery structure can be excited for less than 10 minutes during treatment, or the energy delivery structure can be excited for less than 5 minutes during treatment, or the energy delivery structure can be excited for less than 1 minute during treatment. Can be excited over less than.</p><p num="0144"> The energy delivery structure can be excited by an expandable device at only one location within the patient's renal arteries during treatment. An exemplary method of treating congestive heart failure is to treat the patient's renal tissue so that the treatment is effective in reducing norepinephrine levels in the patient by more than 50%. It may include subjecting to high frequency energy for less than 10 minutes.</p><p num="0145"> Treatment can be effective in reducing norepinephrine levels in close proximity to renal tissue by more than 50%. Applying renal tissue to high frequency energy for less than 10 minutes may include exposing renal tissue to high frequency energy for less than 5 minutes.</p><p num="0146"> Applying renal tissue to high frequency energy for less than 5 minutes involves exposing renal tissue to high frequency energy for less than 1 minute. Exposing the renal tissue to high frequency energy may include raising the temperature in close proximity to the renal tissue to a temperature in the range of approximately 50 ° C to 80 ° C.</p><p num="0147"> Raising the temperature to a temperature in the range of approximately 50 ° C to 80 ° C may include raising the temperature to a temperature in the range of approximately 55 ° C to 75 ° C. Raising the temperature to a temperature in the range of approximately 55 ° C to 75 ° C may include raising the temperature to a target temperature of approximately 68 ° C.</p><p num="0148"> Raising the temperature to a target temperature of 68 ° C. may further include raising the temperature so that the rate of temperature change gradually decreases as the temperature approaches the target temperature. Increasing the temperature so that the rate of temperature change gradually decreases as the temperature approaches the target temperature means increasing the temperature so that the rate of temperature change decreases linearly as the temperature approaches the target temperature. Further may be included.</p><p num="0149"> Exposing the renal tissue to high-frequency energy means inserting a catheter containing multiple electrodes into the renal artery and selectively exciting the multiple electrodes so that the electrodes are positioned close to the renal tissue. And may be included.</p><p num="0150"> Congestive heart failure can be systolic congestive heart failure. Congestive heart failure can be diastolic congestive heart failure. An exemplary method of renal denervation treatment may include delivering RF energy therapy to tissues in close proximity to the renal arteries using the catheter assembly of a renal denervation catheter system. The denervation system may include an RF energy generator that is coupled to the catheter assembly by a controller. This method also uses a catheter assembly to apply a neuroactive stimulus to tissue in close proximity to the renal arteries, and a catheter assembly to assess the stimulated neuroactive response of the tissue and the assessed neuroactivity. It may include finding the parameters of RF energy therapy based on.</p><p num="0151"> The method may also include outputting data related to the evaluated neural activity. Outputting the data may include outputting whether or not a sufficient decrease in neural activity has occurred.</p><p num="0152"> Assessing nerve activity may include adopting at least a first nerve activity measurement and a second nerve activity measurement. Adopting a first nerve activity measure may include adopting a first nerve activity measure and establishing a reference nerve activity measure before initiating delivery of RF energy therapy. Adopting a second neuroactivity measure may include adopting a second neuroactivity measure after initiating delivery of RF energy therapy. The method may also include determining whether the neural activity has changed from a reference value.</p><p num="0153"> Determining whether or not a change in nerve activity has changed from a reference value may include determining whether the change in nerve activity is a threshold value, exceeds the threshold value, or falls below the threshold value. The method may also include terminating RF energy therapy when the change in neural activity is or exceeds a threshold.</p><p num="0154"> Sensing the stimulated neuroactive response may include periodically measuring the stimulated neuroactive response during RF energy therapy. Applying a neuroactive stimulus may include exciting at least one electrode in the catheter assembly. Assessing the stimulated neuroactive response may include monitoring the neural response signal using a second electrode in the catheter assembly.</p><p num="0155"> Delivering RF energy therapy may include delivering RF energy to tissues using at least one electrode and a second electrode. Delivering RF energy therapy may include using a catheter assembly with at least one electrode at the proximal end of the expandable device and a second electrode at the distal end of the device. ..</p><p num="0156"> Delivering RF energy therapy may include using a catheter assembly having at least one electrode and at least one second electrode that are offset laterally and circumferentially with respect to each other.</p><p num="0157"> Delivering RF energy therapy may include the use of multiple electrodes other than at least one electrode and a second electrode. Monitoring the nerve reaction signal includes measuring the amplitude of the nerve reaction signal, measuring the time delay between the nerve stimulation signal and the nerve reaction signal, and measuring the division amplitude of the nerve reaction signal. May contain at least one of.</p><p num="0158"> The method also measures at least one of the amplitude of the neural response signal, the pulse width of the neural response signal, the gradient or change in gradient of the neural response signal, the velocity of the neural response signal, or the time delay of the neural response signal. It may include that.</p><p num="0159"> The method may also include comparing the measured value with a reference measurement of a previous neural response signal. Determining at least one parameter for RF energy therapy may include adjusting at least one parameter based on the evaluated neural activity.</p><p num="0160"> Adjusting at least one parameter may include adjusting the temperature profile of RF energy therapy. Adjusting at least one parameter may include adjusting the length of time at the target temperature of the target temperature profile.</p><p num="0161"> Adjusting at least one parameter may include adjusting the voltage setting of the RF energy generator. Adjusting at least one parameter may include adjusting the voltage setting while keeping the target temperature constant.</p><p num="0162"> The method may also include terminating RF energy therapy after a predetermined time if the assessed neural activity does not fall below the threshold level. The method may also include repositioning the catheter assembly and delivering a second RF energy therapy to a second tissue portion close to the renal artery.</p><p num="0163"> Determining the parameters of RF energy therapy may further include determining the parameters of RF energy therapy based on the assessed neural activity and tissue temperature measurements. Another exemplary method of renal denervation is to apply a first neural activation stimulus to the tissue adjacent to the catheter assembly of the renal denervation system and to use the catheter assembly to apply the first stimulated neural activity of the tissue. Measuring the response, using the catheter assembly to deliver energy therapy to tissues close to the renal arteries, and using the catheter assembly to measure the second neural activity response of the nerve tissue, and the first It may include determining the parameters of energy therapy by comparing the measured nerve activity with the second measured nerve activity.</p><p num="0164"> Comparing the first measured neural activity and the second measured neural activity is associated with the signal amplitudes of the first and second neural activity, the first neural activity and the second neural activity. Time delay, pulse width of first and second nerve activity, rate of first and second nerve activity, and gradient or gradient of first and second nerve activity May include comparing at least one of the changes in.</p><p num="0165"> Another exemplary denervation method is to use an implantable device to deliver energy therapy to tissues close to the lumen of the body, and to use an implantable device to assess the neural activity of the tissue. The assessed neural activity may be used to at least partially determine at least one parameter of energy therapy.</p><p num="0166"> Another exemplary method of renal denervation is positioning the catheter-based assembly in the renal artery in close proximity to the body tissue and using the catheter-based assembly to deliver energy therapy to the body tissue. To assess whether the level of nerve activity in body tissue has decreased during or after energy treatment, and to remove the catheter-based assembly from the renal arteries after the level of nerve activity has decreased sufficiently. It may be included.</p><p num="0167"> Treatment can be effective in reducing norepinephrine levels in patients by more than 50%. Treatment can be effective in reducing norepinephrine levels in body tissues close to the renal arteries by more than 50%.</p><p num="0168"> Treatment can be effective in reducing a patient's systolic blood pressure by at least 5%, or at least 10%, or at least 20%. Treatment can be effective in reducing a patient's diastolic blood pressure by at least 5%, or at least 10%, or at least 20%.</p><p num="0169"> An exemplary renal denervation treatment system is an elongated catheter that includes an elongated catheter that includes an expandable structure at or near the distal end of the catheter. The expandable structure may include a plurality of electrodes. The power supply can be electrically connected to multiple electrodes. The system also excites at least a subset of electrodes at levels of renal denervation energy, excites one or more of the electrodes at levels of neuroactive stimulation, and uses one or more of the electrodes to produce a neuroactive response. It may include a processor that is configured for monitoring.</p><p num="0170"> The nerve activation stimulation level can be a voltage in the range of about 0.1 V to about 5 V applied over about 1 second or less. For example, the nerve activation stimulation level can be about 0.5 V applied over about 0.5 ms.</p><p num="0171"> The above overview of some embodiments is not intended to describe the respective disclosed embodiments or all embodiments of the present disclosure. The drawings and detailed description below exemplify these embodiments more specifically.</p>

<figref num="1A">It is a simplified diagram of an exemplary system for remodeling an organization.</figref><figref num="1B">FIG. 3 is a perspective view of an exemplary expandable device of a catheter.</figref><figref num="1C">It is a top view of the expanded form of the expandable device of FIG. 1B.</figref><figref num="1D">FIG. 3 is a perspective view of an exemplary expandable device.</figref><figref num="1E">FIG. 3 is a perspective view of an exemplary expandable device.</figref><figref num="1F">FIG. 3 is a perspective view of an exemplary expandable device.</figref><figref num="2A">It is a top view of an exemplary electrode assembly.</figref><figref num="2B">FIG. 2A is a partial cross-sectional view AA of FIG. 2A.</figref><figref num="2C">FIG. 2 is a partial cross-sectional view BB of FIG. 2A.</figref><figref num="3A">It is a top view of various exemplary electrode assemblies having a plurality of electrode pads.</figref><figref num="3B">It is a top view of various exemplary electrode assemblies having a plurality of electrode pads.</figref><figref num="3C">It is a top view of various exemplary electrode assemblies having a plurality of electrode pads.</figref><figref num="3D">It is a top view of various exemplary electrode assemblies having a plurality of electrode pads.</figref><figref num="4A">FIG. 3 is a top view of various exemplary electrode assemblies with a single distal electrode pad.</figref><figref num="4B">FIG. 3 is a top view of various exemplary electrode assemblies with a single distal electrode pad.</figref><figref num="4C">FIG. 3 is a top view of various exemplary electrode assemblies with a single distal electrode pad.</figref><figref num="5A">FIG. 3 is a top view of various exemplary electrode assemblies with a single proximal electrode pad.</figref><figref num="5B">FIG. 3 is a top view of various exemplary electrode assemblies with a single proximal electrode pad.</figref><figref num="5C">FIG. 3 is a top view of various exemplary electrode assemblies with a single proximal electrode pad.</figref><figref num="5D">FIG. 3 is a top view of various exemplary electrode assemblies with a single proximal electrode pad.</figref><figref num="5E">FIG. 3 is a top view of various exemplary electrode assemblies with a single proximal electrode pad.</figref><figref num="5F">FIG. 3 is a top view of various exemplary electrode assemblies with a single proximal electrode pad.</figref><figref num="5G">It is a top view of various exemplary unipolar electrode assemblies.</figref><figref num="5H">It is a top view of various exemplary unipolar electrode assemblies.</figref><figref num="5I">It is a top view of various exemplary unipolar electrode assemblies.</figref><figref num="6">FIG. 6 is a cross-sectional view of the system of FIG. 1A used to remodel the body passage.</figref><figref num="7">It is a figure which shows various non-limiting examples of a temperature profile.</figref><figref num="8">It is a figure which shows various non-limiting examples of a temperature profile.</figref><figref num="9">It is a figure which shows various non-limiting examples of a temperature profile.</figref><figref num="10">It is a figure which shows various non-limiting examples of a temperature profile.</figref><figref num="11">It is a figure which shows the experimental result by comparison of the specific non-limiting example of a temperature profile.</figref><figref num="12">It is a figure which shows the experimental result by comparison of the specific non-limiting example of a temperature profile.</figref><figref num="13">It is a figure which shows one Embodiment of a control loop.</figref><figref num="13A">It is a figure which shows another embodiment of a control loop.</figref><figref num="14">It is a figure which shows one Embodiment of a control loop.</figref><figref num="15">It is a figure which shows one non-limiting example of the temperature change over time of an electrode.</figref><figref num="16">FIG. 5 shows one non-limiting example of various properties associated with one electrode during treatment.</figref><figref num="17">FIG. 5 shows one non-limiting example of various properties associated with one electrode during treatment.</figref><figref num="18">FIG. 5 shows one non-limiting example of various properties associated with one electrode during treatment.</figref><figref num="19">FIG. 5 shows one non-limiting example of various properties associated with one electrode during treatment.</figref><figref num="20">FIG. 5 shows one non-limiting example of various properties associated with one electrode during treatment.</figref><figref num="21">FIG. 5 shows one non-limiting example of various properties associated with one electrode during treatment.</figref><figref num="22">FIG. 5 shows one non-limiting example of various properties associated with one electrode during treatment.</figref><figref num="23">FIG. 5 shows one non-limiting example of various properties associated with one electrode during treatment.</figref><figref num="24A">FIG. 5 shows an exemplary screenshot from one embodiment of treatment.</figref><figref num="24B">FIG. 5 shows an exemplary screenshot from one embodiment of treatment.</figref><figref num="24C">FIG. 5 shows an exemplary screenshot from one embodiment of treatment.</figref><figref num="24D">FIG. 5 shows an exemplary screenshot from one embodiment of treatment.</figref><figref num="24E">FIG. 5 shows an exemplary screenshot from one embodiment of treatment.</figref><figref num="24F">FIG. 5 shows an exemplary screenshot from one embodiment of treatment.</figref><figref num="25">It is a figure which shows one experiment which evaluates the efficacy and safety of the exemplary system of renal denervation.</figref><figref num="26">It is a figure which shows one experiment which evaluates the efficacy and safety of the exemplary system of renal denervation.</figref><figref num="27">It is a figure which shows one experiment which evaluates the efficacy and safety of the exemplary system of renal denervation.</figref><figref num="28">It is a figure which shows one experiment which evaluates the efficacy and safety of the exemplary system of renal denervation.</figref><figref num="29">It is a figure which shows one experiment which evaluates the efficacy and safety of the exemplary system of renal denervation.</figref><figref num="30">It is a figure which shows one experiment which evaluates the efficacy and safety of the exemplary system of renal denervation.</figref><figref num="31">FIG. 5 is a schematic representation of an exemplary treatment zone associated with two electrodes.</figref><figref num="32">FIG. 5 is a schematic representation of an exemplary treatment zone associated with two electrodes.</figref><figref num="33">FIG. 5 shows an expandable balloon containing an array of electrodes positioned within the body passage.</figref><figref num="34">FIG. 5 shows an experiment that specifically evaluates the extent of treatment zones formed by electrosurgical procedures in tissues close to the renal arteries.</figref><figref num="35">FIG. 5 shows an experiment that specifically evaluates the extent of treatment zones formed by electrosurgical procedures in tissues close to the renal arteries.</figref><figref num="36">FIG. 5 shows an experiment that specifically evaluates the extent of treatment zones formed by electrosurgical procedures in tissues close to the renal arteries.</figref><figref num="37">FIG. 5 shows an experiment that specifically evaluates the extent of treatment zones formed by electrosurgical procedures in tissues close to the renal arteries.</figref><figref num="38">FIG. 5 shows an experiment that specifically evaluates the extent of treatment zones formed by electrosurgical procedures in tissues close to the renal arteries.</figref><figref num="39">It is a figure which shows the example of the overlapping treatment zone in the course of RF treatment.</figref><figref num="40">It is a figure which shows the example of the overlapping treatment zone in the course of RF treatment .</figref><figref num="41">It is a figure which shows the example of the overlapping treatment zone in the course of RF treatment.</figref><figref num="42">FIG. 5 is a schematic representation of a catheter expandable device (s) including electrodes that stimulate and measure neural signals.</figref><figref num="43">FIG. 5 is a schematic representation of a catheter expandable device (s) including electrodes that stimulate and measure neural signals.</figref><figref num="44">It is a figure which shows the nerve reaction signal before treatment.</figref><figref num="45">It is a figure which shows the neural reaction signal after receiving at least some treatments.</figref><figref num="46">It is a figure which shows one Embodiment of the expandable balloon.</figref><figref num="47">It is a figure which shows the embodiment of the method of renal denervation treatment.</figref><figref num="48">It is a figure which shows the embodiment of the method of renal denervation treatment.</figref><figref num="49">It is a figure which shows the embodiment of the method of renal denervation treatment.</figref><figref num="50A">It is a figure which shows the embodiment of the method of renal denervation treatment.</figref><figref num="50B">It is a figure which shows the embodiment of the method of renal denervation treatment.</figref>

With respect to the following defined terms, these definitions shall apply unless different definitions are given in the claims or elsewhere herein. All numbers are assumed herein to be modified by the term "about", whether explicitly stated or not. The term "about" generally refers to a range of numbers that one of ordinary skill in the art would consider to be equivalent (ie, have the same function or result) to the values described. In many cases, the term "about" may include numbers that are rounded to the nearest significant number.

The description of the numerical range by the end points includes all the numbers within the range (for example, 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4 and 5). As used herein and in the appended claims, the singular form (a, an and the) includes multiple referents unless otherwise explicitly indicated by its content. .. As used herein and in the appended claims, the term "or" is generally used to include "and / or" unless otherwise expressly indicated by its content.

In addition, in this specification, the reference to "one embodiment", "several embodiments", "another embodiment", etc. is that the described embodiment is one or more specific feature parts. Indicates that the structure and / or features may be included. However, such references do not necessarily mean that all embodiments include specific features, structures and / or features. Further, where a particular feature, structure and / or feature is described in connection with one embodiment, such feature, structure and / or feature is explicitly stated unless conflicting content is clearly stated. It should be understood that it can also be used in connection with other embodiments, whether or not it is described in.

The following detailed description should be read with reference to drawings in which similar elements of different drawings are labeled the same. Drawings that are not necessarily on a constant scale show exemplary embodiments and are not intended to limit the scope of the invention.

Physicians use catheters to gain access to the body's internal tissues, especially in or around the body's lumen, such as blood vessels, and to perform treatment by altering the body's internal tissues. For example, balloon angioplasty and other catheters are often used to open arteries that are narrowed due to atherosclerosis.

Catheter can be used to perform renal denervation by RF energy therapy in patients with refractory hypertension. This is a relatively new treatment and has proven to be clinically effective in the treatment of hypertension. In that procedure, RF energy is applied to the walls of the renal arteries to reduce the overactivity of the sympathetic nervous system (often responsible for chronic hypertension) adjacent to the renal arteries. Although this procedure has been shown to be successful in some cases, it is also associated with considerable pain, and existing treatments are relatively difficult and time consuming for physicians to perform accurately. obtain.

Another disorder that affects many patients is congestive heart failure (CHF). CHF is a disease that occurs when the heart is damaged and blood flow to the body's organs is reduced. When blood flow is sufficiently reduced, kidney function changes, resulting in stasis of fluid, abnormal secretion of hormones, and increased constriction of blood vessels. These results increase the work of the heart and further reduce the ability of the heart to pump blood to the kidneys and circulatory system.

The gradual decrease in renal perfusion is thought to be the main cause other than the heart that sustains the downward spiral of CHF. For example, as the heart struggles to pump blood, cardiac output is maintained or reduced, and the kidneys save fluid and electrolytes to maintain the heart's stroke volume. The resulting increase in pressure puts additional overload on the myocardium, which requires the myocardium to work more to pump against higher pressures. The already damaged myocardium is in this case further stressed and damaged by the increased pressure. In addition to exacerbating heart failure, renal failure can lead to a further decline in downward spiral and renal function. For example, in the case of anterior flow heart failure (systolic heart failure) described above, the kidney becomes ischemic. In the case of posterior heart failure (diastolic heart failure), the kidney becomes congested with respect to renal venous hypertension. Therefore, the kidneys can contribute to exacerbating their own disorders.

Kidney function is in three broad categories: filtering blood and excreting waste products produced by the body's metabolism, regulating salt, water, electrolytes and acid-base balance, and essential. It can be summarized as secreting hormones to maintain blood flow in the organs. If the kidneys do not function properly, patients suffer from water retention, decreased urine flow, and accumulation of unwanted toxins in the blood and body. These conditions are thought to occur as a result of decreased renal function or renal failure and increase the work of the heart. In patients with CHF, renal failure further exacerbates the heart due to fluid retention and accumulation of hematological toxins due to impaired kidney function. The resulting hypertension also has a dramatic effect on the progression of cerebrovascular disease and stroke.

The autonomic nervous system is a network of nerves that affects almost all organs and physiology to a variable degree. Generally, this system is composed of sympathetic and parasympathetic nerves. For example, the sympathetic nerve to the kidney crosses the sympathetic nerve chain along the spinal column, synapses within the ganglion or peritoneal ganglion of the sympathetic nerve chain (synapse), and then the ganglion within the "renal nerve". It proceeds to innervate the kidney via posterior fibers. Within the renal nerves that travel along the hilum (arteries and to some extent veins) are the postganglionic sympathetic nerves and the afferent nerves from the kidneys. The afferent nerves from the kidney travel within the dorsal root (if it is a pain fiber), into the ventral root if it is a sensory fiber, then into the spinal cord, and finally into a specialized area of the brain. To reach. Afferent nerves, baroreceptors and chemoreceptors send information from the kidney back through the brain to the sympathetic nervous system, and their ablation or inhibition is seen in renal nerve ablation or denervation, or blood pressure after partial rupture. Contribute at least partially to improvement. Since the baroreceptor response at the carotid sinus level is mediated by the renal afferent nerves, it has also been suggested that loss of the renal afferent nerve response slows the carotid baroreceptor response to changes in arterial blood pressure. And some have been experimentally proven (American J. Physiology and Renal Physiology 279: F491-F501,2000 (this disclosure is incorporated herein by reference)).

In animal models, heart failure disease has been demonstrated to result in abnormally high renal sympathetic activity. Increased renal sympathetic activity leads to reduced removal of water and sodium from the body and increased renin secretion that stimulates aldosterone secretion from the adrenal glands. Increased renin secretion can lead to elevated levels of angiotensin II, which leads to vasoconstriction of the blood vessels that supply the kidneys, and systemic vasoconstriction, all of which reduce renal blood flow and hypertension. Leads to. Decreased renal sympathetic activity, for example due to denervation, can stave off these processes and has, in fact, been clinically demonstrated.

Similar to hypertension, sympathetic overdrive contributes to the development and progression of CHF. The overflow of norepinephrine from the kidney and heart into venous plasma is even higher in CHF patients compared to patients with basic hypertension. Chronic sympathetic stimulation causes the heart to overload directly because the heart increases its output, and indirectly because the contracted vasculature shows higher resistance to pumping by the heart. To work. The strain on the heart to pump more blood increases the weight of the left ventricle and results in cardiac remodeling. As a result of cardiac remodeling, the sympathetic nerve activity of the heart becomes heterogeneous, which further disrupts the synchrony of cardiac contractions. Therefore, remodeling initially helps increase the pumping of the heart, but ultimately reduces the efficiency of the heart. Decreased left ventricular function further activates the sympathetic nervous system and the renin-angiotensin-aldosterone system, promoting a vicious cycle leading from hypertension to CHF.

Embodiments of the present disclosure often relate to power generation and control devices for the treatment of target tissue to achieve a therapeutic effect. In some embodiments, the tissue of interest is a tissue that includes or is close to nerves, including renal arteries and related renal nerves. In other embodiments, the tissue of interest is luminal tissue that may further comprise the affected tissue as found in arterial disease.

In yet another exemplary embodiment of the disclosure, the ability to deliver energy at the desired dose can be used in nervous tissue to achieve a favorable biological response. For example, chronic pain, urinary dysfunction, hypertension, and a wide variety of other persistent illnesses have been found to be affected through the movement of nervous tissue. For example, it has been found that chronic hypertension, which may not respond to drugs, can be ameliorated or eliminated by stopping excessive nerve activity in the vicinity of the renal arteries. It is also known that nerve tissue does not inherently have regenerative properties. Therefore, it may be possible to favorably affect excessive neural activity by interfering with the conduction pathways of neural tissue. When interfering with nerve conduction pathways, it is particularly advantageous to avoid damage to adjacent nerve or organ tissue. The ability to induce and control energy doses is well suited for the treatment of nervous tissue. Precise control of energy delivery, as described and disclosed herein, can be induced in nervous tissue, whether heating or cauterizing energy doses. In addition, a directional application of energy may be sufficient to target nerves without the need for precise contact as would be required with a typical cautery probe. For example, eccentric heating can be applied at a temperature high enough to denature the nervous tissue, without cauterizing the luminal tissue and without requiring perforation of the luminal tissue. However, if it is also desirable to configure the energy delivery surface of the present disclosure to perforate tissue to deliver ablation energy, similar to a cauterization probe with accurate energy doses controlled by power control and generators. There is.

In some embodiments, the effectiveness of denervation therapy is assessed by measurement before, during and / or after treatment, and one or more parameters of treatment are tailored to a particular patient or further treatment. The need for can be identified. For example, the denervation system can include the ability to assess whether the treatment has caused or caused a decrease in neural activity in the target tissue or nearby tissues, which function is feedback for adjusting the parameters of the treatment. Or can indicate the need for further treatment.

Although this disclosure focuses on the use of technology in the vascular system, the technology is also useful for other luminal tissues. Other anatomical structures for which this disclosure can be used are the esophagus, oral cavity, nasopharyngeal cavity, ear canal and tympanic cavity, sinus, arterial system, venous system, heart, laryngeal, trachea, bronchi, stomach, duodenum, ileum. , Colon, ileum, bladder, urinary tract, ejaculatory duct, infusion tract, esophagus, uterine cavity, vaginal tract, and cervical canal. System overview FIG. 1A shows a system 100 that performs treatment in the body passage. System 100 includes control unit 110. The control unit 110 may include an RF generator that delivers RF energy to the catheter device 120. An exemplary control unit and associated energy delivery methods that can be used with the embodiments disclosed herein are incorporated herein by reference in the United States Patent Application Publication No. 1 assigned to the assignee of the invention. It is disclosed in the specification of 2012/0095461. A further example that can be used with the embodiments disclosed herein is the "Tuned RF Energy for Selective Treatment of Atheroma", which was assigned to the assignee of the invention. US Pat. No. 7,742,795 entitled "and Other Target Tissues and / or Structures", US Pat. No. 7,291,146 entitled "Selectable Eccentric Remodeling and / or Ablation of Atherosclerotic Material", and "System for Inducing Desirable Temperature Effects on" It is disclosed in US Patent Application Publication No. 2008/0188912, entitled "Body Tissue," and the entire disclosure is incorporated herein by reference. In some embodiments, especially with some embodiments using unipolar energy delivery, the system is also electrically connected to a ground / common electrode, control unit 110, which can be associated with the catheter device. It may include a separate pad that is otherwise associated with the system 100.

In some embodiments, the control unit 110 may include a processor or may be coupled to the processor to control or record treatment. A processor typically programmables one or more to execute machine-readable program instructions or code to implement some or all of one or more of the embodiments and methods described herein. It includes computer hardware and / or software that often includes a processing unit. The code is memory (optionally read-only memory, random access memory, non-volatile memory, etc.) and / or recording medium (floppy (registered trademark) disk, hard drive, CD, DVD, non-volatile solid state memory card, etc.) ) Is often embodied in tangible media. The code and / or related data and signals can also be transmitted to or from the processor over a network connection (such as wireless network, Ethernet®, Internet, intranet, etc.) and of the code. Some or all may be transmitted between the components of the catheter system and within the processor via one or more buses, often with suitable standard or proprietary communication cards, connectors, cables, etc. Included in the processor. A processor can often be configured to perform the computational and signaling steps described herein by programming the processor, at least in part, in software code, which software code simply provides. It can be written as a single program, a series of separate subroutines, related programs, and so on. The processor may be equipped with standard or proprietary digital and / or analog signal processing hardware, software and / or firmware, providing sufficient processing power to perform the calculations described herein during the treatment of the patient. Desirably, the processor can optionally have a personal computer, notebook It includes a type computer, a tablet computer, a proprietary processing unit, or a combination thereof. It can also include standard or proprietary input devices (such as mice, keyboards, touch screens, joysticks, etc.) and output devices (such as printers, speakers, displays, etc.) associated with modern computer systems, and multiple processes. Processors with units (or even separate computers) can be used in a wide range of centralized or distributed data processing architectures.

In some embodiments, the control software of the system 100 can use a client-server schema to further enhance the usability, flexibility and reliability of the system. The "client" is the system control logic and the "server" is the control hardware. The communication manager notifies the subscribed clients and servers of changes in the system status. The client "knows" about the system state at that time and what commands or decisions should be made based on changes in a particular state. The server acts as a system based on client commands. Because the communication manager is a centralized information manager, the new system hardware may not require changes to the existing client-server relationship, in which case the new system hardware and its associated control logic It simply becomes an additional "subscriber" to the information managed through the communications manager. This control schema can provide the advantage of having a robust central operating program with a fixed base routine, to the base routine to operate new circuit components designed to operate by the system. No changes may be required. Expandable device and electrode assembly With reference to FIG. 1A, the catheter device 120 may include an expandable device 130 which can be a flexible, inflexible, or semi-flexible balloon. The expandable device 130 includes a plurality of electrode assemblies that are electrically connected to the control unit 110. Such electrode assemblies can be electrically configured to be unipolar or bipolar and have additional heat sensing capabilities.

As shown in FIG. 1B, the electrode assembly can be placed on the expandable device 130, shown here in the expanded state, according to the plurality of cylindrical treatment zones A through D. In other embodiments, some of which are further described below, but the expandable device 130 or other component of the treatment system is not in the treatment zone or otherwise delivers therapeutic energy. It may include additional electrode assemblies that are not used or configured as such.

Treatment zones A through D and associated electrode assemblies 140a through d are further shown in FIG. 1C, which shows the "expanded state" of the expandable device 130 in FIG. 1B. In some embodiments, the expandable device is a balloon with a diameter of 4 mm and two electrode assemblies 140a-b. In another embodiment, the expandable device is a balloon with a diameter of 5 mm and three electrode assemblies 140a-c. In some embodiments, the expandable device is a balloon with a diameter of 6 mm, 7 mm or 8 mm and four electrode assemblies 140a-d, as shown in FIG. 1B. A 4 mm balloon with two electrode assemblies 140a, b is shown in FIG. 1D, and a 5 mm balloon with three electrode assemblies 140a-c is shown in FIG. 1E. For any of these configurations, the expandable device is approximately 10 mm to approximately 100 mm or approximately 18 mm to approximately 25 mm, which is the approximately longitudinal span of all treatment zones A to D shown in FIGS. 1B and 1C. It may have a working length of. The electrode assemblies 140a-d can be attached to the balloon using an adhesive.

FIG. 1F schematically illustrates one embodiment of an expandable device that includes an array of unipolar electrodes 190 (however, the array of electrodes shown in FIGS. 1B-1E and other figures is also unipolar. Can be used in the configuration). In some cases, one of the unipolar electrodes 190 on the expandable device can be configured to function as a common electrode or ground electrode for the other electrodes. Alternatively, a separate electrode on the expandable device or an electrode of a different shape and configuration (such as the ring electrode 192 shown by the broken line in Figure 1F), or an electrode on another expandable device (eg,). Electrodes 194) in Figure 1G or electrodes that are otherwise associated with the catheter can be configured as common electrodes. In yet other cases, the ground pad can be secured to the patient's skin to act as a common electrode. Although not explicitly shown in FIG. 1G, the unipolar electrodes are positioned in close proximity to or on the temperature sensing device, respectively, as in other embodiments described herein. be able to. Overlapping and non-overlapping treatment zones With reference to FIG. 1B, treatment zones A-D may be configured to be longitudinally adjacent to each other along the longitudinal axis LL and to form a treatment in which the energies applied by the electrode assembly do not overlap. it can. The treatment applied by the longitudinally adjacent bipolar electrode assemblies 140a-d is circumferentially discontinuous along the longitudinal axis LL. For example, referring to FIG. 1C, the site of injury formed in treatment zone A is, in some embodiments, the site of injury formed in treatment zone B and around the perimeter (relative to LL in this figure). It can be minimally overlapped (laterally).

However, in other embodiments, the energy applied by the electrode assembly, such as the electrode assembly shown in FIG. 1C, is at least to some extent longitudinally, circumferentially, and / or otherwise. Can overlap. 31 and 32 schematically show a non-limiting example of a method in which electrodes 3102 and 3104 can be excited to form overlapping therapeutic zones. Although not specifically shown in FIGS. 31 and 32, the electrodes 3102 and 3104 can each be a pair of bipolar electrodes (or may be a single unipolar electrode). , Can be positioned on the outer surface of the catheter balloon or other expandable device so that they are offset longitudinally and circumferentially with respect to each other (eg, as in FIG. 1C). As shown in FIG. 31, each of the electrodes 3102 and 3104 contains a target temperature zone (its outer boundary is indicated as "TT") and a thermal plume (its outer boundary is indicated as "TP"). It can be associated with a treatment zone (or can be configured to form such a treatment zone in the tissue juxtaposed with the electrodes). In some embodiments, the target temperature zone indicates a region of tissue that is or exceeds the desired target therapeutic temperature, or is within the desired target temperature range. In some embodiments, the heat plume indicates an area of tissue that is not necessarily at or within the target temperature range but exhibits an increase in temperature relative to the untreated zone outside the heat plume.

Whether or not the treatment zones between the electrode / electrode pairs overlap is, but is not limited to, the geometry of the electrodes, the placement density of the electrodes, the positioning of the electrodes, and the ground / common electrode (in the unipolar embodiment). Affected by a wide variety of factors including (s) placement and geometry, energy generator output settings, output voltage, output power, duty cycle, output frequency, tissue characteristics, tissue type, etc. May receive.

In some embodiments, the individual electrodes of a pair of bipolar electrodes can each define their own treatment zone, and such treatment zones can partially or wholly overlap.

In FIG. 31, the heat plumes of the treatment zones overlap, but the target temperature zones do not. In FIG. 32, both the target temperature zone and the thermal plume overlap. In some embodiments, the overlap of treatment zones can extend substantially continuously around the perimeter of the device and / or in the tissue surrounding the body passage. In other embodiments, the treatment zones can be overlapped, but the overlap is not substantially continuous around the perimeter and there may be large discontinuities in the treatment zone.

At least some electrosurgical systems that use an array of electrodes attached to the balloon can form overlapping treatment zones between adjacent electrode pads, and in at least some cases are effective around the perimeter of the body passage. It has been experimentally found to form a substantially continuous treatment zone. In one embodiment, as shown and described in US Patent Application Publication No. 2008/0188912 (incorporated in its entirety by this reference), in particular FIG. 9C (reproduced as FIG. 33 in the present application). Similar catheters and expandable balloons were used to create overlapping treatment zones between adjacent pairs of electrodes so that the treatment zones effectively extended substantially continuously around the perimeter. As shown in FIG. 33, the expandable balloon 20 includes a pair of longitudinally extending bipolar electrode pairs 34 positioned around the perimeter of the balloon. For example, unlike the array of electrodes shown in FIG. 1C, the array of electrodes shown in FIG. 33 is symmetrically arranged on the expandable balloon 20.

In one experiment using an array of catheter-based balloon electrodes similar to the array of electrodes in Figure 33, the various outputs and durations of the high frequency regimen (approximately 60 ° C to approximately 75 over approximately 5 to 120 seconds). Local responses of 14 renal vessels treated or left untreated at ° C) were assessed on days 28 ± 1 and 84. In addition, kidneys from a total of 7 animals were evaluated by light microscopy.

The kidneys and renal arteries were externally implanted with the underlying muscles intact and fixed in 10% neutral buffered formalin. The fixed tissue was then submitted for histopathological treatment and evaluation. Each vessel is trimmed approximately every 3 mm to 4 mm until the tissue is exhausted, treated, embedded in paraffin, sectioned twice at approximately 5 microns (5 μm), hematoxylin eosin (H + E) and elastin. Stained with trichrome (ET). Kidneys were trimmed at three levels (head, central and caudal), treated, embedded in paraffin, sectioned and stained with H + E. All resulting slides were examined by light microscopy.

Evaluation of step sections from 6 acute arteries treated or left untreated with various outputs and durations of the high frequency regimen, as well as evaluation of dependent kidneys, include coagulative necrosis in medial and perivascular tissues. It also showed severe temperature changes characterized by collagen hyalinization. FIG. 34 shows a cross section of the left renal artery (denoted as A) and surrounding tissue treated with a protocol of 75 ° C for 10 seconds with 6 pairs of electrodes. In Figure 34, peripheral thermal damage is the dotted boundary, including damage to several nerve branches, ganglia (short arrows), and parts of adjacent lymph nodes (LNs) (as indicated by arrowheads). Observed within. FIG. 35 shows a cross section of the right renal artery and surrounding tissue treated with a protocol of 75 ° C for 5 seconds with 6 pairs of electrodes. In Figure 35, peripheral damage is observed within the dotted boundaries and includes several nerve branches (as indicated by arrowheads). With reference to FIGS. 34 and 35, the thermal injury extended to the periphery in the most central segment treated in the media of the left and right arteries. The kidneys showed no treatment-related changes. Peripheral treatment was effective in reaching outpatient renal innervation with a radial range up to 10 mm in depth and forming damage. There was minimal noticeable damage to the procedure caused by large-scale balloon therapy that was likely to trigger a significant restenotic response.

36 and 37 show a further cross section of the left renal artery of FIG. 34 at 27 days post-treatment. FIG. 38 shows another representative low-magnification image of RF treatment at 75 ° C. Zones of treatment in FIG. 38 are evident by residual necrotic media and adventitial thickening due to early smooth muscle cell hyperplasia, fibrosis and inflammatory wetness (eg, in parentheses). Figure 38 also shows the expansion of the treatment zone into the adjacent adventitia (as indicated by the dashed line).

Figures 39-41 further show how, in some embodiments, treatment zones can overlap during RF energy treatment. Figures 39-41 show a Vessix V2 catheter positioned in a cylinder filled with a thermal gel during 30 seconds of treatment. FIG. 39 shows a heat-sensitive gel immediately after the start of treatment, with square patches within the gel showing local electrode heating. As the treatment progresses, as shown in FIG. 40, the size of the patch in the gel increases due to heat conduction and comes into close contact. FIG. 41 shows the gel at the completion of 30 seconds of treatment, showing significant overlap in the patches. b. Structure of the electrode assembly With reference to FIG. 1C, each electrode pad assembly has a distal electrode pad 150a-d, an intermediate tail 160a-d, a proximal electrode pad 170a-d, and a proximal tail 180b, d (electrode pad). It contains four main elements (not shown for assemblies 140b and 140c). Details of the structure of the electrode assemblies 140a-d will be shown and described with reference to FIGS. 2A-2C.

FIG. 2A shows a top view of the electrode assembly 200, which is designated as the electrode assembly 140 in FIG. 1C. The electrode assembly 200 is configured as a flexible circuit having a plurality of layers. Such layers can be continuous or discontinuous, i.e. composed of separate parts. Shown in FIGS. 2B and 2C is an insulating bottom layer 202 that provides the basis for the electrode assembly 200. The bottom layer 202 can be made of a flexible polymer such as polyimide. In some embodiments, the bottom layer 202 is approximately 0.5 mil (0.0127 mm) thick. A conductive layer 204 composed of a plurality of separate traces is overlaid on top of the bottom layer 202. The conductive layer 204 can be, for example, a layer of electrodeposited copper. In some embodiments, the conductive layer 204 is approximately 0.018 mm thick. The insulating layer 206 is discretely or continuously overlaid on top of the conductive layer 204 so that the conductive layer 204 is fluid sealed between the bottom layer 202 and the insulating layer 206. Like the bottom layer 202, the insulating layer 206 can be made of a flexible polymer such as polyimide. In some embodiments, the insulating layer 206 is approximately 0.5 mil (0.0127 mm) thick. In other embodiments, the insulating layer 206 is a full or partial polymer coating such as PTFE or silicone.

The electrode assembly 200 shown in FIG. 2A includes a distal electrode pad 208. In this region, the bottom layer 202 forms a rectangular shape. As shown, the electrode assembly 200 can include multiple openings to provide additional flexibility, and the pads, and other parts of the assembly, have curved or curved corners, transitions. Parts and other parts may be included. In some cases, openings and curvilinear / curved features are repeatedly expanded and folded by the expandable device so that in some cases it may be needed when treating multiple sites during the procedure. It can increase the resistance of the assembly to detachment from its expandable device, which can occur when it is unfolded from the protective sheath and may also be retracted into the protective sheath.

The distal electrode pad 208 includes a plurality of separate traces superimposed on top of the bottom layer 202. These traces include a ground trace 210, an active electrode trace 212 and a sensor trace 214. The ground trace 210 includes an elongated electrode support 216 that is offset laterally from the sensor ground pad 218. The sensor ground pad 218 is electrically connected to the elongated support 216 of the ground trace 210 and is positioned in the center of the distal electrode pad 208. The bridge 220 connects the most distal portion of the sensor ground pad 218 to the distal portion of the elongated electrode support 216 of the ground trace 210. The width of the bridge 220 tapers toward the sensor ground pad 218. In some embodiments, the bridge 220 has a relatively uniform and thin width to allow the desired amount of flexibility. The elongated electrode support 216 tapers in width at its proximal end, which is not required. In some embodiments, the elongated electrode support 216 can make a sharp transition to a much thinner trace in its proximal portion, allowing a desired amount of flexibility. In general, the curvature of the traces shown to be constricted is optimized to reduce the balloon recapture force and the possibility of some snugging where sharper contours may be present. The shape and position of the traces are also optimized to provide overall dimensional stability to the electrode assembly 200 to prevent distortion during deployment and use.

The ground trace 210 and the active electrode trace 212 in FIG. 2A share a similar structure. The active electrode trace 212 also includes an elongated electrode support 216. FIG. 2B shows a partial cross section AA of the distal electrode pad 208. The electrode 222 is shown superimposed on a portion of the insulating layer 206 so that the insulating layer 206 allows the electrode 222 to be coupled to the elongated electrode support 216 of the ground trace 210 (of the conductive layer 204). It has multiple passages (eg holes).

As shown in FIG. 2A, the ground electrode trace 210 and the active electrode trace 212 may include a plurality of electrodes. Three electrodes 222 are provided on each electrode trace, but more or fewer electrodes can be used. In addition, each electrode 222 may have radiated corners to reduce the tendency of snugging on other devices and / or tissues. Although the above description of the electrode 222 and the traces associated with the electrode 222 is described in the context of a bipolar electrode assembly, one of ordinary skill in the art will recognize that the same electrode assembly can also function in unipolar mode. For example, as one non-limiting example, the electrodes associated with the active electrode traces 212 and 242 can be used as unipolar electrodes, and the ground trace 210 is separated during excitation of those electrodes.

An exemplary embodiment for signs of renovascular hypertension, having a generally longitudinal length of 4 mm per electrode, including a longitudinal spacing between the electrodes 222, is optimal while avoiding a stenotic reaction. It has been experimentally found to provide effective tissue remodeling results with respect to the size and depth of the injured site. The configuration shown balances the depth of heat penetration and treatment zones while attempting to minimize the number of pairs of electrodes to optimize the flexibility and profile of the final device. Achieved by avoiding thermal damage to the tissues lined up in. However, the configuration shown is not always essential, as the geometry of the electrode size and arrangement can be modified according to the desired therapeutic effect.

Thirty-three Yorksha pigs were subjected to renal denervation (RDN) by Vessix Vascular renal denervation radiofrequency (RF) balloon catheter. Estimated renal denervation by Vessix Vascular electrode design is achieved by a series of settings (depending on electrode length, temperature and duration), with Vessix 16 mm perimeter electrodes and 2 mm and 4 mm with offset design. The safety of the electrodes was compared 7 days and 28 days after the treatment. Histological sections of the renal arteries were examined to assess tissue response, including but not limited to: injury, inflammation, fibrosis and petrification on days 7 and 28.

Treatment of the renal arteries with Vessix Vascular's RDN RF balloon catheter results in a series of changes in the arterial wall and adjacent adventitia, from the acute "harmful" stage to the chronic "reaction / repair". Represents the progression of the arterial / adventitial response to the stage. The treated area within the renal artery was apparent due to the presence of these changes in the arterial wall and its extension into the adjacent adventitial tissue (interpreted as a "treatment zone").

On day 7, all electrodes, treatment temperature or duration, regardless of length, were associated with the major adverse response. On the other hand, 2 mm and 4 mm electrodes were also associated with the initial response / repair response, regardless of the duration of treatment, which was not observed on day 7 with 16 mm RF treatment. The overall extent around the affected artery of the 16 mm electrode was usually minimal to mild / moderate (each less than about 25% to about 25%, respectively), regardless of the duration of treatment. For shorter electrodes (2 mm and 4 mm) with ~ 75% perimeter affected), increased regardless of temperature (more than about 75% ~ 100% marked from mild / moderate perimeter covered respectively) ).

On day 28, frequent minimal intimal neoplasia was observed in all treatment groups except for the shorter 4 mm electrode, regardless of time point. Mild / moderate intimal neoplasia is rarely observed only on day 28, regardless of treatment group, while 16 mm electrodes are mild / moderate relative to shorter 2 mm and 4 mm electrodes. It has been associated with mild and comparable increases in the development of intimal neoplasia.

Endothelial cell exposure (ie, loss) is a common sequelae in the passage of any intervention device and is an expected sequelae for treatment with Vessix Vascular's RDN RF balloon catheter. Due to the importance of the endothelium in preventing thrombus formation, its recovery in exposed areas was monitored. Therefore, the magnitude / extent of luminal surface reendothelialization was elucidated relative to the approximate perimeter of the affected artery.

On day 7, the 2 mm and 4 mm electrodes had more arterial sections with complete but not complete endothelialization, and complete endothelialization was present in all arterial sections of the 2 mm and 4 mm electrodes. The arterial section treated with 16 mm electrodes was not observed to have complete endothelialization on day 7, regardless of dose.

On day 7, inflammation was generally minimal overall regardless of treatment, but both 16 mm electrodes had overall increased inflammation relative to the 2 mm and 4 mm electrodes, regardless of dose. did. Mild / moderate inflammatory wetting was rarely observed with the 2 mm and 4 mm electrodes, but was common and frequent with the 16 mm electrodes.

In the embodiment of FIG. 2A, each electrode 222 is approximately 1.14 mm × 0.38 mm, with a gap of approximately 0.31 mm between the electrodes 222. The electrodes 222 of the ground trace 210 and the active electrode trace 212 are laterally separated by approximately 1.85 mm. In some embodiments, such as the embodiment shown in FIG. 2B, the electrode 222 is a gold pad approximately 0.038 mm thick from the conductive layer 204 and protrudes 0.025 mm over the insulating layer 206. To do. Without limiting the use of other such suitable materials, gold is a good electrode material because it is highly biocompatible, radiation opaque, and conducts electricity and heat. In other embodiments, the thickness of the electrodes of the conductive layer 204 can be in the range of about 0.030 mm to about 0.051 mm. At such a thickness, the relative stiffness of the electrode 222 can be higher than, for example, the copper conductive layer 204. For this reason, multiple electrodes can be used instead of a single electrode to increase flexibility. In other embodiments, the electrodes can be as small as 0.5 mm x 0.2 mm or as large as 2.2 mm x 0.6 mm for the electrode 222.

Optimum design where it is important to balance the thickness of gold on the insulating layer 206 to achieve good flexibility while maintaining sufficient height to provide good tissue contact Although it is a consideration for the formation, this is balanced with the purpose of avoiding the surface height that may cause snugging during the deployment or folding of the balloon. These issues are modified according to other factors of the particular procedure, such as balloon pressure. For many embodiments, electrodes projecting approximately 0.025 mm above the insulating layer 206 have been found to have good tissue contact at balloon expansion pressures as low as less than 10 atm (1013 KPa) and as low as 2 atm (203 KPa). .. These pressures are well below the normal inflatable pressure of angioplasty balloons.

The sensor trace 214 is centrally located on the distal electrode pad 208 and includes a sensor power pad 224 facing the sensor ground pad 218. These pads are used for the power supply and grounding electrode of a thermosensitive device 226 such as a thermocouple (eg T-shaped configuration: copper / constantan) or a thermistor, as shown in the partial cross-section shown in FIG. 2C. You can connect.

The heat sensing device 226 is connected to the sensor power pad 224 on the proximal side and to the sensor ground pad 218 on the distal side. To help reduce the overall thickness, the heat sensitive device 226 is positioned within an opening in the bottom layer 202. In some embodiments, the heat sensing device 226 is a thermistor with a thickness of 0.1 mm, which is unusually thin, approximately two-thirds of industry standards. As shown, the heat sensing device 226 is on the distal electrode pad 208 on the non-tissue side. Therefore, the heat sensing device 226 is trapped between the electrode structure and the balloon when incorporated into a final device such as the catheter 120. This is because surface-mounted electrical components such as thermistors usually have sharp edges and corners, which can be trapped by tissue and are problematic when the balloon is deployed and / or retracted. It is advantageous because it can cause. This arrangement also keeps the soldering connections out of contact with blood, because the solder is usually not biocompatible. In addition, the heat sensitive device can measure the temperature representing the tissue and electrode 222 due to its arrangement. Designs in the prior art usually take one of two approaches: contact with tissue or contact with electrodes. In the case of the present invention, none of these conventional approaches are used.

Due to the rectangular distal electrode pads 208, the combined bottom layer 202, conductive layer 204 and insulating layer 206 narrow in width towards the intermediate tail 228. In this case, the conductive layer 204 is an intermediate ground line 230 and an intermediate active electrode line 232, which are traces having the same spread as the ground trace 210, the active electrode trace 212, and the sensor trace 214 of the distal electrode pad 208, respectively. And formed to include an intermediate sensor line 234.

From the intermediate tail portion 228, the combined bottom layer 202, conductive layer 204 and insulating layer 206 increase in width to form the proximal electrode pad 236. The proximal electrode pad 236 is configured similar to the distal electrode pad 208, and the geometry of the electrodes and the arrangement of the heat sensing devices are essentially the same, but there can be various differences. However, as shown, the proximal electrode pad 236 is offset laterally from the distal electrode pad 208 with respect to the central axis GG extending along the intermediate ground line 230. The intermediate active electrode line 232 and the intermediate sensor line 234 have the same lateral spread as the proximal electrode pads 236 on their respective axes parallel to the central axis GG.

From the proximal electrode pad 236, the combined bottom layer 202, conductive layer 204 and insulating layer 206 are reduced in width to form the proximal tail 238. The proximal tail 238 includes a proximal ground line 240, a proximal active electrode line 242 and a proximal sensor line 244, and an intermediate active electrode line 232 and an intermediate sensor line 234. Proximal tail 238 includes connectors (not shown) to allow coupling to one or more subwiring harnesses and / or connectors, and ultimately to control unit 110. Each of these lines extends along their respective axis parallel to the central axis GG.

As shown, the electrode assembly 200 has an asymmetrical arrangement of the distal electrode pads 208 and the proximal electrode pads 236 about the axis GG. Further, the ground electrodes of both electrode pads are substantially aligned along the axis GG, along with an intermediate ground line 230 and a proximal ground line 240. This arrangement has been found to offer many advantages. For example, by essentially sharing the same ground trace, the width of the proximal tail is in the middle, rather than approximately double the width as if each electrode pad had an independent ground line. It is only about one and a half of the tail part 228. Therefore, the proximal tail 238 is narrower than the two intermediate tails 228.

In addition, arranging the electrode pads to share the ground trace allows control of which electrodes interact with each other. This is not immediately apparent when looking at a single electrode assembly, but becomes apparent when two or more electrode assemblies 200 are assembled into a balloon, for example as shown in Figure 1C. Various electrode pads can be multiplexed, fired and controlled using solid state relays with operating times ranging from about 100 microseconds to about 200 ms or about 10 ms to about 50 ms. it can. Practically, the electrode pads are considered to be actuated simultaneously, but stray currents between adjacent electrode pads of different electrode assemblies 200 are prevented by the rapid actuation of the electrodes in a microburst. This can be done so that adjacent electrode pads of different electrode pad assemblies 200 are operated out of phase with each other. Therefore, the placement of the electrode pads in the electrode assembly allows for a short treatment time of 10 minutes or less total electrode operating time, and some approximate treatment times are as short as 10 seconds, which in the exemplary embodiment is about. 30 seconds. The advantages of short treatment time are minimizing postoperative pain caused when nerve tissue is subjected to energy treatment, shortening vascular occlusion time, reducing side effects of occlusion, and relatively to luminal tissue. Rapid cooling of the lined tissue by hemoperfusion due to a small heat input can be mentioned.

In some embodiments, a common ground is typically a 500kHz 200VAC from the cathode of the electrode, and an RF circuit so that the thermistor signal (in the case of a thermistor) can be sensed and used to control the generator. Has a 1V signal from the thermistor device 226 that requires filtering. In some embodiments, for common grounding reasons, a pair of adjacent electrode thermistors can be used to monitor temperature without even operating on the pair of adjacent electrodes. This provides the possibility of sensing temperature in close proximity to both the distal electrode pad 208 and the proximal electrode pad 236 while operating on only one of them.

With reference to FIG. 1C again, the placement of the electrode pads in each electrode assembly 140a-d also allows for efficient placement on the balloon 130. As shown, the electrode assemblies 140a-d are "inserted" between each other, allowing maximum use of balloon surface area. This is achieved, in part, by separating the electrode pads from each other by setting the longitudinal length of each intermediate tail. For example, the length of the intermediate tail of the electrode assembly 140a is such that the laterally adjacent proximal electrode pads 170b of the laterally adjacent electrode assembly 140b are located next to the intermediate tail 160a of the electrode assembly 140a. The distance is set so that the distal electrode pad 150a and the proximal electrode pad 170a are separated so that they can be inserted. Further, the distal electrode pad 150a of the electrode assembly 140a is inserted between the intermediate tail portion 160b of the electrode assembly 140b and the intermediate tail portion 160d of the electrode assembly 140d. Therefore, the length of each intermediate tail 160a-d also requires that each electrode pad of any one electrode assembly be positioned within a non-adjacent treatment zone.

Maximizing the balloon surface area is also possible, in part, by laterally offsetting both electrode pads of each electrode assembly 140a-d. For example, the lateral offset on the right side of each distal electrode pad 150a-d and the lateral offset on the left side of the proximal electrode pads 170a-d cause some of the electrode pads to overlap laterally with each other. As such, it allows adjacent electrode pad assemblies to be inserted between each other. For example, the distal electrode pad 150a of the electrode assembly 140a laterally overlaps the proximal electrode pad 170b of the electrode assembly 140b. In addition, the distal electrode pad 150b of the electrode assembly 140b laterally overlaps the proximal electrode pad 170c of the electrode assembly 140c. However, the length of each intermediate tail prevents the circumferential overlap of the electrode pads (longitudinal overlap in this figure) and thus maintains the discontinuity of the treatment zone to the longitudinal LL.

The placement and geometry of the electrode pads, as well as the placement and geometry of the tail of the flexible circuit, also fold the balloon, or otherwise deflate the balloon into a relatively compact, unexpanded state. Can be facilitated. For example, in an embodiment having an extended diameter of up to 10 mm, the unexpanded device may have a diameter as small as about 1 mm.

Some embodiments use standard electrode assemblies with the same dimensions and configurations, and the number and relative positions of the electrode assemblies on the outer surface of the balloon depend on the diameter and / or length of the balloon. On the other hand, the geometric shape of the electrode assembly remains unchanged between the sizes of the various balloons. The relative positioning of the electrode assembly with respect to the diameter and / or length of the balloon is, in this case, the desired degree of circumferential and / or axial orientation of the adjacent electrode pads of the adjacent electrode assembly on the balloon of a given size. Can be determined by overlapping or avoidance of. However, in other embodiments, not all electrode assemblies on the balloon need to be identical.

3A-3D show the configuration of alternative electrode pads that can be used with the system 100 of FIG. 1A. FIG. 3A shows an electrode assembly 300 having two electrode pads 302 that are similar to the electrode assembly 200 but are directly adjacent to each other.

FIG. 3B shows an electrode pad assembly 304 configured similar to the electrode assembly 200 but having two electrode pads 306 directly adjacent to each other. Further, the electrode pad 306 has electrodes arranged so as to be transverse to the longitudinal axis LL of FIG. 1C and the GG of FIG. 2A.

FIG. 3C shows an electrode assembly 310 configured similar to the electrode assembly 304, but with three staggered electrode pads 312. Similar to the electrode assembly 304 of FIG. 3B, the electrode pad 312 features electrodes arranged in the transverse direction.

FIG. 3D shows an electrode assembly 314 having an electrode pad 312 having a similar configuration to the electrode assembly 310 but with a larger electrode surface area. Similar to the electrode assembly 304 of FIG. 3B, the electrode pad 316 features electrodes arranged in the transverse direction.

4A-4C show the configuration of alternative electrode pads that can be used with the system 100 of FIG. 1A. FIG. 4A shows an electrode assembly 400, which is configured similar to the electrode assembly 200 but has only a single distal electrode pad 402.

FIG. 4B shows an electrode assembly 404 with a single distal electrode pad 407 having a surface area of the active electrode 408 greater than the ground contact surface area 410, but configured similar to the electrode assembly 400.

FIG. 4C shows an electrode assembly 412 with a single distal electrode pad 414 that is configured similar to the electrode assembly 404 but has a fairly porous construction to allow for greater flexibility. There is.

5A-5F show the configuration of alternative electrodes that can be used with the system 100 of FIG. 1A. In some embodiments, the illustrated electrode configurations can be used with the configurations of FIGS. 4A-4C. FIG. 5A shows an electrode assembly 500 configured similar to the electrode assembly 400, but arranged to include only a single proximal electrode pad 502. The electrode assembly 500 further includes an elongated distal portion 504 attached to the balloon.

FIG. 5B shows the electrode assembly 506, which is configured similar to the electrode assembly 500 but has a relatively large electrode surface area on the electrode pad 508. FIG. 5C shows an electrode assembly 510 having a similar configuration to the electrode assembly 500, but with a relatively large electrode surface area and a larger number of electrodes on the electrode pad 512.

FIG. 5D shows an electrode assembly 514 having a configuration similar to the electrode assembly 510, but with a non-uniform electrode configuration on the electrode pad 512. FIG. 5E shows the electrode assembly 514, which is configured similar to the electrode assembly 500, but has a relatively small electrode surface area and fewer electrodes 518 on the electrode pad 516. The electrode pad 516 also incorporates two heat sensing devices 520 mounted on the same side as the electrodes.

FIG. 5F shows an electrode assembly 522 configured similar to the electrode assembly 514, but with a transversely arranged electrode 524 and a single heat sensing device 526. The electrode assemblies of FIGS. 2-5F can be used in bipolar or unipolar configurations. 5G-5I show additional examples of unipolar electrode configurations. In Figure 5G, there are two parallel arrays of unipolar electrodes 530 on either side of the temperature sensor 532. In Figure 5G, each array of unipolar electrodes 530 has its own separate trace, and the temperature sensor 532 also has its own separate trace. However, in other embodiments, all of the unipolar electrodes 530 of a particular bending circuit assembly can share a single active trace, and one of the two traces of the temperature sensor can also be shared. However, in other embodiments, the temperature sensor power and ground traces may be separate from the unipolar traces (s).

FIG. 5H shows another arrangement of unipolar electrode pads in which all of the unipolar electrodes 536 are coupled to a single trace. FIG. 5I shows another alternative arrangement of unipolar electrodes and temperature sensors. The unipolar electrode pads can be placed in a longitudinal and circumferential offset around the expandable device (as shown in Figure 1C) and are shown in Figures 3A-5F. It may have the same geometric shape and arrangement as the one. Treatment method and control system Device positioning FIG. 6 shows the system 100 of FIG. 1A used to perform treatment method 600 according to one non-limiting embodiment of the present disclosure. Here, the control unit 110 is shown to be operational coupled to the catheter device, where the catheter device is in section S1 of the body passage where the expandable device (having multiple electrode assemblies) requires treatment. It is placed in the body passage so that it is placed adjacent to it. Placement of the catheter device in section S1 can be done according to conventional methods, eg, with a guide wire under fluoroscopy.

When placed in S1, the expandable device can be expanded in the case of a balloon by pressurizing the fluid at, for example, 2 atm (203 KPa) to 10 atm (1013 KPa). This brings the electrodes of the expandable device into contact with the body passage.

In some embodiments, the control unit 110 can measure the impedance in the electrode assembly to confirm the juxtaposition of the electrodes with the body passages. In at least some of these embodiments, treatment can proceed even if juxtaposition is not detected for all of the electrodes. For example, in some embodiments, treatment can proceed if 50% or more of the electrodes are perceived as juxtaposed, allowing juxtaposition that is not completely uniform in the circumferential and / or axial direction. .. For example, in some cases, the catheter may be positioned so that one or more of the proximal electrodes are in the aorta and exposed to blood, and the perceived impedance for such electrodes is. , May not be within a pre-specified range (eg 500 ohms to 1600 ohms), indicating that there is no tissue juxtaposed with those electrodes. In some cases, the system can allow the user the authority to proceed with treatment, even if the electrode / tissue juxtaposition is not uniform. The control unit 110 can then activate the electrodes to form the corresponding number of damaged sites L as indicated by the black squares. During electrode activation, the control unit uses a heat-sensitive device on the electrode pad to dissipate heat from both the electrode and the tissue due to the unique arrangement of the heat-sensitive device that does not touch either the tissue or the electrode. Monitor. In this way, more or less power can be supplied to each electrode pad as needed during treatment.

In some embodiments, the control unit 110 can apply a uniform criterion to determine juxtaposition for all electrodes of the device. For example, the control unit can use the same pre-specified range of resistance measurements for all of the electrodes. However, in other cases, including some, but not all, unipolar applications, different criteria can be applied to different unipolar electrodes to determine juxtaposition. For example, in some unipolar embodiments, each unipolar electrode can define a separate electrical circuit to a common / unrelated electrode (or multiple electrodes) through the tissue, and the features of those circuits ( Resistance) can vary significantly based on the distance between the unipolar and common electrodes, the properties of the tissue between them, and other geometric shapes and properties of the device and surrounding tissue. Thus, in at least some embodiments, for example, the greater the distance between the unipolar electrode and the common electrode (eg, the longer the distance between the two electrodes, the higher the impedance measurement required to determine good juxtaposition. ), It may be desirable to apply criteria for determining juxtaposition. However, in other embodiments, the changes due to these differences in distance and other geometry are not minimal or large, and uniform criteria can be applied.

Figures 24A-24F show one non-limiting example of a series of screenshots displayed by the control unit during the course of treatment. In Figure 24A, the system prompts the user to connect a catheter. In Figure 24B, the system confirms that the catheter has been connected and other information about the connected catheter (eg size / diameter). In FIGS. 24C and 24D, the system can check the juxtaposition of electrodes, indicate which electrodes are juxtaposed or the number of electrodes juxtaposed, and ask for authority to proceed, as described above. In Figure 24C, three electrodes (eg, the first three or "proximal" electrodes) are shown juxtaposed, while in Figure 24D, all electrodes are shown juxtaposed. ing. In FIGS. 24E and 24F, the system can display specific parameters of treatment (eg, power, temperature, time, and number of active electrodes / activated electrodes) both during and after treatment. .. Information about the treatment, such as the parameters and / or other information mentioned above, can be captured by the system and stored in memory.

Returning to FIG. 6, when the predetermined treatment in section S1 is completed, the expandable device is then retracted and moved to untreated section S2, the treatment applied in section S1 is repeated, and so on in section S3. , And can be repeated in any more sections as needed. These sections are shown directly adjacent to each other, but can be separated by some distance.

In some cases, alternative methods other than those shown in Figure 6 are used. For example, in other embodiments, treatment will be performed at only one location in the aisle and it will not be necessary to move the expandable device to multiple locations within the aisle.

Revisiting the example of renal hypertension with excessive reduction in neural activity, this system can be used to induce energy and affect neural activity without perforation or cauterization. Therefore, the illustrated body passage can be assumed to be the renal artery surrounded by the nervous tissue N in sections S1 to S3. Electrodes on the expandable device can be fed to deliver energy in a known direction of the affected nerve N, and the depth of energy penetration depends on the energy dose, the type of electrode (eg, unipolar). It depends on the geometric shape of the electrodes and the bipolar electrode). "System for Inducing Desirable Temperature Effects on Body The US Patent Application Publication No. 2008/0188912, entitled "Tissue", the entire disclosure of which is incorporated herein by reference, is of an electrode that can be considered in some, but not all, embodiments. It describes some considerations regarding the geometry and the volume of the tissue treatment zone. In some cases, using empirical analysis so that the tissue can be first characterized using a catheter device as disclosed and described herein and then targeted to treat the tissue. The impedance characteristics of nerve tissue N can be obtained. Energy delivery and regulation can also be accompanied by cumulative injury modeling.

As shown, each injury site L is formed in the corresponding treatment zones A through D of the expandable device 130. Therefore, any injured site L created in one particular treatment zone A to D does not circumscribe the injured site in adjacent treatment zones A to D at any point along the axis of motion OO. In some embodiments, the therapeutic zone of the expandable device 130 can have more than one electrode pad, so in such cases the damage sites L formed by those electrode pads overlap in the circumferential direction. be able to. In those cases, more injured sites L may be required for a particular anatomy, or a pair of electrode pads are required to perform a diagnostic routine before applying treatment. Nevertheless, there is no circumferential overlap of electrodes in adjacent treatment zones. b. Energy delivery Depending on the particular remodeling effect required, the control unit can excite the electrodes with an average output of about 0.25 watts to 5 watts, or about 0.25 joules to 900 joules, over 1 to 180 seconds. Higher energy treatments can be given with lower power and longer duration, such as 0.5 watts over 90 seconds or 0.25 watts over 180 seconds. In a unipolar embodiment, the control unit can excite the electrode at a maximum of 30 watts for a maximum of 5 minutes, depending on the configuration of the electrode and the distance between the electrode and the common ground. Shorter distances allow less energy to travel over more localized areas with less conduction loss, thus providing lower energy over shorter periods of time. In an exemplary embodiment used in renal denervation, energy is delivered over about 30 seconds in a treatment setting of about 5 watts so that the treatment zone is heated to about 68 ° C during treatment. As mentioned above, the output requirements can vary widely depending on the type and configuration of the electrodes. In general, wider electrode spacing requires higher power, in which case the average power can be higher than 5 watts and the total energy can exceed 45 joules. Similarly, with shorter or smaller pairs of electrodes, it is necessary to reduce the average power and the total energy can be less than 4 joules. Output and duration can in some cases be calibrated to be lower than sufficient to cause serious damage, especially to cauterize affected tissue in blood vessels. The mechanism of cauterizing atherosclerotic sites in blood vessels is described in the document entitled "Vaporization of Atherosclerotic Plaque by Spark Erosion" by Slager et al. (J. of Amer. Cardiol. (June, 1985), pp.1382-6), And Stephen M.

In some embodiments, energy therapy applied to one or both of the patient's renal arteries can be applied at a higher level than is possible without adverse effects in other passages of the body. For example, the body's peripheral and coronary arteries may be susceptible to harmful long-term occlusive reactions when exposed to heat above certain thermal response limits. However, it has been discovered that the renal arteries can be exposed to heating above such thermal response limits without adverse effects.

In some embodiments, energy therapy may be applied to one or both of the patient's renal arteries to affect sympathetic nerve activity in the kidney to suppress both systolic and diastolic forms of CHF. it can. Applying therapeutic thermal energy to tissues in close proximity to the renal arteries can be effective in reducing sympathetic nerve activity to mitigate the biological processes and consequent effects of CHF. In some embodiments, rapid treatment (eg,) is provided to provide a simple treatment for clinical staff while providing a treatment that maximizes the effectiveness of the treatment while minimizing the pain felt by the patient. For treatment times of 10 minutes or less per kidney), mild application of controlled doses of thermal energy is used. The balloon-mounted electrodes and energy delivery methods of the present disclosure provide energy for reducing sympathetic nerve activity associated with chronic hypertension, either with systolic and diastolic CHF or separately from systolic and diastolic CHF. It can be particularly suitable for application.

In some embodiments, the electrode pads described herein are excited to evaluate the tissue of interest, then selectively treat the tissue of interest, and remodeling the treated tissue to obtain the desired therapeutic outcome. Can be achieved. For example, tissue properties can be used to identify tissue treatment areas by using impedance measurements. Tissue can be analyzed using impedance measurements that use electrodes that are circumferentially separated in the body passage. Impedance measurements between adjacent pairs of electrodes can vary if the current path passes through the affected tissue and if the current path passes through, for example, healthy tissue in the luminal wall. Therefore, impedance measurements between the electrodes on both sides of the affected tissue may indicate the site of injury or other type of tissue of interest, while measurements between other pairs of adjacent electrodes are healthy tissue. Can be shown. Other characterizations such as intravascular ultrasound, optical coherence tomography, etc. can be used to identify the area to be treated in conjunction with or as an alternative to impedance measurements. In some cases, tissue properties and / or property profiles can vary from person to person, so it may be desirable to obtain reference measurements of the tissue to be treated to help distinguish adjacent tissues. In addition, tissue properties and / or property profile curves can be normalized to facilitate identification of related gradients, offsets, etc. between different tissues. Impedance measurements can be achieved at one or more frequencies, ideally at two different frequencies (low and high). The low frequency measurement can be performed in the range of about 1kHz to 10kHz or about 4kHz to 5kHz, and the high frequency measurement can be performed in the range of about 300kHz to 1MHz or about 750kHz to 1MHz. Lower frequency measurements primarily represent the resistance component of impedance and closely correlate with tissue temperature, where higher frequency measurements represent the capacitive component of impedance and correlate with disruption and change in cell composition. To do.

The phase angle shift between the resistance component and the capacitance component of the impedance also occurs due to the change in the capacitance between the impedance and the change in the peak between the current and the voltage as a result of the change in the resistance. Phase angle shifts can also be monitored as a means of assessing tissue contact and formation of injured sites during RF denervation.

In some embodiments, remodeling of the lumen of the body can be done by gentle heating in combination with slow or standard dilation. For example, angioplasty balloon catheter structures in which electrodes are placed are pre-dilation, during dilation, and optionally in combination with standard unheated angioplasty dilation pressure or significantly lower dilation pressure. / Or after dilation, a potential can be applied to the vessel wall. Balloon inflatable pressures from 10 atm (1013 kPa) to 16 atm (1621 kPa) are described herein (flexibility circuits on balloons, for example, where they may be suitable for standard angiogenic dilation of a particular site of injury. Modified diastolic treatments combined with appropriate potentials (through electrodes, electrodes deposited directly onto the balloon structure, etc.) can use 10 bar (1013 kPa) to 16 bar (1621 kPa) or 6 bar (16 bar). It can be performed at a pressure of 608 KPa) or less, and in some cases, only 1 atm (101 KPa) to 2 atm (203 KPa). Such moderate diastolic pressures are used herein with respect to tissue characterization, entrainment energy, one or more aspects of eccentricity therapy, and the treatment of diseases of the body's lumen, circulatory system, and peripheral vascular system. Can be combined (or may not be) with other modes of treatment described.

In many embodiments, the gradual heating energy applied before, during and / or after dilation of the lumen of the body can increase the effectiveness of dilation while reducing complications. In some embodiments, such controlled heating with a balloon can exhibit reduced recoil, providing at least some of the benefits of stent-like swelling without the drawbacks of the implant. To do. The benefits of heating can be enhanced (and / or complications are suppressed) by limiting the heating of the outer membrane layer below the harmful reaction threshold. Such heating of the intima and / or membranous can often be provided with a heating time of less than about 10 seconds, often less than 3 seconds (or even 2 seconds). In other cases, very low power can be used for longer durations. By efficiently binding energy to the target tissue by matching the drive potential of the circuit to the phase angle of the target tissue, the desired heating efficiency can be increased, effectively maximizing the area under the power curve. To do. The phase angle fit does not have to be absolute and a perfect phase fit to the characterized target structure may be advantageous, but alternative systems substantially fit the typical target structure. The appropriate potential can be preset so that it may not fit the actual phase angle exactly, but the localization of heating within the target tissue is better than using standard output forms. Can also be significantly better.

In some embodiments, the application of unipolar RF energy is delivered between one of the electrodes on the balloon and the return electrode positioned on the outer skin or the device itself, as described above. can do. Unipolar RF may be desirable in areas where deep damage is required. For example, in a unipolar application, each pair of electrodes may be fed by cathodic rather than having one anode and one cathode per pair. In some embodiments, a combination of unipolar and bipolar RF energy applications can be made, in which case damage sites of varying depth / size are selectively achieved by varying the polarity of the pair of electrodes. can do. c. Target temperature The application of RF energy is controlled to limit the temperature of the target tissue and / or the lined tissue, eg, to limit the heating of the target tissue, so that neither the target tissue nor the lined tissue will sustain irreversible thermal damage. be able to. In some embodiments, the surface temperature range is from about 50 ° C to about 90 ° C. For moderate heating, the surface temperature can be in the range of about 50 ° C to about 70 ° C, while for more aggressive heating, the surface temperature can be in the range of about 70 ° C to about 70 ° C. It can be in the range of 90 ° C. Limit heating to below the surface temperature in the range of about 50 ° C to about 70 ° C so that the temperature of the bulk structure usually remains below 50 ° C to 55 ° C. This can suppress the immune reaction that may lead to stenosis, heat damage and the like. Relatively mild surface temperatures between 50 ° C and 70 ° C are during, immediately after, and / or through the healing response of the tissue to treatment to provide greater vascular lumen and improved blood flow. Alternatively, it can be sufficient to denature and disrupt protein binding 1 hour, 1 day, 1 week, or even more than 1 month after treatment.

In some embodiments, the target temperature can be changed during treatment, eg, depending on the treatment time. FIG. 7 shows one possible target temperature profile for treatment, with a duration of 30 seconds and a 12 second rise from nominal body temperature to a maximum target temperature of about 68 ° C. In the embodiment shown in FIG. 7, the target temperature profile during the 12 second rise step is defined by a quadratic equation, where the target temperature (T) changes with time (t). The coefficients of the equation are set so that the rise from nominal body temperature to 68 ° C follows a trajectory similar to the trajectory of the projectile to the maximum height of its arc under the influence of gravity. In other words, the rise is a constant deceleration of the temperature rise (d).²T / dt²), And there is a linearly decreasing gradient (dT / dt) of temperature rise when reaching 12 seconds and 68 ° C. Such a profile, in which the gradient gradually decreases as it approaches 68 ° C, may facilitate the minimization and / or undershoot of the remaining set target temperature of treatment. In some embodiments, the objective temperature profile of FIG. 7 is equally suitable for bipolar or unipolar treatment, but in at least some unipolar embodiments, the treatment time can be increased.

8, 9 and 10 show additional temperature profiles of interest used in the various embodiments of the present disclosure. FIG. 8 shows profiles with various rise times and set target temperatures (eg, one profile with a rise time of approximately 3 seconds and a set temperature of 55 ° C, a rise time of 5 seconds and 60 ° C. One profile with a set temperature of, one profile with an 8 second rise and a set temperature of 65 ° C, one profile with a 12 second rise and a set temperature of 70 ° C, and a 17 second rise and One profile with a set temperature of 75 ° C).

9 and 10 show temperature profiles using different rise profiles, some of which approach the set target temperature relatively aggressively (eg, "rapid rise" profile) and others of them. Those passively approach the set target temperature (eg, "slow rise" profile). Although the "intermediate elevated rise" temperature profile shown in FIG. 10 has been experimentally found to provide optimal results for at least some treatment protocols, all embodiments of the present disclosure Not limited to this temperature profile, other profiles can be advantageously used in different treatments and in different situations. The elevated elevation in the middle also provides an optimized overall treatment time while avoiding the harmful micro-heat damage that can be caused by a more aggressive heating profile, while targeting the target tissue at the target temperature. It can be an exemplary embodiment in that it heats up efficiently. For each of the illustrated target temperature profiles, a temperature rise that embodies or approximates a quadratic equation can be used, but efficiently heats the tissue, optimizes treatment time, and avoids thermal damage to the target tissue. Any function or other profile can be used. However, in yet other embodiments, it is not necessary to use a temperature profile that achieves all of these objectives. For example, but not limited to, optimization of treatment time may not be essential, at least in some embodiments.

Both tabletop and animal studies were performed to optimize and validate the target temperature profile used in the denervation embodiments of the Vessix system. The following summarizes tabletop experiments and analyzes that support the selection of an intermediate elevated temperature profile as an exemplary embodiment.

Testing was performed to determine what climb time algorithm provided the optimum level of effectiveness and safety. Some previous rise time algorithms simply rose to the set temperature as quickly as possible, but this is not always considered to be the best process of action in at least some situations. The effectiveness was qualitatively evaluated by three dimensionless parameters. The aim was to find an algorithm that would result in a minimal amount of scorching, degeneration and dehydration of tissue in the treatment zone based on visual inspection, while also providing good efficacy.

In order to simulate the body temperature, the water bath was set to 37 ° C., the liver sample was placed in the water bath, and the in vivo conditions were simulated. Good juxtaposition of the device was verified by writing down the impedance value of the pair of electrode-tissue interfaces of each bipolar electrode in contact with the tissue. Higher impedance (&gt; 500 ohms) was used as a criterion for good juxtaposition.

After performing the temperature profiles of FIGS. 9 and 10, liver samples were measured at each treatment site with respect to the length and width of the injured site on the surface, the penetration depth, and the length and width of the injured site at a depth of 2 mm. did. Analysts were unaware of which treatments were given and in what order to reduce reporting bias. Some observations of significant tissue damage were also recorded.

11 and 12 show a spreadsheet-shaped measure of effectiveness formed to correlate penetration depth with other measures of effectiveness. The first is the penetration depth divided by the square root of the area of the damaged area on the surface. This metric associates the depth of damage at the surface damage site with the area of the surface damage site in a dimensionless form. A value of 100% means that the penetration depth was equal to the average size of the damaged area on the surface. The next metric is the area at 2 mm divided by the area on the surface. This metric reveals how much heat penetrates the tissue. A value of 100% means that the area at a depth of 2 mm and the area of the surface are the same. The final metric is the penetration depth at 2 mm divided by the area on the surface x the width of the damaged area. This number provides information about the rough shape of the damaged area and whether energy tends to propagate radially from the electrodes or penetrate tissue. A value of 100% means that the cross-sectional area of the size of the damaged site was equal to the size of the surface of the damaged site.

After careful consideration of all of the experimental data, it was determined that the intermediate elevated rise profile was the best temperature rise algorithm for use in a particular embodiment, but again for other purposes as well. Temperature profiles can also be appropriately used with the disclosed embodiments of the present disclosure. d. Control algorithm 13 and 14 are described above and are based on the target temperature profile as shown in FIGS. 7-10, or other profiles, as described above and as shown in FIGS. 1-6. It illustrates one embodiment of a method of controlling the application of energy in an electrosurgical device, or other device. This control method can be performed using or otherwise using the processing function of the control unit 110 of FIG. 1 and / or the control software described in more detail above. In at least some cases, the control method uses a relatively simple and robust energy generator to simultaneously excite some or other delivery sites of the electrodes with a single output setting (eg voltage). It provides fine-tuning of temperature or other treatment parameters (s) at various treatment sites of the device, which can minimize the cost, size and complexity of the system. The control method can minimize deviations from the target temperature or other treatment parameters (s) and therefore the demands on the energy generator (eg, voltage demands) during any time slice of treatment. Minimize changes in.

In some embodiments, the application of RF energy or other energy is regulated based on the desired temperature profile as described above to block heat undesirably or otherwise conduct heat at the device / tissue interface. It is desirable to provide high instantaneous power application, which can cause a net decrease in heat transfer, and moderately controlled heating to avoid shearing or other damage to the associated tissue at minute levels. .. In other words, maintaining the integrity of the structure at the nearest interface position by reestablishing a temperature close to the desired temperature, avoiding higher temperature fluctuations and the more intense momentary application of the resulting energy. it can. A net loss of thermal conductivity can result from tissue drying, resulting in reduced effective transfer of energy to the target tissue across the electrode / tissue interface. ..

Those skilled in the art have already presented the specific control methods of FIGS. 13 and 14 for illustrative purposes in the context of the particular electrosurgical device described above, but these control methods and similar methods may be used in other electrosurgical methods. You will recognize that it can be applied in favor of the device.

In general, embodiments of the control methods of FIGS. 13 and 14 seek to maintain the various treatment sites at a given target temperature, eg, one of the target temperature profiles of FIGS. 7-10. .. The control method, in this embodiment, is mainly to regulate the output voltage of the RF generator and to determine which of the electrodes is excited in a given time slice (eg, a particular electrode). To maintain by (switching on and off according to the cycle).

Generator power settings, and electrode switching, can be determined by a feedback loop that takes into account the measured temperature and previously desired power settings. During a particular treatment cycle (eg, a 25 ms slice of treatment), each of the electrodes can be identified for one of three states: off, excitation or measurement. In some embodiments, the electrodes are excited and / or measured only if they meet certain criteria (excited electrodes can also be measured) and the default electrode state is off. An electrode identified as an electrode to be excited or measured can be voltageed or sense a temperature signal over a portion of the cycle or throughout the cycle.

The control loop embodiments of FIGS. 13 and 14 provide as many candidate electrodes as possible to the target temperature while minimizing temperature changes and thus minimal changes in voltage requirements per treatment cycle. Designed to stay close to. FIG. 15 shows an exemplary time / temperature plot over four treatment cycles of the electrode showing how one embodiment of the control algorithm maintains the desired temperature.

Embodiments of the control loops of FIGS. 13 and 14 will be described in detail here. Set each electrode to off initially, as shown in step 1300. In step 1302, one of the electrodes is designated as the main electrode for that treatment cycle. As described in more detail below, the main electrodes designated during treatment vary from treatment cycle to cycle (eg, all electrodes are available throughout the cycle). The determination of which electrode to designate as the main electrode is made by accessing a look-up table or by using any other suitable function that identifies the main electrode and changes the selection of the main electrode at each treatment cycle. be able to.

In step 1302, additional electrodes can also be designated as candidate electrodes for excitation and / or measurement during the treatment cycle. The designated additional electrodes can be nominated by having or lacking a particular relationship with the designated main electrode of the treatment cycle.

For example, in some bipolar electrode embodiments, some of the electrodes on the electrosurgical device are the main electrodes when both main electrodes and their additional electrodes are excited simultaneously in the treatment cycle. It may be placed between the electrode and their other electrodes so that there is a potential for leakage current, which interferes with temperature measurements by the associated heat sensing device, the energy delivered at each electrode. The amount of inaccuracies in the amount, or other undesired consequences, can be undesirably caused. For example, in the embodiment shown in FIG. 1C, when the electrode pad 150c is designated as the main electrode, the electrode pads 150d and 170d having a cathode in the immediate vicinity or close to the anode of the electrode pad 150c are such. It may not be considered a candidate for measurement and / or excitation of a particular treatment cycle, as the electrode pads 150d and 170d are in close proximity to the designated main electrode to induce an earth leakage. Further, in this embodiment, the electrode pad 150b having an anode in the immediate vicinity or close to the cathode of the electrode pad 150c may not be considered a candidate, which is also designated as the electrode pad 150b. This is because it is close to the main electrode so as to induce an electric leakage. Further, in this particular embodiment, the electrode pad 170b is also not considered a candidate because the electrode pad 170b is on the same flexed structure as the adjacent electrode pad 150b that induces an earth leakage. Finally, in this particular embodiment, the electrode pads 150a and 170a are considered candidates because they are adjacent to non-candidate electrodes.

As another non-limiting example, in some unipolar electrode embodiments, the candidate electrode is measured or estimated similar to one or more measured or estimated properties of the electrical circuit associated with the main electrode. It is a unipolar electrode having the characteristics of an electric circuit. In other words, in some unipolar systems, it is substantially similar to an electrical circuit defined by a major unipolar electrode (eg, a circuit defined by a unipolar electrode, a common electrode, and a path through the patient's tissue). It may be desirable to exclusively simultaneously excite the unipolar electrodes that define the electrical circuit of the. In some cases, this can facilitate the uniformity of the current during excitation. In other embodiments, a given table or other list or association determines which electrode is the candidate electrode based on the current main electrode.

In at least some embodiments, the switch associated with the non-candidate electrode is opened to isolate the non-candidate electrode from the rest of the system's circuitry. This switch, in at least some embodiments, has different numbers of available electrode pairs available for excitation, assuming that the common ground between the pairs is not affected by the switch to off. It can be used in the same way or as an alternative to maximize it.

In other embodiments, the electrosurgical device can be configured to avoid the possibility of leakage or otherwise consider such leakage, and thus all electrodes of the device are treated. Can be a candidate for excitation and / or measurement during the cycle.

In some embodiments, the assignment of an electrode as a main electrode, a candidate electrode, or a non-candidate electrode is determined by a sequence or array lookup table that specifies the respective state of the electrodes and the order in which the main electrodes are designated. can do. In one non-limiting embodiment, the designation of the main electrode cycles circumferentially through the proximal electrode and then circumferentially through the distal electrode (eg, in Figure 1C, the sequence is 170a). , B, c, d, 150a, b, c, d). However, any pattern or other method can be used, including patterns or methods that in turn optimize the distance to the next, the closeness of the next in turn, or the uniformity of dispersion. ..

In some embodiments, additional conditions can result in a particular electrode set off for a particular treatment cycle and / or the rest of the treatment. For example, as described below, it is possible to overshoot temperatures as high as 4 ° C during the course of treatment (eg, even if the electrodes are not excited as a result of such overshoot). Electrodes are not necessarily set off and are still available for measurement), and in at least some embodiments, if eight consecutive treatment cycles measure temperature overshoot with respect to a particular electrode, that electrode will It is set off for the rest of the treatment, the treatment continues otherwise, and does not otherwise modify the control loop process described below.

In step 1304, the target voltages of the main electrode and the other candidate electrodes are obtained. In this particular embodiment, the target voltage of a particular electrode is determined based on the treatment site of that electrode and the temperature error associated with the final target voltage calculated for that electrode (although not necessarily applied). be able to. Temperature error is the difference between the current temperature at the treatment site (eg, using a heat sensing device associated with an electrode close to the treatment site) and the measured temperature at the moment of treatment. Can be calculated by finding.

Those skilled in the art have described this particular embodiment as using voltage as a control variable, but based on, for example, a known relationship between output and voltage (ie, output is equal to voltage x current or impedance). You will understand that the output can be used as a control variable as an alternative to voltage.

FIG. 14 shows one embodiment of a subroutine that finds the target voltage of an electrode. At 1402, the temperature error from the target (T_e) From the actual temperature (T) (e.g. measured by the thermistor associated with that electrode) to the current target temperature (T)._g) Is subtracted. In 1404, determine if the temperature error calculated in 1402 is greater than 4 ° C (ie, if the target temperature is 68 ° C, then the temperature measured by the thermistor exceeds 72 ° C). to decide). If the temperature error is greater than 4 ° C, the subroutine assigns the electrode at 1406 a target voltage of zero for that treatment cycle. If the temperature error is not greater than 4 ° C, the subroutine goes to 1408 to determine if the temperature error is greater than 2 ° C. If the temperature error is greater than 2 ° C, at 1410 the subroutine assigns the electrode a target voltage that is 75% (or another percentage) of the last assigned target voltage for that electrode. If the temperature error is not greater than 2 ° C, in 1412 the subroutine can assign the target voltage to its electrode based on the following equation:

<maths num="3"><img id="000004" he="7" wi="159" file="JP6130397B2_D0001.tif" img-format="tif" img-content="drawing" /></maths>During the ceremony: V is the target voltage T_eIs the temperature error from the purpose, V_LIs the voltage of the last assigned electrode, K_L, K_PAnd K_IIs a constant n is a time value in the range of 0 seconds to t seconds.

In some embodiments, including the embodiment of FIG. 14, the following equation can be used:

<maths num="4"><img id="000005" he="13" wi="159" file="JP6130397B2_D0001.tif" img-format="tif" img-content="drawing" /></maths>During the ceremony: V is the target voltage T_eIs the temperature error from the purpose, V_LIs the voltage of the last assigned electrode, K_PIs a proportional control constant, K_IIs a constant of integral control.

In some embodiments, it may be advantageous to determine the target voltage using only the voltage of the last assigned electrode, rather than using the average of the voltages (s) from the previous treatment cycle. This is because, in some cases, the use of previous voltages may be the cause of calculation errors in embodiments that focus on fine-tuning the target temperature.

With reference to FIG. 13 again, when the target voltage is obtained for the main electrode and other candidate electrodes, it is determined in step 1306 whether the target voltage of the main electrode is greater than zero. If not greater than zero, at 1308 set the output voltage of the RF generator for that treatment cycle to the lowest target voltage determined at 1304 for the other candidate electrodes. If the target voltage determined for the main electrode in 1304 is greater than zero, then in 1310 the output voltage of the RF generator for that treatment cycle is set to the target voltage for the main electrode.

In step 1312, the main electrode and other candidate electrodes having a target voltage greater than zero are identified as electrodes to be excited. In an alternative embodiment, only the candidate electrodes other than the main electrode are excited when the target voltage obtained for those electrodes is 6 V higher than the set voltage.

In yet another embodiment, only the candidate electrodes other than the main electrode are excited when the target voltage obtained for these electrodes is 1V, 5V or 10V higher than the set voltage. In step 1314, it is determined whether the electrode to be excited is at a temperature higher than 68 ° C at that time. Electrodes at temperatures above 68 ° C are turned off or otherwise not excited during the treatment cycle, and electrodes that otherwise meet the above criteria are excited at a set voltage in step 1316. Another treatment cycle is then initiated and the control loop of FIG. 13 is repeated until treatment is complete. In some embodiments, each treatment cycle does not overlap with the previous and next cycles (eg, the step in FIG. 13 is performed completely before initiating the steps in the next cycle), but in other embodiments. Then, these cycles may overlap at least to some extent.

Figures 16-23 show over time the treatment using the Vessix system for renal denervation, using the control loop of Figure 13 to adjust the actual temperature at the eight electrodes of the device to the desired temperature profile. It is a table of temperature (purpose and actual) and target voltage. The target voltage shown in the table in these figures is not the same as the actual voltage applied to the electrodes, which, as mentioned above, uses the target voltage for only one of the electrodes for each treatment. It should be understood that this is to set the actual voltage applied in the cycle. As shown in FIGS. 16-23, the control loop of FIG. 13 functions to accurately maintain the actual temperature of each electrode of the device at the desired temperature. Similarly, as shown in FIGS. 16-23, the measured impedance, in some cases, reflects the increased mobility of ions in the tissue in response to high frequency RF energy. It may decrease over time (especially at the beginning of treatment).

An exemplary embodiment of the temperature control method described above can be used experimentally to provide an effective reduction in norepinephrine (NEPI) levels when used as part of Vessix's system for renal denervation. I know it. In one experiment, the efficacy and safety of Vessix's system for renal denervation, including assessment of renal NEPI concentration levels at 7 days post-treatment, were healthy at 7 and 28 days post-treatment. Evaluated in young Yorksha pigs. Figure 25 is a table summarizing the study design for this particular experiment. Efficacy of groups 1 and 2 was measured on day 7 in each animal as a percentage reduction in NEPI levels in treated arteries vs. untreated contralateral control kidneys. Figure 26 shows a decrease in percentage NEPI in both groups (as mean ± SD). Over the course of the study, there were no significant changes in body weight, body condition score or clinicopathological parameters in any of the animals. Overall, the average reference vessel diameter was similar across groups at all time points. Lumen acquisition or loss was calculated (mean preliminary autopsy-mean reference diameter) and presented with lumen acquisition similar to that of treated vessels compared to vessels of untreated animals. Representative angiographic images before renal artery treatment, 7 days after RF treatment, and 28 days after RF treatment are shown in FIGS. 27 to 30. Acute or chronic perforations, dissections, thrombi or embolisms were also not detected by angiographic analysis. e. Nerve signal stimulation and monitoring In at least some of the embodiments described above, or in alternative embodiments, renal denervation therapy methods and systems monitor neural signal stimulation and neural signal response in tissues close to the treated renal artery. Can be provided. In some cases, this electrical chart of neural activity can provide an assessment of the effectiveness of denervation therapy and / or provide feedback to regulate the treatment. In at least some embodiments, such electrograms are whether or not neural activity is present and / or whether or not they are shifted (eg, reduced) with respect to the measured reference values. Provides an assessment of the presence of neural tissue in the vicinity of the renal arteries without mapping or quantification.

In one embodiment, it is used to deliver a denervation treatment, such as the peers of the bipolar electrodes on the distal electrode pads 150a-d and the proximal electrode pads 170a-d shown in FIG. 1C. The same electrode assembly can be configured to stimulate neural signals as well as monitor neural signal responses. For example, one of a pair of proximal bipolar electrodes of one of the proximal electrode pads 150a-d can be used to stimulate neural signals and of the distal electrode pads 170a-d. One of a pair of distal bipolar electrodes can be used to monitor neural signal responses. Alternatively, the distal bipolar electrode can be used for stimulation and the proximal bipolar electrode can be used for monitoring. In these or other embodiments, stimulation and sensing can be performed by a pair of electrodes adjacent in the axial or circumferential direction.

Electrodes 222 with sizes, spacings, other geometries and other features as described above in the context of FIG. 2A can be sufficient for stimulation and monitoring of neural signals, but are alternative. In embodiments, the size of the electrodes can be further reduced and / or other features can be modified to provide higher signal resolution. Other modifications to the systems and devices described herein can be made to minimize interference with neural signal stimulation and (particularly) monitoring. For example, in some embodiments, the circuit layout of the system (such as the internal circuitry of the RF generator) and / or the wiring mating, twisting and other features associated with the catheter / flexion circuit are optimized. The inherent capacitance of the circuit can be reduced and the electric magnetic flux can be reduced.

In an alternative embodiment, the electrodes used to stimulate and / or monitor nerve signals may differ from the electrodes used to deliver energy therapy. Stimulation / monitoring electrodes can have position, geometry and other features optimized for stimulation / monitoring, and energy delivery electrodes can have position, geometry optimized for delivery of energy therapy. And may have other features. FIG. 42 shows the electrodes that deliver energy therapy (similar to the electrodes shown in FIG. 10), as well as the distal and proximal ends of the expandable device that stimulate and monitor neural signals. An example of a catheter containing a separate electrode (in the form of a circumferential ring electrode on the part) is shown. FIG. 43 shows an example of a catheter containing a separate proximal expandable device and a distal expandable device carrying a ring electrode that stimulates and monitors neural signals. The electrodes of FIGS. 42 and 43 can be bipolar and unipolar electrodes, respectively, or can form a bipolar electrode between the proximal and distal electrode rings. As shown in FIG. 24D, a schematic of the electrodes can be shown on the user interface to identify the available electrode regions to be excited, and sufficient tissue juxtaposition by impedance measurement. Can be further shown. It should be understood that the schematic image should not be limited to the type of electrode configuration present on the expandable structure, as the user interface may present the electrode configuration in schematic form. The electrode may be one or more of a ring, a pair of bipolar electrodes, a point electrode, an electrode elongated in the axial direction, and the like.

In a unipolar embodiment, the electrode acts as an anode that stimulates and senses during treatment, while a separate cathode is used as ground. The cathode can be located on the expandable structure at one or more points on the catheter body or outside the patient in the form of a ground pad. Signal processing and filtering (as described further below) are desirable options because of the relatively large differences in magnitude between energy delivery and detection of neural responses in unipolar configurations.

The RF generator and other circuitry of control unit 110, shown in FIG. 1A and described with respect to FIG. 1A, can be used to generate nerve stimulation signals and monitor responses, but in other embodiments. , A separate device can be associated with a system that generates nerve stimulation and / or monitors response.

In one embodiment, the nerve stimulation is a voltage in the range of about 0.1V to about 5V, or about 0.5V applied by the first electrode for a period of about 1 second or less or about 0.5 millisecond. This can be followed by pulse width modulation, which can shock the nerve tissue and propagate the nerve signal. The pulsed signal can be of any form in which the square wave is one exemplary form, which efficiently causes neural responses without ascending due to the rapid on-off nature of the waveform. This is to stimulate or form a peak voltage.

Nerve activity can be assessed by measuring one or more of the amplitude of the neural signal in response to the stimulus, the velocity of the neural signal in response to the stimulus, and / or the split amplitude of the neural signal. Here, the division amplitude refers to a net decrease in the nerve conduction signal and a change in the nerve conduction signal as compared with the reference value before the treatment. Pretreatment signals were expected to have relatively larger amplitudes and smoother gradient transitions, while signals from at least some treated nerves were blocked due to treatment. It is expected to have relatively smaller amplitudes and less smooth, steep or broken gradient transitions that exhibit nerve conduction. These measurements can be determined by measuring the change in voltage at the second electrode and / or the time measured between the stimulus and the response, and in at least some embodiments a neural signal. High-pass filtering and / or low-pass filtering can be used to distinguish from background noise.

Currently, interventional energy delivery therapies such as renal denervation are based on anatomical landmarks. In the example of renal denervation, it is known that most of the nerves are located along the length of the renal artery. Post-treatment assessments are based on secondary effects such as NEPI and decreased blood pressure, which are usually not shown immediately and do not show nerve viability.

At the current state of the art, there is no available means for directly assessing the functional behavior of renal nerves in real-time during renal denervation procedures. The solution to this problem is to use alternating or direct current to deliver subliminal or hypostimulatory signals in the vicinity of the renal nerves in the renal arteries to assess their activity before and after renal denervation treatment. It is to be.

High resolution rapid nerve viability measurements can be achieved by multiple local electrodes, such as the electrodes shown in FIGS. 1B and 1C, but the embodiment is for bipolar electrodes in a flexion circuit on a balloon. Note that it is not limited. Any electrode configuration (unipolar or bipolar) suitable for attachment to catheter-based expandable structures can be used, with ring electrodes, linear or spiral electrodes, point electrodes, etc. in baskets, balloons or It can be attached to any other such type of structure used in the catheter system.

The measurement technique uses electrical stimulation from at least one electrode across the nerve pathway to generate action potentials that spread along the excited nerve fibers. The action potential is then recorded at another point. This technique can be used to determine the appropriateness of conduction of nerve impulses as they flow through the nerve, thereby detecting signs of nerve damage. The transmission velocity (nerve conduction velocity) of the impulse is calculated using the distance between the electrodes and the time it takes for the electrical impulse to travel between the electrodes. A decrease in transmission rate indicates nerve damage.

The rate, amplitude and shape of the reaction after electrical stimulation of the renal nerve is measured by multiple electrodes on a balloon catheter. Abnormal findings include delayed conduction, blockade of conduction, lack of reaction, and / or low-amplitude reactions.

With reference to FIGS. 44 and 45, the morphology of electrical signals shows changes in neurotransmission as evidenced by changes in the degree of division combined with slow conduction. FIG. 44 shows a representative neural signal 4401 before treatment or in the reference state. FIG. 45 shows a representative neural signal 4501 after receiving at least some energy treatment. Comparing signal 4401 and signal 4501, it is clear that the amplitude of the neural signal is decreasing, while the pulse width is increasing. It is also clear that the gradient and gradient changes of signal 4501 are much smoother than the gradient and gradient changes of signal 4401. This shows how nerves respond to the energy treatments of the present disclosure, and when energy is delivered, nerve conduction properties are diminished or eliminated, thereby reducing nerve signals and continuity. It becomes untargeted and slower.

Nerve signal measurements can be optimized using signal filtering to filter the effects of cardiac electrical, stimulatory, and system noise from neural sensing circuits to optimize circuit accuracy and sensitivity. .. Signal filtering can be achieved through means such as bandpass filters. Sensitive by the circuit, for example, using a low-pass filter in the range of about 1 Hz to about 500 Hz, where the exemplary value is 100 Hz, and a high-pass filter in the range of about 1 kHz to about 10 kHz, where the exemplary value is 5 kHz. The frequency band of the signal to be measured can be established. The measurements are then used as feedback applied to the energy control algorithms used to regulate the delivery of therapeutic energy.

In a unipolar embodiment, the sensing is from a wider area of tissue, as energy flows from one or more anodes of the electrodes to the cathode (s) of the common ground path. Applying this concept to the embodiments of FIGS. 1B and 1C, an exemplary polarity is to use an external pathway (not shown) as the anode, while electrode assemblies 140a-d are used for neural signal measurements. Serves as a cathode for common grounding circuits. In this seemingly reverse application of energy for sensing purposes, the electrode assemblies 140a-d are closer to the subject nerve tissue and thus have improved sensing accuracy by serving as a cathode for sensing. Can provide sex. During the energy delivery mode of treatment, the polarity of the external patch and electrode assembly 140a-d can be switched such that the electrode assembly 140a-d is the anode and the external patch is the cathode for grounding.

In the bipolar embodiment, the sensing is tissue localization because the anode and cathode of the electrode assemblies 140a-d are in close proximity and therefore the perceived tissue volume is much more localized than in a unipolar configuration. It is from the cathodic area. The proximity of the electrode poles in a bipolar arrangement allows for less energy delivery inherently to excite the tissue due to the proximity of the poles, and inherently higher measurements due to the smaller tissue volume between the poles. It may be desirable because it allows for resolution. In addition, the configuration of electrode assemblies 140a-d provides proximal / distal linear spacing that allows the sensing and measurement of linear movement of neural signals along the pathway as described herein. ..

Nerve signal stimulation and measurement can be performed before, during, and / or after energy therapy. In one embodiment, the nerve activity was evaluated before treatment nerve activity and establish a baseline level of resistance, then again evaluated after treatment to change the threshold level of nerve activity is determined whether caused .. In the target tissue, one or more of a decrease in the amplitude of the neural signal, a degree of division of the signal gradient, an increase in the duration of the neural signal pulse, and an increase in the time between the neural signal pulses are used. The tissue response indicating that denervation has occurred or is occurring can be measured. In other words, a total interruption of nerve activity can be a delayed response to denervation treatment, but some reduction in nerve activity sufficient to show the effectiveness of the treatment is during or immediately after denervation treatment. Can occur in. In an alternative embodiment, effective denervation can be characterized as undetected neural signals in response to a given stimulus.

Evaluation of neural signals can be performed similarly or alternatively during energy therapy. For example, the control algorithm shown in FIG. 13 can be modified to allow time-scale measurements of stimulated nerve activity before or after each electrode activation cycle (such measurements are in milliseconds). , Microseconds, nanoseconds, picoseconds, etc.). Measurements between these cycles can be compared to pretreatment reference values, previous cycle measurements or other standards.

In some embodiments, whether the evaluation of neural activity is performed pre-treatment and post-treatment, periodically between each treatment cycle, or after a certain number of treatment cycles. Data from the assessment of nerve activity can be used to establish or adjust parameters for denervation therapy. For example, in the embodiments shown by FIGS. 13 and 14, the set voltage for each cycle may vary depending on the previously applied voltage and the measured and averaged temperature error, but the total treatment temperature. The time may vary depending on the measured neural activity or the deviation of the measured neural activity from a previously measured or preset reference value. One or more of the measured amplitude of the neural signal, the velocity of the neural signal, and / or the split amplitude can be considered in such an algorithm. Therefore, the total treatment time can be shortened if a large decrease in nerve activity is measured early in denervation treatment. Conversely, if the evaluation of nerve signals does not measure a decrease in nerve activity, the total treatment time can be long. Of course, feedback from the evaluation of neural signals (s) can be used to alter additional or alternative parameters of denervation therapy.

The measurement of neural signals can be directly integrated with the energy delivery and control methods described herein. Once the candidate electrodes are selected and excited according to the control algorithm, additional functions of neural signal measurement can be integrated into the control algorithm, whereby additional regulators of the neural response deliver energy and the therapeutic response. While increasing the accuracy of achieving the above, avoiding the delivery of extra energy to maintain the tissue cell state before treatment as much as possible. As shown in FIG. 13A, a further control loop step 1313 can be used to assess whether the neural signal reduction threshold is met. If the neural signal reduction threshold is not met, the control loop then proceeds to loop step 1314 to determine if the candidate electrode has reached the temperature threshold. If it is determined in loop step 1313 that the nerve has reached the signal reduction threshold, the electrode can be deselected as a candidate electrode and excited. Treatment of small / branched blood vessels and other passages The systems and devices described herein can be advantageously used in situations where other energy-based therapeutic systems and devices are unsuitable. For example, the system and device embodiments described herein can be used in blood vessels and other passageways that are too small to be treated with other catheter-based energy therapy systems. In some cases, the systems and devices described herein can be used in renal arteries or other blood vessels with diameters less than 4 mm and / or lengths less than 20 mm. Other factors, such as twisting of blood vessels and the proximity of the treatment site to areas that should not be treated, are contraindicated or otherwise suitable for treatment with previous devices. It may not be, but it is not the case in at least some embodiments of the systems and devices described herein.

Figures 1D and 1E show 4mm and 5mm balloons with three electrode assemblies, respectively. However, the particular geometry of these electrode assemblies, and the other features described in the preceding section, are those electrode assemblies in balloons of 1 mm, 2 mm or 3 mm, or smaller diameter balloons such as intermediate sizes thereof. Make it easy to use. In some cases (as in some 1 mm embodiments), the balloon may not include the guidewire lumen. FIG. 46 shows one embodiment of a balloon having a body 4601 made of Kapton®, a flexible polyimide membrane available from DuPont , and a shoulder 4602 made of standard balloon material. ing. In some cases, the Kapton® body of the balloon of FIG. 46 is used to separate the flexible circuit assembly used in the balloon, eg, to eliminate the bottom layer 202 shown in FIG. 2B. The need for layers can be eliminated, thereby reducing the profile of the flexible circuit assembly.

Other features of the systems and devices mentioned above can also facilitate their use in relatively small blood vessels. For example, delivering energy therapy to a small diameter blood vessel may require particularly fine control of the amount of energy delivered and / or the temperature rise caused by the therapy. Therefore, the geometry of energy delivery of a particular electrode, control algorithms, and other features described above can make the systems and devices of the invention particularly suitable in such situations.

FIG. 47 schematically shows a typical major renal artery 4701 branching from the aorta 4702 to the kidney 4703. An embodiment of the present disclosure is shown in which the balloon and electrode assembly 4704 of the catheter is extended and positioned for the treatment of tissue. An energy dose is applied and the balloon is then deflated or repositioned.

FIG. 48 schematically shows the main renal artery 4801 and the auxiliary renal artery 4802 branching from the aorta 4803, both extending to the kidney 4804. Auxiliary arteries can range in size from about 1 mm to about 5 mm in diameter. It should be understood that the renal artery of FIG. 48 is a simple schematic, although it may vary from subject to subject in vivo. For example, arteries can vary in diameter, length, twist, position and number. Moreover, these can vary with respect to each artery and each subject. FIG. 48 shows a first balloon catheter A positioned for treatment in a smaller auxiliary artery and a second balloon catheter B positioned for treatment in a larger major renal artery. There is.

In practice, catheter A and catheter B can be integrated if the two arteries are close enough in diameter to allow complete balloon dilation and contact with tissue in the arterial lumen. obtain. It may even be possible to reposition Catheter A and Catheter B along the length of each artery depending on the treatable length of each artery. It may even be possible to treat the major and auxiliary arteries simultaneously if desired by the physician.

To the best of our knowledge, prior to this disclosure, the technical limitations caused by overheating of small arteries, space constraints during operation in luminal areas with smaller cross sections, and difficulty in following twisted paths. Therefore, adjunctive renal artery treatment was not possible. The embodiments of the present disclosure use an expandable catheter-based structure, electrodes of flexible circuits on a balloon, thus eliminating the limitations of "universal sized" devices. The balloon and electrode assemblies of the present disclosure are progressively sized and arranged to facilitate a precisely controlled dose of thermal energy over a gradual range of lumen diameters. In other words, the balloon and electrode assemblies are progressively sized and placed for optimized movement in the corresponding size lumen. The number of electrodes is chosen to avoid overheating of the tissue. The balloon-based expandable structure is capable of traveling to a position with a smaller unexpanded diameter while being flexible. The large surface contact of the expanded balloon allows uniformity in tissue contact while avoiding bending and / or tight space constraints of single point probes or other similar designs.

Auxiliary renal arteries are present in 25% to 30% of human patients, but these patients have been excluded from previous renal denervation studies. In a REDUCE-HTN clinical study (the entire content of Vessix Vascular's clinical study protocol CR012-020 is incorporated herein by reference), a subset of four subjects were placed longitudinally and circumferentially on the balloon surface. Vessix Vascular, Inc., including a 0.014 inch (0.3556 mm) over-the-wire percutaneous balloon catheter with up to eight radiation-impermeable gold electrodes mounted in an offset pattern. Laguna He received successful treatment of the main renal artery and at least one auxiliary renal artery with Hills, CA). In an exemplary embodiment, the catheter is connected to a proprietary automated low power RF bipolar generator that delivers a temperature controlled therapeutic dose of RF energy at about 68 ° C for about 30 seconds. The mean standard office blood pressure (OBP) for this cohort was 189/93 mmHg. In addition to the average of 10.5 denervation of each of the major renal arteries, this cohort was treated with an average of 8 denervation per adjunctive renal artery.

In this study, no perioperative complications were reported for 4 subjects, and angiography immediately after treatment showed no renal artery spasm or any other adverse effects. These four subjects had a mean reduction in OBP of -32 / -16 mmHg (190/97 to 167/91, 175/92 to 129/70, 192/94 to 179/91, 183/87 to 138). It showed improvement 2 weeks after the procedure with / 55).

49 and 50 schematically show a non-limiting example of renal denervation therapy in which energy delivery is selectively delivered using a subset of the electrodes in the electrode assembly. FIG. 49 schematically shows the renal artery 4901 containing the bifurcation 4902. In this example, the balloon and electrode assembly 4903 is positioned within the renal artery so that one of the electrodes 4904 is close to the entrance where the branch joins the renal artery and is therefore not juxtaposed with the vessel wall. As mentioned above in some embodiments, the systems and methods according to the present disclosure selectively excite an electrode or a subset of electrodes juxtaposed with the vessel wall (eg, electrodes 4905 and 4906 in FIG. 49), but the vessel. Electrodes that are not juxtaposed to the wall or a subset of electrodes (eg, electrode 4904) can be configured to be non-excited. Those skilled in the art will appreciate that the electrode assembly and the vessel wall are the result of various other factors, including, but not limited to, twisting of the vessel, changes in vessel diameter, presence or absence of accumulation on the vessel wall, in addition to the example of FIG. You will understand that they are not completely juxtaposed.

Figures 50A and 50B schematically show a non-limiting example of renal denervation therapy in which energy therapy is performed at two locations within the renal artery 5001 using electrode assemblies and balloons. In FIG. 50A, the balloon is positioned so that all of electrodes 5002 to 5005 are within the renal artery 5001 and are potential candidates for excitation. In FIG. 50B, after energy therapy at the location shown in FIG. 50A, the balloon and electrode assembly remains partly in the renal artery 5001 and partly in the aorta 5006. Is pulled out like this. In the positioning shown in FIG. 50B, certain embodiments of the systems and methods of the present disclosure are positioned within electrodes 5002 and 5005 (and / or renal artery 5001 and / or juxtaposed with the wall of renal artery 5001. Only any other electrode that is present) is configured to be selected as a potential candidate for excitation, and the electrode within the aorta 5006 is not specified as a candidate for excitation. As shown by FIGS. 50A and 50B, certain embodiments of the present disclosure join the aorta 5006 to the renal artery 5001, which can be a relatively concentrated area of nervous tissue in at least some patients. It can facilitate the delivery of energy to tissue at or near the entrance.

Although exemplary embodiments have been described in some detail as examples and for clarity of understanding, one of ordinary skill in the art will recognize that various modifications, adaptations and modifications can be used.