INTRAVASCULAR TISSUE DISRUPTION

Medical systems and devices adapted to deliver a fluid agent to target tissue within a patient.

INCORPORATION BY REFERENCE

BACKGROUND

Medical fluid delivery systems have been described that can deliver fluid to a target location within a patient. In some applications a fluid source houses a fluid that is delivered from the fluid source through a delivery device positioned in the patient and into the patient. Needleless applications include a delivery device that has an aperture therein, and fluid is allowed to be moved from the fluid source, through the delivery device, out of the aperture, and into the patient.

Some applications attempt to generate a transient relatively high fluid pressure at a location along the fluid path in an effort to deliver the fluid into the patient at a relatively high velocity. U.S. Pat. No. 6,964,649, for example, describes a fluid source that is capable of generating a transient high pressure to deliver fluid into tissue. Deficiencies of these and other previous attempts are set forth in more detail below.

SUMMARY OF THE DISCLOSURE

One aspect of the disclosure is a method of delivering fluid into a patient, comprising: maintaining a fluid agent under a substantially constant high pressure within a fluid reservoir; opening a fluid control downstream of the fluid reservoir from a closed configuration to allow the fluid agent maintained at substantially constant high pressure to flow under high pressure from the fluid reservoir to a fluid aperture disposed downstream to the fluid control; and delivering the fluid agent at high velocity out of the aperture and into the patient.

In some embodiments opening the fluid control downstream the fluid reservoir comprises opening a fluid control that is disposed external to the patient.

In some embodiments the method further comprises positioning a delivery device comprising the aperture within a renal artery, and wherein the delivering step comprises delivering the fluid agent at high velocity out of the aperture and into the patient such that the fluid agent interacts with nerves surrounding the renal artery and disrupts neural communication along the nerves to reduce hypertension.

In some embodiments maintaining a fluid agent under substantially constant high pressure comprises maintaining a fluid agent at between 750 psi and 5000 psi.

In some embodiments the method further comprises positioning a delivery device comprising the aperture within a lumen, and positioning the aperture such that it faces radially outward from the longitudinal axis of the delivery device. The method can also include expanding an expandable member to position the aperture into engagement with the lumen wall. Expanding the expandable member can reconfigure a fluid delivery line secured to the expandable member.

In some embodiments the method further comprises closing the fluid control to thereby control the volume of the fluid agent that is delivered out of the fluid aperture.

In some embodiments delivering the fluid agent at high velocity out of the aperture and into the patient comprises delivering the fluid agent at between 50 m/sec and 400 m/sec.

In some embodiments the fluid agent flows out of the fluid reservoir at between about 5 mL/min and about 40 mL/min.

In some embodiments delivering the fluid agent at high velocity out of the aperture and into the patient comprises delivering the fluid agent in a fluid pulse with a duration of between about 50 and 500 msec.

In some embodiments delivering the fluid agent comprises delivering the fluid agent in a fluid pulse of between about 10 uL and about 500 uL of the fluid agent.

One aspect of the disclosure is an apparatus for delivering fluid to a target location within a patient's body, comprising: a high pressure source adapted to maintain a fluid within a fluid reservoir at a substantially constant high pressure; a fluid delivery device comprising a fluid delivery aperture, wherein the delivery device is adapted to be positioned within the patient; and a fluid control disposed downstream the high pressure source and upstream the aperture, wherein the fluid control is configured to control the flow of fluid therethrough and to modify fluid communication between the fluid reservoir and the fluid delivery aperture.

In some embodiments the fluid control is a valve with an open configuration and a closed configuration.

In some embodiments the fluid control is adapted to be disposed external to the patient.

In some embodiments the apparatus further comprises an expandable member adapted to reposition the aperture against the lumen wall.

In some embodiments the fluid control is adapted to be activated from an off state to an on state and then back to the off state, with both on/off and off/on transitions less than about 15 msec.

In some embodiments the fluid delivery aperture has a diameter between about 1 mil and about 5 mils.

In some embodiments the high pressure fluid source is adapted to maintain a fluid agent under pressure between 750 psi and 5000 psi within the fluid reservoir.

DETAILED DESCRIPTION

The disclosure herein relates generally to medical devices, and particularly to systems and methods of use for delivering a fluid agent to a target location within a patient. In some embodiments the devices and systems herein are used to deliver a fluid agent out of an aperture in a delivery device, through tissue adjacent the aperture (which may be referred to herein as “intermediate tissue”), and to target tissue that is more distant from the aperture than the tissue adjacent the aperture (which may be referred to herein as “target tissue”). Exposing the target tissue to the fluid agent causes a desired change in the target tissue.

In some embodiments it is desirous to cause minimal damage to the intermediate tissue while delivering the fluid agent to the target tissue. Minimal damage to the intermediate tissue is generally considered similar or less than is caused by a small gauge needle penetrating the intermediate tissue, and substantially less than is caused to the intermediate tissue by the delivery of RF ablation energy delivered at the lumen wall for treatment of a tissue peripheral or distant to the lumen wall. If RF energy is delivered the lumen wall will sustain more damage than the target tissue because the RF energy source is adjacent to the lumen wall and the energy density at the lumen wall is greater than at the target tissue. As described herein the fluid agent pierces through, or penetrates through, the intermediate tissue with minimal damage to the intermediate tissue. One manner in which the damage is minimized is by delivering a high velocity fluid jet out of the aperture. The disclosure herein focuses primarily on creating the high velocity fluid jet by creating a relatively high pressure gradient across a relatively small fluid aperture. The high velocity fluid delivery also ensures that minimal leaking of the fluid agent into the lumen occurs when the fluid agent is delivered out of the aperture.

The one or more apertures can be positioned in any lumen within the body, and as used herein “lumen” includes spaces in the body other than tubular structures. For example without limitation, any portion of the vasculature, the interior of the gastrointestinal tract, the esophagus, urethra, and the stomach are “lumens” as used herein.

In some embodiments the intermediate and target tissues are characterized as the same type of tissue, but the target type of tissue is more distant, relative to the aperture, than the intermediate type of tissue. In some embodiments the intermediate and target tissues are different types of tissue.

An exemplary situation in which it may be desirable to minimize damage to the intermediate tissue is when the fluid is being delivered through the lumen of an arterial wall to target tissue peripheral to the lumen wall. For example, as descried herein, in some uses the fluid is delivered at high velocity through a renal artery lumen and wherein the target tissue is the medial layer and/or adventitial layers, in which nerves that innervate the kidneys are disposed. In some methods of use it is desirable to deliver a fluid agent to the medial and/or adventitial layers to disrupt the neural tissue, while minimizing the damage to the renal artery lumen wall.

The systems herein include a fluid reservoir adapted to house a fluid agent therein. The systems also include a delivery device with at least one aperture adapted to allow for the delivery of the fluid agent from the reservoir and out of the aperture and into the patient at high velocity. The velocity of the fluid exiting the aperture is related to the pressure gradient of the fluid agent across the aperture, among other variables. Some previous approaches have attempted to generate a high transient fluid pressure at a fluid reservoir disposed external to a patient in order to generate a high velocity fluid delivery within the patient. In embodiments herein, however, the systems and methods of use generate the high velocity fluid delivery into the patient by maintaining the fluid in the fluid reservoir at a high pressure. While the fluid agent is being maintained under high pressure in the fluid reservoir, a fluid control distal, or downstream to, the fluid reservoir is opened, which delivers the fluid agent under high pressure out of the fluid reservoir, towards the aperture, and out of the aperture at a high velocity.

FIG. 1illustrates conceptually an exemplary fluid delivery system102that includes high pressure fluid source104that is adapted to maintain a fluid agent under high pressure, a high pressure fluid control, and fluid delivery device106capable of communication with high pressure fluid source104. High pressure fluid source104includes at least one fluid reservoir adapted to house a fluid agent therein. Delivery device106includes at least one fluid delivery lumen adapted to receive fluid from the fluid reservoir, and at least one aperture, or port, adapted to allow the fluid agent to be delivered into the patient from delivery device106.

FIG. 2depicts a portion of an exemplary fluid delivery system illustrating fluid reservoir230adapted to house a fluid agent therein, inline fluid control210, and optional bypass fluid control220. Fluid controls210and220can be any type of suitable valve. Fluid control210is disposed between delivery device inflow201and the fluid reservoir230. Bypass fluid control220“T's” off the outflow line and empties to a low pressure exhaust point such as ambient pressure. During idle, fluid control210is in a closed configuration and fluid control220is in an open configuration. In idle, also referred to herein as the primed state, the fluid in fluid reservoir230is maintained under substantially constant high pressure. When fluid is to be delivered from the reservoir230under high pressure, fluid control220is closed, and fluid control210is then opened for the requisite period of time to cause the fluid to be delivered under high pressure out of the reservoir. Fluid control210is then closed and fluid control220is opened. In some procedures fluid control220may be opened only long enough to relieve pressure in the fluid delivery system. This sequence causes the inflow to the delivery device to be vented through fluid control220and a more rapid pressure decrease on the delivery device. As described above the rapid pressure decrease helps minimize the amount of fluid leaked into the lumen, if desired. The dotted arrows indicate the directions of flows across the two valves. In some embodiments where relatively small amounts of leakage of the delivered agent into the body lumen is allowable, valve220may not be required.

An exemplary advantage in using a system shown inFIG. 2is that because the high pressure source holds therein multiple doses and the valve is operable at high rates, the system can be used for multiple fluid deliveries without re-filling.

In any of the embodiments herein, the fluid source maintained at a substantially constant high pressure may be maintained at high pressure by means of, for example without limitation, pneumatic, hydraulic, or mechanical means such as one or more springs.

FIG. 3illustrates an exemplary high pressure fluid source. The fluid source includes low pressure fluid reservoir340, high pressure fluid pump330, inline fluid control310, and return valve320. When idling, bypass fluid control320is open and inline fluid control310is closed. Fluid is then circulated through low pressure340reservoir during idle. During an injection, fluid control320is first closed for a period of time generating high pressure in the system to prime the fluid source. Fluid control310is then opened for an appropriate duration thereby delivering fluid at a rate consistent with the pump flow rate. Fluid control320is then opened and fluid control310is closed. In both of the described configurations the outflow resistance associated with the delivery device is much higher than the return path resistance. Pressure therefore drops rapidly in the outflow path when the bypass fluid control320is opened. This quick drop in pressure in the outflow path helps prevent leakage of the fluid agent into the lumen in which the medical device is positioned, if in fact this is desired.

Fluid controls as described herein can be any type of suitable valve, such as, for example without limitation, shuttle valves or poppit valves. In some embodiments the valves are actuated by interfacing a control interface with a system controller.

FIG. 4shows an exemplary breadboard fluid control system configured for a pump source described inFIG. 3that was used to investigate the characteristic associated with needle-less injections into renal artery tissues. The system is comprised of an outflow401for interfacing with a delivery catheter, pressure transducer405for monitoring the pressure at the outflow port401, inline fluid control410, bypass fluid control420; low pressure fluid reservoir409, high pressure pump source408, controller interface402, and a personal computer used as a controller (not shown).

FIG. 5illustrates an exemplary embodiment of a high velocity fluid delivery system adapted to deliver a fluid agent under high pressure into a patient. System500includes system controller510, delivery device520, and delivery device control interface530. The system controller may be a completely mechanical system or may comprise an electro-mechanical interface. The system controller (non-sterile) can be designed to be reusable, while the delivery catheter control interface and delivery catheter (sterile) can be designed to be discarded after a single use. In some embodiments, the features of the system controller, delivery device, and control interface are incorporated in a single disposable unit. Delivery device control interface530comprises an optional expandable member control interface, a fluid source, and a fluid control block. The expandable member can be in the form of a balloon, self-expanding structure, or any other suitable expandable or deformable member. In some embodiments the fluid source is a pump capable of delivering appropriate flows at the desired pressures as described herein, or a reservoir maintained at the appropriate operating pressure as described herein. Delivery device520is generally configured for endovascular or endoluminal delivery. Delivery device as used herein can be any type of suitable delivery catheter or other suitable medical device that can be positioned within a patient. The delivery device is shown including catheter shaft521, the proximal end of which interfaces with delivery device control interface530. The distal region of delivery device520comprises expandable member523, radio opaque markers524, a high pressure delivery lumen (not shown), and features associated with facilitating rapid exchange on a guide wire. Delivery device also includes an aperture near expandable member523adapted to deliver fluid into the patient.

FIGS. 6 and 7illustrate an exemplary high pressure fluid source, which can be used as high pressure fluid source104fromFIG. 1. The high pressure fluid source includes power source615, fluid reservoir613with fluid612therein, outflow control valve611, and delivery device610. The fluid source also includes optional fluid input616and optional fluid fill valve617, and vents618in both power source615and fluid reservoir613through which air is pushed or pulled depending on the use of the system. Power source615includes power mechanism614, which in some embodiments can be a spring, compressed gas reservoir as shown, or other suitable mechanisms for generating power. Power mechanism614is adapted to push piston620distally within fluid reservoir613to maintain fluid612in fluid reservoir613under high pressure while valve611is closed.FIG. 6illustrates the system in a primed configuration, ready to delivery fluid612. Fluid612is maintained under a pressure high enough to source an aperture in delivery device610at a pressure sufficient to allow for a high pressure fluid agent injection. In use, after the system is primed as shown inFIG. 6, fluid control611is opened and fluid is delivered from reservoir613, through open control611, and through delivery device610and out an aperture in the delivery device (not labeled but described below).FIG. 7illustrates the system at the conclusion of a high pressure injection after the front face seal619of piston620has seated on the distal surface fluid reservoir613thereby cutting off the flow of fluid to delivery device610. Fluid control611can then be closed in preparation for subsequent injections of fluid. In the embodiment inFIGS. 6 and 7the reservoir houses fluid for one fluid delivery. The fluid delivery step involves delivering the entire volume of fluid housed in reservoir612at one time. The reservoir can subsequently be re-filled with fluid, either manually or automatically. The front face seal619in the embodiment inFIGS. 6 and 7allows for precise control of delivered fluid volume in a system which only requires that valve611be opened rapidly. This is in contrast to the system ofFIG. 2in which valve210must be both opened and closed to facilitate a controlled volume of delivery. One exemplary advantage of the system inFIGS. 6 and 7is primarily in the reduced complexity and therefore cost of the fluid control mechanisms.

FIG. 8is a graph illustrating pressure vs. time and illustrates the pressure of the fluid within the fluid reservoir613inFIGS. 6 and 7, which is represented by the solid line, and the pressure of the fluid distal to fluid control611, which is represented as the dashed line. Time epoch T1is the time period after which the system has been primed (FIG. 6), and pressure822indicates the high fluid pressure of fluid612within fluid reservoir613. Time epoch821indicates the period in which the high pressure fluid is in communication with the delivery system610, and pressure824is the high fluid pressure during the delivery phase. There is a negative pressure difference between time epoch821and time epoch T1. Time epoch T3is the time period following the fluid delivery after seal619closes. During time epoch T3the fluid pressure of fluid612within reservoir613returns to pressure822.

The dashed line inFIG. 8represents the fluid pressure at a location distal to fluid control611. During time epoch T1, after the system is primed, this pressure is zero. During time epoch821when the fluid agent is delivered, control611is initially opened and fluid612is released under pressure from fluid reservoir613. The fluid is forced down the fluid line lumen to the aperture. The pressure distal to fluid control611in time epoch821therefore increases abruptly to pressure824, and after the fluid has been delivered from the aperture, as indicated in time epoch T3, the pressure distal to fluid control611drops abruptly back to ambient.

As can been inFIG. 8, there is a negative pressure change in the fluid in the fluid reservoir as the fluid delivery begins. This change can be made arbitrarily small by increasing the capacitance of power source615. It is of note that a positive pressure transient is not created in fluid at the fluid source during the fluid delivery step because the fluid is primed to be under high pressure. The velocity of the fluid delivered out of the aperture in the delivery device is sufficient to pierce tissue with minimal damage and yet expose the target tissue to a sufficient volume of tissue to disrupt the target tissue as needed.

As used herein, fluid that is “maintained” under high pressure refers at least to the fact that the system is maintained in a primed state under high pressure. When primed under high pressure, a fluid control is then opened distal to the fluid reservoir to release the fluid primed and maintained under high pressure. This is different than systems that generate a high pressure transient at the fluid source and thereby do not require a control valve downstream the fluid reservoir.

FIG. 9illustrates an embodiment of a system in which an exemplary high pressure fluid source915is coupled to elongate delivery device960. In this embodiment the high pressure source comprises a fluid reservoir adapted to house a volume of fluid sufficient for multiple discrete fluid injections and associated control mechanisms capable of controlling the volume of an individual injection. As shown primary power source915is pneumatically driven, but may be, for example, hydraulically or spring driven. Power source915comprises relatively low pressure fluid source930that is used to power pilot valve940. Pilot valve940comprises valve seat941adapted to interface with a high pressure piston945. High pressure piston945is in turn coupled to low pressure piston944. The surface areas of pistons944and945are sized such that the pressure generated in the chamber at the valve seat941by pilot valve940is greater than the pressure generated in the high pressure fluid source. Pilot valve volume adjustment is facilitated by volume adjustment943. Low pressure fluid in low pressure fluid source930is communicated through adjustable fluid resistor932and 3-way valve931to the low pressure side of adjustable pilot valve940. Exemplary usage in the system is as follows. As the pressure generated by the low pressure fluid source930on the pilot valve low pressure piston944is sufficient to generate a pressure greater than that generated in the high pressure fluid, the pilot valve is in the off, or closed, position.

FIG. 9shows valve940in an open, or on, configuration. Before the fluid is delivered a delivery volume is defined by adjusting volume adjustment943some distance away from low pressure piston944surface. When valve931is then momentarily reconfigured for flow from “b” to “a” to flow from “b” to “c”, the low pressure fluid pressure drops to ambient on the low pressure side of pilot valve940. The pilot valve piston then shifts position until it encounters the volume adjustment943and the valve seat is opened. What is meant by momentarily in this context is a time sufficient for the pilot valve piston to shift to the fully open position. On re-attaining the default configuration of valve931where flow is “b” to “a,” low pressure fluid begins to leak back into the low pressure side of the pilot valve940at a rate defined by the value of the adjustable fluid resistor932. The length of time to close the pilot valve940is therefore adjusted by both the length of travel (required volume) defined by adjustment of adjuster943and on the filling rate defined by fluid resistor932. The delivered volume of fluid is therefore the volume associated with period during which the pilot valve is open. In alternative embodiments only one of the two controls932and943are included. In others one will be used as a calibration means and the other as a user control.

The embodiment inFIG. 9can be modified to include a sensor such as a pressure transducer (such as the pressure transducer shown in the embodiment above inFIG. 4) or other means to infer velocity. The sensor can be added, for example, at valve seat941. The sensor is adapted to provide feedback information indicative of the pressure differential across the delivery aperture, or the velocity of the fluid. An exemplary method of use compares the feedback data from the sensor with reference data to determine if the pressure is sufficiently high, or if the velocity is sufficiently high. If either parameter is not high enough damage may occur to the intermediate tissue, which can be disadvantageous when the intermediate tissue is, for example, an arterial wall. Alternatively, if either parameter is not high enough it can be determined that the fluid agent was not delivered at a high enough pressure or velocity and therefore did not adequately reach the target tissue (i.e., the target tissue was not adequately exposed to the fluid agent). If this is the case the method could include delivering one or more jets of fluid, and again determining if either the pressure or velocity were sufficiently high. In addition or alternatively to comparing the peak or plateau pressure to reference data, the time of the rise in pressure from baseline to peak or plateau can be determined and compared to reference data. When the pressure does not rise from baseline to peak or plateau quickly enough, damage to the intermediate tissue may not be minimized. In some embodiments it is determined if the rise in pressure occurs over a time longer than 15 msec, and in some embodiments over a time longer than 5 msec. If it does take longer than the reference time, feedback can be provided that indicates that, for example, the fluid delivery was ineffective or that damage occurred to the intermediate tissue. Towards this end it is also useful to purge the system with one or two test shots prior to deployment of the device adjacent to the target tissue. Doing so insures that air is not trapped in the system. Air trapped in the system can compress, and thereby slow the rise time of the pressure pulse.

FIGS. 10 and 11illustrate alternative embodiments of alternate metering outflow valve variations.FIG. 10illustrates valve1045secured to delivery device1010. InFIG. 10metering adjustment1043is linearly displaced an amount “A” such that linear displacement “A” equates to the expected delivered volume. Piston1043seals against the inner walls of valve1045. Fluid resistor1032has very high fluid resistance and allows fluid to translate from one side of piston1043to the other as adjustments are made. A high pressure source1013feeds fluid into metering valve1045on the upstream side of piston1043. When control valve1011is opened a slight pressure differential develops across piston1043driving it to the right in the figure, closing fluid off at valve1019. Fluid resistor1032is sized such that its resistance is sufficient to limit fluid flow from one side to the other at the change in pressure associated with the piston displacement during fluid delivery. In alternative embodiments the external resistor1032can be incorporated into piston1043or it can be inherent in the design of the interface between piston1043and the cylinder wall.

FIG. 11illustrates an embodiment similar to the embodiment shown inFIG. 10. In the device shown inFIG. 11, when valve1111is opened, a small pressure differential is generated across piston1143by fluid resistor1132. As in the embodiment ofFIG. 10the fluid resistor may be incorporated in the piston or the interface of the piston and the cylinder wall. When valve1111is opened, piston1143will travel distance A and seal against the distal end of the cylinder, thereby delivering a volume equivalent to distance A times the area of the cylinder. When valve1111is closed, pressure will equalize across piston1143and spring1119will return the piston1143to its primed position.

FIGS. 12 and 13illustrate two variations of the system ofFIGS. 6 and 7which incorporate automatic high pressure refilling systems. InFIG. 12, high pressure delivery system1200is similar to the system ofFIGS. 6 and 7with the exception that volume control mechanism1201is incorporated in the high pressure reservoir. High pressure refilling system1210comprises a power source1211interfaced with a high pressure fluid source1212, which in turn is interfaced with high pressure delivery system input valve1217and optional filling valve1213. High pressure refilling system1210is configured such that the pressure within high pressure refilling reservoir1212is maintained at a pressure somewhat greater than the pressure in the high pressure delivery system1200. In use, volume adjustment mechanism1201is adjusted to the appropriate volume. Valve1217is then opened allowing fluid to pass from the refill reservoir to the high pressure delivery reservoir. Valve1217is then closed and the high pressure delivery system is ready to use. Optional valve1213may be used to fill the refilling reservoir. As depicted inFIG. 12the power source1211is a low pressure pneumatic drive where the drive pressure will be equivalent to the low pressure drive pressure times the ratio of the surface areas of the power source piston/high pressure refilling reservoir. InFIG. 13the high pressure delivery system input valve1217has been replaced by a three way valve1302, but other similar components are similarly labeled.

The delivery devices described herein, which are indirectly or directly coupled to the substantially constant high pressure fluid source, have at least one aperture therein adapted to allow a fluid agent to be delivered from the fluid source and out of the aperture under high velocity.

FIGS. 14 and 15illustrate two exemplary distal regions of two exemplary delivery devices.FIG. 14illustrates a distal region of a deliver device1400that includes an over-the-wire configuration for delivery. The delivery device includes catheter shaft1401, comprising high pressure fluid delivery line1405, expandable member1403, a guide wire lumen (not labeled), balloon inflation lumen (not labeled), and radio opaque markers1404. Expandable member1403is shown as a rigid 20 mm long and 6 mm diameter cylindrical balloon but can have other configurations, and is secured to the outer surface of the distal region of catheter shaft1401. High pressure fluid line1405has at least one aperture formed therein in its distal region, and is secured to expandable member1403such that a fluid jet aperture (which is not visible but is included in the device) faces (i.e., opens) radially outward from the long axis of the expandable member1403. The aperture can be anywhere along the length of fluid line1405, but in this embodiment is positioned at the longitudinal center of expandable member1403.

In an exemplary use, the delivery device is primed with fluid so that fluid is disposed in the delivery device fluid delivery line. A delivery catheter, examples of which are well known, is advanced to a region of interest within the patient. A guidewire is then fed through the delivery catheter to the distal end of the delivery catheter. Alternatively, and more commonly the guide wire is delivered to a location adjacent to the target tissue, then the delivery catheter is advanced over the guidewire near the target location. Delivery device1400is then advanced over the guidewire with the guidewire disposed in the guidewire lumen. Once in the desired position, delivery device1400is moved distally relative to the delivery catheter. Catheter shaft1402is advanced to position the jet aperture adjacent to the target tissue (and directly adjacent and engaging the intermediate tissue). Expandable member1403is inflated with fluid advanced through the inflation lumen in catheter shaft1402. A high velocity jet of fluid agent is then delivered as described herein.

Three radio opaque markers1404are also incorporated into the distal region of the delivery device. The two markers1404on catheter1402delineate the axial location of the fluid jet aperture, and the most distal marker1404provides information on the radial orientation of the aperture.

In some embodiment the high pressure delivery line, or lumen, is substantially flush with the outer surface of the balloon (or other expandable member). In these configurations the high pressure lumen does not extend further radially than the outer surface of the balloon. This configuration provides better engagement between the balloon and the lumen wall in which the balloon is disposed and expanded. This provides a better seal between the balloon and the lumen wall, which reduces the likelihood of fluid leaking back into the lumen once it is delivered out of the aperture. In some embodiments the high pressure delivery lumen is integrated into the balloon structure. This can be accomplished by incorporating one or more lumens into the extrusion used to form the balloon. The lumens are maintained during the balloon forming process and the resulting balloon structure would therefore include one or more integrated high pressure delivery lumens. In some embodiments a channel is formed in the balloon to accommodate the high pressure fluid lumen. For example, a channel with a general “U” cross sectional shape is formed in the balloon, and the high pressure lumen is secured within this channel. The high pressure lumen is therefore substantially flush with the outer surface of the balloon.

FIG. 15shows an alternate embodiment of a distal region of a delivery device similar to that shown inFIG. 14and comprising the features of a rapid exchange guide wire configuration. Guide wire1502is shown entering the catheter shaft on the proximal side of balloon1503and exiting the shaft on the distal end of delivery catheter1500. The expandable member1503in this embodiment is a generally spherical inflatable elastomeric balloon. High pressure delivery line1505is secured to the surface of the balloon as described above in the embodiment inFIG. 14.

In an alternative design similar to those shown inFIGS. 14 and 15, the balloon is radially offset relative to the expandable member shaft such that the high pressure line has a substantially straight configuration across the surface of the balloon when the balloon is expanded. The embodiment inFIGS. 16A-16Cenhances the precision with which interface pressure can be measured and controlled. The embodiment inFIGS. 16A-16Cincludes balloon1603that is radially offset with respect to catheter shaft1601. High pressure fluid delivery line1605is secured to balloon1603. High pressure line1605also includes radio opaque markers1604. The embodiment comprises a rapid exchange guide wire interface demonstrated by the path of guide wire1602. Balloon1603is carried on catheter shaft1601which may incorporate a braid or other stiffening elements to facilitate larger torque carrying capacity. General features of the catheter shaft are not shown.FIG. 16Billustrates a cross section of the delivery device ofFIG. 16Aconfigured for delivery and prior to inflation, wherein the delivery device is positioned within vessel1600. In this configuration balloon1603is deflated and folded.FIG. 16Crepresents the balloon in its inflated state where the balloon has a larger diameter then the vessel1600in which it is expanded. In such a configuration the pressure required to expand the balloon will be minimal, and the pressure monitored during inflation will be indicative of that associated with stretching the vessel wall. By recording volume versus pressure the diameter pressure curve ofFIG. 17can be calculated and a desired pressure range can be determined. Such a system can be used to identify the appropriate inflation pressure by monitoring the relative change in modulus as opposed to targeting a particular absolute pressure.

The systems and devices are adapted to be used to deliver a fluid agent to target tissue that is more distant to the aperture than tissue directly adjacent the aperture. The systems can be used to minimize the damage done to the intermediate tissue, and one manner in which this can be accomplished is with fluid delivered at high velocity out of the aperture. An exemplary use is to position the delivery device within a renal artery and deliver a fluid agent out of an aperture at high velocity. The fluid passes through the wall (with minimal damage to the intermediate wall tissue) to a location where it can interact with neural tissue surrounding the renal artery. The interaction of the fluid and nerves disrupts the neural transmission along the nerves, reducing hypertension. Methods of reducing hypertension with a fluid agent delivered out of a delivery device under high velocity are described in U.S. Pat. App. Pub. No. 2011/0257622, filed Mar. 24, 2011, now U.S. Pat. No. 8,840,601, the disclosure of which is incorporated herein by reference. As described above and shown in U.S. Pat. No. 8,840,601, the fluid agent is delivered out of the delivery device, pierces through the renal artery lumen wall, and is exposed to target neural tissue more distant from the lumen to disrupt neural transmission along the nerves and reduce hypertension. The systems, devices, and methods herein provide sufficient penetration of the fluid through the renal artery such that neural tissue is exposed to the fluid, while minimizing the amount of fluid that is leaked back into the renal artery, and thus the vasculature. The systems, devices, and methods herein also provide fluid penetration through the renal artery such that the injury associated with the fluid penetration is minimized at the luminal entry point.

In some systems previously described in the patent literature, the fluid pressure within the fluid source is relatively low prior to and after fluid delivery into the patient, but may be relatively high during fluid delivery and immediately prior in time to the delivery of the fluid. An exemplary disadvantage to these systems is that if the fluid pressure is initially too low, the fluid may not be delivered far enough into the target tissue. For example, in systems use to deliver fluid from the renal artery and into neural tissue surrounding the renal artery to disrupt neural transmission along those nerves, the fluid may ultimately be delivered only partially into the medial layer, when the desired outcome is that the fluid is delivered completely through the medial layer, in which the target nerve tissue is disposed. An additional exemplary disadvantage to these systems is that, because the pressure will drop back down to the relatively low pressure, if the pressure drops off too quickly, the fluid might not penetrate all the way through the medial layer, which is undesirable for reasons set forth above. By maintaining the fluid pressure within the fluid source at a substantially high pressure, the fluid pressure doesn't return to a relatively low pressure, but rather is maintained at the substantially constant high pressure. The potential problems of not penetrating deep enough into the medial layer, and thus failing to sufficiently disrupt neural transmission along the neural pathway, are therefore eliminated.

By delivering a pressure pulse and thereby a fluid stream with rapid rising and falling mean velocity, the fluid, when delivered, will both penetrate through the lumen to surrounding tissue with minimal injury to the tissues at the entry point and minimize leakage of the fluid back into the lumen.

FIG. 18illustrates the pressure waveform generated in the system fromFIG. 4when using a jet aperture of 1.5 mil diameter, as measured in the pressure transducer405. The delivery volume was approximately 35 uL delivered over a period of approximately 200 msec. The pressure transient, as measured at pressure transducer405, associated with the increasing pressure1801occurred over a period of approximately 5 msec, and the pressure transient associated with the release of pressure1802occurred over a similar time frame. The pressure pulse attains a relatively constant plateau pressure of approximately 900 psi.

In some embodiments the diameter of the one or more fluid jet apertures is between about 1 and about 5 mils. In some embodiments the velocity of the fluid jetting from the medical device is between about 50 and about 400 m/sec. In some embodiments the flow rate of the fluid from the constant high pressure source is between about 5 and about 40 mL/min. In some embodiments the duration of the fluid pulse is between about 50 and 500 msec. In yet other embodiments the duration is multiple seconds. In some embodiments the volume of fluid delivered per pulse is between about 10 uL and about 500 uL. In yet other embodiments the delivered volume may be multiple mL's. In some embodiments the time of the transition between the baseline pressure and the elevated pressure, and the time of the transition between the elevated pressure and the baseline pressure (e.g., transitions1801and1802inFIG. 18) is less than about 15 msec, and may be less than 5 msec, and additionally may be less than 1 msec. In general, shorter transition times translate into more efficient penetration and less fluid leaking into the lumen.

As used herein, high pressure refers to pressure above about 750 psi, and includes pressures between 750 psi and 5000 psi. The systems are adapted to maintain the fluid in the fluid reservoir in the high pressure fluid source under pressures of about 750 psi and about 5000 psi.

FIGS. 19A-19Dshow various images of tissue treated with fluid injections exhibiting a pressure pulse similar to that illustrated inFIG. 18, delivered with the system shown inFIG. 4and the delivery catheter shown inFIG. 14.FIG. 19Ashows the luminal surface1901of a sample of porcine renal artery tested in vitro that has been split after the injection such that the entry injury can be viewed. The injectate comprised a blue dye. The injection site is indicated by1902and distinguished by the darkening from the dye. The visibly stained area on the luminal surface is approximately 2 mm long in the radial direction (vertical in image) and about 0.5 mm wide. Darkened area1903corresponds to the location of the high pressure delivery line505. Periventricular adipose tissue darkly stained with injectate is visible at1904.FIGS. 19B and 19Cshow fluoroscopic images taken during an in vivo porcine study. Balloon1903is visible via contrast agent which has been used to inflate the balloon. The balloon is shown in the renal artery where it has been delivered via an endovascular approach. In this study the injectate contained both a fluoroscopic contrast agent and a blue dye.FIG. 19Bshows the balloon and surrounding tissue just prior to an injection.FIG. 19Cshows the balloon and surrounding tissue just after an injection. The injectate is visible inFIG. 19Cat1905.FIG. 19Dis a photograph from the necropsy of the same treatment zone from another animal. Darkened area1906within the dotted line shows the stained injury zone in contrast and beside a non-injured zone1907on a renal artery.

FIGS. 21A and 21Bare fluoroscopic images and illustrate the cloud of a 70% ETOH/30% Contrast injectate, where the delivery parameters were 1.5 mL over 9 seconds at approximately 80 m/sec, facilitated by a 1200 psi pressure pulse through a delivery system similar in configuration to that ofFIG. 15. A dashed white line has been drawn to highlight the injectate cloud2110. A guide wire2101can be seen extending through a renal artery of a pig and delivery catheter2100can be seen at the bottom right in the figures. Radio opaque marker2102located adjacent the injection aperture is visible within the contrast cloud.FIG. 21Bis a view of the same injectate cloud from a different angle which demonstrates a greater than 180 degree radial spread of injectate around the long axis of the renal artery. Inflatable balloon2103is visible inFIG. 21B.

FIGS. 20A-20Dillustrate different generalized waveforms2000useful in needle-less injection of fluids into periluminal spaces.FIG. 20Arepresents the type of waveform depicted inFIG. 18where the region between the rising and falling transitions2003is relatively flat. Exemplary features include the rapid transitions associated with the onset of the pressure pulse and the decay of the pressure pulse. A rapid onset pressure transition2001is important in creating a well-defined injury of minimal size wherein the injectate is primarily delivered through the injury with very little leakage around the injury entry surface. Similarly a very rapid final decay transition2002is important in minimizing leakage of fluid around the injury entry surface. When it is required that the low pressure leakage be minimized on the pressure decay portion of the pulse it is useful to create the jet aperture adjacent to the distal plug in the high pressure delivery line. In this fashion entrapped air will be washed out easily during priming prior to actual jetting. If this step is not performed, air may be trapped distal to the jet orifice, and compressed during the pressure rise portion of the jet cycle. On pressure decay this air will re-expand and force a small volume of injectate out through the jet orifice. This is of primary importance when the injectate is comprised of very toxic or ablative materials and minimizing injury to non-target tissues is required. Transition times should be at least less than 15 msec and preferably less than 5 msec as demonstrated in the experiments described herein, and optimally less than 1 msec. Apart from leakage, a sharp rising edge facilitates better penetration. Once an entry injury has been created it is often the case that pressure can be dropped and injectate will spread on the distal side of a well-defined puncture injury. In such a procedure, injury to the tissues at the entry site associated with the injectate can be minimized while larger volumes of injectate can be delivered deeper into the tissue without increasing the depth of injury.FIGS. 20B and 20Cillustrate two pressure waveforms useful in producing such injuries. InFIG. 20B, after the peak pressure is attained the pressure is allowed to trail off via a ramp to a pressure still sufficient to penetrate through the entry injury. At the end of the pulse the pressure is rapidly dropped for the reasons set forth here.FIG. 20Dis similar to that ofFIG. 20Bexcept that as opposed to ramping down pressure an initial short high pressure peak2004is used to create the injury, which is then followed by a lower pressure plateau of sufficient pressure and duration to deliver the requisite volume of injectate to an appropriate depth via the entry injury. In some situations it may be useful to spread that injectate more evenly through the depth of tissue, in which the pulse ofFIG. 20Ccould be desirable. Alternatively the volume of injectate may be additionally regulated by delivering multiple pulses at a specific location, wherein the pulses may be comprised of various combinations of those described herein and/or various delivery velocities.

With reference to the treatment of hypertension by renal nerve ablation (examples of which are described in more detail in U.S. Pat. App. Pub. No. 2011/0257622), the volume of injectate delivered may be increased via multiple injections in a single location or multiple injections in multiple sites, or a large volume delivered to one site and allowed to spread. When delivering injectate at one site via multiple injections, the spreading of the injectate may be monitored by fluoroscopy when a contrast agent is comprised in the injectate. The number of injections may be controlled by watching how the injectate spreads under fluoroscopy, and stopping the procedure when the desired spread has occurred. When injecting at multiple sites a device such as that ofFIG. 15may be relocated for each injection or alternatively a device similar to that ofFIG. 14may incorporate multiple parallel injection systems, wherein each line is coupled to a single fluid source or individual fluid sources. Devices described in U.S. Pat. App. Pub. No. 2011/0257622 can also be modified to be used with any of the system components described herein and according to any of the methods herein.

FIG. 17illustrates a typical pressure diameter profile associated with an artery. An appropriate pressure at the interface between the jet aperture of the medical device and the luminal wall is important when minimal injury at the luminal surface of the vessel and control of the depth of injectate delivery is desired. The greater the interface pressure, the smaller the luminal injury and the greater control of penetration depth. However, if the interface pressure is increased too much the vessel may be injured. A balance must therefore be reached between interface pressure vessel distension. A typical vessel exhibits a low modulus during initial extension, begins to stiffen, and then exhibits a much higher modulus. As the vessel is extended further into the high-modulus region the tissue will be damaged. Region1702indicates a target region of interface pressure where damage to the vessel can be minimized and interface pressure is high enough to create a clean puncture of the lumen wall.

In the embodiments illustrated inFIGS. 14 and 15, high pressure delivery lines1405and1505have a 14 mil outer diameter and 12 mil inner diameter polyimide tube. The delivery apertures, not visible in the figures as they are too small, are 1.5 mil. The total length of the delivery lines is approximately 32 inches.

The following describes the expected fluid dynamic behavior for a fluid delivery system that includes a long fluid pipe with an exit aperture near the distal end, as do the embodiments inFIGS. 5 and 6. The description particularly applies where the fluid delivery line has an inner diameter of approximately 12 mil and the delivery aperture is in the range of about 0.5 to about 5 mil, or more particularly about 2 mil. For such systems the fluid velocity will be described by the equation:

Where P is the pressure differential across the exit aperture, Beta is the ratio of the diameter of the delivery tube inner diameter/diameter of the aperture, p is the density of the delivered fluid and Cdis the coefficient of discharge. Experimental data collected demonstrates a value for Cdin the range of about 0.5 to about 0.8 with a value of about 0.65 being typical for the configuration listed above. Experimental data collected from such a system demonstrated 1.5 mL delivered in 9 seconds through a 2 mil diameter exit aperture at 1200 psi, using a delivery fluid with a density of approximately 1.1 gm/mL. Using the relation average_velocity=Volume_delivered/(duration*Area_aperture), this implies an average delivery velocity of 82 m/sec. Using the functional relation described above and a Cdof 0.65, the average fluid velocity would be approximately 78 m/sec at 1200 psi as measured at the exit valve. Given the expected pressure loss across the 32 in long, 12 mil diameter delivery tube at the average flow rate, this would imply a pressure differential of approximately 1135 psi across the exit aperture. CO2cartridges provide a means for maintaining a constant pressure within the constant pressure source as the internal pressure in a CO2cartridge will remain relatively constant at a given temperature as long as there remains a mixture of gas and liquid within the cartridge. Pressure could hence be adjusted by adjusting the temperature of the cartridge. The following table lists the internal pressure as a function of temperature for a CO2cylinder containing CO2in both liquid and vapor phases.

Exemplary fluid agents that can be delivered, such as to treat neural tissue peripheral to body lumens, using any of the methods, systems, and devices herein, can be found in U.S. Pat. App. Pub. No. 2011/0257622, U.S. Pat. App. Pub. No. 2011/0104061, and U.S. Pat. App. Pub. No. 2011/0104060, the complete disclosures of which are incorporated by reference herein.

In some embodiments the systems herein can be used to ablate target tissue. When performing localized ablations of tissue, it is often advantageous to use an ablatant that is chosen to specifically target a particular tissue or tissue function, and to impart minimal effects on adjacent tissues. In all cases the residence time of an ablatant cocktail will be dependent on the rate of its removal by normal body functions which include uptake by the capillary bed and the lymphatic system. When using a well targeted ablatant it will often be the case that it will have very little effect on the tissues associated with the normal removal processes. In such cases, the body will remove the ablatant as efficiently and quickly as possible. In such a situation it will be of great advantage to add to the ablatant cocktail some non specific ablatant, or an ablatant specifically targeted to impede capillary and or the lymphatic uptake to slow the body's ability to remove therapy targeted ablatant and thereby increase its residence time and thereby the magnitude of its effect for a given delivered volume and concentration.

Use of ablatants targeted at neural function such as guanethidine, reserpine, tetrodotoxins, botulinum toxin, or other ablatants have particular significance in the treatment of hypertension, such as in the ablation of renal nerves. These ablatants may have some effect on capillary uptake but should have little to no effect on lymphatic uptake.

It has been recently noted under by fluoroscopy that there is a significant increase in residence time for a contrast agent that has been injected in combination with a general ablatant such as ethanol (ETOH) vs. the same contrast agent which was injected in combination with saline. In these experiments a cocktail comprising 30% Ultravist 300 (a contrast agent) and either 70% ETOH or 70% saline by volume were observed over time for decay in contrast as measure fluoroscopically. The observation was that the contrast was observable for a longer period of time in the surrounding tissues when injected with ETOH as compared to when injected with saline. The general ablatant increased the residence time for the contrast agent compared to saline.

One aspect of the disclosure is a method of treating hypertension (e.g., but not limited to, from within the renal artery, such as in the applications incorporated by reference herein) by delivering a cocktail of a general ablatant (e.g., ethanol, glacial acetic acid, etc.) and an ablatant targeted at neural function. The targeted ablatant can be any of those listed herein. In one embodiment the cocktail comprises ethanol as the general ablatant and guanethidine as the targeted ablatant. The general ablatant will increase the residence time of the guanethidine and achieve a more successful ablation of the renal nerves.

One aspect of the disclosure is a method of treating hypertension by sequentially delivering a relatively smaller amount of a general ablatant, followed or preceded by delivery of the targeted ablatant. The general and targeted ablatants can be any of those described herein or any other suitable ablatants. The amount of general ablatant will be an amount smaller than is typically delivered to ablate the nerves, but is sufficient to increase the residence time of the targeted ablatant by inhibiting the body's ability to clear the targeted ablatant.

One aspect of the disclosure is a method of treating hypertension by delivering a cocktail of an ablatant targeted to neural function and an ablatant specifically targeted to impede capillary and/or the lymphatic uptake to slow the body's ability to remove therapy targeted ablatant. In this aspect a general ablatant could also be added to the cocktail in even smaller amounts than in the previous aspect.