WO2020247218A1

WO2020247218A1 - Atraumatic occlusive system with compartment for measurement of vascular pressure change

Info

Publication number: WO2020247218A1
Application number: PCT/US2020/034626
Authority: WO
Inventors: Erik Dean OLSON; David Benjamin Jaroch; Patrick Charles Mccain; Aravind Arepally
Original assignee: Surefire Medical Inc
Current assignee: Trisalus Life Sciences Inc
Priority date: 2019-06-04
Filing date: 2020-05-27
Publication date: 2020-12-10
Anticipated expiration: 2021-12-04
Also published as: CN113905676A; JP7171951B2; CA3139118A1; CA3139118C; EP3979923A4; US20210236135A1; US12433597B2; JP2022525699A; US20200383688A1; CN113905676B; EP3979923A1

Abstract

An atraumatic vessel occlusive system includes a flexible tubular member with an infusion lumen, a vessel occluder mounted at the distal end of the tubular member, and a pressure sensor located within a chamber defined by the occluder. The occluder has a braided construct provided with a fluid impermeable membrane over its proximal portion and a fluid permeable covering over its distal portion. The pressure sensor is adapted to sense pressure within the vessel through the fluid permeable membrane without being subject to the effects of turbulent flow at the exit of the infusion lumen. The accurately sensed pressure can be used to determine a dwell time for the occluder.

Description

ATRAUMATIC OCCLUSIVE SYSTEM WITH COMPARTMENT FOR MEASUREMENT

OF VASCULAR PRESSURE CHANGE

BACKGROUND OF THE INVENTION

1. Field of the Invention

[0001] The present invention relates to catheter-based occlusive systems and intravascular methods to deliver a therapeutic agent for the treatment of disease.

2. State of the Art

[0002] Veins are designed to carry blood from the tissue back to the heart. This results in several physiological differences relative to the arteries. Key among these features is that they are configured to carry a relatively large volume of low-pressure blood. They therefore tend to have larger lumens and less muscle and elastic tissue relative to comparable arteries.

Temporary occlusion of the vein therefore requires a device with large diameter sufficient to fill the venous channel without exerting high radial forces on the weaker vessel walls.

[0003] The most common occlusion device is the vascular balloon. These devices function by inflating a flexible or semi flexible membrane using fluid pressure through a lumen in communication with an operator. The inflation of the balloon to an appropriate size is typically monitored by fluoroscopy by injection of precise quantities of contrast fluid to inflate the balloon, followed by infusion of a bolus of contrast through the infusion lumen of the device to determine if blood flow persists. Balloon volume must be closely monitored as even small degrees of over inflation result in high radial force applied to the vessel wall.

[0004] In the arterial network, the use of balloons is common place. The structure of the arterial vessels, having a thick layer of muscle and elastic fiber matrix, allows for a high degree of variability in inflation of the device without rupture. [0005] In distinction, the venous system presents a number of challenges when using balloons. The larger veins require larger balloon diameters, making precise control of inflation challenging. Furthermore, the weaker and less elastic structure of the vein is less resistant to the high radial force exerted by the balloon. This in turn results in complications such as vessel rupture and dissection.

[0006] Co-owned US Pat. Nos. 9,770,319 and 9,968,740 to Chomas teach several therapeutic catheter-based dynamic microvalve occlusion systems that automatically open and close based on relative fluid pressure conditions about proximal and distal sides of the microvalve. These occlusive systems provide excellent occlusion while exerting low radial force on the vessel wall. However, the systems described in Chomas are not adapted to provide the user accurate information on the pressurization to which the treated vessels are subject or whether the interstitial fluid pressure in the treated tissue is overcome. In particular, the interstitial fluid surrounds and exerts pressure upon the vessels. The interstitial fluid pressure in a tumor is a physiological parameter with demonstrated predictive value for a tumor’s aggressiveness, drug delivery, as well as response to treatments such as radiotherapy and chemotherapy. The interstitial fluid pressure is generally high relative to the blood pressure within the vein, indicating a strong inclination of molecules to flow from the interstitial fluid into the veins. Thus, the interstitial fluid pressure biases the vein against therapeutic uptake.

SUMMARY

[0007] An atraumatic vessel occlusive system includes a flexible tubular member having a proximal end, a distal end, and defining an infusing lumen extending between its proximal and distal ends, a diametrically adjustable vessel occluder mounted at the distal end, and at least one pressure sensor. [0008] In an embodiment, the flexible tubular member includes an inner catheter longitudinally displaceable relative to an outer catheter. The inner catheter defines the infusion lumen with a distal orifice and a flush lumen is defined at least in part by the outer catheter and preferably between the inner and outer catheters.

[0009] In an embodiment, the occluder is coupled to the distal ends of each of the outer and inner catheters such that when the inner catheter is longitudinally displaced in a distal direction relative to the outer catheter, the occluder diametrically collapses into an elongate ovoid delivery configuration sized for passage through a vessel, and when the inner catheter is longitudinally displaced in a proximal direction relative to the outer catheter, the occluder diametrically expands into an occlusive configuration adapted to extend across the wall of the vessel. The expanded occlusive configuration defines a chamber within the occluder. The occluder has a fluid impermeable proximal portion and a fluid permeable distal portion that allows fluid communication between the vessel distal of the occluder and the chamber.

[0010] In accord with one aspect of the system, the structure of the occluder is formed as a microvalve of flexible braided filaments with low radial force that will not over-pressurize the wall of a vessel in which it is deployed. A fluid impermeable membrane is provided over the proximal portion of the braided construct. The distal portion of the braided construct is covered in a fluid permeable coating or covering.

[0011] In accord with an embodiment of the system, a first pressure senor is positioned within the chamber of the occluder. As a result of the fluid communication between the chamber and the vessel, the first pressure sensor is adapted to sense pressure in the vessel in real time. Further, because the first pressure sensor is shielded from the vessel by the fluid permeable membrane, the first pressure sensor is not subject to the effects of turbulent flow occurring at the distal orifice of the infusing lumen, as described further below. [0012] During therapeutic agent delivery, pressure readings can be used to confirm placement of device and confirm absence of collateral flow in vessels distal to the tip of the device. Collateral flow is a condition in which circulation of blood is established through the enlargement of minor vessels and re-routing of vessels with those of adjacent parts when a vein or artery is functionally impaired. It can be important that no collateral flow exists to ensures that a fluidic therapeutic agent infused through infusion lumen of device will reach target tissue in the organ, and not be re-routed to non-target tissue. The change in pressure gradient running from the arterial to venous side is caused by the difference in volume within the vessels in the direction of flow. The arterial side has less volume than does the venous side, resulting in a pressure drop as blood flows from arteries to veins. The characteristic increase in pressure when a vein is occluded is an indicator that there is not collateralization of the tissue compartment, as collateral flow will offer an alternative path for blood flow and will prevent a pressure increase.

[0013] In accord with another aspect of the system, a second pressure sensor is positioned proximal to the diameter of the occluder. A gradient between the first and second pressure sensors can directly determine when pressure in the vessel increases relative to systemic pressure. The presence of both sensors allows for real time calculation of such gradient.

[0014] In accord with another aspect of the system, an actuation handle is provided at proximal ends of the inner and outer catheters to effect relative displacement thereof. In addition, a first port is provided at the handle in fluid communication with the inner catheter for delivering a first fluid into the infusion lumen and out into the vessel. A second port is also provided at the handle in fluid communication with the outer catheter for delivering a second fluid through the flush lumen, into the chamber, and out of the fluid permeable distal portion of the occluder. [0015] In accord with a method, the system is advanced to a target vessel of an organ in accord with known procedures. In a preferred method, the device is tracked through the venous system in the delivery configuration. The first and/or second pressure sensors are utilized to obtain a systemic reference pressure. The handle is actuated to retract the inner catheter relative to the outer catheter and thereby deploy the occluder into the occlusive configuration within the vein, in which it has a squatter, ovoid shape with an expanded diameter. The occluder occludes venous flow as the pressure of the blood flow within the vein applies force against the distal side of the occluder.

[0016] Blood fills the chamber of the occluder through the fluid permeable coating or covering. Alternatively, a fluid is infused through the flush lumen to fill the chamber and flow out into the vessel, thus placing the chamber and vessel in fluid continuity. The first pressure sensor within the chamber of the occluder is then able to provide a constant pressure monitoring of the vessel on the distal side of the occluder.

[0017] A therapeutic agent is then infused through the infusion lumen and out of the distal orifice, beyond the occluder. Infusion of therapy proceeds while pressure is monitored, allowing a user to determine if over pressurization is experienced and if interstitial fluid pressure within the tissue of the organ is overcome. The infusion of therapy can create local eddy currents in the fluid near the tip of the device. While this could otherwise prevent accurate readings of pressure during infusion if the sensor is placed at the device tip, the sensor by being placed within the chamber is protected from such currents. The apertures in or permeability of the distal portion of the occluder allows for fluid communication between the chamber and the distal vascular compartment. During infusion, pressure in the distal vasculature and the chamber equalize due to the apertures in the distal membrane. However, these apertures are sufficiently small to dampen turbulence generated by the distal tip, allowing for stable pressure readings by the first sensor. The stable pressure readings permit accurately identifying the pressure at the arterial side of the occluder.

[0018] The second sensor, located proximal to the expanded occluder can be used to monitor systemic pressure during infusion. Using the data from the first and second sensors, it can be more directly determined when pressure distal of the occluder increases relative to systemic pressure. The presence of both sensors allows for real time calculation of pressure differentials, while a single tip based sensor requires determining a systemic reference point prior to device deployment and subsequent infusions.

[0019] Then, during infusion of a therapeutic agent, the pressure gradient between the arterial side of the vein (from the first pressure sensor) and the return venous side (from the second pressure sensor) is monitored. If the gradient identifies a higher pressure on the distal side, such indicates that there is not yet collateralization of the tissue compartments, as collateral flow will offer an alternative path for blood flow and will prevent such pressure gradient. Infusion of therapy proceeds while pressure is monitored, allowing the user to determine if over-pressurization is experienced and if interstitial fluid pressure within the tissue is overcome.

[0020] In addition, according to one aspect of the method, the therapeutic agent can be infused at a flow rate that will generate a vascular pressure gradient which increases therapeutic diffusion rate through the venous and capillary vasculature. A dwell function can be applied to optimize diffusion of the therapeutic agent into the tissue given a measured pressure gradient. The dwell time of the dwell function will depend on the therapeutic agent and the measured pressure gradient. The larger the measured pressure gradient, a shorter dwell time is required for optimal diffusion of the therapeutic agent into the tissue.

[0021] The occluder can remain expanded within the vessel for the duration of the dwell time until the therapy has been infused and therapeutic uptake to occur without being washed away in venous blood flow. The proximal handle is then actuated to collapse the occluder, and the system is then removed from the anatomy.

BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Fig. l is a perspective view of an atraumatic occlusive system as described in an embodiment herein.

[0023] Fig. 2 is an enlarged schematic side elevation view of the distal side of the system of Fig. 1, shown with an occluder in a reduced diameter configuration for guidance to a target vessel.

[0024] Fig. 3 is a view similar to Fig. 2, shown with the occluder in an enlarged diameter configuration for occlusion of the target vessel.

[0025] Fig. 4 is a flow chart of a method of using the system.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0026] With reference to the following description, the terms“proximal” and“distal” are defined in reference to a user of the device, with the term“proximal” being closer to the user’s hand, and the term“distal” being further from the user such as to be located further within a body of the patient during use.

[0027] Apparatus and methods are described herein related to the use of a system to inject a therapeutic agent into a primary vessel communicating with a diseased tissue of an organ, for example, a tumor. For example, the tumor to be treated can be a solid tumor. In some cases, the tumor can be a cancerous tumor, such as a tumor specific to, by way of example only, cancer of the pancreas, kidney, liver, lung, or uterus.

[0028] As described herein, a treatment system is used to provide a therapeutic agent into a solid tumor by targeted infusion of the treatment into a region of tissue. The therapeutic agent is injected under relatively high pressure into a region of an organ or other defined area of tissue served by one or more feeder vessels. [0029] Turning now to Figs. 1 and 2, an atraumatic vessel occlusive system 10 is shown. The system 10 includes a flexible tubular member 12 having a proximal end 14 a distal end 16. The tubular member 12 defines an infusing lumen 18 extending between its proximal and distal ends. A diametrically adjustable vessel occluder 20 is mounted at the distal end 16 of the tubular member. The system also includes at least one pressure sensor 22, 24, located and functioning as described below.

[0030] In an embodiment, the flexible tubular member 12 includes an inner catheter 30 telescopically advanceable within an outer catheter 32. The inner catheter 30 has a proximal end 34 and distal end 36, and the outer catheter 32 also has a proximal end 38 and distal end 40. The infusion lumen 18 is preferably defined through the inner catheter 30 and opens to a distal axial orifice 84, and a separate flush lumen 42 is preferably defined in the toroidal space between the inner and outer catheters. Alternatively, the flush lumen may extend through the wall of either of the inner and outer catheters 30, 32.

[0031] In accord with a preferred aspect of the system, an actuation handle 50 is provided at the proximal ends 34, 38 of the inner and outer catheters 30, 32 to effect relative

displacement of the thereof. The actuation handle 50 includes a stationary member 52 and a movable member 54, such as a slide longitudinally displaceable relative to the stationary member. The stationary member 52 is provided with a side port 56, and a strain relief 58 connects the proximal end 38 of the outer catheter 32 to the stationary member 52. The side port 56 is in fluid communication with the outer catheter 32. The movable slide 54 is coupled to the inner catheter 30. A hypotube 60 is coaxially inserted around the proximal end of the inner catheter 34 to provide mechanical support of the inner catheter. The proximal end of the slide 54 defines an infusion port 62 that is fluidly coupled to the proximal end 34 of the inner catheter 30. The actuation handle 50 also includes a releasable lock 64 that, when actuated, can retain the movable member 54 and stationary member 62 in relatively fixed longitudinal positions. The handle 50 may also include a display 66 and associated memory and logic to permit the display of real-time and/or stored pressure data read from the first and second sensors 22, 24, as well as calculated relationships between the pressures read from sensors 22, 24, such as a gradient between the two. Button 68 near display permits actuation of the logic and display as well as cycling through various logic functions.

[0032] The occluder 20 is a microvalve comprising a braided construct of filaments 70. The proximal end of the filaments 70 are coupled to, and preferably rigidly fixed to, the distal end 40 of the outer catheter 32, and the distal end of the filaments 70 are coupled to, and preferably rigidly fixed to, the distal end 36 of the inner catheter 30. The general construct of the braided valve portion of such a microvalve device is described in detail in co-owned US Ser. Nos. 8,696,698 and 9,770,319, both of which are hereby incorporated by reference herein in their entireties. Longitudinal displacement of the inner catheter 30 relative to the outer catheter 32 results in the microvalve moving between a first elongate ovoid configuration of smaller diameter (Fig. 2) adapted for guiding to a deployment location in a vessel, and a second squatter ovoid configuration of a larger diameter adapted for occlusion of the vessel (as shown in Fig. 3). That is, in both the first and second configurations, the microvalve is of an ovoid configuration and has a generally symmetrically shape about a longitudinal central axis A and a plane P orthogonal to the central axis A of the microvalve at its area of maximum diameter. It is recognized that the occluder can be moved through the first and second configurations, and any size of configuration therebetween to best suit the vessel in which it is used. The lock 64 on the handle 50 can facilitate retaining the occluder 20 in a desired size configuration during therapeutic treatment. The system 10 can be advanced in the first elongate configuration to a deployment location in a blood vessel over a guidewire (not shown) inserted through the infusion lumen 18 of the inner catheter 30. The interior of the occluder 20 defines a chamber 82. [0033] In accord with one aspect of the occluder 20, a fluid impermeable membrane 72 is provided over the proximal portion 74 of the braided construct. Suitable materials for the impermeable membrane include elastomeric natural and artificial rubbers, silicones, styrenics, olefmics, copolyesters, polyurethanes and polyamides. In accord with another aspect of the occluder, a fluid permeable coating or covering 76 is provided over a distal portion 78 of the braided construct. Suitable materials for the fluid permeable coating 76 include elastomeric natural and artificial rubbers, silicones, styrenics, olefmics, copolyesters, polyurethanes and polyamides processed so as to have micro or macro scale perforations, channels, pores, or fibrous rather than continuous morphology. This may be accomplished by physical perforation techniques, by electrospinning or melt spinning fibers, by inclusion of soluble components that can be removed during processing to leave pores or voids, and by the addition of open pore foaming agents or other suitable technology. The coating or covering 76 can include a material placed over the outer surface of the filaments 70, within the inner surface of the filaments, or a combination thereof. The coating or covering 76 can extend only between the filaments. The coating or covering 76 can be free-floating on the filaments or can be rigidly fixed to the filaments. The coating or covering 76 can be applied by dip coating, spraying, sewing, bonded application, or other suitable technology. The fluid permeable material 76 can be an otherwise impermeable material made permeable by perforations or apertures 80. The fluid permeable material may be formed with interstices or openings 80 providing a permeability that meets the requirements of fluid permeability, as described below. The apertures, perforations, interstices, openings, etc. (collectively referred to hereinafter as‘apertures’ 80) within the fluid permeable material may be geometrically arranged. The total cross-sectional surface area of the apertures should be sufficiently large so as to facilitate measurement of physiological response and infusion pressure while dampening short duration turbulent flow. Most preferably, apertures should be arranged in a radially symmetric fashion so as to maintain uniform radial bending properties of the device.

[0034] As the flush lumen between the inner catheter and outer catheter is in fluid communication with the proximal infusion port, a pressure sensor may reside within this space and still monitor pressure experienced at the distal tip as long as the proximal infusion port is sealed (creating a closed pressure chamber in communication with the distal tip of the catheter). Sensor responsiveness within this chamber is governed by the cross-sectional surface area of the flush lumen and by the length between the sensor and the distalmost aperture. The delay in pressure response time decreases with increasing cross-sectional area and decreasing length. For example, a device having a flush lumen with a cross-sectional area of 0.5mm² and a sensor located 100cm from the distal aperture will require 2-5 seconds to respond and stabilize to a change in pressure; whereas, a device having a flush lumen with a cross-sectional area of 0.5mm² and a sensor located 50cm from the distal aperture will require 1-3 seconds to respond and stabilize to a change in pressure; and whereas, a device having a flush lumen with a cross-sectional area of 2mm² and a sensor located 100cm from the distal aperture will require 0.1-0.5 seconds to respond and stabilize to a change in pressure. The proximity of the sensor is therefore governed by the duration of the physiological response intending to be monitored. For instance, the infusion of therapeutics may be administered over a range of time. For infusions occurring in seconds and having transient pressure changes, the sensor should be placed within a space of sufficient cross-sectional surface area and at a sufficiently short distance from the distal aperture so as to monitor pressure changes occurring within a second (or less). Moreover, the pores at the distal end of the filter should be sufficiently small and have a relatively low cross-sectional area so that pressure fluctuations on the order of 0.01-0.2 seconds are dampened while the sensor responds in the 0.2-1 second time frame. [0035] In one embodiment, a first pressure sensor 22 is mounted within the chamber 82. The first pressure sensor 22 may be mounted on the outer wall of the portion of the inner catheter 30 that extends within the occluder (as shown), on an inner portion of the filamentary braid, or another structure located within the chamber. The material covering or coating 76 on the distal portion 78 of the occluder 20 must be sufficiently fluid permeable such that when the occluder is positioned in a fluid-filled vessel and the chamber 82 is filled with a fluid, both the chamber and the distal vessel compartment will be subject to the same pressure conditions. Thus, the first pressure sensor 22 can accurately sense the fluid pressure conditions external of the occluder in the distal vascular compartment of the target vessel. However, the fluid permeable material 76 should effect a sufficient barrier to dampen turbulence generated at the orifice 84 of the infusion lumen during therapeutic infusion and the pressure effects thereof from causing pressure instability at the interior chamber of the occluder and a consequent deleterious effect on obtaining accurate pressure readings of the distal vascular compartment of the target vessel.

[0036] In accord with another preferred aspect of the system, a second pressure sensor 24 is preferably positioned proximal to the occluder 20. The second pressure sensor 24 is adapted to sense and monitor systemic pressure. The second pressure sensor 24 is also used in conjunction with the first pressure sensor 22 to determine pressure differentials; i.e., to determine when the distal vascular compartment pressure is higher than systemic pressure and by how much.

[0037] The use of both the first and the second sensors 22, 24 allows for a real time calculation of the pressure gradient across the occluder 20. As an alternative, the first pressure 22 alone can be used to determine a pressure gradient by obtaining a reference or baseline pressure reading prior to opening the occluder 20 across the vessel wall. Subsequent pressure readings from the first pressure sensor 22 are then compared to the baseline pressure to determine a gradient. The use of the gradient is described below.

[0038] Turning now to Fig. 4, in accord with a method of using the system, the distal end of the system is advanced at 100 in the first elongate configuration to a target vessel of an organ in accord with known procedures. In that manner, the system 10 can be tracked over a guidewire through the venous system to the intended location. The target vessel is preferably a vein receiving a return supply of blood from an organ. By way of example, the organ can be the liver and the target vessel can be the saphenous vein, or the organ can be pancreas and the target vessel can be portal vein. Other organs can be similarly treated through associated target vessels, preferably wherein the target vessel is a vein.

[0039] The handle 50 is then actuated to move the inner catheter 30 relative to the outer catheter 32 and expand the diameter of the occluder 20 at 102 to bring the outer surface of the occluder into apposition with the vessel wall. The handle lock 64 can be operated to fix the occlusive configuration (size and shape) of the occluder 20 within the vessel. The occluder 20 occludes venous flow as the arterial side pressure of the blood flow within the vein applies force against the distal side of the occluder which urges the occluder into an open, expanded configuration.

[0040] Blood may begin to fill the chamber 82 of the occluder 20 through the apertures 80 of the fluid permeable coating or covering. Additionally or alternatively, a fluid such as saline or a similar flushing fluid can be infused from the second port 56, through the flushing lumen 42, and into the chamber 82 of the occluder. Because of the apertures 80 in the distal portion 78 of the occluder, the occluder does not necessarily inflate under pressure of the flushing fluid; rather the flushing fluid is intended to place the first sensor 22 in continuous fluid contact with the blood located external of the occluder. Once there is fluid continuity at 104, the pressure outside the occluder 20 and through the apertures can be sensed in real-time at the first sensor at 106. A baseline pressure reading of the vessel is preferably obtained.

[0041] Then, the therapeutic agent is infused at 108 through the infusion lumen 18 and out of the distal orifice 84 of the inner catheter, beyond the occluder 20. Infusion of therapy proceeds while pressure in the vessel distal of the occluder and optionally proximally of the occluder is monitored. The infusion of therapy out of the orifice of the infusion lumen can create local eddy currents in the fluid near the distal tip of the system. In prior systems, these eddy currents could prevent accurate pressure monitoring of the vessel conditions during infusion. In distinction therefrom, the first pressure sensor 22, within the chamber and shielded by the fluid permeable material, is protected from the deleterious effects of the eddy currents that obscure accurate monitoring. The apertures in or permeability of the distal portion of the occluder allows for fluid communication between the chamber and the distal vascular compartment. During infusion, pressure in the distal vasculature and the chamber equalize due to the apertures in the distal membrane. However, these apertures are sufficiently small and geometrically arranged as to dampen turbulence generated by the distal tip, allowing for stable pressure readings by the embedded first sensor. The stable (non-turbulent) pressure readings permit accurately identifying the pressure at the arterial side of the occluder. In addition, the second sensor 24, located proximal to where the expanded occluder 20 meets the vessel wall can be used to monitor at 110 the systemic pressure in real-time during infusion. This accurate pressure data can be used to determine pressure conditions within the tissue of the organ; i.e., whether over pressurization conditions exist and/or whether the interstitial fluid pressure within the tissue of the organ is overcome.

[0042] The second sensor 24 will be completely shielded from turbulent flow by the impermeable portion of the occluder 20. It therefore monitors physiological pressure variations from heartbeat, breathing, and other physiological phenomena. These variations from physiological phenomena occur on the 100s of milliseconds to seconds timeframe. The distal first sensor 22 also measures changes from physiological phenomena, as well as infusion of therapy and turbulence. Turbulence occurs over a very short time frame and can be filtered based on reference to the smoother pressure profile of the second sensor 24. While the porous nature of the distal occluder 20 geometry physically‘prefilters’ the majority of noise from turbulent flow that would otherwise occur around the first sensor 22, in one embodiment of the method, it is contemplated that the noise from physiological phenomena is also reduced.

Variations in measured pressure due to heartbeat, breathing, and other physiological phenomena registered on the proximal second sensor 24 can be subtracted from the distal first sensor 22 measurement, leaving only the pressure changes associated with infusion. In accord with the method, data processing of the received pressure data from the first and second sensors 22, 24 uses a filtering function to subtract turbulent flow data (short time frame pressure variation) and a subtraction function to remove variation due to broader physiological change. The filtering algorithm produces a pressure reading resulting from only the infusion of therapeutic agent through the infusion lumen.

[0043] Further, the real-time data from the first and second sensors allows a more direct determination of when pressure distal of the occluder increases relative to systemic pressure; i.e., when the first sensor senses higher pressure than the second sensor, as determined at 110.

[0044] During infusion of the therapeutic agent, the calculated gradient between the arterial feed of the vein (from the first pressure sensor) and the return venous side (from the second pressure sensor) permits monitoring progress of the therapeutic treatment at 112.

[0045] If the gradient identifies a higher pressure on the distal side, such indicates that there is not yet collateralization of the tissue compartments, as collateral flow will offer an alternative path for blood flow and will prevent such pressure gradient. Infusion of therapy proceeds while pressure is monitored, allowing the user to determine if over-pressurization is experienced and if interstitial fluid pressure within the tissue is overcome.

[0046] According to another aspect of a method with the system, the therapeutic agent can be infused through the device at a flow rate that will generate a vascular pressure gradient which increases the therapeutic diffusion rate through the venous and capillary vasculature.

[0047] To appreciate this advantage it is necessary understand that molecules residing within the blood or other fluid filter through the vessel based on pressure differentials between the fluid within the vessel and the surrounding tissues. In the arterial side, pressure is typically higher within the vessel than the surrounding interstitial pressure. This positive pressure gradient forces molecules out of the arterial end of the capillary bed and into the tissue. As blood travels through the arterial vessel, pressure drops, reducing the positive pressure gradient until no gradient is present and pressure mediated filtration of molecules through the vessel halts. On the venous side of the capillary bed a negative gradient is present, causing reabsorption of molecules back into the venous side capillaries and into systemic circulation. The change in pressure from the arterial side to the venous side is a result of difference in volume within the vessels in the direction of flow; the arterial side has less volume than the venous side resulting in a pressure drop as blood flows from arteries to veins.

[0048] When a vein becomes blocked by expansion of the occluder 20 across the vein, blood flow stops. Blood, being an incompressible fluid composed primarily of water, then equilibrates to the arterial side pressure.

[0049] The resulting change in pressure increases the volume of vessels experiencing a positive pressure gradient to the surrounding tissue, including venous vessels. This allows material to diffuse from the blood vessel outward throughout the entire tissue volume. The effect takes place in tissues that normally have a negative pressure gradient in which fluid and molecules would normally filter from the tissue into the vasculature. Thus, treatment of tissue on both the arterial and venous side is enabled. The duration and extent of the diffusion across the vessel wall and into the tissue can be controlled by the duration during which the occluder is left in the enlarged second configuration. Pressure may be further modulated by injecting one or more additional volumes of fluid into the venous network distal of the occluder. For example, one or more bolus injections of saline can be injected into the vessel to modify uptake of the therapeutic agent.

[0050] More specifically, the system when in position is used to sense pressure in the vessel volume distal of the occluder. This permits confirmation that the pressure in this volume is increased relative to a baseline pressure. Then, a therapeutic agent is infused through the infusion lumen into the vessel volume. The occluder is left open in the expanded configuration within the vessel according to a dwell function that identifies parameters for optimum diffusion across the vessel wall. For example, the dwell function can depend on the therapeutic agent (e.g., size of the molecule and molecular interaction with the vessel wall) and the measured pressure gradient. Holding other parameters constant, the larger the measured pressure gradient, the less time is required for optimal diffusion of the therapeutic agent into the tissue. The dwell time for a therapeutic maximizes the time in which the therapeutic resides within the target vasculature or, in other words, leaves the occluder open until the concentration of therapeutic in the blood of the vessel approaches zero and the concentration of the therapeutic in the surrounding target tissue increases to maximum availability from the dose. As the occluder blocks blood flow, this time is dependent upon the metabolic requirements of the tissue. In most cases the occluder may remain in place for up to 30 minutes before ischemic damage occurs to the tissue. This duration may be increased by the use of infusates that partially or totally replace the oxygen and nutrient requirements of the target tissues. By way of exemplar, such infusates include oxygenated saline or phosphate buffered solutions, Ringer’s solutions, cellular growth mediums such as RPMI, MEM (minimal essential media), and DMEM, and intravenous sugar solutions such as 5% dextrose solution. Baring the metabolic needs of the surrounding tissue, the diffusion rate of the therapeutic molecule as predicted by molecular mass and positive pressure gradient measurements from the pressure sensor can be used to calculate therapeutic diffusion depth for a given dwell time. As capillaries typically rest no further than lOOpm from a given volume of tissue, the dwell time can be calculated to ensure full penetration of therapeutic to this depth.

[0051] A typical diffusion rate for a small molecule such as doxorubicin is on the order of 0.2-1 pm/sec at physiological pressure differentials of 10-30mmHg from the vessel to surrounding tissue, allowing the drug to diffuse through the 100 pm tissue volume in 2-8 minutes. Higher molecular weight biological protein-based agent such as Immunoglobulin G (IgG) have much lower diffusion rates on the order of 0.0002 pm/sec at physiological pressure differentials of 10-30mmHg, resulting in a diffusion time of 60 minutes to fully penetrate a 100 pm tissue volume. As the pressure differential increases, the rate of diffusion increases.

[0052] Various models can be used to calculate the diffusion rate of a molecule through the tissue. Most such models are based around Fick’s law of diffusion in which diffusion occurs in response to a concentration gradient expressed as the change in concentration due to a change in position. The local rule for molecular movement or flux J is given by Fick's 1st law of diffusion:

[0054] in which the flux J [cm ² s ¹] is proportional to the diffusivity c [cm²/s] and the

d C

negative gradient of concentration,— [cm ³ cm ¹] or [cm ⁴].)

[0055] Then, the distance of molecular penetration can be estimated by considering steady-state transport in one spatial dimension, wherein c(x) is concentration as a function of distance x, c(0) = co is the source concentration, and x is the distance from the source, such that c®0 as x®oo. Assuming first order uptake kinetics, with an uptake rate of k_uc, then for diffusion-dominated transport,

[0057] where, D is the diffusivity and d_p is the characteristic penetration distance. It is calculated how long it takes for the concentration (c₀) to approach 0, i.e., such that the therapeutic agent has diffused out of the vessel and into the surrounding tissue. Thus, the diffusive transport can be used to calculate a transport rate of the therapeutic agent and determine, in whole or in part, the consequent dwell time at which the occluder is to remain in an open expanded configuration post-infusion for appropriate therapeutic uptake into the target tissue.

[0058] It is also known that transport of molecules can be affected by pressure gradients. For convection-dominated transport with first-order kinetics based on the pressure differential between the vessel and the interstitial tissue, the equation can be applied with dp = u/ku, where u is the fluid velocity. As before, it is calculated how long it takes for the concentration (c₀) to approach 0, i.e., such that the therapeutic agent has diffused out of the vessel and into the surrounding tissue. Thus, the measured pressure gradient from the first and second sensors 122, 124 can be used to calculate a transport rate of the therapeutic agent and determine, in whole or in part, the consequent dwell time at which the occluder is to remain in an open expanded configuration post-infusion for appropriate therapeutic uptake into the target tissue.

[0059] Other factors such as the osmotic pressure can also be considered, measured, evaluated, modified, and used to determine a transport rate of the therapeutic agent and calculate, in whole or in part, the consequent dwell time at which the occluder is to remain in an open expanded configuration post-infusion for appropriate therapeutic uptake into the target tissue. [0060] In addition, it is contemplated that the factors such as diffusion, pressure gradient, and/or osmotic pressure may be used in combination of two more to calculate a dwell time at which the occluder is to remain in an open expanded configuration post-infusion for appropriate therapeutic uptake into the target tissue.

[0061] Once the dwell time is complete and the dose of agent has been delivered 114, no additional therapeutic agent is delivered at 116. The proximal handle 50 is then actuated at 118 to collapse the occluder 20, and the system is then removed at 120 from the patient.

[0062] In accord with another method, substantially similar to the prior method, the system used includes a first (single) pressure sensor (and no second pressure sensor). All operations can be similarly performed with the exception that instead of constant real-time systemic pressure monitoring from the second sensor by which to compare the real-time, sensed distal vessel volume pressure from the first sensor in determining a pressure gradient, a baseline pressure is measured with the first pressure sensor prior to expanding the occluder across the vessel wall and used as a comparator for determining the gradient.

[0063] There have been described and illustrated herein embodiments of systems and methods for intravascular delivery of a therapeutic agent through a vessel to a tissue, such as an organ. While particular embodiments of the invention have been described, it is not intended that the invention be limited thereto, as it is intended that the invention be as broad in scope as the art will allow and that the specification be read likewise. Thus, it is recognized that the systems and methods may be applied to both humans and animals. Also, while examples of organs and disease states have been provided, such lists are not meant to be exclusive and the systems and methods are intended to be used where ever they would have therapeutic utility, in association with any such organs, disease states, and with any appropriate therapeutic agents now known or hereinafter discovered or developed. Also, the flexible tubular member can be any catheter arrangement meeting the needs of the device claimed, i.e., permitting passage of the therapeutic agent and actuation of the occluder. Further, while a preferred occluder has been described, other occluders may be used as well to assemble the systems and accomplish the methods described herein. It will therefore be appreciated by those skilled in the art that yet other modifications could be made to the provided invention without deviating from its scope as claimed.

Claims

WHAT IS CLAIMED IS:

1. A system for temporarily occluding a blood vessel, comprising:

a) a flexible tubular member having a proximal end and a distal end, an infusion lumen extending between the proximal and distal ends, the infusion lumen having a distal orifice at the distal end;

b) an expandable occluder comprising a braided construct of filaments mounted at the distal end of the tubular member, the braided construct having a proximal portion and a distal portion, the proximal portion provided with a fluid impermeable cover and the distal portion covered in a fluid permeable cover, a chamber defined within the occluder,

the distal end of the tubular member extending through the occluder such that the orifice opens distal of the occluder; and

c) a first pressure sensor located within the chamber and in pressure communication with a space communicating with the orifice, wherein the fluid permeable cover protects the first pressure sensor from eddy currents generated adjacent the orifice when the orifice is located in blood and an infusate is infused through the infusion lumen.

2. The system of claim 1, wherein:

occluder defines a central axis and a central plane orthogonal to the central axis, and the occluder is symmetrical about the central axis and symmetrical about the central plane.

3. The system of claim 1, wherein:

the flexible tubular member includes a first catheter and a second catheter

longitudinally displaceable relative to each other, the first catheter defining the infusion lumen, and a flush lumen defined at least partly through the second catheter.

4. The system of claim 3, further comprising:

an actuation handle having a stationary member and a movable member movable relative to the stationary member,

the movable member longitudinally fixed relative to the first catheter, and

the stationary member longitudinally fixed relative the second catheter.

5. The system of claim 4, wherein the handle includes, a first port on the movable member for introducing a first fluid into the first catheter, and a second port on the stationary member for introducing a second fluid between the first and second catheters,

the flush lumen defined at least partly between the first and second catheters.

6. The system of claim 1, further comprising:

a second pressure sensor located outside the chamber and out of pressure communication with the space communicating with the orifice.

7. The system of claim 6, wherein the second pressure sensor is fixed to the flexible tubular member at a location proximal of the first pressure sensor.

8. A system for temporarily occluding a blood vessel, comprising:

a) an outer catheter having a proximal end and a distal end;

b) an inner catheter having a proximal end and a distal end with an orifice, the inner catheter extending within the outer catheter, wherein the inner catheter defines an infusion lumen having an orifice at the distal end of the inner catheter, and the space between the outer and inner catheter defines a flush lumen;

c) an actuation handle coupled to the proximal ends of the outer and inner catheters to effect longitudinal displacement of one of the outer and inner catheters relative to the other;

d) a first port coupled to the actuation handle to allow infusion of an infusate into the infusion lumen;

e) a second port coupled to the actuation handle to allow infusion of a flush agent into the flush lumen;

f) an expandable occluder having a proximal portion and a distal portion, the proximal portion provided with a fluid impermeable cover and the distal portion covered in a fluid permeable cover, a chamber defined within the occluder,

the flush lumen in fluid communication with the chamber, and the inner catheter extending through the occluder such that the orifice opens distal of the occluder; and

g) a first pressure sensor located within the chamber and in pressure communication with a space communicating with the orifice.

9. The system of claim 8, wherein the fluid permeable cover protects the first pressure sensor from eddy currents generated adjacent the orifice when the orifice is located in blood and the infusate is infused through the infusion lumen.

10. The system of claim 9, further comprising:

11. The system of claim 10, wherein the second pressure sensor is fixed to the flexible tubular member at a location proximal of the first pressure sensor.

12. The system of claim 9, wherein the occluder includes a braided construct of filaments mounted at the distal ends of the inner and outer catheters, and the fluid impermeable cover and fluid permeable cover are attached to the braided construct.

13. A system for delivering a therapeutic agent to a blood vessel of patient, comprising:

a) a flexible tubular member having a proximal end and a distal end, an infusion lumen extending between the proximal and distal ends, the infusion lumen having a distal orifice at the distal end, wherein when the device is inserted into the blood vessel and a therapeutic agent is infused through the orifice, turbulence is induced in the blood in the blood vessel about the orifice;

b) an expandable occluder mounted at the distal end of the tubular member, a chamber defined within the occluder, the distal end of the tubular member extending through the occluder such that the orifice opens distal of the occluder; and

c) a first pressure sensor to sense fluid pressure in the blood vessel distal of the occluder, wherein when the therapeutic agent is infused through the orifice, the first pressure sensor is isolated from the turbulence.

14. The device of claim 13, wherein the first pressure sensor is located at the interior of the occluder, and a fluid permeable portion of the occluder isolates the first pressure sensor from the turbulence.

15. A method of treating a patient with a therapeutic agent, comprising:

a) providing a system according to claim 13;

b) advancing the occluder of the system to a target vein of an organ;

c) expanding the occluder within the target vein;

d) initiating delivery of a therapeutic agent through the infusion lumen and out of the orifice; e) using the first pressure sensor to monitor pressure in the target vein distal of the occluder during the delivery;

f) using the monitored pressure to determine an endpoint of delivery; and

g) ending delivering at the determined endpoint.

16. The method of claim 15, wherein:

the device includes a second pressure sensor to sense fluid pressure in the blood vessel proximal of the occluder, and

determining a pressure gradient between the pressures sensed by the first and second pressure sensors,

wherein using the monitored pressure includes using the pressure gradient.

17. The method of claim 15, further comprising:

prior to delivering the therapeutic agent, communicating fluid between the first pressure sensor and the target vein distal of the occluder,

the first pressure sensor located at the interior of the occluder, and a fluid permeable portion of the occluder separates the first pressure sensor from the blood in the target vein, the communicating fluid causing at least one of (i) blood to flow into the interior of the chamber or (ii) a flushing agent to be injected through a flushing lumen of the flexible tubular member and into the interior of the occluder and out of the occluder.

18. A method of delivering a therapeutic agent to a patient, comprising:

a) providing a system for temporarily occluding a blood vessel, including,

i) a flexible tubular member having a proximal end and a distal end, an infusion lumen extending between the proximal and distal ends, the infusion lumen having a distal orifice at the distal end, wherein when a therapeutic agent is infused through the orifice, eddy currents are generated about the orifice, and

ii) an expandable occluder mounted at the distal end of the tubular member, the occluder defining a chamber, the distal end of the tubular member extending through the occluder such that the orifice opens distal of the occluder,

iii) a first pressure sensor to sense fluid pressure in the blood vessel distal of the occluder, the first pressure sensor isolated from pressure changes induced by the eddy currents; b) advancing a distal end of the system to a target vein of an organ;

c) expanding the occluder within the target vein;

d) communicating fluid between the chamber of the occluder and the target vein distal of the occluder;

e) sensing a baseline pressure in the target vein distal of the occluder;

f) delivering a therapeutic agent through the infusion lumen and out of the orifice; and g) using the first pressure sensor to monitor pressure in the target vein distal of the occluder during the delivery.

19. The method of claim 18, further comprising:

using a pressure gradient between the monitored pressure and baseline pressure to determine progress of the delivery.

20. The method of claim 18, further comprising:

using a pressure gradient between the monitored pressure and baseline pressure to determine a dwell time in which to keep the occluder expanded within the target vein.

21. The method of claim 20, further comprising:

leaving the occluder expanded within the vein for at least the determined dwell time.

22. The method of claim 18, wherein the baseline pressure is measure with the first pressure sensor prior to expanding the occluder within the vein.

23. The method of claim 18, wherein the baseline pressure is monitored with a second pressure sensor located to sense fluid pressure in the blood vessel proximal of the occluder.

24. A method of measuring pressure in a vessel distal of an artificial temporary vessel occluder delivered into the vessel, comprising:

a) providing a system for temporarily occluding a blood vessel, including, i) a flexible tubular member having a proximal end and a distal end, an infusion lumen extending between the proximal and distal ends, the infusion lumen having a distal orifice at the distal end, wherein when a therapeutic agent is infused through the orifice, eddy currents are generated about the orifice, and

ii) an expandable occluder mounted at the distal end of the tubular member, the distal end of the tubular member extending through the occluder such that the orifice opens distal of the occluder,

iii) a first pressure sensor to sense fluid pressure in the blood vessel distal of the occluder, the first pressure sensor isolated from pressure changes induced by the eddy currents, and

iv) a second pressure sensor to sense fluid pressure in the blood vessel proximal of the occluder, the second pressure sensor isolated from the blood distal of the occluder by the occluder when the occluder is expanded across the blood vessel;

b) advancing a distal end of the system into a vessel;

c) communicating fluid between the chamber of the occluder and the vessel distal of the occluder;

d) sensing a baseline pressure in the vessel distal of the occluder with the first sensor;

e) sensing a baseline pressure in the vessel proximal of the occluder with the second sensor; and

f) performing a function on the data received from the first and second sensors to remove variations in the data from the first sensor due to physiological phenomena.

25. A method according to claim 24, further comprising:

infusing a therapeutic agent through the infusion lumen and out of the distal orifice; and performing a function on the data received from at least the first sensor to remove variations in the data due to turbulent flow from the therapeutic agent exiting the distal orifice.

26. A method of delivering a therapeutic agent into a target tissue through a vessel,

comprising:

a) providing a system for temporarily occluding a blood vessel, including,

i) a flexible tubular member having a proximal end and a distal end, an infusion lumen extending between the proximal and distal ends, the infusion lumen having a distal orifice at the distal end, wherein when a therapeutic agent is infused out of the orifice, eddy currents are generated about the orifice, and

b) advancing a distal end of the system into a vessel;

c) expanding the occluder to block blood flow past the occluder within the vessel;

d) then infusing at least one therapeutic agent through the infusion lumen and out of the distal orifice into the vessel distal of the occluder; and

e) leaving the occluder expanded for at least a dwell time sufficient for transport of the at least one therapeutic agent through the vessel wall and into a target tissue.

27. The method according to claim 26, wherein infusion of the therapeutic agent generates a pressure gradient in the vessel on the proximal and distal sides of the occluder, and the pressure gradient, at least in part, affects the transport of the therapeutic agent.

28. The method according to claim 27, wherein the system includes a first pressure sensor to measure a first fluid pressure of blood in the vessel distal of the occluder, and a second pressure sensor to measure a second fluid pressure of blood in the vessel proximal of the occluder, and the measured pressure gradient is a differential between the first and second fluid pressures.

29. The method according to claim 26, wherein the dwell time is calculated based, at least in part, on the diffusion rate of a molecule of the therapeutic agent.

30. The method according to claim 29, wherein the diffusion rate of the molecule is predicted, at least in part, by the molecular mass of the molecule.

31. The method according to claim 26, wherein one of the at least one therapeutic agent at least partially replaces the oxygen and/or nutrient requirements of the target tissue.

32. The method according to claim 26, wherein the transport rate of the therapeutic agent is calculated, at least in part, by osmotic characteristics of the therapeutic agent in the vessel.