Non-invasive occlusion system with lumen for measuring changes in vascular pressure

Abstract

A non-invasive vascular occlusion system includes a flexible tubular member having an infusion lumen, a vascular occluder mounted at the distal end of the tubular member, and a pressure sensor located in a chamber defined by the occluder. The occluder has a braided structure, which is provided with a fluid-impermeable membrane on its proximal portion and a fluid-permeable cover on its distal portion. The pressure sensor is suitable for sensing the pressure in the blood vessel through the fluid-permeable membrane without being affected by turbulence at the outlet of the infusion lumen. The accurately sensed pressure can be used to determine the residence time of the occluder.

Description

Technical Field

[0001] The present invention relates to catheter-based occlusion systems and intravascular methods for delivering therapeutic agents for treating disease. Background Art

[0002] Veins are designed to carry blood from tissue back to the heart. This results in several physiological differences relative to arteries. Key among these features is that they are configured to carry relatively large volumes of low-pressure blood. As a result, they tend to have larger lumens and less muscle and elastic tissue relative to comparable arteries. Temporary occlusion of veins, therefore, requires a device that has a large enough diameter to fill the venous passageway without exerting high radial forces on the weaker vessel walls.

[0003] The most common occlusion device is the vascular balloon. These devices work by inflating a flexible or semi-flexible membrane using fluid pressure through a lumen that communicates with the operator. Inflation of the balloon to the proper size is typically monitored by fluoroscopy, which inflates the balloon by injecting a precise amount of contrast fluid, followed by a bolus of contrast through the device's infusion lumen to determine whether blood flow is sustained. Balloon volume must be closely monitored because even small degrees of overinflation can result in radial forces being applied to the vessel wall.

[0004] The use of balloons is common in arterial networks. The structure of arterial vessels, with a thick muscle layer and elastic fiber matrix, allows for a high degree of variability in the inflation of the device without rupture.

[0005] Differently, the venous system presents many challenges when using a balloon. Larger veins require larger balloon diameters, making precise control of inflation challenging. Additionally, the less elastic and smaller structure of the veins offers less and less resistance to the high radial forces applied by the balloon. This in turn leads to complications such as vessel rupture and dissection.

[0006] Co-owned U.S. Patent Nos. 9,770,319 and 9,968,740 to Chomas teach several dynamic microvalve occlusion systems based on therapeutic catheters that automatically open and close based on relative fluid pressure conditions proximal and distal to the microvalve. These occlusion systems provide excellent occlusion while applying low radial forces on the vessel wall. However, the system described in Chomas is not suitable for providing the user with accurate information about the pressurization experienced by the treated vessel or whether the interstitial fluid pressure in the treated tissue is overcome. In particular, the interstitial fluid surrounds the blood vessels and exerts pressure on them. The interstitial fluid pressure in a tumor is a physiological parameter that has clear predictive value for the aggressiveness of the tumor, drug delivery, and response to treatments such as radiotherapy and chemotherapy. The interstitial fluid pressure is generally high relative to the blood pressure in the veins, indicating a strong tendency for molecules to flow from the interstitial fluid into the veins. Therefore, the interstitial fluid pressure biases the absorption of the treatment by the veins. Summary of the invention

[0007] A non-invasive vascular occlusion system includes a flexible tubular member having a proximal end, a distal end and defining an infusion lumen extending between the proximal end and the distal end, a vascular occluder with adjustable diameter mounted at the distal end, and at least one pressure sensor.

[0008] In one embodiment, the flexible tubular member comprises an inner catheter longitudinally displaceable relative to the outer catheter. The inner catheter defines an infusion lumen having a distal opening, and the flushing lumen is at least partially defined by the outer catheter and preferably between the inner and outer catheters.

[0009] In one embodiment, the occluder is connected to the distal end of each of the outer catheter and the inner catheter so that when the inner catheter moves longitudinally in the distal direction relative to the outer catheter, the occluder contracts along the diameter into an elongated oval delivery configuration, which is sized to pass through the blood vessel, and when the inner catheter moves longitudinally in the proximal direction relative to the outer catheter, the occluder expands along the diameter into an occlusion configuration suitable for extending across the blood vessel wall. The expanded occlusion 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 blood vessel and the chamber distal to the occluder.

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

[0011] According to an embodiment of the system, a first pressure sensor is positioned within the chamber of the occluder. Due to the fluid communication between the chamber and the blood vessel, the first pressure sensor is adapted to sense the pressure in the blood vessel in real time. In addition, because the first pressure sensor is isolated from the blood vessel by a fluid permeable membrane, the first pressure sensor is not affected by turbulence occurring at the distal orifice of the infusion lumen, as further described below.

[0012] During therapeutic agent delivery, pressure readings can be used to confirm placement of the device and to confirm the absence of collateral flow in the vessel distal to the tip of the device. Collateral flow is a condition in which blood circulation is established when venous or arterial function is compromised through the enlargement of small vessels and rewiring of vessels to adjacent parts. It is important that collateral flow is absent to ensure that fluid therapeutic agents infused through the infusion lumen of the device will reach the target tissue in the organ and will not be redirected to non-target tissue. The change in pressure gradient from the arterial side to the venous side is caused by the difference in volume within the blood vessel in the direction of flow. The volume on the arterial side is smaller than the venous side, resulting in a drop in pressure as blood flows from the artery to the vein. The characteristic increase in pressure when a vein is occluded is an indicator that there is no collateralization of the tissue compartment, as the collateral flow will provide an alternative path for blood flow and will prevent an increase in pressure.

[0013] According to another aspect of the system, a second pressure sensor is positioned proximal to the occluder diameter. The gradient between the first and second pressure sensors can directly determine when the pressure in the vessel increases relative to systemic pressure. The presence of two sensors allows this gradient to be calculated in real time.

[0014] According to another aspect of the system, an actuating handle is disposed at the proximal ends of the inner and outer catheters to achieve relative displacement thereof. In addition, a first port in fluid communication with the inner catheter is disposed at the handle for delivering a first fluid into the infusion lumen and outflowing into the blood vessel. A second port is also disposed at the handle and in fluid communication with the outer catheter for delivering a second fluid into the chamber through the flushing lumen and outflowing from the fluid-permeable distal portion of the occluder.

[0015] According to one method, the system is advanced to the target vessel of the organ according to a known procedure. In a preferred method, in the delivery configuration, the device is tracked through the venous system. The first and / or second pressure sensors are used to obtain a systemic reference pressure. The actuation handle is used to retract the inner catheter relative to the outer catheter, and thereby the occluder is deployed in the vein into an occluding configuration, wherein the occluder has a crouching oval shape with an expanded diameter. When the blood flow pressure in the vein applies a force to the distal side of the occluder, the occluder blocks the flow of the vein.

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

[0017] The therapeutic agent is then infused through the infusion lumen and from the distal orifice, over the occluder. The therapeutic infusion is performed while monitoring the pressure, allowing the user to determine whether an overpressure has been experienced and whether the tissue fluid pressure within the organ tissue has been overcome. The therapeutic infusion can generate local vortices in the fluid near the tip of the device. Although this may hinder accurate readings of pressure during infusion if the sensor is placed at the tip of the device, the sensor can be protected from such vortices by placing the sensor in the chamber. The pores or permeability in the distal portion of the occluder allow fluid communication between the chamber and the distal vascular cavity. During infusion, the pressure in the distal vascular system and the chamber is balanced due to the pores in the distal membrane. However, these pores are small enough to damp the turbulence generated by the distal tip, allowing stable pressure readings of the first sensor. Stable pressure readings allow accurate identification of the pressure at the arterial side of the occluder.

[0018] A second sensor located proximal to the expanded occluder can be used to monitor systemic pressure during infusion. Using data from the first and second sensors, it is more straightforward to determine when pressure distal to the occluder increases relative to systemic pressure. The presence of two sensors allows for real-time calculation of pressure differentials, whereas a single tip-based sensor requires determination of a system reference point prior to device deployment and subsequent injection.

[0019] Then, during the infusion of the 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, this indicates that there has not been collateralization of the tissue compartment, as the collateral flow will provide an alternative path for blood flow and will prevent this pressure gradient. Infusing the therapeutic while monitoring the pressure allows the user to determine if hypertension is being experienced and if tissue fluid pressure within the tissue is being overcome.

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

[0021] The occluder can remain expanded within the vessel for the dwell duration until the therapy has been infused and absorption of the therapy has occurred without being washed away in the venous blood flow. The proximal handle is then actuated to collapse the occluder and the system is then removed from the anatomical structure. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 is a perspective view of an atraumatic occlusion system described in an embodiment of the present invention.

[0023] Figure 2 yes Figure 1 An enlarged schematic side view of the distal side of the system of FIG. 1 , showing the occluder in a reduced diameter configuration for guidance into a target vessel.

[0024] Figure 3 is similar to Figure 2 , showing the occluder in an enlarged diameter configuration for occluding a target blood vessel.

[0025] Figure 4 is a flow chart of a method of using the system. DETAILED DESCRIPTION

[0026] Referring to the following description, the terms "proximal" and "distal" are defined with reference to a user of the device, wherein the term "proximal" is closer to the user's hand and the term "distal" is farther away from the user, such as further inside a patient's body during use.

[0027] The devices and methods described herein involve using a system to inject a therapeutic agent into a major blood vessel that is in communication with a diseased tissue (e.g., a tumor) of an organ. For example, the tumor to be treated may be a solid tumor. In some cases, the tumor may be a cancerous tumor, such as tumors specific to pancreatic cancer, kidney cancer, liver cancer, lung cancer, or uterine cancer, just as examples.

[0028] As described herein, a therapeutic system is used to deliver a therapeutic agent to a solid tumor by targeted infusion of the therapeutic agent into a tissue region. The therapeutic agent is injected under relatively high pressure into an organ region or other defined region of tissue served by one or more supply vessels.

[0029] Now go to Figure 1 and Figure 2 , shows an atraumatic vascular occlusion system 10. The system 10 includes a flexible tubular member 12 having a proximal end 14 and a distal end 16. The tubular member 12 defines an infusion lumen 18 extending between its proximal and distal ends. A diameter-adjustable vascular occluder 20 is mounted at the distal end 16 of the tubular member. The system also includes at least one pressure sensor 22, 24, the location and function of which are described below.

[0030] In one embodiment, the flexible tubular member 12 includes an inner catheter 30 that can be telescopically advanced within an outer catheter 32. The inner catheter 30 has a proximal end 34 and a distal end 36, and the outer catheter 32 also has a proximal end 38 and a distal end 40. The infusion lumen 18 is preferably defined through the inner catheter 30 and leads to the distal axial orifice 84, and a separate flushing lumen 42 is preferably defined in the annular space between the inner catheter and the outer catheter. Alternatively, the flushing lumen can extend through the wall of either the inner catheter 30 or the outer catheter 32.

[0031] According to a preferred aspect of the system, an actuation handle 50 is disposed at the proximal ends 34, 38 of the inner catheter 30 and the outer catheter 32 to achieve relative displacement thereof. The actuation handle 50 includes a stationary member 52 and a movable member 54, such as a slider that can be longitudinally displaced 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 slider 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 to the inner catheter. The proximal end of the slider 54 defines an infusion port 62, which is fluidically coupled to the proximal end 34 of the inner catheter 30. The actuation handle 50 also includes a releasable lock 64, which can hold the movable member 54 and the stationary member 62 in a relatively fixed longitudinal position when actuated. The handle 50 may also include a display 66 and associated memory and logic to allow for display of real-time and / or stored pressure data read from the first and second sensors 22, 24, as well as a calculated relationship between the pressures read from the sensors 22, 24, such as a gradient between the two. A button 68 near the display allows for actuation of the logic and display and cycling through the various logic functions.

[0032] The occluder 20 is a microvalve that includes a braided structure of filaments 70. The proximal end of the filaments 70 is coupled to and preferably rigidly fixed to the distal end 40 of the outer catheter 32, and the distal end of the filaments 70 is coupled to and preferably rigidly fixed to the distal end 36 of the inner catheter 30. The general structure of the braided valve portion of this microvalve device is described in detail in co-owned U.S. Patent Nos. 8,696,698 and 9,770,319, both of which are incorporated herein by reference. The longitudinal displacement of the inner catheter 30 relative to the outer catheter 32 causes the microvalve to be in a first elongated oval configuration (a smaller diameter) suitable for being guided to the deployed position in the blood vessel. Figure 2 ) and a second squat oval configuration of a larger diameter suitable for occluding a blood vessel (e.g. Figure 3That is, in both the first and second configurations, the microvalve is an oval configuration and has a generally symmetrical shape about the longitudinal center axis A and a plane P orthogonal to the microvalve center axis A at its maximum diameter region. It should be appreciated that the occluder can move through the first and second configurations, as well as any size configuration therebetween, to best fit the blood vessel in which the occluder is used. The lock 64 on the handle 50 can help to hold the occluder 20 in a desired size configuration during therapeutic treatment. The system 10 can be advanced to a deployed position in a blood vessel in the first elongated configuration by 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] According to one aspect of the occluder 20, a fluid-impermeable membrane 72 is provided on the proximal portion 74 of the braided structure. Suitable materials for impermeable membranes include elastic natural and artificial rubbers, silicones, styrene, olefins, copolyesters, polyurethanes and polyamides. According to another aspect of the occluder, a fluid-permeable coating or covering 76 is provided on the distal portion 78 of the braided structure. Suitable materials for fluid-permeable coating 76 include elastomeric natural and artificial rubbers, silicones, styrene, olefins, copolyesters, polyurethanes and polyamides, which are processed to have microscopic or macroscopic perforations, channels, holes or fibers rather than continuous forms. This can be achieved by physical perforation techniques, by electrostatic spinning or melt spinning fibers, by including soluble components that can be removed during processing to leave holes or gaps, and by adding open-cell foaming agents or other suitable technologies. Coating or covering 76 may include materials placed on the outer surface of filament 70, in the inner surface of filaments or in their combination. Coating or covering 76 may extend only between filaments. The coating or covering 76 can float freely on the filament, or can be rigidly fixed to the filament. The coating or covering 76 can be applied by dipping, spraying, suturing, combined application or other suitable techniques. The fluid permeable material 76 can be an impermeable material made permeable by perforations or pores 80. As described below, the fluid permeable material can be formed with gaps or openings 80, which provide permeability that meets the fluid permeability requirements. The pores, perforations, gaps, openings, etc. (hereinafter collectively referred to as "pores" 80) can be arranged in a certain geometric shape within the fluid permeable material. The total cross-sectional area of ​​the pores should be large enough to help measure physiological responses and infusion pressures while damping short-duration turbulence. Most preferably, the pores should be arranged in a radially symmetrical manner to maintain the uniform radial bending properties of the device.

[0034] Since the flush lumen between the inner and outer catheters is in fluid communication with the proximal infusion port, the pressure sensor can reside within this space and, as long as the proximal infusion port is sealed (creating a closed pressure chamber that communicates with the distal tip of the catheter), the pressure sensor still monitors the pressure experienced at the distal tip. The sensor responsiveness within this chamber is determined by the cross-sectional area of ​​the flush lumen and the length between the sensor and the most distal aperture. The delay in pressure response time decreases with increasing cross-sectional area and decreasing length. For example, a pressure sensor with a cross-sectional area of ​​0.5 mm 2 A device with a flush lumen and a sensor located 100 cm from the distal orifice would require 2-5 seconds to respond and stabilize to changes in pressure; however, a device with a cross-sectional area of ​​0.5 mm 2 A device with a flush lumen and a sensor located 50 cm from the distal orifice would require 1-3 seconds to respond and stabilize to changes in pressure; and having a cross-sectional area of ​​2 mm 2 An arrangement with a flush lumen and a sensor located 100 cm from the distal pore will require 0.1-0.5 seconds to respond and stabilize pressure changes. Therefore, the proximity of the sensor is controlled by the duration of the physiological response intended to be monitored. For example, an infusion of a therapeutic agent may be administered over a period of time. For infusions that occur within a few seconds and have transient pressure changes, the sensor should be placed in a space with sufficient cross-sectional area and at a sufficiently short distance from the distal pore to monitor pressure changes that occur within one second (or less). In addition, the holes at the distal end of the filter should be small enough and have a relatively low cross-sectional area so that pressure fluctuations on the order of 0.01-0.2 seconds are damped when the sensor responds in the time range of 0.2-1 seconds.

[0035] In one embodiment, the first pressure sensor 22 is mounted in the chamber 82. The first pressure sensor 22 can be mounted on the outer wall of the portion of the inner catheter 30 extending in the occluder (as shown), on the inner portion of the filament braid, or on another structure located in the chamber. The material covering or coating 76 on the distal portion 78 of the occluder 20 must have sufficient fluid permeability so that when the occluder is positioned in a fluid-filled blood vessel and the chamber 82 is filled with fluid, both the chamber and the distal vascular cavity will be subject to the same pressure conditions. Therefore, the first pressure sensor 22 can accurately sense the fluid pressure conditions outside the occluder in the distal vascular cavity of the target vessel. However, the fluid permeable material 76 achieves sufficient barrier effect to damp the turbulence and pressure effects thereof generated at the orifice 84 of the infusion lumen during therapeutic infusion, thereby avoiding causing pressure instability at the internal chamber of the occluder, and thus producing the consequent harmful effects on obtaining accurate pressure readings of the distal vascular cavity of the target vessel.

[0036] According to 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 the pressure differential; that is, to determine when and how much the distal vascular cavity pressure is higher than the systemic pressure.

[0037] The use of the first and second sensors 22, 24 allows for real-time calculation of the pressure gradient across the occluder 20. Alternatively, the first pressure sensor 22 can be used alone to determine the 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 the gradient. The use of the gradient is described below.

[0038] Now go to Figure 4 According to a method of using the system, the distal end of the system is advanced to a target vessel of an organ in a first elongated configuration at 100 according to known procedures. In this manner, the system 10 can be tracked through the venous system via a guidewire to a desired location. The target vessel is preferably a vein that receives a blood return supply from the organ. For example, the organ may be the liver and the target vessel may be the saphenous vein, or the organ may be the pancreas and the target vessel may be the portal vein. Other organs may be similarly treated via an associated target vessel, 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 so that the outer surface of the occluder is juxtaposed with the vessel wall. The handle lock 64 can be operated to fix the occluding configuration (size and shape) of the occluder 20 within the vessel. The occluder 20 blocks the venous flow when the pressure of the arterial side of the blood flow in the vein applies a force to the distal side of the occluder, which forces the occluder into the open, expanded configuration.

[0040] Blood can begin to fill the chamber 82 of the occluder 20 through the pores 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 injected into the chamber 82 of the occluder. Due to the pores 80 in the distal portion 78 of the occluder, the occluder does not have to expand under the pressure of the flushing fluid; instead, the flushing fluid is intended to place the first sensor 22 in continuous fluid contact with the blood located outside the occluder. Once there is fluid continuity at 104, the pressure outside the occluder 20 and through the pores can be sensed in real time at the first sensor at 106. A baseline pressure reading of the blood vessel is preferably obtained.

[0041] Then, at 108, the therapeutic agent is infused through the infusion lumen 18 and from the distal orifice 84 of the inner catheter, beyond the occluder 20. While monitoring the pressure in the blood vessels distal to the occluder and optionally proximal to the occluder, the infusion of the treatment continues. Infusing the treatment from the orifice of the infusion lumen can generate local vortices in the fluid near the distal tip of the system. In existing systems, these vortices may hinder accurate pressure monitoring of vascular conditions during infusion. In contrast, the first pressure sensor 22, which is shielded by a fluid-permeable material in the chamber, is protected from the harmful effects of vortices that hinder accurate monitoring. The pores or permeability of the distal portion of the occluder allow fluid communication between the chamber and the distal vascular cavity. During infusion, the pressure in the distal vascular system and the chamber is balanced due to the pores in the distal membrane. However, these pores are small enough and are geometrically arranged to damp the turbulence generated by the distal tip, thereby allowing stable pressure readings by the embedded first sensor. Steady (non-turbulent) pressure readings allow accurate identification of the pressure at the arterial side of the occluder. Additionally, a second sensor 24 located proximal to where the expanded occluder 20 meets the vessel wall can be used to monitor systemic pressure during the infusion in real time at 110. This accurate pressure data can be used to determine pressure conditions within the organ tissue; i.e., whether an overpressure condition exists and / or whether interstitial fluid pressure within the organ tissue is overcome.

[0042] The second sensor 24 is completely shielded from turbulence by the impermeable portion of the occluder 20. Therefore, it monitors physiological pressure changes caused by heartbeat, breathing and other physiological phenomena. These changes from physiological phenomena occur in time frames of 100 milliseconds to several seconds. The distal first sensor 22 also measures changes from physiological phenomena, as well as infusions of treatment and turbulence. Turbulence occurs in very short time frames and can be filtered based on the smoother pressure distribution of the reference second sensor 24. Although the porous nature of the distal occluder 20 geometry physically "pre-filters" most of the noise from turbulence that would otherwise appear around the first sensor 22, in one embodiment of the method, it is expected that the noise from physiological phenomena will also be reduced. Changes in measured pressure due to heartbeat, breathing and other physiological phenomena recorded on the proximal second sensor 24 can be subtracted from the measurements of the distal first sensor 22, leaving only pressure changes associated with infusion. According to the method, data processing of pressure data received from the first and second sensors 22, 24 uses a filter function to subtract turbulence data (short time frame pressure changes) and a subtraction function to remove changes due to more extensive physiological changes. The filtering algorithm produces a pressure reading that is produced only by the infusion of the therapeutic agent through the infusion lumen.

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

[0044] During infusion of the therapeutic agent, at 112 , the calculated gradient between the arterial supply (from the first pressure sensor) and the return venous side (from the second pressure sensor) of the vein allows the progress of the therapy to be monitored.

[0045] If the gradient identifies a higher pressure on the distal side, this indicates that there has been no collateralization of the tissue compartment, as the collateral flow will provide an alternative path for blood flow and will prevent this pressure gradient. Therapeutic infusion is performed while monitoring pressure, allowing the user to determine if hypertension is being experienced and tissue fluid pressure within the tissue is being overcome.

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

[0047] In order to understand this advantage, it is necessary to understand that molecules residing in the blood or other fluids are filtered through the blood vessels based on the pressure difference between the fluid in the blood vessels and the surrounding tissues. On the arterial side, the pressure in the blood vessels is usually higher than the surrounding interstitial pressure. This positive pressure gradient forces molecules to leave the arterial end of the capillary bed and enter the tissue. As the blood travels through the arterial vessels, the pressure drops, thereby reducing the positive pressure gradient until there is no gradient and the pressure-mediated filtration of molecules through the blood vessels stops. There is a negative gradient on the venous side of the capillary bed, causing the molecules to be reabsorbed back into the venous side capillaries and enter the systemic circulation. The pressure change from the arterial side to the venous side is the result of different volumes within the blood vessels in the direction of flow; the arterial side has a smaller volume than the venous side, causing the pressure of the blood to drop as it flows from the artery to the vein.

[0048] Blood flow stops when the vein becomes occluded due to the expansion of the occluder 20 across the vein. The blood, which is an incompressible fluid composed primarily of water, then equilibrates to the arterial side pressure.

[0049] The resulting pressure change increases the volume of the blood vessel that experiences a positive pressure gradient to the surrounding tissue, including the venous vessels. This allows material to diffuse outward from the blood vessel to the entire tissue volume. This effect occurs in tissues that typically have a negative pressure gradient, in which fluids and molecules would normally be filtered from the tissue into the vascular system. Thus, tissue treatment of both the arterial and venous sides is achieved. The duration and extent of diffusion through the vessel wall and into the tissue can be controlled by the duration of the occluder remaining in the expanded second configuration. The pressure can be further adjusted by injecting one or more additional volumes of fluid into the venous network distal to the occluder. For example, one or more salt bolus injections can be injected into the blood vessel to modify the absorption of the therapeutic agent.

[0050] More specifically, the system is used to sense the pressure in the vascular volume distal to the occluder when in place. This allows confirmation that the pressure in the volume has increased relative to the baseline pressure. The therapeutic agent is then infused into the vascular volume through the infusion lumen. The occluder remains open in an expanded configuration within the vessel according to a dwell function that identifies the parameters for optimal diffusion through the vessel wall. For example, the dwell function may depend on the therapeutic agent (e.g., the size of the molecule and the interaction of the molecule with the vessel wall) and the measured pressure gradient. Keeping other parameters constant, the greater the measured pressure gradient, the less time is required for the therapeutic agent to optimally diffuse into the tissue. The residence time of the therapeutic agent maximizes the time the therapeutic agent resides in the target vascular system, or in other words, the occluder is opened until the concentration of the therapeutic agent in the vascular blood approaches zero and the concentration of the therapeutic agent in the surrounding target tissue increases to the maximum availability from the dose. Since the occluder blocks blood flow, this time depends on the metabolic needs of the tissue. In most cases, the occluder can remain in place for up to 30 minutes before ischemic damage occurs to the tissue. The duration can be increased by using infusates that partially or completely replace the oxygen and nutrient requirements of the target tissue. For example, such infusates include oxygenated saline or phosphate buffered solutions, Ringer's solution, cell growth media (such as RPMI, MEM (minimum essential medium) and DMEM), and intravenous sugar solutions (such as 5% glucose solution). The diffusion rate of the therapeutic molecule predicted by the molecular mass and positive pressure gradient measurement from the pressure sensor can be used to calculate the therapeutic diffusion depth for a given residence time, taking into account the metabolic needs of the surrounding tissue. Since capillaries generally reside no more than 100 microns away from a given tissue volume, the residence time can be calculated to ensure that the therapeutic agent fully penetrates to this depth.

[0051] At a physiological pressure differential of 10-30 mmHg from blood vessels to surrounding tissue, the typical diffusion rate of small molecules (such as doxorubicin) is on the order of 0.2-1 micrometers per second, allowing the drug to diffuse through a 100 micrometer volume of tissue in 2-8 minutes. Higher molecular weight biological protein-based agents (such as immunoglobulin G (IgG)) have a much lower diffusion rate of the order of 0.0002 micrometers per second at a physiological pressure differential of 10-30 mmHg, resulting in a diffusion time of 60 minutes to completely penetrate a 100 micrometer volume of tissue. As the pressure differential increases, the diffusion rate also increases.

[0052] Various models can be used to calculate the diffusion rate of molecules through tissues. Most such models are based on Fick's law of diffusion, in which diffusion occurs in response to a concentration gradient expressed as a change in concentration due to a change in position. The local rule for the molecular motion or flux J is given by Fick's first law of diffusion:

[0053]

[0054] Where, the flux J [cm -2 s -1 ] and diffusion rate [cm 2 / s] and negative concentration gradient [cm -3 cm -1 ] or cm -4 ] is proportional to.

[0055] The distance that a molecule permeates can then be estimated by considering steady-state migration in one spatial dimension, where c(x) is the concentration as a function of distance x, and c(0) = c 0 is the source concentration, and x is the distance from the source, so that when , Assuming first-order absorption kinetics, with k u c absorption rate, then for diffusion-dominated migration,

[0056] ,in

[0057] where D is the diffusion rate, and d p is the characteristic penetration distance. Calculate the concentration (c o ) approaches 0, i.e., such that the therapeutic agent has diffused out of the vessel and into the surrounding tissue. Thus, diffusion migration can be used to calculate the migration rate of the therapeutic agent and determine in whole or in part the subsequent residence time that the occluder remains in an open, expanded configuration after infusion in order to properly absorb the therapeutic agent into the target tissue.

[0058] It is well known that the migration of molecules is affected by pressure gradients. For convection-dominated migration with first-order kinetics based on the pressure difference between vascular and interstitial tissue, the equation can be applied as dp = u / ku, where u is the fluid velocity. As described above, the concentration (c o ) approaches zero, i.e., such that the therapeutic agent has diffused out of the blood vessel and into the surrounding tissue. Thus, the measured pressure gradients from the first and second sensors 122, 124 can be used to calculate the migration rate of the therapeutic agent and determine, in whole or in part, the subsequent residence time that the occluder is maintained in the open, expanded configuration after infusion in order to properly absorb the therapeutic agent into the target tissue.

[0059] Other factors such as osmotic pressure may also be considered, measured, evaluated, modified, and used to determine the migration rate of the therapeutic agent and calculate in whole or in part the subsequent residence time that the occluder maintains an open, expanded configuration after infusion to allow for proper absorption of the therapeutic agent into the target tissue.

[0060] Additionally, it is contemplated that factors such as diffusion, pressure gradients, and / or osmotic pressure may be used in conjunction with two or more factors to calculate the residence time that the occluder will remain in the open, expanded configuration following infusion to allow for proper absorption of the therapeutic agent into the target tissue.

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

[0062] According to 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 performed similarly, except that when determining the pressure gradient, instead of constant real-time systemic pressure monitoring from the second sensor (with which the real-time sensed distal vessel volume pressure from the first sensor is compared), the baseline pressure is measured with the first pressure sensor before the occluder is extended across the vessel wall and used as a comparator for determining the gradient.

[0063] Embodiments of systems and methods for intravascular delivery of therapeutic agents to tissues (such as organs) through blood vessels have been described and illustrated herein. Although specific embodiments of the present invention have been described, this does not mean that the present invention is limited thereto, as it is intended that the present invention is broad as far as the art allows, and the specification is read equally. Therefore, it is recognized that the system and method can be applied to both humans and animals. In addition, although examples of organs and disease states have been provided, these lists are not meant to be exclusive, and these systems and methods are intended to be used anywhere where they will have therapeutic utility, associated with any such organ, disease state, and any suitable therapeutic agent now known or discovered or developed thereafter. In addition, the flexible tubular member can be any catheter arrangement that meets the needs of the device claimed, i.e., allows the passage of therapeutic agents and the actuation of the occluder. In addition, although preferred occluders have been described, other occluders can also be used to assemble the system and implement the method described herein. Therefore, those skilled in the art will understand that other modifications can be made to the provided invention without departing from the scope of the claimed protection.

Claims

1. A system for temporarily occluding a blood vessel, comprising: a) a flexible tubular member having a proximal end and a distal end, the flexible tubular member comprising an infusion lumen extending therethrough between the proximal end and the distal end, the infusion lumen having a distal orifice at the distal end; b) an expandable occluder comprising a braided structure of filaments mounted at the distal end of the flexible tubular member, the braided structure having a proximal portion and a distal portion, the proximal portion being provided with a fluid-impermeable covering and the distal portion being covered in a fluid-permeable covering, the interior of the occluder enclosing a chamber, The distal end of the flexible tubular member extends through the occluder so that the orifice opens distal to the occluder; and c) a first pressure sensor located within the chamber and in pressure communication with a space in communication with the orifice, wherein the fluid permeable covering protects the first pressure sensor from turbulence generated adjacent the orifice when the orifice is located in blood and an infusate is infused through the infusion lumen, and wherein the fluid permeable covering is configured to have sufficient permeability to allow fluid continuity between the chamber and the portion of the blood vessel distal to the occluder and to dampen the effects of fluid turbulence on the first pressure sensor caused by infusion of infusate through the infusion lumen and exiting the orifice.

2. The system of claim 1, wherein: The occluder extends longitudinally along a central axis, and the occluder is symmetrical about the central axis and about a central plane perpendicular to the central axis.

3. The system of claim 1, wherein: The flexible tubular member includes a first conduit and a second conduit longitudinally displaceable relative to one another, the first conduit defining the infusion lumen, and a flushing lumen defined at least partially through the second conduit.

4. The system according to claim 3, further comprising: an actuation handle having a stationary member and a movable member movable relative to the stationary member, The movable member is longitudinally fixed relative to the first conduit, and The stationary member is longitudinally fixed relative to the second conduit.

5. The system according to claim 4, wherein: The actuating handle comprises: a first port on the movable member fluidly coupled to the first conduit and configured to introduce a first fluid into the first conduit, and A second port on the stationary member is fluidly coupled to the second conduit and is configured to introduce a second fluid through the irrigation lumen, wherein the irrigation lumen extends between the first conduit and the second conduit.

6. The system according to claim 1, further comprising: A second pressure sensor is located outside the chamber and is not in pressure communication with the space in communication with the orifice.

7. The system according to claim 6, wherein: The second pressure sensor is secured to the flexible tubular member at a location proximal to 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, the outer catheter having a lumen extending through the outer catheter from the proximal end of the outer catheter to the distal end of the outer catheter; b) an inner catheter having a proximal end and a distal end with an orifice, the inner catheter extending through the lumen of the outer catheter, wherein the inner catheter includes an infusion lumen extending from the proximal end of the inner catheter to the distal end of the inner catheter and opening into the orifice at the distal end of the inner catheter, wherein a flushing lumen extends through at least a portion of the space between the outer catheter and the inner catheter; c) an actuation handle coupled to a proximal end of the outer catheter and a proximal end of the inner catheter, the actuation handle being configured to longitudinally displace one of the outer catheter and the inner catheter relative to the other; d) a first port coupled to the actuation handle, the first port configured to receive an infusion of an infusate into the infusion lumen; e) a second port coupled to the actuation handle to allow infusion of an irrigation agent into the irrigation lumen; f) an expandable occluder having a proximal portion and a distal portion, the proximal portion being provided with a fluid-impermeable covering and the distal portion being covered in a fluid-permeable covering, the interior of the occluder enclosing a chamber, wherein the flushing lumen is in fluid communication with the chamber, and the inner catheter extends through the occluder such that the orifice opens distally of the occluder; and g) a first pressure sensor located within the chamber and in pressure communication with the space communicating with the orifice, the first pressure sensor being adapted to sense pressure, wherein the fluid-permeable covering is located between the orifice and the first pressure sensor, and the fluid-permeable covering is configured to have sufficient permeability to allow fluid continuity between the chamber and the portion of the blood vessel distal to the occluder and to dampen the effects of fluid turbulence caused by infusion of an infusate through the infusion lumen and out of the orifice on the first pressure sensor, the first pressure sensor being adapted to maintain fluid communication with the portion of the blood vessel distal to the occluder.

9. The system according to claim 8, further comprising: A second pressure sensor is located outside the chamber and is not in pressure communication with the space in communication with the orifice.

10. The system according to claim 9, wherein: The second pressure sensor is secured to the outer catheter at a location proximal to the first pressure sensor.

11. The system according to claim 8, wherein: The occluder includes a braided structure of filaments mounted at distal ends of the inner catheter and the outer catheter, and the fluid-impermeable cover and the fluid-permeable cover are attached to the braided structure.

12. A system for delivering a therapeutic agent to a patient's blood vessel, comprising: a) a flexible tubular member having a proximal end and a distal end, the flexible tubular member comprising an infusion lumen extending through the flexible tubular member between the proximal end and the distal end, the infusion lumen having a distal orifice at the distal end, wherein when the flexible tubular member is inserted into a blood vessel and a therapeutic agent is infused through the orifice, turbulence is induced in blood in the blood vessel around the orifice; b) an expandable occluder mounted at said distal end of said tubular member, the chamber being surrounded by said occluder, The distal end of the tubular member extends through the occluder such that the orifice opens distally of the occluder; and c) a first pressure sensor configured to sense fluid pressure in a blood vessel distal to the occluder, wherein when a therapeutic agent is infused through the orifice and fluid turbulence is generated in the blood vessel, the occluder is provided with a fluid permeable distal portion positioned between the orifice and the first pressure sensor, and the fluid permeable distal portion is configured to have sufficient permeability to allow fluid continuity from the chamber to the portion of the blood vessel distal to the occluder and to dampen the effects of the fluid turbulence on the first pressure sensor.

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