Adjustable dual-occlusion catheters

Abstract

Systems and methods for delivery of therapeutic materials into targeted region of a vessel may include controlling the pressure within an occluded region. In any of these methods and apparatuses the method may include controlling the size and / or pressure of the occluded region by controlling a lateral expansion of one or both occluding balloons. In some cases one or both balloons may include a lateral expansion region configured to adjust the length of one or both balloons to controllably adjust the size of (and / or pressure within) an occluded region. In some cases this may be used to occlude / exclude one or more anatomical regions.

Description

ADJUSTABLE DUAL-OCCLUSION CATHETERSPRIORITY CLAIM

[0001] This patent application claims priority to U.S. provisional patent application no. 63 / 710,007, titled “ADJUSTABLE DUAL-OCCLUSION CATHETERS,” filed on October 21, 2024 and herein incorporated by reference in its entirety.INCORPORATION BY REFERENCE

[0002] All publications and patent applications mentioned in this specification are herein incorporated by reference in their entirety to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.FIELD

[0003] This disclosure relates to delivering therapeutic materials, and devices and methods of using them.BACKGROUND

[0004] The embodiments described herein relate generally to methods for delivering a therapeutic material to treat a patient. In some cases the treatment is for treatment of cancer, such as, but not limited to pancreatic cancer. In general, it may be beneficial to controllably isolate and occlude a local region within a blood vessel by expanding a pair of expandable members (e.g., balloons). Typically the size of this occluded region is fixed, based on the relative positions of the expandable members. It has been proposed to adjust the size of the occluded region by moving one expandable member relative to the other, e.g., using a telescoping configuration in which the expandable members are on separate elongate members. However, such devices are complex and may require one or more cycles of expansion and collapse and then re-expansion to adjust the size.

[0005] Further, it would be particularly helpful to provide apparatuses and methods in which the pressure within an occluded region may be controlled with precision in order to deliver a therapeutic agent, particularly in regions in which side branches may be present, and may complicate the regional control of the pressure.

[0006] For example, in some cases (e.g., cancer therapies) it may be particularly helpful to occlude regions of so that a therapeutic agent may be applied locally. Such treatments may be more effective than systemic delivery and may avoid dose-limited toxicity. Localized therapy can be desirable for targeted therapies. For example, one such treatment can include local intraarterial delivery of chemotherapy. Intra-arterial infusion allows higher drug concentration to reach the tumor, overcoming the problem of poor blood flow to tumor mass in comparison tohealthy tissue. Furthermore, intra-arterial chemotherapy can also take advantage of the first pass effect of chemotherapeutic s, generating higher-level drug concentrations at the tumor cell membrane and therefore, enhancing cellular drug uptake as compared to intravenous infusion. Lastly, local delivery can reduce systemic side effects.

[0007] Described herein are methods and apparatuses that may address these needs.SUMMARY OF THE DISCLOSURE

[0008] Described herein are dual occlusion catheters (e.g., dual-balloon occlusion catheters) for isolating a region of a vessel between the occluders (e.g., balloons), for delivery of pressurized fluid between the balloons in which the region between the balloons can be adjusted dynamically, including when detecting a side branch, in order to occlude the side branch. These methods may be used for a localized method for treatment of cancer, or any other therapeutic use.

[0009] These methods and apparatuses may include a drug delivery catheter that is configured as a multi-occlusion balloon catheter in which one or both occluders (e.g., balloons) include a variable expansion region that may change the lateral length of the occluder based on the applied pressure. These multi-occlusion balloon catheters may comprise at least two balloons that are connected to the same (or in some cases a different) pressure source to control expansion of the occluder (e.g., balloon). At a first inflation pressure (or range of pressures) the first and second occluders may be expanded radially outward to occlude a region of a vessel. The first and second occluders may be fixed relative to each other. A second (typically higher) pressure or range of inflation pressures may be used to laterally expand one or both occluders to reduce the size of the space between (and / or increase the pressure between) the pair of occluders. A fluid delivery port is positioned between the occluders. Any of these catheters may optionally include a pressure transducer configured to sense pressure between the occluders to optimize delivery technique.

[0010] Although in general, the apparatuses described herein may include an occluder that is configured as a balloon, other occluders (e.g., mechanical expanders, such as baskets, splines, etc.) may be used. For example, any of the balloons described herein may be instead adapted for use by a mechanically expandable member that may be covered by a fluid-impermeable material.

[0011] A dual occlusion catheter apparatus may include: an elongate catheter body; a first balloon at a distal end region of the elongate catheter body; a second balloon that is adjacent to the first balloon by a fixed distance, wherein the second balloon comprises a variable expansion region that is configured to expand the second balloon laterally towards the first balloon when a pressure within the second balloon exceeds a lateral expansion pressure that is greater than aradial expansion pressure, wherein the second balloon is configured to expand radially when the pressure within the second balloon exceeds the radial expansion pressure; an inflation line coupled to both the first and second balloons; and a delivery port between the first ballon and the second balloon.

[0012] The first balloon may include a second variable expansion region that is configured to expand the first balloon laterally towards the second balloon when the pressure within the first balloon exceeds the lateral expansion pressure. In some cases the second variable expansion region may be configured to expand the first balloon laterally towards the second balloon when the pressure within the first balloon exceeds a second lateral expansion pressure that is different from the first lateral expansion pressure.

[0013] The variable expansion region may generally be configured to expand laterally (rather than radially or in addition to radially), primarily without further radially expanding the rest of the balloon. Thus, the structure of the radial expansion region may be configured so that this portion of the balloon, which is continuous with (and is simply part of) the rest of the balloon, expands laterally when further pressure is applied. For example, the variable expansion region may have a different thickness than a region of the second balloon outside of the variable expansion region. In some cases the variable expansion region comprises a different material than a region of the second balloon outside of the variable expansion region (e.g., a material that has a different elasticity). Alternatively or additionally the variable expansion region and / or the rest of the balloon outside of the variable expansion region) may comprise a constraining features (such as a belt, cover, sleeve, etc.). The constraining feature may prevent expansion at lower pressure but may allow expansion at higher pressure and / or may encourage lateral expansion. In some cases the constraining feature over all or a portion of the balloon outside of the variable expansion region may be configured to prevent or limit further radial expansion of this region, so that expansion is preferentially applied to the variable expansion region at further (higher) pressures.

[0014] The radial expansion region may be configured to expand laterally (at higher pressures than the non- variable expansion region) in steps or stages, or continuously. In some examples the variable expansion region is configured to have a plurality of lateral expansion positions corresponding to different pressures exceeding the lateral expansion pressure.

[0015] Any of these apparatuses may include one or more pressure sensors. In some cases a pressure sensor may be configured to detect pressure within a vessel region that is between the first and second balloons. For example, the pressure sensor may sense pressure from the delivery port for the therapeutic agent (e.g., between the expandable members); alternatively the pressure sensor may be positioned anywhere on the region between the expandable members that isconfigured to form part of the occluded region. The output of this pressure sensor (e.g., the occluded region pressure sensor) may be received by one or more controllers, including a therapeutic agent delivery controller and / or the expansion controller, e.g., to provide feedback for deploying the apparatus and / or delivery of the therapeutic agent.

[0016] The apparatuses described herein may also include a pressure sensor configured to sense pressure within the balloons (which may be inflated from the same pressure line). This inflation pressure sensor may provide input to one or more controller (e.g., an expansion controller). Thus, any of these apparatuses may include an expansion controller configured to control the distance between the first and second balloons by controlling the pressure within the balloons, including controlling expansion / collapse of the variable expansion region(s).

[0017] Any of these apparatuses may include a therapeutic agent delivery controller configured to control the delivery of a therapeutic agent from the delivery port. The expansion controller and therapeutic agent delivery controller may be part of the same controller or may be separate. In some cases a system controller may be included which may coordinate activity of the expansion controller and / or therapeutic agent delivery controller.

[0018] Any of these apparatuses may include one or more sensors for sensing the vessel and / or the region around the vessel (e.g., the vessel wall, including determining / detecting vasa vasorum and / or branching vessels). For example, any of these apparatuses may include an imaging sensor at the distal end region configured to image a region of a vessel adjacent to a distal end region. Imaging sensors may include optical sensors, ultrasound sensors, thermal sensors, etc. In some cases, the sensor(s) may be optical coherence tomography (OCT) sensors. The sensor(s) may be poisoned on the catheter body (e.g., within the region between the two balloons, or proximal to the balloons, or distal to the balloons, or any combination of these). In some cases the sensor(s) may be on a surface of one or both balloons. In some cases the sensor(s) may be on a separate elongate body that is extendable through a lumen of the catheter elongate body (e.g., may be insertable / retractable through a lumen of the catheter elongate body); the exit from the catheter elongate body may be the distal end (e.g., the guidewire lumen or a second lumen) or a lateral port, e.g., between the balloons, proximal to the balloons or distal to the balloons.

[0019] Further, any of these apparatuses may include a guidewire lumen extending through the elongate body. The guidewire lumen may extend through the entire length of the catheter elongate body. In some cases the guidewire lumen may be a rapid exchange lumen at the distal end region of the elongate body.

[0020] Any of these apparatuses may include a handle region at a proximal end of the elongate body that is configured to couple to a source of inflation pressure and a therapeutic agent source.

[0021] In some examples a dual occlusion catheter apparatus includes: an elongate catheter body; a first balloon at a distal end region of the elongate catheter body wherein the first balloon comprises a first variable expansion region; a second balloon that is adjacent to the first balloon by a fixed distance, wherein the second balloon comprises a second variable expansion region, further wherein the first and second variable expansions are configured to expand laterally towards each other when a pressure within the first and second balloons exceeds a lateral expansion pressure that is greater than a radial expansion pressure, wherein the first and second balloons are configured to expand radially when the pressure within the first and second balloon exceeds the radial expansion pressure; an inflation line coupled to both the first and second balloons; and a delivery port between the first ballon and the second balloon.

[0022] The variable expansion region is so called because it may vary the lateral extent of the expandable member (e.g., balloon) in a controllable manner. In some cases the expansion of the variable expansion region may be controlled based on the applied pressure. The variable expansion region may equivalently be referred to as a lateral expansion region.

[0023] Also described herein are methods of using any of these apparatuses. In particular, these methods may be configured to occlude side branches within the vessel and / or to adjust the pressure withing an occluded region and / or to occlude (and therefore deliver a therapeutic agent) to a narrower region, without having to move the deployed catheter.

[0024] For example described herein are methods of occluding a region of a vessel that may include: introducing a distal end of a dual occlusion catheter apparatus into a vessel within a body; occluding a region of the vessel by applying a first pressure to the dual occlusion catheter to inflate a first balloon and a second balloon, wherein the occluded region has a first volume; determining a pressure of the occluded region; reducing a volume of the occluded region by increasing the pressure within the first and second balloons so that a variable expansion region of the first and / or second balloons expands laterally into the occluded region; and applying a therapeutic agent into the occluded region from a fluid port positioned between the first and second balloons.

[0025] Any of these methods may include applying the first pressure by applying a pressure that is between greater than or equal to a radial expansion pressure and less than a lateral expansion pressure. The radial expansion pressure may be the pressure to radially expand the portion of the balloon(s) that is / are outside of the variable expansion region and may be, e.g., between 3-30 atm (e.g., between 5-25 atm, between 5-20 atm, between 5-18 atm, etc.). Anyappropriate radial expansion pressure may be used. The lateral expansion pressure is greater than the radial expansion pressure, and may be configured to be 5% greater than the radial expansion pressure or more (e.g., 10% or more greater, 15% or more greater, 20% or more greater, 25% or more greater, 30% or more greater, etc.). Increasing the pressure within the first and second balloons may include increasing the applied pressure to greater than or equal to the lateral expansion pressure. At or above the lateral expansion pressure the variable expansion region may expand laterally (and / or radially).

[0026] Reducing the volume of the occluded region may comprise reducing the volume if the pressure indicates a side branch. In some cases increasing the pressure within the first and second balloons comprises expanding the variable expansion region of the first and / or second balloons laterally to occlude a side branch of the vessel.

[0027] These apparatuses may be used in any appropriate vessel. For example, introducing the distal end of the dual occlusion catheter apparatus into the vessel may include introducing the distal end of the dual occlusion catheter apparatus into an artery. The artery may comprise a pancreatic artery or a splenic artery.

[0028] These methods may include delivering (at a controlled pressure) one or more therapeutic agents through the delivery port in the occluded / isolated region of the vessel. Any appropriate therapeutic agent may be used, including immunoagents, small molecules, nanoparticles, etc. In some (nonlimiting) examples the therapeutic agent is a cancer-treatment agent. The therapeutic agent may be an immuneagent. In some cases the therapeutic agent is selected from the group (5-fluorouracil (5-FU), Aldesleukin, Axitinib, Bleomycin, Carboplatin, Cetuximab, Cisplatin, Cyclophosphamide, Dacarbazine, Doxorubicin Hydrochloride, doxorubicin liposomal non-pegylated (un-coated), doxorubicin liposomal pegylated (PEGcoated), Floxuridine, Gemcitabine Hydrochloride, Irinotecan Hydrochloride Liposome, Lanreotide Acetate, leucovorin (antidote to folic acid antagonist used with 5FU), Methotrexate, Mitomycin, Mitoxantrone, Nivolumab, Olaparib, Oxaliplatin, Sorafenib Tosylate, Temsirolimus, Thiotepa, Topotecan Hydrochloride, Vinblastine Sulfate, vincristine sulfate).

[0029] This application may be related to, and may be used in conjunction with any of the embodiments described in U.S. patent application no. 18149649, titled “METHODS FOR DELIVERY OF THERAPEUTIC MATERIALS TO TREAT CANCER,” filed on 1 / 3 / 2023, which is a continuation of U.S. patent application no. 17 / 558,577, filed on 12 / 21 / 2021, now U.S. patent no. 11,541,211, which is a continuation of U.S. patent application Ser. No. 16 / 685,950, filed Nov. 15, 2019, now U.S. Patent Application Publication No. 2020 / 0206481, which is a continuation of U.S. patent application Ser. No. 15 / 351,922, filed Nov. 15, 2016, now U.S. Pat. No. 10,512,761, which is a continuation-in-part of U.S. patent application Ser. No. 14 / 958,415,filed Dec. 3, 2015, now abandoned, which is a continuation-in-part of U.S. patent application Ser. No. 14 / 870,833, filed Sep. 30, 2015, now U.S. Pat. No. 9,463,304, which is a continuation of U.S. patent application Ser. No. 14 / 293,603, filed Jun. 2, 2014, now U.S. Pat. No. 9,457,171, which claims priority to and the benefit of U.S. Provisional Patent Application No. 61 / 830,218, filed Jun. 3, 2013. U.S. patent application Ser. No. 14 / 293,603 is also a continuation-in-part of U.S. patent application Ser. No. 12 / 958,711, filed Dec. 2, 2010, now U.S. Pat. No. 8,821,476, which claims priority to and the benefit of U.S. Provisional Patent Application No. 61 / 265,845, filed Dec. 2, 2009, each of the disclosures of which is incorporated herein by reference in its entirety.

[0030] One advantage of the methods and apparatuses described herein is the ability to vary the distance in occluded region between the two balloons, without physically having to move the balloons. This may allow the catheter to be smaller in size / diameter than conventional catheters, allowing targeting smaller vessels and more tortious anatomy, and allowing more pushability and trackability. Having fewer lumens may also make it easier to use by an operator. Additionally, if it is desired to occlude part of the anatomy (e.g., a side branch, an ostium, aneurysmal section etc.), one (or both) balloons can be expanded to exclude the anatomical section.

[0031] Any of the apparatuses and methods described herein may be used with a controller that is configured to ensure that a set pressure is achieved in the occluded segment. For example, the controller (e.g., control unit) may be configured to determine or receive a preset pressure setting; this preset pressure setting may control the flow rate of the injection of fluid from the apparatus by the infusion port, and may be controlled to maintain the set pressure as fluid is injected into the occluded segment.

[0032] Also described herein are pres sure- sensing dual occlusion catheter apparatuses that are configured to provided highly reliable and stable pressure measurements, even while applying material (e.g., drug material) into an occluded region of a vessel. These pressuresensing dual occlusion catheter apparatuses may advantageously provided much larger cross-sectional area pressure-sensing channel that opens into the occluded region relatively far (e.g., greater than 2 mm, greater than 3 mm, greater than 4 mm, greater than 5 mm, greater than 7 mm, etc.) from the infusion site (e.g., infusion exit) on the pressure-sensing dual occlusion catheter apparatus. The same lumen used for measuring pressure may also be used to flush the space between an inner member and an outer member forming the pressure-sensing dual occlusion catheter.

[0033] Note that these pressure-sensing dual occlusion catheter apparatuses may be configured to adjust the position between the occluders by changing the length of the regionsbetween the occluders. Alternatively or additionally, the spacing between the occluders may be adjusted as described above (and in greater detail in FIGS. 2-7C, below).

[0034] For example, described herein are pressure-sensing dual occlusion catheter apparatuses, the apparatus comprising: an elongate catheter body comprising an inner member nested within and extending distally from a lumen of an outer member; a first occluder at a distal end region of the inner member; a second occluder at a distal end region of the outer member; an infusion exit on the outer member distal to the second occluder; a flush and pressure measurement channel between an outer surface of the inner member and an inner surface of the outer member, wherein the flush and pressure measurement channel opens from a distal end face of the outer member; a proximal handle having an infusion port, and a flush and pressure sensing port in fluid communication with the flush and pressure measurement channel; and a pressure sensor configured to be connected to the flush port and to measure pressure between the first occluder and the second occluder from the distal end face.

[0035] The cross-sectional area of the flush and pressure measurement channel may be at least 10% or more (e.g., 12.5% or more, 15% or more, 17.5% or more, 20% or more, 22.5% or more, 25% or more, etc.) of a cross-sectional area of the lumen of the outer member.Specifically, the distal-facing opening into the flush and pressure measurement channel may have a cross-sectional area that is at least 10% or more (e.g., 12.5% or more, 15% or more, 17.5% or more, 20% or more, 22.5% or more, 25% or more, etc.) of a cross-sectional area of the lumen of the outer member. For example, the cross-sectional area of the distal-facing opening into the flush and pressure measurement channel may be 20% or more of the cross-sectional area of the lumen of the outer member.

[0036] In any of these apparatuses the first and second occluders may be balloons.Alternatively, the occluders may be expandable baskets, cages, or other barriers.

[0037] The inner member may be slidably disposed within the outer member. Thus the size of the occluded region of the vessel may be adjusted either as described herein, or by adjusting the relatively position of the balloons by adjusting the position of the inner member relative to the outer member (e.g., by advancing or retracting it distally / proximally.

[0038] In any of these apparatuses, the infusion port may be in fluid communication with the infusion exit. The infusion port may be connected to a therapeutic agent delivery controller, which may receive input from the pressure sensor (e.g., to adjust the rate, amount or timing of material being delivered based on the pressure). The proximal handle may further comprise one or more inflation ports in fluid communication with a lumen within the first occluder and a lumen within the second occluder, which may be coupled to an expansion controller to control inflation / expansion of the occluders. In any of these apparatuses the expansion controller mayreceive input form the pressure sensor and may automatically or semi-automatically adjust the expansion of the occluders (or the amount of pressure within the occluders) based on the pressure, e.g., to release occlusion if the pressure exceeds a safety threshold, or to increase the pressure within the expanders (within a predefined range) if the pressure in the occluded region is below a threshold value or range.

[0039] In general, the infusion exit may be spaced from the distal-facing distal end opening of the outer member. For example, the distal end opening may be 2 mm or more (e.g., 3 mm or more 4 mm or more 5 mm or more, etc.) from the distal end face of the outer member. The pressure sensor may be coupled and / or integrated with the flush port. In some cases the pressure sensor may be coupled to a Y-connector along with the finish port.

[0040] For example, described herein are pressure-sensing dual occlusion catheter apparatus, the apparatus comprising: an elongate catheter body comprising an inner member nested within and extending distally from a lumen of an outer member; a first balloon at a distal end region of the inner member; a second balloon at a distal end region of the outer member; an infusion exit on the outer member distal to the second balloon; a flush and pressure measurement channel between an outer surface of the inner member and an inner surface of the outer member, wherein the flush and pressure measurement channel opens from a distal end face of the outer member, wherein the opening into the flush and pressure measurement channel at the distal end face has a cross-sectional area that is at least 15% or more of the cross-sectional area of the lumen of the outer member; a proximal handle having an infusion port in fluid communication with the infusion exit and a flush and pressure sensing port in fluid communication with the flush and pressure measurement channel; and a pressure sensor configured to be connected to the flush port and to measure pressure between the first balloon and the second balloon from the distal end face.

[0041] Also described herein are methods of sensing pressure within an occluded region of a vessel. For example, a method may include: positioning a pressure-sensing dual occlusion catheter apparatus within the vessel so a distal end of an inner member of the pressure-sensing dual occlusion catheter apparatus extends distally out of a lumen of an outer member of the pressure-sensing dual occlusion catheter apparatus; expanding a distal occluder on the inner member of the pressure-sensing dual occlusion catheter apparatus and a proximal occluder on the outer member of the pressure-sensing dual occlusion catheter apparatus to occlude the region of the vessel; and sensing pressure through a distal end face of the outer member via a pressure sensor in fluid communication with a flush and pressure measurement channel between an outer surface of the inner member and an inner surface of the outer member, wherein the flush and pressure measurement channel opens from the distal end face of the outer member.

[0042] Any of these methods may include flushing the lumen of the outer member to lubricate a region between the inner member and the outer member by applying flushing solution through the flush port and out of the distal end face, prior toexpanding the distal occluder and proximal occluder.

[0043] Any of these methods may include applying a fluid material into the occluded region through an infusion exit on a slide of the outer member, and in some cases concurrently sensing pressure while applying the fluid material. In general, pressure sensing may be done in real- or near-real time. Any of these methods may include the application of fluid material into the occluded region based on the sensed pressure, or adjusting the application of fluid material into the occluded region based on the sensed pressure (e.g., increasing the application of fluid material if the pressure is below a threshold; decrease or pausing the application of fluid material into the occluded region if the pressure exceeds a threshold, etc.

[0044] Sensing pressure may include sensing pressure through the opening into the flush and pressure measurement channel at the distal end face having a cross-sectional area that is at least 10% or more (e.g., 12.5% or more, 15% or more, 17.5% or more, 20% or more, 25% or more, etc.) of a cross-sectional area of the lumen of the outer member. For example, the distal end face may have a cross-sectional area that is at least 20% or more of the cross-sectional area of the lumen of the outer member.

[0045] All of the methods and apparatuses described herein, in any combination, are herein contemplated and can be used to achieve the benefits as described herein.BRIEF DESCRIPTION OF THE DRAWINGS

[0046] Novel features of embodiments described herein are set forth with particularity in the appended claims. A better understanding of the features and advantages of the embodiments may be obtained by reference to the following detailed description that sets forth illustrative embodiments and the accompanying drawings.

[0047] FIG. 1 is an illustration of a pancreas and related structure in a human.

[0048] FIG. 2 is a schematic illustrations of a dual-occlusion catheter apparatus as described herein.

[0049] FIGS. 3A-3C illustrate one example of a distal end region of a dual occlusion catheter apparatus, showing three different states of lateral deployment.

[0050] FIGS. 3D-3H show sections through the distal end region of the dual occlusion catheter apparatus of FIGS. 3A-3C.

[0051] FIGS. 4A-4C illustrate one example of a distal end region of a dual occlusion catheter apparatus, showing three different states of lateral deployment.

[0052] FIGS. 5A-5C illustrate one example of a distal end region of a dual occlusion catheter apparatus, showing three different states of lateral deployment.

[0053] FIGS. 6A-6C illustrate one example of a distal end region of a dual occlusion catheter apparatus, showing three different states of lateral deployment.

[0054] FIGS. 7A-7C illustrate one example of a distal end region of a dual occlusion catheter apparatus, showing three different states of lateral deployment.

[0055] FIG. 8 schematically illustrates an example of a method of occluding a region of a vessel and locally applying a therapeutic agent using and any of the apparatuses described herein.

[0056] FIGS. 9A-9B show an example of a dual-occlusion catheter apparatus configured to measure and / or monitor pressure through a flush port that exits from the distal end of the outer catheter offset from the infusion exit and within the occluded region. FIG. 9A shows the apparatus in the flushing configuration. FIG. 9B shows the apparatus in the pressure sensing configuration, coupled to a pressure sensor.

[0057] FIG. 9C shows a section (C) through a region of the apparatus of FIGS. 9A-9B.

[0058] FIG. 9D is a graph comparing pressure monitored / measured through the flush lumen as shown in FIG. 9G to a pressure wire in an animal model.

[0059] FIG. 10 schematically illustrates an example of a method of sensing pressure in an occluded region using a dual-occlusion catheter apparatus configured to measure pressure through a flush channel / lumen as described herein.DETAILED DESCRIPTION

[0060] Apparatuses (devices, systems, etc.) and methods described herein can be used to deliver one or more therapeutic agents to a local region of the body. In some cases, these methods and apparatuses may be used to deliver one or more agents (e.g., compounds, compositions, etc. including drugs, biologies, cells, etc.) to a target tissue in or adjacent to an adventitia specifically through the vasa vasorum. In particular, these methods and apparatuses may be specifically configured to deliver one or more agents from with a vein into the tissue through the vasa vasorum without damaging the vasa vasorum, so that relatively large particles can be quickly and effectively delivered to the tissue specifically through the vasa vasorum.

[0061] In general, these apparatuses may include dual-occlusion catheters that may adjustably control the size of an occluded region between two occluders (e.g., balloons) without needing to remove (or collapse) the occluders once positioned. This may allow for faster and easier deployment, as well as controlling the pressure within the occluded region, which may be important when delivering a therapeutic agent across the vessel wall, and insome cases through the vasa vasorum. For example these apparatuses and methods may be particularly important to occlude one or more side branches without having to remove and / or reposition the apparatus.

[0062] These methods and apparatuses may be used to treat any appropriate tissue, including, but not limited to cancerous tissue. For examples, these apparatuses and methods may relate to the treatment of cancerous tumors or any other target tissue. In some embodiments, the method comprises: identifying a region of a vessel near (e.g., adjacent) to a target tissue that has vasa vasorum; administering a dose (and in particular a therapeutically effective dose) of an agent to an isolated vein section near the target region that includes vasa vasorum. In any of these methods and apparatuses, the density and / or diameter (e.g., average diameter, etc.) of the vasa vasorum may be determined and the agent may be delivered by occulting a region of vein that is both sufficiently dense in vasa vasorum and sufficiently close to the target region (e.g., is fed by the vasa vasorum within the vein). For example, the methods and apparatuses described herein may include selectively occluding a region of a vessel, such as a vein, that includes (and in some cases is sufficiently dense in) vasa vasorum and applying one or more agents (e.g., drugs, cells, etc.) into the occluded region of the vessel so that the agent is taken up by the vasa vasorum in a manner that does not harm or occlude the vasa vasorum, to treat the target region with the agent.

[0063] In one non-limiting example, these methods and apparatuses may be used in any appropriate body region, including, but not limited to the bile duct, e.g., for treatment of pancreatic cancer or other localized cancer. Tumors localized around the bile duct (cancer of the pancreatic head, primary and secondary liver tumors, and cholangiocarcinoma) may benefit from localized delivery through the bile duct itself. The bile duct can be exogenously accessed through an endoscopic retrograde cholangiopancreatogram (ERCP) catheter, one can envision delivery of a double balloon catheter into the bile duct using established ERCP technique. After localizing the double balloon catheter to the area of bile duct involved / adjacent to the tumor, that area of bile duct is isolated by inflating the two balloon elements. In the event a side branch is included within the occluded region, the side branch may be occluded by laterally expanding one or both balloons, as described herein, without having to remove and / or reposition the apparatus.Chemotherapeutic elements may then be infused between the two balloons. By controlling the pressure between two balloon elements, the chemotherapeutic agent will diffuse out the wall of the bile duct and into the tissue.

[0064] FIG. 2 illustrate an example of an apparatus as described herein. In general, this apparatus is configured as a dual occlusion catheter apparatus having an elongate body 212. The elongate catheter body extends from a proximal handle region 215 that may include ports forconnecting to a source of therapeutic agent to be delivered and a pressure source, for controlling deployment of the dual occluders (when the occluders are configured as inflatable elements). In the examples shown herein the occluders (occluding elements) are configured as balloons. It should be understood that any appropriate occluders may be used, including mechanical occluders, such as expandable baskets or other structures.

[0065] In FIG. 1 the proximal handle region 215 is coupled to an expansion controller 220 that may be connected to and / or may include a pressure source (not shown). The expansion controller 220 in this example includes a pressure line / expansion line 224 that is shown connected to a pressure / expansion connector 236 which is part of a pressure / expansion port 238 on the handle region 215. The connector may be a locking connector. In some cases the connector is a Luer-type locking connector.

[0066] The proximal handle region 215 is also shown connected to a fluid line 224 via a drug (e.g., therapeutic agent) port 228 including a connector 226. The therapeutic agent connector 226 may also be a locking connector and couples to the fluid line 224 to put the fluid line in fluid communication with the therapeutic agent delivery controller 222. The therapeutic agent delivery controller 222 may be connected to a source of therapeutic agent, such as a reservoir, syringe, etc. (not shown).

[0067] The proximal handle region may be configured to be hand-held to allow insertion, removal, rotation (e.g., torquing), of the apparatus. The elongate body (which may be any appropriate length, e.g., between 10 cm and 5 m (between 10 cm and 2 m, between 20 cm and 2 m, etc.). The elongate body may also include one or more lumen extending the length of the elongate body, including a guidewire lumen. The proximal end region of the apparatus may include a port for a guidewire 218, as shown in FIG. 2.

[0068] The distal end region of the apparatus shown in FIG. 2 includes a first (e.g. proximal) balloon 276 at the distal end region of the elongate catheter body and a second (e.g., distal) balloon 277. Both the first and second balloons are shown at fixed positions on the elongate body (outer surface) 212. The region between the balloons includes side opening delivery port 262. In any of these apparatuses one or more sensors (e.g., imaging sensors 251) may be included. In FIG. 2 an imaging sensor (e.g., ultrasound sensor) is shown mounted on the elongate body just distal to the delivery port, but between the pair of balloons. The distal balloon 277 in FIG. 2 is shown in both a collapsed configuration and (in dotted lines) an expanded configuration 277’, in which pressure applied through the inflation lumen 275 to both balloons causes the distal and proximal balloons to expand radially outward.

[0069] In the example shown in FIG. 2, the proximal balloon 276 includes a variable expansion region 266 on a distal side of the balloon. The variable expansion region is shownshaded. In the unexpanded configuration there is no difference between the variable expansion region and the rest of the balloon (the more proximal end of the balloon). This proximal balloon includes a first expansion state 246 (shown by dashed lines) to which this first (proximal) balloon expands when the pressure applied to the proximal and distal ballons reaches a radial expansion pressure threshold from the inflation lumen 275. However, if the pressure applied to the balloons exceed a lateral expansion pressure, the variable expansion region 266 may expand laterally (and distally) as well as radially, as shown by the dashed lines into a second expanded configuration 248.

[0070] In general, the second (distal) balloon 277 is adjacent to the first balloon 276 by a fixed distance. The first (proximal) balloon 276 includes the variable expansion region. The variable expansion region is configured to expand laterally towards the second balloon when a pressure within the first and second balloons exceeds a lateral expansion pressure that is greater than a radial expansion pressure. The distal end region shown in FIG. 2 is shown partially transparent so that the inflation line (inflation lumen) 275 that is coupled to both the first and second balloons is visible, as is the delivery line coupling the fluid line 224 for the therapeutic agent to the delivery port 262 that is between the first ballon and the second balloons.

[0071] Different configurations of the distal end region are contemplated. In FIG. 2 a single variable expansion region is shown. In some case two variable expansion regions may be included and may be configured to expand laterally together or at different pressures. For example, FIGS. 3A-3C illustrate an example of a distal end region of an apparatus including a first (proximal) balloon 376 and a second (distal) balloon 377. The first balloon 376 includes a first variable expansion region 366 and the second balloon 377 includes a second variable expansion region 365. In FIG. 3A the first and second variable expansion regions are shown fully expanded (e.g., the pressure applied through the inflation lumen 375 is greater than both the radial expansion pressure for the balloons and the lateral expansion pressure for the variable expansion regions. As mentioned in some cases the first and second variable expansion regions may be configured to have different lateral expansion pressures so that they may be separately expanded.

[0072] In FIG. 3A the delivery port 362 is shown between the balloons on the catheter body 312 and is connected to a delivery lumen 363 that may be connected to and / or controlled by a therapeutic Agent delivery controller, as shown in FIG. 2. Both the balloons are inflated by the same inflation lumen 375. However, in some cases separate inflation lines may be used for each balloon. In FIG 3A, with both balloons expanded, and the variable expansion regions 366, 365 fully expanded, the distance between the two balloons is shown 360.

[0073] FIG. 3B shows an example of the distal end region of the elongate body 312 in which the pressure applied to expand the balloons through the inflation lumen 375 is greater than the radial expansion pressure and the variable expansion regions 366, 365 are partially laterally expanded. Each of the variable expansion regions includes a partially un-inflated region 366’, 365’ that remains uninflated until (as shown in FIG. 3A) the pressure is high enough. Thus, the distance between the two balloons 360’ is greater than the distance between the fully-deployed balloons 360 in FIG. 3A. The pressure applied, and therefore the expansion state of the variable expansion regions of the balloons, may be controlled by an expansion controller, as shown in FIG. 2. The expansion controller may monitor the pressure within the inflation lumen (and therefore the balloons) and may adjust the applied pressure accordingly. The expansion controller may include one or more valves, pumps, etc. to apply positive (and optionally negative) pressure to control the pressure within the balloons and therefore the expansion state.

[0074] In FIG. 3C the pressure applied through the inflation lumen 375 is above the radial expansion pressure but below the lateral expansion pressure, and thus the variable inflation regions are shown deflated 366’, 365’ and the distance between the expanded balloons 360” is greater than either the distance in FIGS. 3 A and 3B.

[0075] FIGS. 3D-3H illustrate sections (shown by the labeled lines D-H in FIG. 3A, corresponding to FIGS. 3D-3H) through the distal end region. In FIG. 3D (section D-D’ in FIG.3 A), a section through the catheter body 312 proximal to both balloons is shown. The catheter body includes a central guidewire lumen 373. In some examples the guidewire lumen is not centrally located. A delivery lumen 363 and an inflation lumen 375 are also shown. In some cases a multi-lumen extrusion may be used for these lumen. In some examples one or more additional lumen may be included.

[0076] FIG. 3E shows an example of section E-E’ in FIG. 3A, which passes through the inflated first balloon, in a region of the balloon that is not part of the variable expansion region. The section shows the proximal balloon 378 which is in fluid communication with the inflation lumen through an inflation port 376 (e.g. an opening into the inflation lumen 375). The catheter body 312 includes the guidewire lumen 373 and the delivery lumen 363.

[0077] FIG. 3F shows an example of section F-F’ in FIG. 3A, passing through the region between the balloons, including the delivery port 362, putting the delivery lumen 363 in fluid communication with the occluded region. The inflation lumen 375 and guidewire lumen 373 are closed.

[0078] FIG. 3G shows an example of section G-G’ in FIG. 3A, which passes through the inflated second balloon, in a region of the second balloon that is not part of the variable expansion region. The section shows the distal balloon 377 which is in fluid communication withthe inflation lumen through a second inflation port 376’ (e.g. in this example, an opening into the inflation lumen 375). The catheter body 312 includes the guidewire lumen 373 and the delivery lumen 363.

[0079] Finally, FIG. 3H shows a section through the catheter body 312 distal to the first and second balloons, enclosing just the guidewire lumen 373 in this example.

[0080] In any of these apparatuses a lumen may be included through the catheter to allow the flow of material (e.g., blood) past the occluded region (e.g., as a bypass). For example a lateral side of the proximal region may include an opening through region including the balloons that may allow fluid to fluid through the region even while the intermediate vessel region is being occluded.

[0081] FIGS. 4A-4C illustrate another example of a distal end region of an apparatus including a pair of occluding balloons, similar to that shown in FIG. 2. In this example only one of the two balloons includes a variable expansion region 466. In this example the variable expansion region is part of the first balloon 476 that is on the catheter body 412 proximal to the distal second balloon 477. A delivery port 462 is shown between the two balloons. The figure is shown partially transparent so that the inflation lumen 475 and delivery lumen 463 are visible. In this example the variable expansion region 466 is fully deployed, e.g., by inflating the first balloon (and the second balloon) to a pressure exceeding the radial expansion pressure and the lateral expansion pressure. In some cases it may be preferable to include the variable expansion region on the proximal balloon. Alternatively, the variable expansion region may be on the distal balloon.

[0082] FIG. 4B shows an example of the variable expansion region 466 partially deployed, in which a portion of the variable expansion region is at least partially un-inflated 466’. The distance between the balloons in FIG. 4B 460’ is larger than the distance between the balloons in FIG. 4A 460.

[0083] FIG. 4C shows the apparatus of FIGS. 4A-4B with the proximal and distal balloons expanded, but with the variable expansion region not inflated 466’, e.g., when the applied pressure is greater than the radial expansion pressure but less than the lateral expansion pressure. In FIGS. 4A-4C the second balloon is the same size as the fully inflated first balloon (including the variable expansion region). In some cases the second balloon may be smaller (radially and / or in length); alternatively in some cases the second balloon may be larger (radially and / or in length). The distance between the balloons in FIG. 4C 460” is substantially longer than the distance between the balloons in FIGS. 4A-4B.

[0084] In general, the balloons including a variable expansion region may be formed in any appropriate manner so that the variable expansion region expands laterally (and in some casesradially) at a higher pressure than the rest of the balloon, which otherwise fully deploys (e.g., radially) but for the variable expansion region at the lower, radial expansion pressure. In some cases the variable expansion region may comprise a support or sheath on or in the portion of the balloon forming the variable expansion region that may prevent expansion until the pressure within the balloon exceeds a threshold pressure (e.g., the lateral expansion pressure).

[0085] FIGS. 5A-5C illustrate an example of a distal end region having a first balloon 576 and a second balloon 577, each with a variable expansion region 566, 565. The variable expansion regions are on the side of the balloons adjacent to the other balloon. A delivery port 562 is between the two balloons, and the balloons are shown mounted on the catheter body 512. In FIG. 5A the balloons are shown deflated, and undeployed. For example, the applied pressure is less than the radial expansion pressure. In FIG. 5B the pressure is increased to the radial expansion pressure and the first 576 and second 577 balloons are radially expanded / inflated. The variable expansion regions 566, 565 are not expanded, as they are constrained by a cuff (shown as the shaded region in FIGS. 5A-5C). The distance between the balloons 560 is indicated by the arrow. FIG. 5C shows the balloons, including the variable expansion regions, fully expanded, so that the distance 560’ is less than the distance in FIG. 5B. In FIG. 5C the pressure applied within the balloons is greater than the lateral expansion pressure, so that the force due to the pressure on the variable expansion regions of the balloons is sufficiently high to overcome the constrictive forces applied by the cuff / sleeve.

[0086] In some cases the variable expansion regions may be configured to expand at a greater pressure based on a thickness of the material forming the balloon, which may be non-uniform. In some examples the variable expansion regions may have a greater thickness than the rest of the expandable portion of the balloon. In some cases the material properties of the variable expansion regions may be different than the rest of the balloon (e.g., elasticity / stiffness, etc.).

[0087] The variable expansion regions may be non-uniform. A non-uniform variable expansion region may expand laterally (and / or radially) so as to have distinct lateral positions, as illustrated in FIGS. 6A-6B. In this example the variable expansion regions is configured as a gradient. This may be achieved by having a gradient of thickness and / or a gradient of retaining / constriction, for example, by including a support, sleeve, etc. over the variable expansion region that is non-uniform.

[0088] In FIGS. 6A-6C the first balloon 676 and the second balloon 677 are affixed to the catheter body 612 with a delivery port 662 between them. Each balloon includes a variable expansion region 666, 665, that is configured so that as the pressure increases to the radial expansion pressure the apparatus may transition from an undeployed configuration (shown inFIG. 6 A) to a first deployed configuration, shown in FIG. 6B, in which the balloons are radially expanded but the variable expansion regions of the balloons are not expanded. Thereafter, the application of pressure greater than a lateral expansion pressure may result in the lateral and radial expansion of the variable expansion regions, as shown in FIG. 6C. In some cases this expansion may be sufficiently gradual so that it may be controlled by the operation of incremental changes in pressure applied. The expansion state of the balloons may be monitored, e.g., using fluoroscopy, ultrasound, etc. Thus, the distance between the balloons 660, 660’ may be adjusted.

[0089] In some cases the variable expansion region(s) may be configured so that a constraining element applies an increasing constraining force along the lateral direction of the variable expansion regions. This may also be configured to limit the lateral and / or radial expansion of the balloon, as shown in FIGS. 7A-7C. In this example both the first and second balloons 776, 777 each include a variable expansion region 766,765 and both the first and second variable expansion regions are configured as constricting regions in which greater force (expansion force as applied by the applied pressure) is need to allow expansion along the length. In FIG. 7A the apparatus is shown in the inactive state, with the balloons collapsed. The balloons 776, 777 are arranged on the catheter body 712 with the delivery port 762 between them. In FIG.7B the pressure is increased to greater than the lateral expansion pressure and the variable expansion regions begin expanding. In FIG. 7C the pressure is greater than the lateral expansion pressure in FIG. 7B and the distance 760’ between the balloons is smaller than the distance 760 in FIGS. 7B.

[0090] In use, these apparatuses may occlude a vessel so that an agent may be delivered within the occluded region for transfer across the vessel wall. FIG. 8 shows a generic method of using the apparatuses described herein. In this example the method may include introducing a distal end of any of the dual occlusion catheter apparatuses described herein into a vessel within a body 801. The apparatus is typically delivered with the balloons in the un-inflated configuration. A guidewire may be used to position the apparatus (e.g., which may ride over the guidewire that is pre-positioned). Guidance may be performed using imaging.

[0091] Once the distal end region is positioned, the targeted region may be occluded. For example, a region of the vessel may be occluded by applying a first pressure (that is equal the radial expansion pressure, but less than the lateral expansion pressure) to the dual occlusion catheter to inflate a first balloon and a second balloon 803. The resulting occluded region has an occluded volume (e.g., a first volume or a first occluded volume).

[0092] Once occluded, it may be determined if the volume can sustain the pressure used to deliver the agent across the vessel wall. For example, this may be performed by determining apressure of the occluded region 805. In some cases applying fluid (e.g., without therapeutic agent or with therapeutic agent) into the occluded region and checking the pressure. If the pressure over time changes faster than a threshold, this may indicate a leak due to a branched vessel. The methods described herein may then occlude the branched region by further laterally expanding the balloons (e.g., the variable expansion region). For example, the volume of the occluded region may be reduced by increasing the pressure within the first and second balloons so that a variable expansion region of the first and / or second balloons expands laterally into the occluded region 807. This process (e.g., sensing pressure over time, further laterally expanding, etc.) may be iteratively repeated until the pressure over time is sustained. Thereafter, therapeutic agent may be applied (or additional therapeutic agent applied) into the occluded region from a fluid port positioned between the first and second balloons 809.

[0093] Similar method may be used in any appropriate region of the body. For example, FIG.1 illustrates a liver 10, the gall bladder 20, and the pancreas 30 situated within an abdominal cavity (not shown) of a mammal (e.g., a human). The pancreas 30 is a gland organ which is part of the digestive and endocrine system of vertebrates. The pancreas 30 is both an endocrine gland producing hormones, including insulin, glucagon, and somatostatin, as well as an exocrine gland, secreting pancreatic juice containing digestive enzymes that pass to the small intestine. These enzymes help in the further breakdown of the carbohydrates, protein, and fat in the chyme. As shown, the common bile duct leads from the gall bladder to the pancreas 30. These methods and apparatus may be used to treat any of these regions, e.g., by insertion into a vessel 54, 48, 46, 42, 44, 34, 52, 54). In a variation of the method described above using balloons as the occlusion elements, the same catheter can be used to isolate arterial branches supplying the head of the pancreas via the hepatic artery or superior mesenteric artery. One such clinical possibility is treatment of pancreatic cancer with the tumor located in the head of the pancreas. After placement of the catheter device in the respective artery, the infusion of contrast through the infusion port can identify the branches most proximate to the tumor, and then after occluding the distal and proximal portion of the artery around the branch(es), the chemotherapeutic agent can be delivered selectively to the area of interest in the pancreas.

[0094] In some embodiments, a method can include introducing a catheter device into a splenic artery. The catheter device can include an inner catheter, a first expandable occlusion element coupled to the inner catheter, an outer catheter defining a first lumen configured to introduce a therapeutic biologic / agent to one or more target pancreatic vessels, a second lumen configured to slidably receive at least a portion of the inner catheter, and a second expandable occlusion element coupled to the outer catheter and disposed proximally to the first occlusion element. The catheter is advanced to a target pancreatic portion of the splenic artery. A regionof the target pancreatic portion of the splenic artery is selectively isolated, and the therapeutic biologic / agent is injected into the isolated region. In some embodiments, the therapeutic biologic / agent includes stem cells. In some embodiments, the method further includes advancing at least a portion of the catheter device to an ostium of a celiac artery, its hepatic branch, or if necessary, the superior mesenteric artery (based on individual anatomy). In some embodiments, a contrast dye is injected into the isolated region and isolation of a pancreatic magnum artery and / or a dorsal pancreatic artery can be confirmed. In some embodiments, a guidewire can be disposed through the infusion lumen to focally perforate the vascular lumen in the isolated area to increase exogenous cell penetration into the pancreatic tissue. In some embodiments, the therapeutic biologic can be introduced into the isolated segment or region to enhance cellular transmigration across the endothelial cells prior to introduction of the therapeutic biologic.

[0095] In some embodiments, a method can include introducing a catheter device into a bile duct. In use, the catheter device can be placed at a desired location within the bile duct and used to infuse a therapeutic agents into the bile duct which will diffuse through the bile duct into the pancreas. A therapeutic agent can be injected through the catheter device and into the isolated region of the bile duct.

[0096] The infusion pressure in the isolated blood vessel region can be measured with pressure monitoring through the infusion lumen of the catheter (with a manometer (not shown) in line with infusion port).

[0097] The apparatuses described herein can also be provided in a kit. In some embodiments, a kit can further include one or more biologic / therapeutic agents (e.g., for delivery to the pancreas), a stylet(s); one or more catheters adapted and configured for accessing the vessels; a dilator; a guidewire; a guide catheter; capsules for direct connection of biological materials / cells to the infusion port of the catheter; a manometer to monitor the pressure in the isolated area; and / or a pump to regulate the infusion rate of cells / biologics. In some embodiments, any of the components of a kit can be packaged together and collectively sold as a catheter device or can be packaged independently or in subgroups and sold together or separately.

[0098] As mentioned, the catheter devices described herein can include one or more sensors that can provide relative information such as, for example, position of the occlusion members, movement of the actuator, flow rate of the biological agent, and / or any other suitable information. In some embodiments, a sensor can be disposed within the fluid delivery lumen that can be configured to determine a flow rate of irrigation and / or a biological / therapeutic agent therethrough.

[0099] In some embodiments, radiopaque markers of gold or tantalum, for example, can also be provided on or in the catheter and / or within or on the balloon(s) and / or on an outer catheter toaid in visualization and to assist in monitoring the position of at least a portion of a catheter device on an imaging device (e.g., a fluoroscope, an X-Ray, a Magnetic Resonance Imaging (MRI) scan, a computerized tomography (CT) scan, and / or the like) during a procedure. In some embodiments, an inner catheter can optionally be coated with a lubricous material, such as silicone, acrylamide, or a hydrophilic polyurethane coating, to ease retraction. Similarly, the outer catheter and the occlusion elements can be coated with the lubricous material to ease advancement through a guiding catheter and / or a tortuous vessel.

[0100] In some embodiments, an outer diameter of the catheter and non-deployed balloons can be, for example, between about 6 French and about 8 French and thus, can be used with, for example, a 7-9 French guiding catheter (if need be).Pressure Sensing Catheters

[0101] Also described herein are pres sure- sensing dual occlusion catheter apparatus and method of sensing pressure within an occluded region using them. These catheters may be distinct from the catheters described above or may included one or more features of these catheters. For example, the catheters described in FIGS. 2-8 may be adapted to be pressure sensing catheters and may include any of the features described herein.

[0102] For example, FIGS. 9A-9B illustrate an example of a pressure-sensing catheter. The pres sure- sensing dual occlusion catheter apparatus 900 includes an elongate catheter body comprising an inner member (inner catheter body 813) nested within and extending distally from a lumen of an outer member (outer catheter body 815). The inner catheter body may be fixed relative to the outer catheter body, or in some variations may be slidably disposed within the lumen of the outer catheter body 815. Thus the proximal handle 835 may be coupled to the outer catheter body and may include a slidable member coupled to the inner catheter.

[0103] The pres sure- sensing dual occlusion catheter also includes a first occluder 848 at a distal end region of the inner member 813 (as well as one or more marker bands 892) and a second occluder 877 at a distal end region of the outer member 815, as well as one or more marker bands 891. In FIG. 9A the occluders are shown as balloons that may be inflated by applying pressurized fluid through an inflation port 836 (jointly or separately).

[0104] The pres sure- sensing dual occlusion catheter may also include an infusion exit 861 on the outer member distal to the second occluder that is in fluid communication with an infusion port 826. As in FIG. 2, the infusion may be controlled by a therapeutic agent delivery controller, and the inflation may be controlled by an expansion controller.

[0105] Any of these apparatuses may include a flush and pressure measurement channel 883’ between an outer surface of the inner member 813 and an inner surface of the outer member 815. The flush and pressure measurement channel opens from a distal end face 883 of the outermember. In general this flush and pressure measurement channel may be fluidly connected to a flush port 850 on the proximal end (e.g., on the handle 835). The flush and pressure measurement channel may be used, typically prior to expanding the occluders and / or prior to insertion into the vessel, to finish the region between the inner and outer members, e.g., to lubricate them. For example either or both the lumen of the outer member 815 and the outer surface of the inner member 813 may include a lubricous coating (e.g., a hydrophilic coating) that may be activated by water (e.g., saline, etc.). In FIG. 9A the arrows at the distal-facing opening into the flush and pressure measurement channel 883 indicate flushing.

[0106] The proximal handle 835 may include the infusion port 826, and the flush and pressure sensing port 850 that is in fluid communication with the flush and pressure measurement channel. Any of these ports may include a valve (including hemostasis valve) or the like. Any of these ports may include a split connector (e.g., Y-connector).

[0107] FIG. 9B shows an example of the pres sure- sensing catheter with a pressure sensor 885 coupled in communication with the flush and pressure measurement channel 883’ to monitor pressure between the occluders (e.g., an occluded region of a vessel. The pressure sensor may include an output (display, etc.) and / or may be connected to a controller or other electronics. In some cases the pressure sensor 855 is connected to controller controlling the application of material and / or pressure to inflate / release inflation of the occluders. In general, the pressure sensor may be configured to be connected to the flush port and to measure pressure between the first occluder and the second occluder from the distal end face.

[0108] FIG. 9C shows a non-limiting example of a cross section through the catheter 900 shown in FIG. 9A and 9B (at section C). This example illustrates the spaces in and between the inner 813 and outer 815 shafts including the infusion (e.g., distal inflation 876 on the inner member / shaft and proximal inflation 874 on the outer member / shaft), as well as an optional guidewire lumen 877 through the inner member 813. FIG. 9C also shows the flush and pressure measurement channel 833’ between the inner and outer members.

[0109] The infusion exit 862 in FIGS. 9A-9C is a small hole in the wall of the outer shaft about 2-3 mm from the end of the shaft. The pressure sensing location created by the space between the inner and outer shafts opens at the end of the outer shaft just distal from the infusion exit hole. This spacing may help maintain a reliable distance between the two.

[0110] The Flush port that may be is used to prime the inner and outer lumen with fluids to overcome friction when adjusting (sliding) the spacing between the occluders forms a direct connection to the region isolated by occluders and hence allows measurement of pressure through this port.

[0111] Any appropriate pressure sensor may be used. For example the pressure sensor may be coupled to the flush port to readout pressure. One example of a pressure transducer that may be used is the Centurian Compass™ pressure transducer” (Medine).

[0112] The use of the pressure sensing from the flush and pressure measurement channel is surprisingly effective, and is comprarable to the use of a ‘gold standard’ pressure wire, while being much simpler and easier to use. For example, FIG. 9 illsutrates and example of a measurement of pressure using an apparatus such as the one shown in FIGS. 9A-9B. As shown by the comparison in FIG. 9D, the resulting pressure sensing may be performed in real time, including while applying material, and provides high accuracy. In this example, saline / contrast infusion showed near-perfect correlation. The use of pressure measurements during a procedure may be used to verify that a good seal has been formed, occluding the region, and that no leak, no side branches, etc., are present. Continuous monitoring during use before and while inflating the occluders may also detect the present of a side branch, which was occluded initially but may become exposed during the procedure.

[0113] FIG. 10 illustrates a method of sensing pressure using an apparatus as described herein. In FIG. 10, the method includes positioning a pressure-sensing dual occlusion catheter apparatus within the vessel 1003, so a distal end of an inner member of the pres sure- sensing dual occlusion catheter apparatus extends distally out of a lumen of an outer member of the pressuresensing dual occlusion catheter apparatus. Optionally, the catheter may be flushed through the flush and pressure measurement channel 1001. The method may include expanding a distal occluder on the inner member of the pressure-sensing dual occlusion catheter apparatus and a proximal occluder on the outer member of the pressure-sensing dual occlusion catheter apparatus to occlude the region of the vessel 1007. The method may also include sensing pressure 1009 through a distal end face of the outer member via a pressure sensor in fluid communication with a flush and pressure measurement channel between an outer surface of the inner member and an inner surface of the outer member, wherein the flush and pressure measurement channel opens from the distal end face of the outer member. The sensed pressure may be transmitted stored and / or displayed. In some cases the sensed pressure may be used to control the application of material.

[0114] Where methods and / or events described above indicate certain events and / or procedures occurring in certain order, the ordering of certain events and / or procedures may be modified. Additionally, certain events and / or procedures may be performed concurrently in a parallel process when possible, as well as performed sequentially as described above.

[0115] When a feature or element is herein referred to as being "on" another feature or element, it can be directly on the other feature or element or intervening features and / or elementsmay also be present. In contrast, when a feature or element is referred to as being "directly on" another feature or element, there are no intervening features or elements present. It will also be understood that, when a feature or element is referred to as being "connected", "attached" or "coupled" to another feature or element, it can be directly connected, attached or coupled to the other feature or element or intervening features or elements may be present. In contrast, when a feature or element is referred to as being "directly connected", "directly attached" or "directly coupled" to another feature or element, there are no intervening features or elements present. Although described or shown with respect to one embodiment, the features and elements so described or shown can apply to other embodiments. It will also be appreciated by those of skill in the art that references to a structure or feature that is disposed "adjacent" another feature may have portions that overlap or underlie the adjacent feature.

[0116] Terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. For example, as used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms "comprises" and / or "comprising," when used in this specification, specify the presence of stated features, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, steps, operations, elements, components, and / or groups thereof. As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items and may be abbreviated as " / ".

[0117] Spatially relative terms, such as "under", "below", "lower", "over", "upper" and the like, may be used herein for ease of description to describe one element or feature's relationship to another element(s) or feature(s) as illustrated in the figures. It will be understood that the spatially relative terms are intended to encompass different orientations of the device in use or operation in addition to the orientation depicted in the figures. For example, if a device in the figures is inverted, elements described as "under" or "beneath" other elements or features would then be oriented "over" the other elements or features. Thus, the exemplary term "under" can encompass both an orientation of over and under. The device may be otherwise oriented (rotated 90 degrees or at other orientations) and the spatially relative descriptors used herein interpreted accordingly. Similarly, the terms "upwardly", "downwardly", "vertical", "horizontal" and the like are used herein for the purpose of explanation only unless specifically indicated otherwise.

[0118] Although the terms “first” and “second” may be used herein to describe various features / elements (including steps), these features / elements should not be limited by these terms, unless the context indicates otherwise. These terms may be used to distinguish one feature / element from another feature / element. Thus, a first feature / element discussed belowcould be termed a second feature / element, and similarly, a second feature / element discussed below could be termed a first feature / element without departing from the teachings of the present invention.

[0119] Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise”, and variations such as “comprises” and “comprising” means various components can be co-jointly employed in the methods and articles (e.g., compositions and apparatuses including device and methods). For example, the term “comprising” will be understood to imply the inclusion of any stated elements or steps but not the exclusion of any other elements or steps.

[0120] In general, any of the apparatuses and methods described herein should be understood to be inclusive, but all or a sub-set of the components and / or steps may alternatively be exclusive, and may be expressed as “consisting of’ or alternatively “consisting essentially of’ the various components, steps, sub-components or sub-steps.

[0121] As used herein in the specification and claims, including as used in the examples and unless otherwise expressly specified, all numbers may be read as if prefaced by the word "about" or “approximately,” even if the term does not expressly appear. The phrase “about” or “approximately” may be used when describing magnitude and / or position to indicate that the value and / or position described is within a reasonable expected range of values and / or positions. For example, a numeric value may have a value that is + / - 0.1% of the stated value (or range of values), + / - 1% of the stated value (or range of values), + / - 2% of the stated value (or range of values), + / - 5% of the stated value (or range of values), + / - 10% of the stated value (or range of values), etc. Any numerical values given herein should also be understood to include about or approximately that value, unless the context indicates otherwise. For example, if the value "10" is disclosed, then "about 10" is also disclosed. Any numerical range recited herein is intended to include all sub-ranges subsumed therein. It is also understood that when a value is disclosed that "less than or equal to" the value, "greater than or equal to the value" and possible ranges between values are also disclosed, as appropriately understood by the skilled artisan. For example, if the value "X" is disclosed the "less than or equal to X" as well as "greater than or equal to X" (e.g., where X is a numerical value) is also disclosed. It is also understood that the throughout the application, data is provided in a number of different formats, and that this data, represents endpoints and starting points, and ranges for any combination of the data points. For example, if a particular data point “10” and a particular data point “15” are disclosed, it is understood that greater than, greater than or equal to, less than, less than or equal to, and equal to 10 and 15 are considered disclosed as well as between 10 and 15. It is also understood that each unit betweentwo particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0122] Although various illustrative embodiments are described above, any of a number of changes may be made to various embodiments without departing from the scope of the invention as described by the claims. For example, the order in which various described method steps are performed may often be changed in alternative embodiments, and in other alternative embodiments one or more method steps may be skipped altogether. Optional features of various device and system embodiments may be included in some embodiments and not in others.Therefore, the foregoing description is provided primarily for exemplary purposes and should not be interpreted to limit the scope of the invention as it is set forth in the claims.

[0123] The examples and illustrations included herein show, by way of illustration and not of limitation, specific embodiments in which the subject matter may be practiced. As mentioned, other embodiments may be utilized and derived there from, such that structural and logical substitutions and changes may be made without departing from the scope of this disclosure. Such embodiments of the inventive subject matter may be referred to herein individually or collectively by the term “invention” merely for convenience and without intending to voluntarily limit the scope of this application to any single invention or inventive concept, if more than one is, in fact, disclosed. Thus, although specific embodiments have been illustrated and described herein, any arrangement calculated to achieve the same purpose may be substituted for the specific embodiments shown. This disclosure is intended to cover any and all adaptations or variations of various embodiments. Combinations of the above embodiments, and other embodiments not specifically described herein, will be apparent to those of skill in the art upon reviewing the above description.

Claims

CLAIMSWhat is claimed is:

1. A dual occlusion catheter apparatus, the apparatus comprising:an elongate catheter body;a first balloon at a distal end region of the elongate catheter body;a second balloon that is adjacent to the first balloon by a fixed distance, wherein the second balloon comprises a variable expansion region that is configured to expand the second balloon laterally towards the first balloon when a pressure within the second balloon exceeds a lateral expansion pressure that is greater than a radial expansion pressure, wherein the second balloon is configured to expand radially when the pressure within the second balloon exceeds the radial expansion pressure;an inflation line coupled to both the first and second balloons; anda delivery port between the first ballon and the second balloon.

2. The apparatus of claim 1, wherein the first balloon comprises a second variable expansion region that is configured to expand the first balloon laterally towards the second balloon when the pressure within the first balloon exceeds the lateral expansion pressure.

3. The apparatus of claim 1, wherein the first balloon comprises a second variable expansion region that is configured to expand the first balloon laterally towards the second balloon when the pressure within the first balloon exceeds a second lateral expansion pressure that is different from the first lateral expansion pressure.

4. The apparatus of claim 1, wherein the variable expansion region has a different thickness than a region of the second balloon outside of the variable expansion region.

5. The apparatus of claiml, wherein the variable expansion region comprises a different material than a region of the second balloon outside of the variable expansion region.

6. The apparatus of claim 1, wherein the variable expansion region comprises a constraining region.

7. The apparatus of claim 6, wherein the constraining region comprises a belt or sleeve.

8. The apparatus of claim 6, wherein the variable expansion region is configured to have a plurality of lateral expansion positions corresponding to different pressures exceeding the lateral expansion pressure.

9. The apparatus of claim 1, further comprising a pressure sensor configured to detect pressure within a vessel region that is between the first and second balloons.

10. The apparatus of claim 1, further comprising an expansion controller configured to control the distance between the first and second balloons by controlling the pressure within the balloons.

11. The apparatus of claim 1, further comprising a fluid delivery controller configured to control the delivery of a therapeutic agent from the delivery port.

12. The apparatus of claim 1, further comprising an imaging sensor at the distal end region configured to image a region of a vessel adjacent to a distal end region.

13. The apparatus of claim 1, further comprising a guidewire lumen extending through the elongate body.

14. The apparatus of claim 1, further comprising a handle region at a proximal end of the elongate body configured to couple to a source of inflation pressure and a therapeutic agent source.

15. A dual occlusion catheter apparatus, the apparatus comprising:an elongate catheter body;a first balloon at a distal end region of the elongate catheter body wherein the first balloon comprises a first variable expansion region;a second balloon that is adjacent to the first balloon by a fixed distance, wherein the second balloon comprises a second variable expansion region, further wherein the first and second variable expansions are configured to expand laterally towards each other when a pressure within the first and second balloons exceeds a lateral expansion pressure that is greater than a radial expansion pressure, wherein the first and second balloons are configured to expand radially when the pressure within the first and second balloon exceeds the radial expansion pressure; an inflation line coupled to both the first and second balloons; anda delivery port between the first ballon and the second balloon.

16. A method, the method comprising:introducing a distal end of a dual occlusion catheter apparatus into a vessel within a body;occluding a region of the vessel by applying a first pressure to the dual occlusion catheter to inflate a first balloon and a second balloon, wherein the occluded region has a first volume;determining a pressure of the occluded region;reducing a volume of the occluded region by increasing the pressure within the first and second balloons so that a variable expansion region of the first and / or second balloons expands laterally into the occluded region; and applying a therapeutic agent into the occluded region from a fluid port positioned between the first and second balloons.

17. The method of claim 16, wherein applying the first pressure comprises applying a pressure that is between greater than or equal to a radial expansion pressure and less than a lateral expansion pressure.

18. The method of claim 17, wherein increasing the pressure within the first and second balloons comprises increasing the applied pressure to greater than or equal to the lateral expansion pressure.

19. The method of claim 16, wherein reducing the volume of the occluded region comprises reducing the volume if the pressure indicates a side branch.

20. The method of claim 16, wherein increasing the pressure within the first and second balloons comprises expanding the variable expansion region of the first and / or second balloons laterally to occlude a side branch of the vessel.

21. The method of claim 16, wherein introducing the distal end of the dual occlusion catheter apparatus into the vessel comprises introducing the distal end of the dual occlusion catheter apparatus into an artery.

22. The method of claim 21, wherein the artery comprises a pancreatic artery or a splenic artery.

23. A pressure-sensing dual occlusion catheter apparatus, the apparatus comprising:an elongate catheter body comprising an inner member nested within and extending distally from a lumen of an outer member;a first occluder at a distal end region of the inner member;a second occluder at a distal end region of the outer member;an infusion exit on the outer member distal to the second occluder;a flush and pressure measurement channel between an outer surface of the inner member and an inner surface of the outer member, wherein the flush and pressure measurement channel opens from a distal end face of the outer member; a proximal handle having an infusion port, and a flush and pressure sensing port in fluid communication with the flush and pressure measurement channel; and a pressure sensor configured to be connected to the flush port and to measure pressure between the first occluder and the second occluder from the distal end face.

24. The apparatus of claim 23, wherein a cross-sectional area of the flush and pressure measurement channel is at least 15% or more of a cross-sectional area of the lumen of the outer member.

25. The apparatus of claim 24, wherein the cross-sectional area of the flush and pressure measurement channel is 20% or more of the cross-sectional area of the lumen of the outer member26. The apparatus of claim 23, wherein the first occluder is a balloon and the second occluder is a balloon.

27. The apparatus of claim 23, wherein the inner member is slidably disposed within the outer member.

28. The apparatus of claim 23, wherein the infusion port is in fluid communication with the infusion exit.

29. The apparatus of claim 23, wherein the proximal handle further comprises one or more inflation ports in fluid communication with a lumen within the first occluder and a lumen within the second occluder.

30. The apparatus of claim 23, wherein the infusion exit is 2 mm or more from the distal end face of the outer member.

31. The apparatus of claim 23, wherein the pressure sensor is coupled to the flush port.

32. A pres sure- sensing dual occlusion catheter apparatus, the apparatus comprising:an elongate catheter body comprising an inner member nested within and extending distally from a lumen of an outer member;a first balloon at a distal end region of the inner member;a second balloon at a distal end region of the outer member;an infusion exit on the outer member distal to the second balloon;a flush and pressure measurement channel between an outer surface of the inner member and an inner surface of the outer member, wherein the flush and pressure measurement channel opens from a distal end face of the outer member, wherein the opening into the flush and pressure measurement channel at the distal end face has a cross-sectional area that is at least 15% or more of the cross-sectional area of the lumen of the outer member;a proximal handle having an infusion port in fluid communication with the infusion exit and a flush and pressure sensing port in fluid communication with the flush and pressure measurement channel; anda pressure sensor configured to be connected to the flush port and to measure pressure between the first balloon and the second balloon from the distal end face.

33. A method of sensing pressure within an occluded region of a vessel, the method comprising:positioning a pressure-sensing dual occlusion catheter apparatus within the vessel so a distal end of an inner member of the pressure-sensing dual occlusion catheter apparatus extends distally out of a lumen of an outer member of the pressuresensing dual occlusion catheter apparatus;expanding a distal occluder on the inner member of the pressure-sensing dual occlusion catheter apparatus and a proximal occluder on the outer member of the pressure-sensing dual occlusion catheter apparatus to occlude the region of the vessel; andsensing pressure through a distal end face of the outer member via a pressure sensor in fluid communication with a flush and pressure measurement channel between an outer surface of the inner member and an inner surface of the outer member, wherein the flush and pressure measurement channel opens from the distal end face of the outer member.

34. The method of claim 33, further comprising flushing the lumen of the outer member to lubricate a region between the inner member and the outer member by applying flushingsolution through the flush port and out of the distal end face, prior toexpanding the distal occluder and proximal occluder.

35. The method of claim 33, further comprising applying a fluid material into the occluded region through an infusion exit on a slide of the outer member.

36. The method of claim 35, further comprising concurrently sensing pressure while applying the fluid material.

37. The method of claim 35, further adjusting the application of fluid material into the occluded region based on the sensed pressure.

38. The method of claim 33, wherein sensing pressure comprises sensing pressure through the opening into the flush and pressure measurement channel at the distal end face having a cross-sectional area that is at least 15% or more of a cross-sectional area of the lumen of the outer member.

39. The method of claim 38, wherein the distal end face has a cross-sectional area that is at least 20% or more of the cross-sectional area of the lumen of the outer member.

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