Trapping flowing debris within blood vessels and other body lumens

Abstract

and a control wire attached to one or more of the mesh debris traps and configured to control the opening of the mesh debris traps. A method of collecting debris, comprising: inserting a device for capturing debris from a fluid flow into a body lumen, locking the device to prevent it from being moved downstream by the fluid flow, controlling the opening of mesh debris traps included in the device, and removing the device from the body along with the debris captured in the debris traps. Related apparatus and methods are also described.

Description

[Technical Field]

[0001] Related Applications This application is a PCT application claiming priority to U.S. Provisional Patent Application No. 63 / 398,546, filed August 17, 2022, and U.S. Provisional Patent Application No. 63 / 400,866, filed August 25, 2022, the entire contents of which are incorporated herein by reference.

[0002] Technical Field Some embodiments of the present disclosure relate to methods and devices for trapping debris flowing along a lumen, and more particularly, but not exclusively, to methods and devices for trapping debris that are controlled from outside the body to enable or disable trapping. [Background technology]

[0003] Blood-borne debris such as emboli, calcified particles, plaque and detached plaque particles, tissue particles (myocardial tissue, endothelial tissue, etc.), particles from foreign bodies (metals, polymers, etc.) are potentially dangerous and can cause illness, injury, and pathological events that require medical treatment.

[0004] For example, in transcatheter aortic valve implantation (TAVI), particles were detected in 99% of patients by diffusion-weighted magnetic resonance imaging (DWI or DW-MRI). The amount of debris associated with the vascular bed (valve tissue, arterial wall, calcification) was significantly higher, and additional particles included atherosclerotic plaque, myocardial tissue, endothelial tissue, and foreign particles of unknown origin, such as polymers and air bubbles.

[0005] Additional background art includes the following:

[0006] International Patent Application Publication No. WO2019 / 064223 to Brandeis describes an aortic protection device comprising a mesh lumen shaped and sized to extend along the aorta from the cardiac side of the brachiocephalic artery's exit from the aorta to distal to the left subclavian artery's exit from the aorta, the mesh lumen being arranged to change the porosity of the mesh pores in response to an external control.

[0007] International Patent Application Publication No. WO2017 / 042808 by Eli describes an embolic protection device including a porous deflection screen that includes a filter and is positioned along the wall of the aortic arch to expand and cover the entrances of arteries branching from the aorta; an embolus collecting portion that includes a cylinder that expands and is positioned along the wall of the descending aorta, and is pressed against the wall of the descending aorta to lock the porous deflection screen; and a connecting portion that connects the porous deflection screen and the embolus collecting portion and is positioned to lock the porous deflection screen against the wall of the aortic arch.

[0008] Debris Heterogeneity across Different Valve Types Captured by a Cerebral Protection System during Transcatheter Aortic Valve Replacement - Focus on Stroke Risk and Prevention, Tobias Schmidt et al., published in J. Am.Coll.Cardiol.Intv.2018 Jul, 11 (13) 1262-1273.

[0009] The disclosures of all documents mentioned above and throughout the specification, and of all documents cited within those documents, are hereby incorporated by reference. Summary of the Invention

[0010] The present disclosure relates in some embodiments to methods and devices for trapping debris flowing along a lumen, and more particularly, but not exclusively, to methods and devices for trapping debris that are controlled from outside the body to enable or disable trapping.

[0011] According to one aspect of some embodiments of the present disclosure, there is provided a device for capturing debris from a blood flow within an aorta, the device comprising: an expandable stent shaped and sized to expand against a wall of a body lumen; a plurality of mesh debris traps attached to the stent; and a control wire attached to one or more of the mesh debris traps and configured to control the opening of the mesh debris traps.

[0012] According to some embodiments of the present disclosure, the expandable stent has a shape and size to expand against the wall of the aorta.

[0013] According to some embodiments of the present disclosure, the expandable stent has a shape and size to expand against the wall of the vena cava.

[0014] According to some embodiments of the present disclosure, the control wire is sized to extend from a location of the device inside the patient's body to outside the patient's body.

[0015] According to some embodiments of the present disclosure, the mesh debris trap is arranged to be controlled to open and close from outside the patient's body by the control wire.

[0016] According to some embodiments of the present disclosure, at least some of the mesh debris traps are arranged to be controlled to open and close separately from at least some of the other mesh debris traps.

[0017] According to some embodiments of the present disclosure, a plurality of control wires are provided, each configured to control a separate group of the mesh debris traps.

[0018] According to some embodiments of the present disclosure, the mesh debris trap is positioned in a normally closed state even when the device is expanded against the wall of the body lumen.

[0019] According to some embodiments of the present disclosure, the mesh debris trap is configured to allow passage of a medical instrument through a tubular lumen defined by the interior of the device when the device is expanded against the wall of the body lumen.

[0020] According to some embodiments of the present disclosure, the mesh debris trap comprises a mesh leaf having a base attached to the stent wall and a rim located upstream of the base of the mesh leaf.

[0021] According to some embodiments of the present disclosure, the mesh debris trap comprises mesh leaves having bases attached to the stent wall and edges located downstream from the bases of the mesh leaves.

[0022] According to some embodiments of the present disclosure, the mesh debris trap includes a marker that allows for detecting whether the mesh debris trap is open or closed.

[0023] According to some embodiments of the present disclosure, the marker comprises a marker suitable for detection by an imaging modality selected from the group consisting of X-ray, ultrasound, and magnetic resonance imaging (MRI).

[0024] According to some embodiments of the present disclosure, the marker is located at a mesh debris trap opening.

[0025] According to some embodiments of the present disclosure, the mesh debris trap is positioned such that mesh debris trap openings are distributed at different distances along the direction of blood flow through the device.

[0026] According to some embodiments of the present disclosure, at least some of the levels of the mesh debris trap are arranged to be enclosed separately from at least some other levels of the mesh debris trap.

[0027] According to some embodiments of the present disclosure, the mesh debris trap comprises a mesh having a pore size in the range of 1000 to 30 microns.

[0028] According to some embodiments of the present disclosure, the mesh debris trap openings distributed at different distances along the blood flow direction include mesh pore openings of different sizes.

[0029] According to some embodiments of the present disclosure, the mesh debris traps are arranged longitudinally along the device such that, when open, the openings of the open mesh debris traps overlap when viewed along the direction of blood flow.

[0030] According to some embodiments of the present disclosure, the different sized mesh pore openings are arranged such that larger pore sizes are upstream of smaller pore sizes.

[0031] According to some embodiments of the present disclosure, the mesh pore size includes at least three levels: 1000 microns, 400 microns, and 200 microns.

[0032] According to some embodiments of the present disclosure, mesh debris trap openings at the same distance along the blood flow direction include mesh pore openings of different sizes.

[0033] According to some embodiments of the present disclosure, when the plurality of mesh debris traps are opened, the trap openings cover the entire cross-sectional area of ​​the lumen defined by the expandable stent, transverse to the direction of blood flow.

[0034] According to some embodiments of the present disclosure, a mesh debris trap opening is configured to conform to the lumen wall when the mesh debris trap is not open.

[0035] According to some embodiments of the present disclosure, the mesh debris trap opening is arcuately shaped.

[0036] According to some embodiments of the present disclosure, the mesh debris trap opening is formed in a triangular shape.

[0037] According to some embodiments of the present disclosure, a mesh debris trap opening comprises a loop for passing a control wire to open said mesh debris trap.

[0038] According to some embodiments of the present disclosure, the mesh debris trap opening is flexible, allowing surgical instruments to bend through the mesh debris trap opening and pass along the device.

[0039] According to some embodiments of the present disclosure, expansion of the stent against the wall of a lumen anchors the device and resists migration in the direction of blood flow.

[0040] According to some embodiments of the present disclosure, the device is anchored to resist migration in the direction of blood flow by being connected to an anchoring stent that is expanded against the lumen wall upstream of the device.

[0041] According to some embodiments of the present disclosure, the anchoring stent is shaped and sized for anchoring upstream of the brachiocephalic trunk.

[0042] According to some embodiments of the present disclosure, the anchoring stent is shaped and sized for anchoring upstream of the carotid artery.

[0043] According to some embodiments of the present disclosure, the device is configured to be attached to an aortic protection device.

[0044] According to some embodiments of the present disclosure, the device is configured as part of an aortic protection device.

[0045] According to an aspect of some embodiments of the present disclosure, there is provided a method of collecting debris, the method comprising inserting into a body lumen a device for capturing debris from a fluid flow, locking the device against downstream movement by the fluid flow, controlling the opening of a mesh debris trap included in the device, and removing the device from the body together with debris captured in the debris trap.

[0046] According to some embodiments of the present disclosure, the locking includes locking downstream of a predicted source of the debris.

[0047] According to some embodiments of the present disclosure, the body lumen is a blood vessel.

[0048] According to some embodiments of the present disclosure, the blood vessel is an artery.

[0049] According to some embodiments of the present disclosure, the artery is the aorta.

[0050] According to some embodiments of the present disclosure, the method further includes inserting an instrument along and upstream of the device for performing a cardiac procedure.

[0051] According to some embodiments of the present disclosure, the method further includes performing the cardiac procedure after opening the mesh debris trap.

[0052] According to some embodiments of the present disclosure, the device is used in addition to the use of an aortic protection device.

[0053] According to some embodiments of the present disclosure, the blood vessel is a vein.

[0054] According to some embodiments of the present disclosure, the method is performed on a patient whose condition is expected to release or generate debris into the veins.

[0055] According to some embodiments of the present disclosure, the method is performed on a patient prior to a medical procedure that is expected to release debris into a vein or that is expected to generate debris in a vein.

[0056] According to some embodiments of the present disclosure, the method further includes unlocking the device, repositioning the device, and relocking the device.

[0057] According to some embodiments of the present disclosure, the method further includes closing the mesh debris trap before removing the device from the body.

[0058] According to some embodiments of the present disclosure, closing the mesh debris trap occurs after performing a cardiac procedure.

[0059] According to some embodiments of the present disclosure, opening the mesh debris trap includes controlling only a subgroup of the mesh debris trap.

[0060] In accordance with an aspect of some embodiments of the present disclosure, there is provided a method of collecting debris during a cardiac procedure, the method comprising inserting a device for capturing debris to a location within an aorta, inserting a medical instrument for performing the cardiac procedure, performing the cardiac procedure, and removing the device from a body with debris captured in a debris trap within the device.

[0061] According to some embodiments of the present disclosure, the debris trap within the device is controlled to close prior to the removing.

[0062] According to some embodiments of the present disclosure, the debris trap within the device is controlled to be released prior to performing the cardiac procedure.

[0063] According to some embodiments of the present disclosure, the cardiac procedure is a cardiac procedure selected from the group consisting of an electrophysiology procedure, a patent foramen ovale (PFO) procedure, a heart valve repair, open heart surgery, a percutaneous aortic valve replacement (PAVR), a percutaneous aortic valve implantation (PAVI), a transcatheter aortic valve implantation (TAVI), and a transcatheter aortic valve replacement (TAVR).

[0064] According to some embodiments of the present disclosure, the debris trap within the device is controlled to be released after or during a procedure selected from the group consisting of an aneurysm procedure, an arteriosclerosis stent procedure, a balloon dilation procedure, a drug delivery procedure, a kidney procedure, a surgical procedure involving treatment of an artery, and an aortic atherosclerosis treatment.

[0065] According to some embodiments of the present disclosure, the cardiac procedure includes a pace-up step, and a cardiac procedure debris trap within the device is controlled to be released after the pace-up step.

[0066] According to some embodiments of the present disclosure, the cardiac procedure includes a pace-down step, and a cardiac procedure debris trap within the device is controlled to be released after the pace-down step.

[0067] According to an aspect of some embodiments of the present disclosure, there is provided a method of preventing debris from reaching the lungs, the method comprising inserting a device for capturing debris into a location within a vein, controlling a debris trap within the device to open and collect debris from the vein, performing a medical procedure, and removing the device for capturing debris from the body.

[0068] According to some embodiments of the present disclosure, prior to removing the device, the debris trap is controlled to be closed.

[0069] According to some embodiments of the present disclosure, the removing includes removing along with debris trapped in a debris trap within the device.

[0070] According to some embodiments of the present disclosure, the method further comprises administering an anticoagulant prior to the removing.

[0071] According to some embodiments of the present disclosure, the debris trap within the device is controlled to be released after or during a procedure selected from the group consisting of a renal procedure, an aneurysm procedure, an injury, an open injury, an amputation, an injury in a disaster situation, an injury due to trauma, an injury due to blunt trauma, a medical procedure involving cardiac assistance, a medical procedure involving pulmonary assistance, a medical procedure involving extracorporeal membrane oxygenation (ECMO), open surgery, and a pressure injury.

[0072] Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this disclosure belongs.Although methods and materials similar or equivalent to those described herein can be used to practice or test the embodiments of this disclosure, exemplary methods and / or materials are described below.In case of conflict, the patent specification, including definitions, shall prevail.In addition, materials, methods, and examples are merely illustrative and are not necessarily intended to be limiting.

[0073] Several embodiments of the present disclosure are described, by way of example only, with reference to the accompanying drawings and images. It is emphasized below that the details shown, with particular reference to the drawings, are for the purpose of illustration and for the purpose of providing a detailed description of embodiments of the present disclosure. Similarly, from viewing the description in conjunction with the drawings, it will become apparent to those skilled in the art how embodiments of the present disclosure may be practiced. [Brief explanation of the drawings]

[0074] [Figure 1A] 1 is a simplified block diagram of debris flowing downstream and a device positioned to trap the debris, according to an exemplary embodiment; [Figure 1B] 1 is a simplified block diagram of debris flowing downstream and a device positioned to trap the debris, according to an exemplary embodiment; [Figure 2A] 1 is a simplified schematic diagram of a debris trapping device according to some illustrative embodiments; [Figure 2B] 1 is a simplified schematic diagram of a debris trapping device according to some illustrative embodiments; [Figure 2C] 1 is a simplified schematic diagram of a debris trapping device according to some illustrative embodiments; [Figure 2D] 1 is a simplified schematic diagram of a debris trapping device according to some illustrative embodiments; [Figure 2E] 1 is a simplified schematic diagram of a debris trapping device according to some illustrative embodiments; [Figure 2F] 1 is a simplified schematic diagram of a debris trapping device according to some illustrative embodiments; [Figure 3A] 1 is a simplified schematic diagram of a debris trapping device according to an example embodiment; [Figure 3B] 1 is a simplified diagrammatical schematic diagram of a debris trapping device according to an exemplary embodiment; [Figure 4A] FIG. 2 is a simplified diagram illustrating an example embodiment of a debris trapping device. [Figure 4B] FIG. 2 is a simplified diagram illustrating an example embodiment of a debris trapping device. [Figure 4C] FIG. 2 is a simplified diagram illustrating an example embodiment of a debris trapping device. [Figure 5A] 1 is a photograph of a debris trapping device according to an example embodiment. [Figure 5B] 1 shows a simplified diagram of a debris trapping device according to an example embodiment; [Figure 6A] 1 is a photograph of a debris capture device according to an example embodiment; [Figure 6B] 1 is a photograph of a debris capture device according to an example embodiment; [Figure 6C] 1 is a photograph of a debris capture device according to an example embodiment; [Figure 7A] 1 is a simplified diagram of a debris capture device positioned in an aorta according to an exemplary embodiment. [Figure 7B] 1 is a simplified diagram of a debris capture device positioned in an aorta according to an exemplary embodiment. [Figure 7C] 1 is a simplified diagram of a debris capture device positioned in an aorta according to an exemplary embodiment. [Figure 7D] 1 is a simplified diagram of a debris capture device positioned in an aorta according to an exemplary embodiment. [Figure 7E] 1 is a simplified diagram of a debris capture device positioned in an aorta according to an exemplary embodiment. [Figure 7F]FIG. 1 is a simplified diagrammatic view of an aortic protection device deployed in conjunction with a debris trapping device according to one example embodiment of the present invention. [Figure 7G] FIG. 1 is a simplified diagrammatic view of a device including combined aortic protection and debris trapping, according to one example embodiment of the present invention. [Figure 7H] FIG. 1 is a simplified diagrammatic view of a device including combined aortic protection and debris trapping, according to one example embodiment of the present invention. [Figure 7I] 1 is a simplified diagrammatic view of a device including a combination of aortic protection and two positions or levels of debris trapping, according to an exemplary embodiment of the present invention. [Figure 7J] 1 is a simplified diagrammatic view of a device including a combination of aortic protection and two positions or levels of debris trapping, according to an exemplary embodiment of the present invention. [Figure 8] 1 is a simplified diagram of potential locations of a debris trapping device in an aorta, according to some exemplary embodiments. [Figure 9] 1 is a simplified diagram of potential locations of a debris trapping device in a vein, according to some exemplary embodiments. [Figure 10] FIG. 1 is a simplified flowchart of a method for collecting debris, according to an example embodiment. [Figure 11] 1 is a simplified flowchart diagram of a method for collecting debris during a cardiac procedure, according to an example embodiment. [Figure 12] FIG. 1 is a simplified flowchart diagram of a method for preventing debris from reaching the lungs, according to an example embodiment. DETAILED DESCRIPTION OF THE INVENTION

[0075] The present disclosure relates in some embodiments to methods and devices for trapping debris flowing along a lumen, and more particularly, but not exclusively, to methods and devices for trapping debris that are controlled from outside the body to enable or disable trapping.

[0076] Overview - Device Embodiments

[0077] An aspect of some embodiments relates to a device for trapping debris flowing through a lumen in a body (eg, debris flowing within a blood vessel).

[0078] Throughout this specification and claims, the term "debris" is used to include thrombi, emboli, microemboli, calcified particles, body tissue particles, myocardial tissue particles, polymer particles, polymer microparticles, foreign body particles within the body lumen, endothelial tissue particles, unorganized thrombi, organized thrombi, plaque particles, particles in the bloodstream, and other undesirable particles found in bodily fluids. The term "debris" also includes stones of various bodily origin (i.e., kidney stones, gallbladder stones, spleen stones, pancreatic stones, etc.).

[0079] In some embodiments the device has controls that can enable or disable the trap, i.e. enable the debris trap pocket to a state where it traps debris and disable the debris trap pocket to a closed state, In some embodiments the debris trap pocket comprises a mesh, optionally a flexible mesh, with a particular pore size and is intended to trap debris larger than the particular pore size.

[0080] Throughout this specification and claims, the term "mesh" means a material that has holes or apertures that allow particles smaller than the holes or apertures to pass through.

[0081] Throughout this specification and claims, the term "mesh" is used interchangeably with the terms membrane, film, knit, polymer, electrospun polymer, nitinol mesh, and biodegradable membranes of polymeric and / or biological origin.

[0082] In some embodiments, the control means extends from the device outside the patient's body, hi some embodiments, the control means is a wire that, when acted upon outside the body, opens and closes the debris trap pocket.

[0083] In some embodiments, when the pocket is closed, any debris within the pocket is retained within the pocket, and the procedure for removing the device from the body also retains the debris within the pocket, allowing the debris to be removed from the body.

[0084] In some embodiments, the device has debris trapping pockets disposed along the inner circumference of the stent. When the pockets are activated (i.e., opened), they optionally extend toward the center of the stent and optionally completely cover a cross section of the stent. In some embodiments, when the pockets extend toward the center of the stent, they are sufficiently flexible to lie against a medical device extending through the stent, and optionally seal the cross section of the stent against the medical device. In some embodiments, when the pockets extend toward the center of the stent, they are sufficiently flexible to lie against a medical device extending through the stent like a curtain, and optionally seal the cross section of the stent against the medical device.

[0085] In some embodiments, the debris trap pocket is normally closed, i.e., fluid can pass through the debris trap pocket with low resistance and fluid is not filtered through the debris trap pocket. A closed debris trap pocket is also referred to as a state in which the device for capturing debris is open (not enabled to trap debris). A potential advantage of such an embodiment is that fluid flow is unimpeded until something occurs that causes debris to be filtered and / or trapped. In some embodiments, the trap may only be enabled during medical procedures known to generate debris. One non-limiting example of such a use is when the device is placed in the aorta and enabled during a cardiac procedure or during pacing down after a cardiac procedure, when blood flow is known to increase and debris flow is likely to increase. Allowing blood to flow unimpeded until a time known or suspected to cause an increase in debris flow downstream is potentially advantageous.

[0086] In some embodiments, the debris trap pocket is normally open, i.e., fluid filters through it. An open state of the debris trap pocket means that the debris trapping device is enabled to trap debris. A potential advantage of such an embodiment is that there is no need to determine when to initiate trapping, since fluid is constantly filtering through and trapping debris. In some embodiments, trapping may continue for all or most of the time the device is deployed in place. One non-limiting example of such use is when the device is placed in a vein to prevent debris from reaching the patient's lungs. In some embodiments, the device is optionally placed in the veins of a patient who has suffered an accident that crushes a limb. It is known that such an accident can generate blood clots and / or other debris that can travel to the lungs, and the device can be used in a vein, such as a vena cava, to trap debris and prevent it from reaching the lungs. In some embodiments, such prevention can last throughout a medical procedure performed on the patient, if there is concern that the procedure will generate debris.

[0087] In some embodiments, the debris trap pocket is opened and enabled to filter and / or trap debris from the fluid flow, in some embodiments, enabling requires the physician to continuously apply force to hold the debris trap pocket open, and when the physician ceases applying force, the debris trap pocket closes.

[0088] In some embodiments, the pockets are located at several distances along the axial direction of the stent. When activated, the pockets optionally extend toward the center of the stent and can optionally completely cover the cross section of the stent at each of several distances (also referred to as several levels) along the axial direction of the stent. A potential advantage of constructing a device with multiple levels of pockets is that the device can be longer and thinner than if the trapped debris was all at one level, as the trapped debris is distributed along the stent, potentially carrying the trapped debris within the closed pockets when the device is removed from the body.

[0089] In some embodiments, the control means is configured to control all levels of the pocket. In some embodiments, the control means is configured to control one or more of the levels of the pocket separately from other levels of the pocket. In some embodiments, the control means includes individual control means for each level of the pocket.

[0090] In some embodiments, each of the levels contains pockets made of mesh with different pore sizes. In some embodiments, the levels are arranged such that larger pores are located upstream of smaller pores relative to the direction of flow within the stent. Such embodiments may provide the advantage of trapping debris of different sizes at different distances along the stent, distributing the trapping of different sized debris along different levels, and retaining the trapped debris in closed pockets when the device is removed from the body, allowing the device to be longer and thinner as the debris is distributed than if the trapped debris were all in one level.

[0091] Overview – Potential Locations for Devices

[0092] An aspect of some embodiments relates to the location of a lumen within the body where a device for trapping debris flowing through the lumen is located.

[0093] Typically, the device includes a stent that can expand to the diameter of the lumen and expands to push against the lumen wall. In some embodiments, expansion causes the stent to seal against the lumen wall, preventing debris from flowing between the stent and the lumen wall. In some embodiments, expansion locks the stent in place and prevents the stent from sliding along the lumen wall, even when debris-trapping pockets are engaged and fluid flow along the lumen could apply pressure to the pockets and push the stent downstream.

[0094] Some non-limiting exemplary locations are described with respect to trapping debris in the bloodstream, where the lumen through which the blood flows is an artery and / or vein.

[0095] An exemplary location may be the descending aorta, which is an artery with a relatively large diameter and a relatively long lumen for placement of an embodiment of the device.

[0096] An exemplary location may be the abdominal aorta.

[0097] Thus, embodiments of the device may include one or more levels of debris trapping pockets and may therefore be short or long and suitable for different locations, for example, when placed in the descending aorta, embodiments of the device may include multiple levels of pockets.

[0098] An exemplary location may be the aortic arch, where the descending aorta is an artery with a relatively large diameter and a curved portion of the lumen for placement of an embodiment of the device.

[0099] An exemplary location may be, for example, the ascending aorta between the cardiac arteries and the brachiocephalic trunk.

[0100] An exemplary location is the vena cava where blood enters the heart before being pumped to the lungs, where debris can cause significant damage.

[0101] Overview - Non-limiting examples of usage

[0102] An aspect of some embodiments relates to a method of using a debris trapping device.

[0103] In some embodiments, the device is inserted into the body and advanced along a body lumen to a predetermined location. Once in position, the device includes a stent that expands and presses against the lumen wall. By way of non-limiting example, the stent may include a shape-memory material, and the stent expands as it is pushed out of the catheter.

[0104] In some embodiments, a catheter is used to insert the device into the body. In some embodiments, the catheter may optionally be a standard vascular access catheter. Contemplated catheter diameters include those ranging from 5 French to 12 French. In some embodiments, the catheter may optionally be a small-bore femoral access catheter. Contemplated catheter diameters include those ranging from 5 French to 8 French.

[0105] In some embodiments, the device is designed for radial access.

[0106] In some embodiments, the debris trapping device is optionally inserted through the same femoral access as the instrument for the additional medical procedure (such as a balloon stent graft) or through the patient's other leg, i.e., a femoral access that is not via the same leg as the access for the additional medical procedure.

[0107] Optionally, in some embodiments, a medical instrument may be passed through and / or alongside the debris trapping device in order to perform a medical procedure upstream of the debris trapping device.

[0108] If appropriate, debris trapping pockets are optionally enabled when debris needs to be trapped. In some embodiments, the pockets extend toward the center of the stent to cover a cross-section of the lumen, and all fluid flowing along the lumen passes through the debris trap pocket. In some embodiments, the pockets extend toward the center of the stent and are positioned to fit snugly along a catheter used to direct medical instruments upstream through the device, closing off a cross-section of the lumen, so that fluid flowing along the lumen passes through the debris trap pocket.

[0109] A typical time when debris trapping is required is during a surgical procedure or other medical procedure that may release debris particles.

[0110] As a non-limiting example, the debris trapping device is optionally activated when surgery is performed on the heart (for non-limiting example, the mitral valve). Such surgery may release sediment particles that may have accumulated on the mitral valve. Optionally, such particles are trapped rather than allowed to flow along the arteries (where they could reach and damage the kidneys, brain, or heart).

[0111] As a non-limiting example, the debris trapping device is optionally activated when a therapeutic procedure is performed on the body, which may release emboli such as blood clots, but optionally trap such particles before they enter the right side of the heart instead of allowing the heart to pump them towards the lungs, where they may be damaged.

[0112] Overview – Medical Use

[0113] An aspect of some embodiments includes using a debris trapping device downstream of a location where a medical procedure is performed. In some embodiments, the medical procedure may release debris to flow with bodily fluids (such as, by way of non-limiting example, blood), and the debris trapping device is optionally enabled before the medical procedure begins to trap the debris and prevent it from flowing and reaching a location within the body where it may cause harm.

[0114] In some embodiments, when a medical procedure is performed on the heart, an embodiment of a debris trapping device is optionally deployed downstream of the heart, for example in the aorta, to trap debris generated by the procedure.

[0115] As a non-limiting example, debris trapping devices are optionally enabled when surgery is performed on the mitral valve. Such surgery typically releases sediment particles that may have accumulated on the mitral valve, trapping them rather than allowing them to flow along the arteries (where they could reach and damage the kidneys, brain, or heart).

[0116] In some embodiments, when a medical procedure is performed on the body, debris may be released and travel along the veins toward the heart. The debris may include emboli, such as blood clots. If debris is allowed to enter the heart from the venous system, the heart pumps the debris toward the lungs. Emboli in the lungs can cause damage. In some embodiments, a debris trapping device is placed at the entrance to the heart, for example, at the vena cava, to prevent debris from entering the heart and traveling toward the lungs. In some embodiments, the intravenous debris trapping device is optionally enabled before starting the medical procedure.

[0117] In some embodiments, when a body is involved in an accident, blood clots may accumulate in the body part involved in the accident. A debris trapping device may optionally be placed at the entrance to the heart, for example, at the vena cava, to prevent debris from entering the heart and continuing toward the lungs. In some embodiments, the intravenous debris trapping device is optionally activated before commencing medical surgery aimed at treating the body part damaged in the accident.

[0118] Overview - Relationship with other devices

[0119] An aspect of some embodiments relates to a debris trapping device that is attached to and / or integrally constructed with an additional medical device.

[0120] As a non-limiting example, one embodiment of the debris trapping device may optionally be attached to and / or be part of an aortic protection device such as that described in the above-referenced International Patent Application Publication No. WO 2019 / 064223 to Brandeis.

[0121] An aspect of some embodiments relates to a debris trapping device that is used in addition to the use of additional medical equipment.

[0122] As a non-limiting example, one embodiment of the debris trapping device may be used as an option in addition to using the aortic protection device described in the above-mentioned International Patent Application Publication No. WO2019 / 064223 to Brandeis.

[0123] By way of non-limiting example, one embodiment of the debris trapping device may be used as an option in addition to the equipment used in the procedure also known as Percutaneous Aortic Valve Replacement (PAVR), Percutaneous Aortic Valve Implantation (PAVI), Transcatheter Aortic Valve Implantation (TAVI), or Transcatheter Aortic Valve Replacement (TAVR).

[0124] In some embodiments, the debris trapping device is optionally deployed first, and the instrument optionally passes through the debris trapping device. In some embodiments, the instrument optionally passes through the debris trapping device even while the debris trapping pocket is activated. In some embodiments, the edges or edges of the pocket are flexible enough to allow the instrument to pass through, optionally maintaining contact with the instrument, filtering the blood and potentially trapping debris.

[0125] Before describing at least one embodiment of the present disclosure in detail, it is to be understood that the present disclosure is not necessarily limited in its application to the details of construction and the arrangement of elements and / or methods set forth in the following description and / or illustrated in the drawings and / or examples. The present disclosure is capable of other embodiments and of being practiced or carried out in various ways.

[0126] Reference is made to FIG. 1A, which is a simplified block diagram illustrating debris flowing downstream and devices positioned to trap the debris, according to an exemplary embodiment.

[0127] FIG. 1A shows one debris source 102 (e.g., a calcified heart valve releasing calcium fragments during a medical procedure, or a blood embolus from shattered tissue) that releases debris 104 that flows along a body lumen 101 (e.g., an artery such as the aorta, or a vein such as a vena cava). The debris reaches a debris capture device 106. Downstream of the debris capture device 106, fluid (e.g., blood) now depleted of some or all of the debris trapped by the debris capture device 106 continues to form a flow 108. The fluid reaches an organ 110 that could potentially benefit from being freed from the debris. Such organs could be the lungs (in which case the debris capture device 106 is placed in a vein, optionally a vena cava), the heart, and / or the brain (in which case the debris capture device 106 is placed in the aorta), and / or the kidneys (in which case the debris capture device 106 is placed in the aorta or abdominal aorta), to name a few non-limiting examples.

[0128] In some embodiments, the debris capture device 106 optionally has at least two states: an open state that does not trap debris and allows fluid to pass with maximum flow and minimum resistance to flow, and a closed state that captures debris and allows cleaner fluid with less or no debris to pass through to reach the organ 110.

[0129] In some embodiments, the debris capture device 106 includes debris trapping leaves or pockets that extend across the cross section of the debris capture device 106, and the trapping leaves or pockets include a mesh material that filters fluid and prevents debris from passing through.

[0130] The mesh material may include mesh with pore sizes of 1000 microns, 200 microns, 150 microns, 130 microns, 100 microns, 75 microns, 50 microns, 30 microns, and may include mesh with a minimum of 10 microns.

[0131] Optionally, in some embodiments, the debris capture device 106 is controlled 114 by a controller 116 to switch between two states.

[0132] Optionally, in some embodiments, the controller 116 is enabled by a physician.

[0133] In some embodiments, the controller 116 is operatively connected to the sensors and is optionally automatically enabled by programming the enabling of the debris trapping device 106 based on the sensor readings.

[0134] As one non-limiting example, during a TAVI procedure, the heart is artificially paced (called pace-up) to cause the heart to pump less blood before implantation of the aortic valve begins. The implantation process can release debris into the bloodstream. At such times (pace-up), it may be desirable for the debris capture device 106 to be automatically enabled to capture debris and prevent it from flowing downstream toward organs that could potentially be affected by debris in the blood.

[0135] As one non-limiting example, during a TAVI procedure, post-implant, the heart may be slowed down (called pace-down) to allow the heart to pump more blood. The increased blood flow may cause debris to escape from the site of the medical procedure. At such times (pace-down), it may be desirable for the debris capture device 106 to be automatically enabled to capture debris and prevent it from flowing downstream toward organs that may potentially be affected by debris in the blood.

[0136] Sensors that can be used to automatically activate the debris capture device 106 include sensors that provide heart rate.

[0137] In some embodiments, the heart rate sensor may optionally be located separately from the debris capture device 106 and provide data to the controller 116 .

[0138] In some embodiments, a physician manually enables and / or disables the controller 116, whether following the principles for automatic enablement described above or principles related to the method of a particular medical procedure.

[0139] In some embodiments, a physician manually enables and / or disables the controller 116 based on specific activities associated with the medical procedure being performed. As one non-limiting example, when a medical instrument is moved along a lumen, e.g., the aorta, the movement may release particles, and the debris trapping device may optionally be enabled to trap the particles. As another non-limiting example, when a medical instrument is being repositioned, the movement may release particles, and the debris trapping device may optionally be enabled to trap the particles. As yet another non-limiting example, when a balloon is planned to be inflated, the inflation may release particles, and the debris trapping device may optionally be enabled to trap the particles.

[0140] In some embodiments, the controller 116 may optionally be a control wire 116. In some embodiments, the control wire 116 is optionally attached at one end to the debris trapping device 106 and extends at the other end outside the patient's body.

[0141] Reference is now made to FIG. 1B, which is a simplified block diagram illustrating debris flowing downstream and devices positioned to trap the debris, according to an exemplary embodiment.

[0142] 1B shows one debris source 122 that emits debris that flows 124 along a body lumen 121. The debris reaches a debris trapping device 126 that includes several (two or more) debris-trapping traps 126A, 126B or groups of traps 126A, 126B. Downstream of the first debris-trapping trap 126A, the fluid continues to flow 128A, minus some or all of the debris trapped by the debris-trapping trap 126A.

[0143] In some embodiments, the fluid 128A reaches a second debris trapping trap 126B, after which the fluid continues into flow 128B, minus some or all of the debris trapped by the debris trapping trap 126B.

[0144] The fluid reaches organs 130 that potentially benefit from being kept out of reach of debris.

[0145] In some embodiments, the debris capture device 126 is optionally controlled 134A, 134B by one or more controllers 136A, 136B to switch between an OPEN state and a CLOSED state.

[0146] In some embodiments, the debris capture device 126 is optionally controlled by a single controller.

[0147] In some embodiments, one or more of the debris-trapping traps 126A, 126B, or one or more groups of traps 126A, 126B, are optionally controlled separately. In some embodiments, the debris-trapping traps 126A, 126B, or groups of traps 126A, 126B, are controlled independently of each other.

[0148] Reference is made to Figures 2A-2F, which show simplified schematic diagrams of debris trapping devices according to some exemplary embodiments.

[0149] Figure 2A shows a debris capture device 204 that includes a stent 206 having leaves 208, debris traps 208, or debris collecting pockets 208 that can be opened (closed to the wall of the stent 206) and closed (bent toward the center of the lumen defined by the stent 206). Figure 2A also shows optional wire(s) 210 that, in some embodiments, are used to control activation of the debris collecting pockets 208. Figure 2A also shows the direction of fluid flow 202.

[0150] FIG. 2A shows a debris capture device 204 with the bases of the leaves 208 attached to a stent 206 and the free edges of the leaves 208 facing upstream relative to the direction of fluid flow 202. FIG.

[0151] Figure 2B shows a debris capture device 214 that includes a stent 206 having leaves 218 or debris traps 218 or debris collecting pockets 218 that can be open (closed to the wall of the stent 206) and closed (bent towards the center of the lumen defined by the stent 206). Figure 2B also shows optional wire or wires 210 that, in some embodiments, are used to control activation of the debris collecting pockets 218. Figure 2B also shows the direction of fluid flow 202.

[0152] FIG. 2B shows the debris capture device 214 with the base of the leaves 218 attached to the stent 206 and the free edges of the leaves 218 facing downstream relative to the direction of fluid flow 202 .

[0153] Figure 2C shows a debris capture device 224 including a stent 206 with leaves or debris traps or debris collecting pockets 228, 229 at two different levels relative to the direction of fluid flow 202 along the lumen defined by the stent 206. The leaves or debris traps or debris collecting pockets 228, 229 can be open (close to the wall of the stent 206) and closed (bend towards the center of the lumen defined by the stent 206). Figure 2C also shows an optional wire or wires 210 that, in some embodiments, are used to control the activation of the debris collecting pockets 228, 229.

[0154] FIG. 2C shows the debris capture device 224 with the base of the leaves 228 attached to the stent 206 and the free edges of the leaves 228 facing upstream relative to the direction of fluid flow 202.

[0155] Figure 2D shows a debris capture device 234 including a stent 206 with leaves or debris traps or debris collecting pockets 238, 239 at two different levels relative to the direction of fluid flow 202 along the lumen defined by the stent 206. The leaves or debris traps or debris collecting pockets 238, 239 can be open (close to the wall of the stent 206) and closed (bend towards the center of the lumen defined by the stent 206). Figure 2D also shows an optional wire or wires 210 for controlling activation of the debris collecting pockets 238, 239 in some embodiments.

[0156] 2D shows a debris capture device 234 in which the bases of leaves 238 are attached to the stent 206 with the free edges of leaves 238 facing upstream relative to the direction of fluid flow 202, and the bases of leaves 239 are attached to the stent 206 with the free edges of leaves 239 facing downstream relative to the direction of fluid flow 202. The two levels of leaves 238, 239 face in different directions with the free edges facing each other.

[0157] Figure 2E shows a debris capture device 244 including a stent 206 with leaves or debris traps or debris collecting pockets 248, 249 at two different levels relative to the direction of fluid flow 202 along the lumen defined by the stent 206. The leaves or debris traps or debris collecting pockets 248, 249 can be open (close to the wall of the stent 206) and closed (bend towards the center of the lumen defined by the stent 206). Figure 2D also shows an optional wire or wires 210 for controlling activation of the debris collecting pockets 248, 249 in some embodiments.

[0158] 2D shows a debris capture device 244 in which the bases of leaves 248 are attached to the stent 206 with the free edges of leaves 248 facing downstream relative to the direction of fluid flow 202, and the bases of leaves 249 are attached to the stent 206 with the free edges of leaves 249 facing upstream relative to the direction of fluid flow 202. The two levels of leaves 248, 249 point in different directions with the free edges pointing away from each other.

[0159] 2F shows a debris capture device 254 including a stent 206 with leaves or debris traps or debris collecting pockets 258, 259 at two different levels relative to the direction of fluid flow 202 along the lumen defined by the stent 206. The leaves or debris traps or debris collecting pockets 258, 259 can be open (close to the wall of the stent 206) and closed (bend towards the center of the lumen defined by the stent 206).

[0160] FIG. 2F shows a debris capture device 254 with the bases of the leaves 258 , 259 attached to the stent 206 and with the free edges of the leaves 258 , 259 facing downstream relative to the direction of fluid flow 202 .

[0161] FIG. 2F is also intended to illustrate that the length of a leaf 258 at one level may not be equal to the length of a leaf 259 at another level.

[0162] As shown in Figures 2C to 2E, there may be more than one level of leaves.

[0163] In some embodiments, different levels of debris-trapping leaves or pockets may have different pore sizes in the mesh through which the leaves filter fluid and trap debris.

[0164] In some embodiments, the different pore sizes at the different levels are arranged such that the larger pore sizes are located upstream of the smaller pore sizes.

[0165] Potentially, one or more potential advantages may be realized by trapping different sizes of debris at different levels.

[0166] Debris of different sizes is trapped at different levels. When the debris trap is closed and the device is optionally removed from the patient's body, the debris can be distributed along different levels depending on the debris size, so that removal is of a longer, thinner device, less likely to potentially injure the patient.

[0167] Trapping smaller sized debris by filtering through smaller pore sizes can impede fluid flow, e.g., blood flow, and can have adverse effects on the patient. In some embodiments, smaller pore sizes can be used for the shortest possible time when maximum debris flooding is expected, and larger pore sizes can be used for longer periods of time to prevent larger debris particles from flowing downstream.

[0168] In some embodiments, the different pore sizes of the different traps are controlled separately, with larger pore size traps being controlled separately from smaller pore size traps.

[0169] In some embodiments, the different pore sizes at the different levels are controlled separately, with larger pore sizes being controlled separately from smaller pore sizes.

[0170] In some embodiments, during a medical procedure, a physician selects when and with which pore size traps to activate.

[0171] Reference is made to FIG. 3A, which is a simplified schematic diagram of a debris trapping device according to an exemplary embodiment.

[0172] FIG. 3A shows a debris capture device 302 including a stent 304 and debris capture leaves 306 that are open in an activated state.

[0173] FIG. 3A shows a cross section of a debris capture device 302 along a lumen defined by a stent 304, parallel to the direction of fluid flow or opposite to the direction of fluid flow.

[0174] FIG. 3A shows that in some embodiments, when the debris trapping leaves 306 are open, the entire cross-sectional area of ​​the debris trapping device 302 is covered.

[0175] In some embodiments, the debris capture leaves 306 are covered with a mesh having a pore size selected according to the size of debris that should not pass through the debris capture device 302 .

[0176] FIG. 3A also shows that a medical instrument can pass through the center 308 of the debris capture device 302, displacing the debris capture leaves 306, if desired.

[0177] In some embodiments, the debris capture leaves 306 are flexible and fit snugly against the medical device, continuing to filter fluid and providing filtration of a cross-sectional area around the medical device.

[0178] Reference is made to FIG. 3B, which is a simplified schematic diagram of a debris trapping device according to an exemplary embodiment.

[0179] FIG. 3B shows a debris capture device 312 including a stent 314 and debris capture leaves 316, 318 that are open in an activated state.

[0180] FIG. 3B shows a cross section of the debris capture device 312 parallel to the direction of fluid flow, either in the direction of fluid flow or opposite to the direction of fluid flow, along the lumen defined by the stent 314.

[0181] FIG. 3B shows that in some embodiments, when the debris trapping leaves 316, 318 are opened, the entire cross-sectional area of ​​the debris trapping device 312 is covered.

[0182] In some embodiments, the debris capture leaf 316 is covered by a mesh having a first pore size and the debris capture leaf 318 is covered by a mesh having a second, different pore size.

[0183] In some embodiments, it is sufficient for one group of debris trapping leaves (e.g. only debris trapping leaves 316 or only debris trapping leaves 318) to be open in order to cover the entire cross-sectional area of ​​the debris trapping device 312.

[0184] In some embodiments, debris trapping leaves with meshes of different hole sizes are optionally separately controllable: the debris trapping device 312 may be enabled with only a first hole size, or only a second hole size, or both hole sizes.

[0185] As a non-limiting example, a 200 micron hole size can optionally be used to protect downstream locations of the debris trapping device.

[0186] By way of non-limiting example, pore sizes of 100 microns or less, e.g., 30 microns, may optionally be used to protect locations downstream of the debris capture device in certain medical indications, such as protecting the kidneys in patients where the kidneys are at particular risk, protecting the liver in patients where the liver is at particular risk, protecting the pelvic organs in patients where the pelvic organs are at particular risk, protecting the lungs by preventing debris from entering the right ventricle of the heart and from there into the lungs in medical procedures on the extremities, pelvis, etc.

[0187] FIG. 3B also shows that a medical instrument can pass through the center of the debris capture device 312, pushing the debris capture leaves 316, 318 aside, if desired.

[0188] In some embodiments, one or more of the debris-trapping leaves 316, 318 are optionally controlled to change the pore size of the mesh of the debris-trapping leaves 316, 318. By way of non-limiting example, the debris-trapping leaves 316, 318 may optionally be lengthened, for example, by pulling on the free edge or tip of the debris-trapping leaf 316, 318. When the free edge or tip of the debris-trapping leaf 316, 318 is pulled and the leaf is stretched, the pores are reformed and smaller debris particles are optionally trapped by the debris-trapping leaf 316, 318.

[0189] Reference is made to Figures 4A-4C, which are simplified diagrammatic illustrations of one example embodiment of a debris trapping device.

[0190] FIG. 4A shows a debris capture device 402 having a stent 404 with leaves 406 or debris traps 406 or debris collecting pockets 406 .

[0191] FIG. 4A shows that the tips 408 of the leaves 406 optionally contact the medical implement 407 passing through the debris capture device 402 .

[0192] FIG. 4A also shows an exemplary direction of fluid flow 401.

[0193] In some embodiments, the debris-collecting pocket 406 optionally includes a marker that allows for detection of whether the debris trap is open or closed. In some embodiments, the marker is suitable for detection by various imaging modalities, such as x-ray and / or ultrasound and / or magnetic resonance imaging (MRI). In some embodiments, the marker is optionally located at the tip 408.

[0194] FIG. 4A shows one embodiment of a debris trap having a central leading edge 408 of the trap and a debris trap or debris pocket lip 409 that extends towards the wall of the stent 404 .

[0195] Figure 4B shows a portion of the debris capture device 402, including one wall of the stent 404 and one of the leaves 406. Figure 4B shows pockets 410 or debris traps 410 into which debris can flow with the fluid flow 401. The leaves 406 allow the fluid to pass through, trapping debris particles larger than the pore size of the mesh on the leaf in the pocket-like trap 410.

[0196] When the debris trapping device 402 is optionally disabled, the trap is closed and contains the debris trapped within the trap.

[0197] In some embodiments, the debris trapping device 402 is optionally removed from the patient's body along with the trapped debris.

[0198] 4C shows a cross section of the stent 404 and one of the debris trapping traps 410 of the debris trapping device 402. The debris trap 410 is shown open and extending towards the centre of the stent 404.

[0199] In some embodiments, the debris trap 410 may extend beyond the center of the stent 404, but is flexible enough to allow a medical device to push the debris trap 410 aside slightly to allow passage therethrough.

[0200] In some embodiments, when the multiple debris traps 410 are opened, the debris traps 410 optionally cover the entire cross section of the stent 404 and allow the medical device to pass through the debris traps 410 with only a slight push past them.

[0201] In some embodiments, the debris trapping traps 410 may extend to the center of the stent 404 or may not reach the center of the stent 404, and when some of the debris trapping traps 410 are opened, the debris trapping traps 410 optionally cover the entire cross section of the stent 404, allowing medical devices to pass through the debris trapping traps 410 with only a slight push past them.

[0202] FIG. 4C shows a view along the direction of fluid (eg, blood) flow, illustrating that debris flowing along the device is likely to be trapped by debris trap 410.

[0203] When the debris capture device 402 comprises multiple open debris traps 410 covering the entire cross section of the stent 404, Figures 4A-4C show that debris larger than the mesh pore size of the debris traps 410 will be captured by the debris traps 410.

[0204] When the debris capture device 402 comprises multiple open debris traps 410, even if the traps are displaced by the medical device, the debris mesh traps 410 cover the cross-sectional area of ​​the stent 404 that is not occupied by the medical device, and debris larger than the mesh pore size of the debris traps 410 is captured by the debris traps 410.

[0205] Reference is made to FIG. 5A, which is a photograph of a debris trapping device according to an exemplary embodiment.

[0206] FIG. 5A shows a debris capture device 500 comprising a stent 502 and leaves 504 or debris traps 504 or debris collecting pockets 504 .

[0207] FIG. 5A does not show the mesh covering the leaves 504.

[0208] 5A shows an optional narrowing end 506 of the debris capture device 500. The narrowing end 506 allows the debris capture device 500 to be pulled into a catheter for removal from a patient's body. The narrowing end 506 can potentially pull the device 500 into the catheter and aid in compressing the device as it enters the catheter.

[0209] In some embodiments, the debris trap 504 confines the debris that it has trapped as the device 500 is retracted into a catheter and removed from the body along with the trapped debris.

[0210] Reference is now made to FIG. 5B, which is a simplified diagram of a debris trapping device according to an exemplary embodiment.

[0211] FIG. 5B shows a debris capture device 510 comprising a stent 512 and leaves 514 or debris traps 514 or debris collecting pockets 514 .

[0212] FIG. 5B shows a mesh covering the leaf 514.

[0213] 5B shows an optional narrowing end 516 of the debris capture device 510. The narrowing end 516 allows the debris capture device 510 to be pulled into a catheter for removal from a patient's body. The narrowing end 516 can potentially pull the device 510 into the catheter and aid in compressing the device as it enters the catheter.

[0214] In some embodiments, the debris trap 514 confines the debris that it traps as the device 510 is retracted into a catheter and removed from the body along with the trapped debris.

[0215] Please refer to Figures 6A-6C, which are photographs of a debris trapping device according to an exemplary embodiment.

[0216] 6A-6C show a debris trapping device that is gradually enabled.

[0217] 6A-6C show a stent 602, a debris trap tip 604 or debris trapping leaf tip 604, a control wire guide 608, and a control wire 606 threaded through a loop in the tip 604. FIG.

[0218] FIG. 6A shows the leaf tips 604 in intimate contact with the stent 602 .

[0219] FIG. 6B shows wires 606 pulling leaf tips 604 together.

[0220] FIG. 6C shows wire 606 pulling on leaf tips 604 to completely close off the cross-section of the lumen defined by stent 602.

[0221] In some embodiments, the control wire guide 608 is optionally a lumen or pipe. In some embodiments, the control wire guide 608 is optionally constructed from nitinol or a polymer.

[0222] In some embodiments, there are one or more control wire guides 608. In the exemplary embodiment shown in Figures 6A-6C, two control wire guides 608 are shown.

[0223] In some embodiments, the number of control wire guides 608 is optionally an even number, for example, 2, 4, 6, 8, etc.

[0224] In some embodiments, the number of control wire guides 608 does not necessarily have to be an even number.

[0225] When the cross section of the lumen defined by the stent 602 is completely closed, all fluid flowing through the lumen must pass through the leaves. In embodiments where the leaves are covered with a mesh, all fluid flowing through the lumen must pass through the mesh.

[0226] A medical device can be passed through the lumen of the device. It will be apparent that a medical device can be passed through the lumen of the device when the leaves are tightly attached to the stent 602 or the cross section is partially closed. Note that the wire 606 can always be slightly loosened to allow a medical device to pass through and slightly tightened against the medical device to close it off.

[0227] Reference is now made to Figures 7A-7C, which are simplified illustrations of a debris capture device positioned in an aorta, according to an exemplary embodiment.

[0228] 7A shows a debris trapping device 704 optionally having one or more levels of debris traps 706. The debris trapping device 704 is optionally located in the descending aorta 702.

[0229] FIG. 7A also shows a medical instrument 708 or catheter 708 or control wire 708 for a medical instrument passing through the debris capture device 704, with the debris capture device 704 in an activated state, i.e., with the trap open and the leaves extending toward the middle of the descending aorta.

[0230] 7A shows a debris particle 707 trapped in a debris trap 706. Once the debris trap 706 is optionally closed, the trapped debris 707 can optionally be removed from the body along with the debris trapping device 704.

[0231] 7B shows pockets 714 formed by open trap edges 710 that extend toward the center 716 of the lumen defined by the debris capture device 704. Each trap has an opening 712 that allows debris to flow down into the pocket 714.

[0232] 7C shows a debris trapping device 704 optionally having one or more levels of debris traps 706. The debris trapping device 704 is optionally located in the descending aorta 702.

[0233] Figure 7C also shows a medical instrument 708 or catheter 708 or control wire 708 for a medical instrument passing through the debris capture device 704, with the debris capture device 704 in a disabled state, i.e., with the traps closed or collapsed and the leaves tightly against the walls of the debris capture device 704.

[0234] Reference is made to FIG. 7D, which is a simplified illustration of a debris capture device positioned in an aorta, according to an exemplary embodiment.

[0235] 7D shows a debris capture device 723 that includes a stent 724, a mesh wall 725, and optionally one or more levels of debris traps 726. The debris capture device is optionally located in the descending aorta 722.

[0236] FIG. 7D also shows a medical instrument 728 or catheter 728 or control wire 728 for the medical instrument passing through the debris capture device, with the debris capture device in an activated state, i.e., trap 726 is open and the leaves of trap 726 extend toward the center of stent 724.

[0237] 7D also shows a particle, indicated by an "X" 729, flowing downstream along the lumen defined by the stent 724. A portion of the particle 729 is shown inside the trap 726. Once the debris trap 726 is optionally closed, the trapped debris 729 can optionally be removed from the body along with the debris capture device 723.

[0238] In some embodiments, the mesh walls 725 of the debris capture device may be flexible enough that the mesh walls 725 bend inward toward the center of the stent 724 when fluid passes through the debris capture device.

[0239] Reference is made to FIG. 7E, which is a simplified illustration of a debris capture device positioned in an aorta, according to an exemplary embodiment.

[0240] 7E shows a debris capture device that includes a stent 744 and optionally has one or more levels of debris traps 746. The debris capture device is optionally located in the descending aorta 742.

[0241] 7E also shows a marker 742 attached to the debris trap 746. The marker 742 is selected to be opaque to one or more imaging modalities, allowing a physician to visualize whether the trap 746 is open or closed using one of the imaging modalities.

[0242] Reference is now made to FIG. 7F, which shows a simplified diagrammatic view of an aortic protection device deployed in conjunction with a debris trapping device, according to an exemplary embodiment of the present invention.

[0243] FIG. 7F shows an aortic protection device 752 (e.g., an aortic protection device such as those described in International Patent Application Publication No. WO 2019 / 064223 to Brandeis, supra) deployed in the aorta along with a debris trapping device 754, various embodiments of which are described herein.

[0244] 7F shows a debris trapping device 754 deployed within the lumen defined by the aortic protection device 752. Various other locations for the debris trapping device 754 may be selected, some non-limiting examples of which are listed below. Not within the lumen defined by the aortic protection device 752, but upstream of the aortic protection device 752. downstream of the aortic protection device 752, rather than within the lumen defined by the aortic protection device 752. Partly within the lumen defined by the aortic protection device 752 and partly upstream of the aortic protection device 752. Partly within the lumen defined by the aortic protection device 752 and partly downstream of the aortic protection device 752.

[0245] FIG. 7F shows a cross section of the aorta extending from the proximal heart 756 to the distal heart 758, including the aortic arch.

[0246] 7F shows an aortic protection device 752 within the aorta. The aortic protection device 752 includes a mesh 760 at the aortic arch and two optional wires 762, 764 attached to the mesh 760. The mesh 760 covers the arterial outlets of the brachiocephalic artery 765, the left common carotid artery 766, and the left subclavian artery 767.

[0247] The mesh 760 may prevent debris that flows with the blood in the aorta from entering the arteries.

[0248] Note that in some embodiments, mesh 760 may optionally extend more or less than shown in Figure 7F. As a non-limiting example, mesh 760 may extend much farther in the aorta distal to the heart to cover more of the arterial outlet from the aorta.

[0249] In some embodiments, the mesh 760 optionally has controlled porosity (e.g., controlled to vary from larger to smaller pore sizes) to better protect against debris entering the side branch arteries.

[0250] In some embodiments, mesh 760 is optionally controlled to vary its porosity to completely block blood flow into the side branch artery.

[0251] In some embodiments, optionally, the mesh 760 is controlled to change its porosity for a limited period of time, for example, a few seconds (e.g., 10 seconds, 30 seconds, 60 seconds, 90 seconds) or at most a few minutes (e.g., 2 minutes, 3 minutes, 4 minutes, 5 minutes).

[0252] In some embodiments, optionally, the mesh 760 is controlled to change its porosity and completely block blood flow into the side branch artery for a limited period of time, for example, a few seconds (e.g., 10, 30, 60, 90 seconds) or at most a few minutes (e.g., 2, 3, 4, 5 minutes).

[0253] In some embodiments, the debris trapping device 754 is placed in the aorta after placing the aortic protection device 752 in the aorta. By way of non-limiting example, the aortic protection device 752 is optionally positioned and expanded first, and the debris trapping device 754 is optionally inserted into the lumen defined by the aortic protection device 752, positioned, and deployed.

[0254] In some embodiments, by way of non-limiting example, if the debris trapping device 754 is located upstream or downstream of the aortic protection device 752, the insertion order and / or location and / or deployment of the devices may be independent of each other.

[0255] In some embodiments, the aortic protection device 752 and the debris trapping device 754 are optionally operated independently of each other.

[0256] In some embodiments, the aortic protection device 752 and / or the debris trapping device 754 are optionally enabled in connection with steps performed in a medical procedure performed elsewhere in the patient's body (e.g., a medical procedure performed on a heart valve, other part of the heart, or even upstream of the left side of the heart, or upstream of the right side of the heart).

[0257] Reference is now made to Figures 7G and 7H, which show simplified diagrammatic representations of a device including combined aortic protection and debris trapping, according to an exemplary embodiment of the present invention.

[0258] 7G and 7H, which show a device 770 including a locking portion 772, a stent-like lumen 773, a debris trapping portion 775, and an optional gradually narrowing end 776 of the device 770.

[0259] FIG. 7G is an isometric view of device 770, and FIG. 7H is a planar view of device 770.

[0260] In some embodiments, device 770 optionally includes a mesh 774 covering lumen 773. Optionally, mesh 774 acts to filter debris from entering branch arteries, as described, for example, in the aforementioned International Patent Application Publication No. WO 2019 / 064223 to Brandeis.

[0261] Reference is now made to Figures 7I and 7J, which are simplified diagrammatic illustrations of a device including a combination of aortic protection and two positions or levels of debris trapping, according to an exemplary embodiment of the present invention.

[0262] 7I and 7J, which show a device 780 including a locking / anchoring portion 782, a first debris trapping portion 783, a stent-like lumen 784, a second debris trapping portion 785, and an optional gradually narrowing end 786 of the device 780.

[0263] 7I is an isometric view of device 780, and FIG. 7J is a side view of device 780. FIG.

[0264] In some embodiments, device 780 optionally includes a mesh (not shown) covering stent-like lumen 784. Optionally, the mesh acts to filter debris from entering branch arteries, as described, for example, in the aforementioned International Patent Application Publication No. WO 2019 / 064223 to Brandeis.

[0265] In some embodiments, the first debris trapping portion 783 and the second debris trapping portion 785 optionally include a mesh for filtering the fluid and trapping debris.

[0266] In some embodiments, the first debris trapping portion 783 and the second debris trapping portion 785 optionally comprise meshes with holes of different sizes.

[0267] As a non-limiting example, in some embodiments, the pore size of the first debris trapping section 783 may optionally be 30 microns.

[0268] In some embodiments, the first debris trapping portion 783 may optionally be enabled separately from the enabling of the second debris trapping portion 785 .

[0269] In some embodiments, the first debris trapping section 783 may optionally be enabled during medical procedures known to result in large amounts of debris being released, for example, during the pace-up and / or pace-down phases of a TAVI procedure.

[0270] As a non-limiting example, in some embodiments, the pore size of the second debris trapping section 785 may optionally be 200 microns.

[0271] In some embodiments, the second debris trapping portion 785 may optionally be enabled for a longer period of time, for example because a mesh with pores larger than 30 microns creates a smaller pressure differential and the body may tolerate such a filter for a longer period of time.

[0272] In some embodiments, the stented lumen 784 may optionally be covered with a mesh to optionally block debris exiting laterally from the stented lumen 784 .

[0273] By way of non-limiting example, in some embodiments, the pore size of the optional mesh covering the stented lumen 784 may optionally be 120 microns.

[0274] As a non-limiting example, in some embodiments, the pore size of the optional mesh covering the stent-like lumen 784 may optionally be between the pore size of the first debris trapping portion 783 and the pore size of the second debris trapping portion 785.

[0275] In Figures 7I and 7J, Enabling and disabling the locking or locking action of the locking / locking portion 782; Enabling and disabling the debris trap of the first debris trap portion 783; Varying the mesh size of the optional mesh covering the stented lumen 784; Enabling and disabling the debris trap of the second debris trap section 785; and Pushing or pulling the optional narrowing end 786 of the device 780 to put the device in place and / or remove the device; Not shown are optional control wires that may be used to control one or more of the

[0276] Reference is made to FIG. 8, which is a simplified illustration of potential locations of a debris trapping device in the aorta, according to some exemplary embodiments.

[0277] FIG. 8 shows the aorta 802 and shows detailed portions of the aorta: the ascending aorta 806, the aortic arch 808, and the descending aorta 812, which includes the thoracic and abdominal aorta.

[0278] FIG. 8 also shows the location of the openings to the coronary arteries 804 and the openings to the arteries 810 leading to the brain (the brachiocephalic artery, the left common carotid artery, and the left subclavian artery).

[0279] FIG. 8 illustrates various potential locations that may be selected for placement of the debris trapping device, including a first location 816 in the ascending aorta 806, a second location 818 in the aortic arch 808, a third location 820 in the descending aorta 812, and a fourth location 822 further downstream in the thoracic or abdominal aorta.

[0280] In some embodiments, a debris trapping device is placed in the vein to prevent debris from reaching the lungs.

[0281] Reference is made to FIG. 9, which is a simplified illustration of potential locations of a debris trapping device within a vein, according to some exemplary embodiments.

[0282] 9 shows a vena cava 902 and a debris trapping device 904 located within the vena cava 902. The vena cava 902 collects blood from the veins into the right atrium of the heart 908. The heart pumps the blood to the lungs. If debris reaches the lungs, it can be very harmful.

[0283] In some embodiments, a debris trapping device 904 is placed in the vena cava 902 to block such debris.

[0284] In some embodiments, the debris trapping device 904 traps the debris and is eventually removed from the body along with the debris.

[0285] In some embodiments, the debris trap within the debris trapping device 904 is closed to contain the trapped debris before being removed from the body along with the debris.

[0286] In some embodiments, an anticoagulant is optionally administered to disrupt and / or dissolve thrombus trapped by the device before the device is removed from the body.

[0287] Below are described some non-limiting examples of how the debris trapping device can be used.

[0288] Reference is now made to FIG. 10, which is a simplified flowchart of a method for collecting debris in accordance with an exemplary embodiment.

[0289] Figure 10 shows Inserting (1002) a device into a body lumen for capturing debris from a fluid flow; locking the device (1004) so ​​that it is not moved downstream by fluid flow; controlling (1006) the opening of a mesh debris trap included in the device; and removing the device from the body along with the debris trapped in the debris trap (1008).

[0290] Reference is now made to FIG. 11, which is a simplified flowchart of a method for collecting debris during a cardiac procedure, according to an exemplary embodiment.

[0291] Figure 11 shows inserting a device (1102) into a location within the aorta to capture debris; Inserting a medical device for performing a cardiac procedure (1104); performing cardiac procedures (1106); and removing (1108) the debris trapping device from the body along with the debris trapped in the debris traps within the device.

[0292] Reference is now made to FIG. 12, which is a simplified flowchart of a method for preventing debris from reaching the lungs, according to one example embodiment.

[0293] Figure 12 shows inserting a device into an intravenous location for capturing debris (1202); controlling (1204) a debris trap in the device to open and collect debris from the vein; performing medical procedures (1206); and removing (1208) the device for capturing debris from the body.

[0294] It is expected that many related types of meshes will be developed during the life of the patent that matures from this application, and the scope of the term mesh is intended to pre-emptively include all such new technologies.

[0295] The terms "comprising," "including," "having," and conjugations thereof mean "including but not limited to."

[0296] The term "consisting of" means "including and limited to."

[0297] The term "consisting essentially of" means that a composition, method, or structure may include additional components, steps, and / or moieties, provided that the additional components, steps, and / or moieties do not materially alter the basic and novel characteristics of the claimed composition, method, or structure.

[0298] As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. For example, "a unit" or "at least one unit" includes plural units and can also include combinations thereof.

[0299] The words "example" and "exemplary" are used herein to mean "serving as an example, instance, or illustration." An embodiment described as "example" or "exemplary" is not necessarily to be construed as preferred or advantageous over other embodiments and / or does not necessarily exclude features of other embodiments from being incorporated.

[0300] "Optionally" is used herein to mean "provided in some embodiments and not provided in other embodiments." Any particular embodiment of the present disclosure may include multiple "optional" features unless those "optional" features contradict each other.

[0301] Throughout this application, various embodiments of the present disclosure may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and is not an inflexible limitation on the scope of the present disclosure. Thus, the description of a range should be considered to specifically disclose all of the possible subranges and individual numerical values ​​within that range. For example, description of a range such as 1 to 6 specifically discloses subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as individual numerical values ​​within that range, e.g., 1, 2, 3, 4, 5, and 6. This applies regardless of the magnitude of the range.

[0302] When a range of values ​​is provided herein (e.g., any pair of numbers connected by "10-15," "10 to 15," or other range designations), it is intended to include any number (fractional or integer) within the limits of the range provided, unless the context clearly dictates otherwise. The phrases "range between" a first designated number and a second designated number, and "range," "range to," "range to," or "range including" (or other similar range terminology) "from" a first designated number to a second designated number, are used interchangeably herein and are meant to include the first and second designated numbers and all fractional and integer values ​​therebetween.

[0303] Unless otherwise indicated, numbers used herein, and any numerical ranges based thereon, are approximations within the accuracy of reasonable measurement and rounding errors, as will be understood by one of ordinary skill in the art.

[0304] As used herein, the term "method" means manner, means, techniques, and procedures for accomplishing a given task, including, but not limited to, those known to practitioners in the fields of chemistry, pharmacology, biology, biochemistry, and medicine, or those that can be readily developed by practitioners from known manners, means, techniques, and procedures.

[0305] It should be understood that certain features of the present disclosure, which are for clarity described in the context of separate embodiments, may also be provided in any combination of these features in a single embodiment. Conversely, multiple features of the present disclosure, which are for brevity described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or with respect to other described embodiments as appropriate. A given feature described in the context of various embodiments should not be construed as essential to that embodiment, unless the particular embodiment is inoperable without that element.

[0306] While this disclosure has been described in conjunction with specific embodiments thereof, many alternatives, modifications, and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications, and variations that fall within the spirit and broad scope of the appended claims.

[0307] It is the intention of the applicants that all publications, patents, and patent applications mentioned in this specification be incorporated herein by reference in their entirety to the same extent as if each individual publication, patent, and patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application should not be construed as an admission that such reference is available as prior art to the present invention. Nor should it necessarily be construed as limiting, to the extent that section headings are used. In addition, the priority document of this application, if any, is incorporated herein by reference in its entirety.

Claims

1. 1. A device for capturing debris from a blood flow in an aorta, comprising: an expandable stent having a shape and size for expansion against a wall of a body lumen; a plurality of mesh debris traps attached to the stent; a control wire attached to one or more of the mesh debris traps and configured to control the opening of the mesh debris traps. device.

2. the expandable stent has a shape and size to expand against the wall of the aorta; The device of claim 1 .

3. the expandable stent has a shape and size to expand against the wall of the vena cava; 3. A device according to claim 1 or 2.

4. the control wire is sized to extend from a location of the device within the patient's body to an exterior of the patient's body. A device according to any one of claims 1 to 3.

5. the mesh debris trap is arranged to be opened and closed by the control wire from outside the patient's body. A device according to any one of claims 1 to 4.

6. At least some of the mesh debris traps are arranged to be opened and closed separately from at least some other mesh debris traps. A device according to any one of claims 1 to 5.

7. a plurality of control wires, each configured to control a separate group of said mesh debris traps; A device according to any one of claims 1 to 5.

8. the mesh debris trap is positioned in a normally closed state even when the device is expanded against the wall of the body lumen. A device according to any one of claims 1 to 5.

9. the mesh debris trap is configured to allow passage of a medical instrument through a tubular lumen defined by the interior of the device when the device is expanded against a wall of the body lumen; A device according to any one of claims 1 to 8.

10. the mesh debris trap comprises mesh leaves having bases attached to the stent wall and edges located upstream of the bases of the mesh leaves; A device according to any one of claims 1 to 9.

11. the mesh debris trap comprises mesh leaves having bases attached to the stent wall and edges downstream of the bases of the mesh leaves; A device according to any one of claims 1 to 9.

12. the mesh debris trap includes a marker that allows detecting whether the mesh debris trap is open or closed; A device according to any one of claims 1 to 11.

13. the mesh debris trap is positioned such that mesh debris trap openings are distributed at different distances along the direction of blood flow through the device; A device according to any one of claims 1 to 12.

14. the mesh debris trap comprises a mesh having a pore size ranging from 1000 microns to 30 microns; The device of claim 13.

15. the mesh debris trap openings distributed at different distances along the blood flow direction include mesh pore openings of different sizes; 15. A device according to claim 13 or 14.

16. the mesh debris traps are oriented longitudinally along the device such that, when open, the openings of the opened mesh debris traps overlap when viewed along the direction of blood flow.

15. A device according to claim 13 or 14.

17. the different sized mesh pore openings are arranged such that larger pore sizes are upstream of smaller pore sizes; 16. The device of claim 15.

18. the mesh debris trap openings at the same distance along the blood flow direction include mesh pore openings of different sizes; A device according to any one of claims 1 to 17.

19. the mesh debris trap opening comprises a loop for passing a control wire to open said mesh debris trap; A device according to any one of claims 1 to 18.

20. the mesh debris trap opening is flexible to allow a surgical instrument to bend through the mesh debris trap opening and pass along the device; A device according to any one of claims 1 to 19.

21. expansion of the stent against the wall of the body lumen anchors the device and resists migration in the direction of blood flow; A device according to any one of claims 1 to 18.

22. The device is anchored to resist movement along the direction of blood flow by being connected to an anchoring stent that is expanded against the lumen wall upstream of the device. A device according to any one of claims 1 to 21.

23. The anchoring stent has a shape and size for anchoring upstream of the brachiocephalic trunk.

23. The device of claim 22.

24. The anchoring stent has a shape and size for anchoring upstream of the carotid artery.

23. The device of claim 22.

25. The device is configured to be attached to an aortic protection device. A device according to any one of claims 1 to 24.

26. The device is configured as part of an aortic protection device. A device according to any one of claims 1 to 24.

27. 1. A method for collecting debris, comprising: inserting a device into a body lumen for capturing debris from a fluid flow; locking the device from being moved downstream by the fluid flow; controlling the opening of a mesh debris trap included in the device; removing the device from the body along with debris trapped in the mesh debris trap; A method comprising:

28. The body lumen is a blood vessel.

28. The method of claim 27.

29. The blood vessel is an artery.

29. The method of claim 28.

30. The artery is the aorta.

30. The method of claim 29.

31. further comprising inserting an instrument along the device and upstream of the device for performing a cardiac procedure.

31. The method of claim 30.

32. further comprising performing a cardiac procedure after opening the mesh debris trap.

30. The method of claim 29.

33. The device is used in addition to the use of an aortic protection device.

33. The method according to any one of claims 27 to 32.

34. The blood vessel is a vein.

29. The method of claim 28.

35. The method is performed on a patient prior to a medical procedure that is expected to release debris into a vein or that is expected to generate debris in a vein.

35. The method of claim 34.

36. further comprising closing the mesh debris trap before removing the device from the body. The method according to any one of claims 27 to 35.

37. and closing the mesh debris trap occurs after performing a cardiac procedure.

37. The method of claim 36.

38. opening the mesh debris traps includes controlling only a subgroup of the mesh debris traps; The method according to any one of claims 27 to 36.

39. 1. A method of collecting debris during a cardiac procedure, comprising: inserting a device into a location within the aorta to capture debris; inserting a medical instrument to perform a cardiac procedure; performing the cardiac procedure; removing the device for trapping debris from the body along with the debris trapped in a debris trap within the device; A method comprising:

40. the debris trap within the device is controlled to close prior to the removing; 40. The method of claim 39.

41. The debris trap within the device is controlled to be released prior to performing the cardiac procedure.

41. The method according to any one of claims 39 to 40.

42. The cardiac procedure comprises: electrophysiological procedures, patent foramen ovale (PFO) procedures, Heart valve repair, open heart surgery, Percutaneous Aortic Valve Replacement (PAVR), Percutaneous Aortic Valve Implantation (PAVI), Transcatheter Aortic Valve Implantation (TAVI), and Transcatheter Aortic Valve Replacement (TAVR) a cardiac procedure selected from the group consisting of 42. The method according to any one of claims 39 to 41.

43. The debris trap within the device comprises: Aneurysm procedures, Arteriosclerosis stent procedure, Balloon dilation procedure, drug delivery techniques, kidney procedures, Surgical procedures involving the treatment of arteries, and Atheromatous aortic treatment controlled to be released after or during the procedure selected from the group consisting of 43. The method according to any one of claims 39 to 42.

44. the cardiac procedure includes a pace-up step; A cardiac procedure debris trap within the device is controlled to be released after the pace-up step.

44. The method according to any one of claims 39 to 43.

45. the cardiac procedure includes a pace-down step; A cardiac procedure debris trap within the device is controlled to be released after the pace-down step.

45. The method according to any one of claims 39 to 44.

46. 1. A method for preventing debris from reaching the lungs, comprising: inserting a device into an intravenous location to capture debris; controlling a debris trap in the device to open and collect debris from the vein; Carrying out medical procedures; removing the debris capturing device from the body; A method comprising:

47. Prior to removing the device, the debris trap is controlled to be closed.

47. The method of claim 46.

48. The removing includes removing together with debris trapped in a debris trap within the device.

48. The method of claim 46 or 47.

49. further comprising administering an anticoagulant prior to said removing.

49. The method according to any one of claims 46 to 48.

50. The debris trap within the device comprises: kidney procedures, aneurysm procedures, damage, open lesions, Disconnection, Damage in disaster situations, traumatic injuries, blunt trauma injuries, medical procedures, including cardiac support; medical procedures, including pulmonary support; medical procedures, including extracorporeal membrane oxygenation (ECMO); Open surgery, and Pressure damage controlled to be released after or during treatment selected from the group consisting of 50. The method of any one of claims 46 to 49.

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