阅读说明：本技术 可动态重新配置的微阀保护装置 (Dynamically reconfigurable microvalve protection device ) 是由 B.平楚克 J.E.乔马斯 D.B.亚罗赫 于 2018-03-13 设计创作，主要内容包括：在治疗过程中用于在血管中使用的血管内微阀装置,包括导管和联接到导管的过滤器阀。过滤器阀可动态地重新配置,以基于过滤器阀周围的局部流体压力条件自动地阻止以及允许流体流动通过血管。在实施例中,过滤器阀具有固定到导管的近侧端部、和可以在导管之上可移动的远侧端部。内导管的管腔将治疗剂递送超过阀。该装置用于提供其中将治疗剂灌注到器官中的治疗。(An intravascular microvalve device for use in a blood vessel during treatment includes a catheter and a filter valve coupled to the catheter. The filter valve may be dynamically reconfigured to automatically block and allow fluid flow through the blood vessel based on local fluid pressure conditions surrounding the filter valve. In an embodiment, the filter valve has a proximal end fixed to the catheter, and a distal end movable over the catheter. The lumen of the inner catheter delivers the therapeutic agent beyond the valve. The device is used to provide a treatment in which a therapeutic agent is perfused into an organ.)

1. An intravascular microvalve device for temporary use within a blood vessel of a patient during an intravascular procedure, the blood vessel having a blood vessel wall, the microvalve device comprising:

a) a flexible catheter sized for introduction into the blood vessel, the catheter having proximal and distal ends, an outer surface, a lumen extending between the proximal and distal ends, and an opening at a distal port; and

b) a filter valve having a proximal end and a distal end, said filter valve comprising a plurality of filamentary strands, each said strand having a proximal portion, a middle portion, and a distal portion, said proximal portion of said strand being secured to said outer surface of said catheter at a location proximal to said orifice, said middle portion of said strand extending radially outward from said outer surface and toward said orifice, and said distal portion of said strand being inverted relative to said middle portion and back to said outer surface of said catheter, said distal portion being coupled to said outer surface of said catheter,

wherein the filter valve is dynamically movable in accordance with local fluid pressure conditions surrounding the filter valve once the filter valve is in a deployed state in the blood vessel such that,

when fluid pressure is higher on a proximal side of the filter valve, the filter valve assumes a first configuration having a first diameter that is smaller than a diameter of the blood vessel such that flow is permitted through the blood vessel in a proximal-to-distal direction around the filter valve, and

when the fluid pressure is higher on a distal side of the filter valve, the filter valve assumes a second configuration having a second diameter that is relatively larger than the first diameter, and in which the filter valve is adapted to contact the blood vessel wall to act as a barrier to flow through the blood vessel in a distal-to-proximal direction around the filter valve.

2. The device of claim 1, wherein the distal portion of the strand is secured to the outer surface of the catheter.

3. The device of claim 1, wherein the distal portion of the strand is movably retained around the outer surface of the catheter.

4. The device of claim 1, wherein the filter valve comprises a porous polymeric material over a proximal portion of the filter valve.

5. The device of claim 4, wherein the filter valve comprises a porous polymeric material over a distal portion of the filter valve.

Technical Field

The present invention relates generally to valves for performing medical embolization therapy, and in particular to a valve that increases the penetration of a treatment agent into a target vessel and reduces the backflow of the treatment agent into non-target vessels.

Background

Embolization, chemoembolization, and radioactive embolization therapies are commonly used clinically to treat a range of diseases such as multiple vascular liver tumors, uterine fibroids, secondary cancer metastases in the liver, pre-operative treatment of multiple vascular meningeal tumors in the brain, and bronchial artery embolization for the treatment of hemoptysis. The embolic agent may be embodied in different forms, such as beads, liquid, foam, or gel placed in the arterial vasculature. The beads may be uncoated or coated. In the case of bead coating, the coating may be a chemotherapeutic agent, a radioactive agent, or other therapeutic agent. When it is desired to embolize small blood vessels, small bead sizes (e.g., 10 μm-100 μm) are used. When larger vessels are to be embolized, a larger bead size (e.g., 100 μm-900 μm) is typically selected.

While minimally invasive or limited invasive embolic treatment has generally been considered to provide good results, it has a small incidence of non-targeted embolization that can lead to adverse events and morbidity. Perfusion with perfusion microcatheters allows for bi-directional flow. That is, the use of a microcatheter to infuse an embolic agent allows not only the blood and the infused embolic agent to move forward, but also the blood and the embolic agent to be pushed back (regurgitated). The reflux of the therapeutic agent results in non-targeted damage to the surrounding healthy organs. In interventional tumor embolization procedures, the goal is to bombard cancer tumors with radiation or chemotherapy. It is important to maintain forward flow throughout the entire vascular tree in the target organ in order to deliver the treatment into the distal vasculature where it may be most effective. This problem is magnified in patients with a low blood supply tumor or who have undergone chemotherapy, where slow flow limits the dose of therapeutic agent delivered, and reflux of therapeutic agent to non-target tissues can occur well before the physician has delivered the desired dose.

During the embolic perfusion process, the pressure in the blood vessel changes at multiple locations in the vascular tree. Initially, the pressure is high at the proximal side and decreases over the length of the vessel. When there is a pressure drop, forward flow of the treatment occurs. If there is no pressure drop across a section of the vessel, the treatment will not flow downstream. If there is a higher pressure at one location, such as at the orifice of the catheter, the embolic therapy flows in a direction toward the lower pressure. If the pressure generated at the orifice of the perfusion catheter is greater than the pressure in the vessel proximal to the catheter orifice, some portion of the perfused embolic treatment travels upstream (regurgitation) into the non-target vessel and non-target organs. This phenomenon can even occur in vessels with strong forward flow if the perfusion pressure (the pressure at the catheter orifice) is high enough.

During the embolization procedure, the embolizing agent occludes the distal blood vessel and prevents fluid from draining into the capillary system. This results in an increase in pressure in the distal vasculature. As the pressure increases, the pressure gradient decreases and, thus, flow slows or stops in the distal vasculature. Later in the embolization procedure, the larger vessel becomes embolized and the pressure increases proximally until there is a system that effectively has a constant pressure throughout the system. The effect is that flow is slow even in larger vessels and distal embolic agent no longer advances into the target (tumor).

In current clinical practice with perfusion catheters, physicians attempt to perfuse emboli at pressures that do not cause reflux. In doing so, the physician slows the perfusion rate (and perfusion pressure) or stops perfusion altogether. The clinical impact of current perfusion catheters and techniques is twofold: low dose of therapeutic emboli delivered, and distal malabsorption into the target vessel.

Furthermore, backflow can be a time sensitive phenomenon. Sometimes, reflux occurs as a reaction to the injection of the embolic agent, where reflux occurs quickly (e.g., on a millisecond timescale) in a manner that is too fast for a human operator to react. Furthermore, reflux may occur briefly, followed by a temporary restoration of forward flow in the vessel, however additional reflux occurs thereafter.

Fig. 1 shows a conventional (prior art) embolization treatment in a hepatic artery 106. The catheter 101 delivers an embolic agent (bead) 102 in the hepatic artery 106 for the purpose of embolizing the target organ 103. It is important to maintain forward flow of blood (directional arrow 107) during perfusion of the embolic agent 102, as forward flow serves to carry the embolic agent 102 deep into the vascular bed of the target organ 103.

The injection of the embolic agent 102 is continued until a backflow of the contrast agent is visible in the distal region of the hepatic artery. Typically, since the embolic agent 102 is rarely directly visible, a contrast agent may be added to the embolic agent 102. The addition of contrast agent allows the backflow of contrast agent (shown by arrow 108) to be visible, which indicates backflow of embolic agent 102. Reflux may undesirably cause the embolic agent 102 to be delivered into the auxiliary artery 105 proximal to the end of the catheter 101. The presence of the embolic agent 102 in the secondary artery 105 causes non-target embolization in a non-target organ 104, which non-target organ 104 may be another lobe of the liver, the stomach, the small intestine, the pancreas, the gall bladder, or other organ.

Non-targeted delivery of embolic agents can have significant adverse effects on the human body. For example, in liver therapy, non-targeted delivery of embolic agents can have undesirable effects on other organs including the stomach and small intestine. In uterine fibroid treatment, non-targeted delivery of embolic agents may embolize one or both ovaries, resulting in loss of menstrual cycle, minor ovarian damage that may reduce fertility, premature menopause, and in some cases, significant damage to the ovaries. Other unexpected adverse events include unilateral deep hip pain, hip necrosis, and uterine necrosis.

Typically, interventional radiologists attempt to reduce the amount of reflux and the effects of reflux by slowly releasing the embolic agent and/or by delivering a reduced dose. The additional time, complexity, increased X-ray dose to the patient and physician (longer monitoring of the patient), and the possibility of reduced efficacy make slow delivery of embolic agents suboptimal. Moreover, reducing the dose often results in the need for multiple subsequent treatments. Even when the physician views a reduction in the amount of reflux, the local flow conditions at the tip of the catheter change too quickly for the physician to control, and thus a fast transient reflux condition can occur throughout the perfusion process.

U.S. patent No. 8,696,698, previously incorporated herein, describes a microvalve infusion system for infusing embolic agents to a treatment site in a manner that overcomes many of the previously noted problems of infusion using infusion catheters alone. Referring to prior art fig. 2A and 2B, a microvalve perfusion system 200 includes a dynamically adjustable filter valve 202 coupled to a distal end of a delivery catheter 204. The delivery conduit and filter valve extend within the outer conduit 206. The filter valve 202 is naturally spring biased by the configuration of its filamentary element 208 to automatically partially expand within the blood vessel as the filter valve 202 is deployed from the outer catheter 206; and the filter valve 202 is coated with a polymer coating 210 having a pore size suitable for filtering the embolic therapeutic agent. More specifically, the filter valve 202 has an open distal end 212 and is coupled relative to the delivery catheter 204 such that embolic agent that perfuses through the delivery catheter 204 and exits from a distal orifice 214 of the delivery catheter 204 flows out within an interior 216 of the filter valve. In view of this configuration, upon perfusion, an increase in fluid pressure within the filter valve results and causes the filter valve 202 to open, extend across the blood vessel, and thereby prevent backflow of the perfused embolic agent. In addition, when the fluid is pressurized through the delivery catheter and into the filter valve, the downstream pressure in the blood vessel increases, which facilitates maximizing the uptake of the therapeutic delivery agent into the target tissue. Furthermore, the filter valve is responsive to local pressure around the valve, which thereby enables substantially unrestricted forward flow of blood in the vessel, and reduces or stops backflow (backflow or backward flow) of embolic agent introduced into the blood.

However, the device of U.S. patent No. 8,696,698 has certain problems, which may not always be advantageous. In many of the disclosed figures 44, the device is shown with a large distal diameter, which limits tracking ability in tortuous branch vasculature. The distal end of the device in the collapsed, undeployed state is defined by the dimensions of the outer catheter 206, and the dimensions of the outer catheter 206 can be significantly larger than the outer diameter of the delivery catheter 204 supporting the filter valve 202, and significantly larger than the outer diameter of a guidewire (not shown) used to guide the microvalve to a target location within a blood vessel. Therefore, tracking the filter valve into the smaller vessel branch does not have the desired reliability. In addition, once the device is tracked to the treatment site, the deployment of the filter valve needs to overcome the friction between the filter valve and the outer catheter. Overcoming such forces can potentially wear the polymer coating on the filter valve. Improvements to this design are provided in other figures disclosed in U.S. patent No. 8,696,698 such that the outer diameter dimension of the distal aspect of the device is reduced to a manner that would facilitate tracking. However, once any of the embodiments of the filter valve 202 in U.S. patent No. 8,696,698 are shown in the open configuration, they assume an open frustoconical shape, which allows the backflow of therapeutic embolic agent to enter the valve. This can result in retention of the therapeutic agent in the filter valve, particularly under conditions of slow forward flow within the blood vessel, which can potentially result in incomplete administration.

Disclosure of Invention

A perfusion device is provided that includes an outer catheter, and an inner perfusion catheter extending through the outer catheter, and a dynamically adjustable filter valve coupled to both the outer catheter and the inner catheter. The filter valve is formed of a natural spring-biased filamentary construction biased to radially expand and having a proximal end and a distal end. A proximal end of the filter valve is coupled to the distal end of the outer catheter, and a distal end of the filter valve is coupled to the distal end of the inner catheter. The filter valve has a closed filtering distal portion, wherein the proximal and distal portions of the valve are separated by a circumference around a maximum diameter of the filter valve. The internal infusion catheter is configured to deliver a therapeutic embolic agent distal to the closed distal portion of the filter valve.

The filter valve can be manually displaced between the open and closed configurations by longitudinally displacing the distal end of the inner catheter relative to the distal end of the outer catheter. By distally displacing the inner catheter relative to the outer catheter, the filter valve is moved into a stowed configuration suitable for delivery to a treatment site. In the collapsed configuration, the tip is tapered and assumes a form that has excellent tracking capabilities along a guidewire to be advanced to a treatment site. To deploy the filter valve, the inner catheter is retracted relative to the outer catheter to cause the filter valve to reconfigure, resulting in radial expansion toward the vessel wall. In addition, the spring bias of the valve also acts to radially expand the filter valve, particularly when a pressure differential is experienced on opposite sides of the filter valve. In a preferred aspect of the invention, the proximal portion of the filter valve has a different radial expansion force than the distal portion of the filter valve. More preferably, the proximal portion has a substantially greater radial expansion force than the distal portion. Once the filter valve is in the deployed, open configuration, i.e., with the distal tip in the retracted position relative to the delivery position, the filter valve dynamically responds to the local pressure surrounding the filter valve. During dynamic response operation, substantially unrestricted forward flow of blood in the blood vessel is permitted while preventing reverse flow to prevent backflow of the therapeutic agent within the blood vessel.

When the infusion set is retracted at the end of the procedure, the inner catheter may be further retracted into the outer catheter (such that the filter valve is substantially inverted and received within the outer catheter) to thereby capture and contain any therapeutic agent remaining on the filter valve.

Drawings

Prior art FIG. 1 shows a conventional embolization catheter in a hepatic artery, with embolization agent regurgitated into non-target organs.

Prior art FIGS. 2A and 2B are schematic views of a prior art filter valve apparatus, shown in an undeployed configuration and a deployed configuration, respectively.

Fig. 3A and 3B are schematic views of an exemplary embodiment of a therapeutic filter valve device in a deployed state and an undeployed state, respectively.

Fig. 4 is a schematic illustration of the distal end shape of the deployed filter valve device.

Fig. 5 is a schematic view of another shape of the distal end of the deployed filter valve device.

Fig. 6A-6D are exploded schematic views of the exemplary embodiment of the filter valve device of fig. 3A and 3B in use, with the distal end of the illustrated device positioned within a blood vessel.

Fig. 7 is a perspective distal end view of the distal end of the filter valve device in a deployed configuration.

Fig. 8A-8C are schematic views of the distal end of the filter valve device in an undeployed and deployed configuration, indicating the respective positions of the radiopaque marker bands.

FIG. 9 is a graph indicating variable pressure control distal to the filter valve device.

Fig. 10A-10C are schematic views of a deployed filter valve device using variable pressure control to selectively perfuse a main vessel and a branch vessel.

Fig. 11 is a schematic distal end view of an alternative coating configuration for a filter valve device.

Fig. 12 is a schematic distal end view of another coating configuration for a filter valve device.

Fig. 13 is a schematic distal end view of yet another alternative coating configuration for a filter valve device.

Fig. 14 is a schematic distal end view of a braid angle configuration for any of the filter valve devices.

Fig. 15 is a schematic distal end view of another configuration for a filter valve device.

Fig. 16 is a schematic distal end view of yet another configuration for a filter valve device.

Fig. 17A-17C are schematic views of a distal end for yet another configuration of a filter valve apparatus in undeployed, partially deployed, and fully deployed configurations.

Fig. 18 is a distal end view of the filter valve device of fig. 17A-17C illustrating one arrangement of wires in the distal portion of the filter valve.

Fig. 19 is a distal end view of the filter valve device showing an alternative arrangement of wires in the distal portion of the filter valve.

Fig. 20 is a schematic view of another embodiment of a therapeutic filter valve device in a state ready for introduction into a patient.

Fig. 21 is a schematic view of the therapeutic filter valve device of fig. 20 collapsed within an introducer sleeve for deployment into a patient.

Fig. 22 is a schematic view of the device of fig. 20 deployed within a blood vessel.

Fig. 23 is a schematic view of the device of fig. 20 deployed within a vessel and dynamically reconfigured when subjected to relatively high pressures at its distal portion resulting from perfusion of perfusate through the device under pressure.

Fig. 24 is a schematic view of another embodiment of a therapeutic filter valve device in a state prior to being ready for introduction into a patient.

Fig. 24A is a schematic view of the device of fig. 24 collapsed within an introducer sleeve for deployment into a patient.

Fig. 25 is a schematic view of the device of fig. 24 deployed within a blood vessel.

FIG. 26 is a schematic view of the device of FIG. 24 deployed within a vessel and dynamically reconfigured when its distal portion is subjected to relatively high pressures resulting from perfusion of perfusate through the device under pressure.

Fig. 27 is a schematic view of another embodiment of a therapeutic filter valve device.

Fig. 28 is a schematic view of another embodiment of a therapeutic filter valve device in a state ready for introduction into a patient.

Fig. 29 and 30 are schematic illustrations of alternative configurations of the device of fig. 28 deployed within a blood vessel.

Fig. 31 is a schematic view of the device of fig. 28 perfusing an perfusate at a target location.

Detailed Description

The terms "proximal" and "distal" are defined in terms of a user's hand with reference to the human body and components of the devices and systems described herein that are intended to be operated by the hand of the user. Wherein, unless an alternative definition is specifically provided, the term "proximal" is closer to the user's hand and the term "distal" is farther from the user's hand.

A first exemplary embodiment of a microvalve device 300 according to the present invention is seen in fig. 3A and 3B. It should be noted that the corresponding portions of the system illustrated in fig. 3A and 3B are not shown in proportion to their intended dimensions, but rather the distal portions are shown greatly enlarged for purposes of explanation. (other embodiments herein are similarly illustrated with a significantly enlarged distal portion for purposes of explanation.) as shown in FIG. 3A, the apparatus 300 includes: a flexible outer catheter 302 having a proximal end 304 and a distal end 306; a flexible inner delivery catheter 308 extending through the outer catheter 304 and longitudinally displaceable relative to the outer catheter 304, and having a proximal end 310 and a distal end 312; and a filter valve 314 coupled to the distal ends 306, 312 of the outer and inner catheters 304, 308. The proximal end 310 of the inner catheter is preferably mounted to the hub 316 with a rigid tubular coupling member 318. The tubular coupling member 318 is preferably a stainless steel hypotube or similar structure. An infusion lumen 320 is defined through the distal end 312 of the inner catheter from the hub 316 and is adapted to deliver a therapeutic agent including an embolic agent from outside the patient's body (not shown) into a target vessel (artery or vein) of the patient. The proximal end 304 of the outer catheter 302 preferably includes a sidearm port 322, the sidearm port 322 being in fluid communication with an annulus 324 and for flushing the filter valve annulus 324, the annulus 324 being formed between the inner catheter 304 and the outer catheter 308 and extending into the interior of the filter valve 314. Such as flushing such space with a lubricant comprising saline, acts to reduce friction between the inner and outer catheters to facilitate longitudinal movement therebetween.

A first radiopaque marker band 326 is provided at the distal end 312 of the inner catheter 308 and a second, preferably larger, radiopaque marker band 328 is provided at the distal end 306 of the outer catheter 302. A third radiopaque marker band 330 is provided to the inner catheter 308 in a defined positional relationship relative to the second marker band 328. For example, the third marker band 330 may be co-longitudinally positioned with the second marker band 328 when the inner catheter 308 and the outer catheter 302 are positioned such that the filter valve 314 is in the deployed configuration, as shown in fig. 3A and discussed below. Fig. 3B illustrates the microvalve device 300 in an undeployed configuration and the relative positioning of the three marker bands 326, 328, 330. During use of the device 300, the relative in vivo positions of the marker bands 326, 328, 330, as observed by fluoroscopy, indicate the displacement of the distal ends 306, 312 of the inner and outer catheters and the resulting configuration of the filter valve, as discussed in more detail below.

A handle 332 is optionally provided at or adjacent the proximal end of the inner catheter 308 and the outer catheter 302 (including the tubular coupling member 318) to controllably longitudinally displace the inner and outer catheters relative to one another. By way of example only, the handle 322 may include a standard slider assembly, e.g., in the form of a spool (spool) and shaft, that translates a user's manual longitudinal movement into a desired and controlled longitudinal displacement between the inner and outer catheters. As yet another alternative, the handle may include a knob 334 connected to the lead screw that translates the user's manual rotational movement into a desired and controlled longitudinal displacement between the distal ends of the inner and outer catheters, such as shown by arrow 336 (fig. 3B).

The inner conduit 308 is between 2 and 8 feet in length and has an outer diameter between 0.67 and 3mm (corresponding to conduit dimensions 2 to 9 French) and is made of: a liner made of fluorinated polymer such as Polytetrafluoroethylene (PTFE) or Fluorinated Ethylene Propylene (FEP); a braid made of metal such as stainless steel or titanium, or polymer such as polyethylene terephthalate (PET) or liquid crystal polymer; and an outer coating made of polyether block amide thermoplastic elastomer resin such as PEBAX ®, polyurethane, polyamide copolymer, polyester copolymer, fluorinated polymers such as PTFE, FEP, polyimide, polycarbonate, or any other suitable material; or any other standard or special material used in the manufacture of catheters for use in the bloodstream.

The outer catheter 302 comprises polyurethane, polyamide copolymer, polyester copolymer, fluorinated polymers such as PTFE, FEP, polyimide, polycarbonate, or any other suitable material. The outer catheter 302 may also comprise a braid composed of a metal such as stainless steel or titanium, or a polymer such as PET or liquid crystal polymer, or any other suitable material. The wall thickness of the outer catheter 302 is preferably in the range of 0.05mm to 0.25mm, with a more preferred thickness of 0.1mm to 0.15 mm.

The distal end 340 of the filter valve 314 is fused or otherwise fixedly coupled (longitudinally fixed and rotationally fixed) adjacent the distal end 312 of the inner catheter 308 but preferably slightly displaced proximally from the distal end 312 of the inner catheter 308; and the proximal end 342 of the filter valve is fused or otherwise coupled at or adjacent the distal end 306 of the outer catheter 302.

The filter valve 314 is constructed of one, two or more metals (e.g., stainless steel or nickel titanium alloy (Nitinol)) or polymer wires 350 that form a generally closed shape when deployed and when not subjected to external forces. Where polymer filaments are utilized, filaments 350 may be composed of PET, polyethylene naphthalate (PEN), liquid crystal polymers, fluorinated polymers, nylon, polyamide, or any other suitable polymer. If desired, when polymer filaments are utilized, one or more metal filaments may be utilized in conjunction with the polymer filaments. In the case of a wire, it may be a radiopaque material to facilitate tracking of the filter valve 314 and the configuration of the filter valve 314 in vivo, in accordance with an aspect of the present invention. In the deployed expanded diameter configuration, the shape of the filter valve 314 can be changed by fluid forces. Preferably, the wire 350 is not bonded to each between its ends, thereby enabling the valve to automatically open and close quickly in response to dynamic flow conditions. The plurality of wires 350 of the filter valve are preferably braided and are capable of movement relative to each other between the ends thereof. As discussed below, the wires are spring biased (i.e., they have a "shape memory") to assume a desired angle of intersection relative to each other, enabling the valve to self-assume a desired shape.

In the device shown in fig. 3A, the shape presented is generally spherical, although as described below, the shape may be generally frustoconical. (for purposes herein, the term "generally spherical" should be understood to include not only spherical shapes but also generally circular shapes including spherical portions, or circular rectangles 314a such as shown in FIG. 4, or portions thereof. for purposes herein, the term "generally frustoconical" should be understood to include not only generally frustoconical shapes, but also truncated hyperboloids, truncated parabolas, and any other shape 314b that begins at the circular proximal end 342b at the distal end 306 of the outer catheter 302, diverges therefrom, and returns to closed at the distal end 340b of the filter valve adjacent the distal end 312 of the inner catheter 308, as shown in FIG. 5). In all embodiments, the shape of the filter valve 314 is closed at or adjacent the respective ends 306, 312 of the outer and inner conduits 302, 308 and may be defined by a proximal hemispherical portion 346 and a distal hemispherical portion 348, or by two tapered portions, or by a proximal spherical portion and a distal tapered portion, or by a proximal tapered portion and a distal spherical portion, or by any of the aforementioned shapes having intervening shape portions therebetween, which preferably join together at the maximum diameter ends of the respective portions. As such, it can be appreciated that the proximal and distal portions 346, 348 of the filter valve 314 are not required to be longitudinally symmetric in configuration and may be asymmetric, as is evident in the undeployed configuration of the filter valve 314 shown in fig. 3B. The joined proximal and distal portions may each have filaments oriented at different braid angles, as discussed below. In addition, the proximal and distal portions may be mechanically joined via the ends of the wire, or joined by a filter material, as will be discussed in more detail below.

The filter valve 314 is designed to be manually reconfigured between an undeployed configuration and a deployed configuration by movement of the inner and outer catheters relative to each other, wherein in each of the undeployed and deployed configurations, the distal end of the filter valve extends outside and distally of the distal end of the outer catheter. As shown in fig. 3B and 6A, in the undeployed configuration, the filter valve 314 is provided with a smaller maximum diameter suitable for tracking the device over a guidewire 360 (fig. 6A) through a blood vessel 362 to a treatment site. The inner catheter 308 is displaced distally (in the direction of arrow 380) relative to the outer catheter 302 to stretch or otherwise cause the filter valve to assume an elongated configuration with a tapered tip that facilitates trackability over the guidewire 360. In this collapsed, undeployed configuration, the inner catheter 308 is preferably pushed as distally as possible relative to the outer catheter 302. In a preferred embodiment, the unexpanded, elongated configuration of the filter valve tapers distally over at least 50%, preferably at least 75% of its length.

Then, referring to fig. 6B, once the filter valve is positioned at the treatment site in the blood vessel 362, the inner catheter 308 can be retracted (in the direction of arrow 382) relative to the outer catheter 302 to expand the filter valve 314 and cause the filter valve to assume a (initially) partially deployed configuration within the blood vessel in which the filter valve does not form a seal against the blood vessel wall 362. In this configuration, it is possible for both upstream and downstream fluid flow through the filter valve based on the relative fluid pressures at the proximal and distal sides of the filter valve. Alternatively or thereafter, as shown in fig. 6C, the inner catheter 308 may be retracted further (as indicated by arrow 384) relative to the outer catheter 302 to more fully expand the filter valve 314 to form a seal against the vessel wall 362. This configuration of the filter valve 314 is also shown in fig. 7. When retracted into the configuration shown in fig. 6B, the proximal end of filter valve 314 forms a distally facing planar or concave surface 368 (in this regard, it is understood that a distally facing convex or convex conical surface is present in the undeployed configuration of the filter valve); while the proximally facing surface remains unchanged in shape and is generally a smooth convex surface. Then, with the filter valve deployed, embolic 388 is delivered under pressure distally through and out of the inner catheter, distally to the filter valve and into the blood vessel. Delivering embolic agent in this manner will result in a downstream pressure change that initially results in a higher pressure distal to the filter valve than upstream of the filter valve, thereby quickly sealing to the vessel wall and directing all perfusion pressure downstream. In this open position, the filter valve prevents embolic agent from traveling upstream in the proximal "backflow" direction through the filter valve. Further, since the filter valve is closed in shape and embolic agent is delivered distally of the filter valve, 100% of the delivered dose is provided to the patient; i.e. without any possibility of the dose remaining inside the filter valve. Furthermore, when the pressure at the proximal surface of the filter valve is higher than the pressure at the distal surface of the filter valve, the shape of the proximal surface of the deployed filter valve presents a reduced resistance to blood passing through the filter valve in the downstream direction, but presents surfaces facing distally in different orientations, and one orientation is substantially perpendicular to the vessel wall and has a significant resistance to flow in the upstream direction, so as to prevent backflow.

Turning now to fig. 8A-8C, the radiopaque first, second, and third marker bands 326, 328, 330 described above facilitate determining the in vivo configuration of the filter valve. Referring to fig. 8A, by way of example only, while three marker bands 326, 328, 330 are shown spaced apart, the filter valve 314 may be indicated in an undeployed configuration. In fig. 8B, the filter valve 314 may be indicated in a partially deployed configuration with the inner catheter 308 retracted relative to the outer catheter 302 by the third marker band 330 being offset substantially closer to the second marker band 328. Under fluoroscopy, fig. 8C will show two bands 326, 328 with the second marker band obscuring the third marker band 330 (fig. 8B), indicating a fully deployed configuration. Other relative relationships of the marker bands are possible to provide a fluoroscopic marker as to the status of the filter valve.

Referring now to fig. 9, when the filter valve is advanced to a treatment site within a blood vessel in an undeployed configuration, a very small pressure differential (e.g., 2.5 mmHg) is created between the proximal and distal sides of the filter valve. When the filter valve is partially open, i.e., deployed but not extended to the vessel wall (indicated as '25%' deployment in fig. 9), a small but relatively larger pressure differential (e.g., 5 mmHg) is created between the proximal and distal sides of the filter valve. When the filter valve is fully open such that the filter valve contacts the vessel wall (indicated as '50%' deployment), a greater pressure differential (e.g., 10 mmHg) is created between the proximal and distal sides of the filter valve. When the filter valve is fully open and the infusate is perfused through the orifice of the inner catheter to a position distal to the filter valve, a significantly greater pressure differential (e.g., 10-20 mmHg) is created between the proximal side and the distal side of the filter valve. Referring to fig. 10A-10C, the range of differential pressures generated can be used to selectively treat vessels having different diameters downstream of the filter valve. Referring to fig. 10A, the perfusate is directed downstream to at least the largest target vessel 370 by the significant flow and pressure drop created between the proximal and distal sides of the filter valve. Then, referring to fig. 10B, an additional smaller target branch vessel 372 that resists infusion at the initial perfusate pressure is infused, creating an increase in differential pressure by increasing the fluid pressure of the perfusate. Finally, referring to fig. 10C, by again increasing the pressure differential, an even smaller target branch vessel 374 may be infused. Similarly, to the extent that treatment is intended to be limited to only certain vessels, the distal pressure may be limited to a pressure lower than that required to infuse smaller vessels.

According to one aspect of the invention, the valve is preferably capable of being configured into its closed position for removal from the patient after completion of the embolotherapy procedure. In one configuration for post-treatment removal from the patient, the valve is simply withdrawn in the deployed configuration. In another configuration, the inner catheter 308 is further retracted relative to the outer catheter 302 to reverse part or all of the distal filter valve 348 into the proximal valve 346 to accommodate embolic agents that may potentially remain on the filter valve after treatment. In yet another configuration, as shown in fig. 6D, the inner catheter is retracted even further (in the direction of arrow 386) relative to the outer catheter to invert the entire filter valve 314 into the outer catheter 302 to fully contain any embolic agent that may potentially remain on the filter valve after treatment.

Now, as discussed in previously incorporated U.S. patent No. 8,696,698, three parameters help define the performance and properties of the deployed filter valve: the radial (outward) force of the valve, the time constant during which the valve changes from the closed state to the open state, and the pore size of the filter valve.

In a preferred embodiment, the filter valve expands into the deployed configuration when the inner and outer catheters are first displaced to move the distal end of the filter valve relative to the proximal end of the filter valve and thereby shorten the valve and expand the valve into the deployed configuration. However, once deployed, when the pressure at the distal orifice of the inner catheter is greater than the blood pressure, the filter valve fully expands to the vessel wall (i.e., reaches an open state). When blood flows upstream, or in a proximal to distal direction, where the pressure is greater than the pressure at the inner catheter orifice, the filter valve is also in a deployed but closed state (where the filter valve is retracted from the vessel wall). Furthermore, when the radial expansion force on the filter valve (i.e. the expansion force of the filter valve itself and the force generated by the pressure of the distal blood vessel on the distal surface area of the valve) is greater than the radial compression force on the filter valve (i.e. the pressure generated by the pressure of the proximal blood vessel on the proximal surface area of the filter valve), the filter valve fully expands, causing the valve to assume an open configuration. Thus, the radial expansion force of the filter valve is selected to be low (as described in more detail below) such that a normal blood flow in the downstream distal direction will prevent the deployed filter valve from reaching an open state. This low expansion force is different from that of prior art stents, stent grafts, distal protective filters and other vascular devices which have significantly higher radial expansion forces. It is to be understood that the expansion force is low enough that it will not cause the inner catheter to move relative to the outer catheter; such relative movement is preferably effected only by the user of the device.

The radial expansion force of the braid is described by Jedwab and Clerc (Journal of Applied Biomaterials, Vol. 4, 77-85, 1993 (Journal of Applied Biomaterials, 1993, 4 th 1993, pages 77-85)) and is subsequently updated by DeBeule (DeBeule et al, Computer Methods in biomedicine and biomedicine Engineering, 2005 (2005, Computer Methods of biomechanical and Biomedical Engineering, DeBeule et al)):

wherein K₁、K₂、K₃Is a constant given by the following equation:

and I_pSurface and polar moment of inertia for the braided filament, E is the Young's modulus of elasticity for the filament, and G is the shear modulus for the filament. These material properties, together with the initial braid angle (β)₀) And finallyBraiding angle (beta), stent diameter (D)₀) Together with the number of filaments (n) influences the radial force of the weaving valve.

In one exemplary embodiment, the filter valve 314 is constructed of twenty-four polyethylene terephthalate (PET) filaments 350, each having a diameter of 0.1mm and being pre-formed into an 8mm diameter mandrel and a braid angle of 130 ° (i.e., the filaments are spring-biased or have shape memory to assume an angle of 130 ° with respect to each other when the valve assumes a fully expanded state and opens in a truncated cone configuration). The filament 350 preferably has a young's modulus of greater than 200MPa and the filter valve 314 preferably has a radial force of less than 40mN in the fully deployed position (i.e., in the position in which the filament exhibits its shape memory). More preferably, the filter valve 314 has a radial force of less than 20mN in the fully deployed position; and even more preferably, the filter valve 314 valve has a radial force of about 10mN in the deployed position (where the term "about" as used herein is defined to mean ± 20%).

In one embodiment, when subjected to perfusion pressure at the distal orifice 358 of the inner catheter, the filter valve 314 moves between a deployed position that allows downstream fluid to pass (closed) and a deployed position that prevents fluid from passing (open) in a static fluid (e.g., glycerol) having a viscosity approximately equal to the viscosity of blood (i.e., approximately 3.2 cP) within 0.067 seconds. For purposes herein, the time taken to move from a closed position to an open position in a static fluid is referred to as the "time constant". According to another aspect of the invention, the filter valve 314 is arranged such that the time constant of the filter valve 314 in the fluid having the viscosity of blood is between 0.01 seconds and 1.00 seconds. More preferably, the filter valve 314 is arranged such that the time constant of the filter valve in the fluid having the viscosity of blood is between 0.05 seconds and 0.50 seconds. The time constant of the filter valve 314 may be adjusted by varying one or more of the parameters described above (e.g., number of filaments, modulus of elasticity of the filaments, diameter of the filaments, etc.).

According to one aspect of the invention, the deployed filter valve opens and closes fast enough to achieve high capture efficiency of the embolic agent in the presence of rapidly changing pressure conditions. More specifically, as shown in fig. 6C, with the inner and outer catheters displaced to open the filter valve to the vessel wall 362, when the pressure at the distal orifice 358 of the inner catheter 308 (distal of the deployed filter valve 314) increases above the pressure in the vessel 362, the seal between the periphery of the filter valve and the vessel wall increases, thus preventing back-streaming emboli. It is important to note that pressure is transmitted throughout the vasculature (vasculature) in the blood at the speed of sound (1540 m/s), and that the valve opens and closes in response to pressure changes within the blood vessel. Since the expandable filter valve responds to pressure changes, it reacts much faster than the flow rate of emboli in the blood (0.1 m/s), thereby preventing backflow of any emboli.

As will be understood by those skilled in the art, the braid geometry and material properties of the wire 350 are closely related to the radial force and time constant of the filter valve. Thus, according to one aspect of the invention, the filter valve is adapted for use in a variety of blood vessels having different diameters and flow conditions, each embodiment may have unique optimizations. For example only, in one embodiment, the filter valve 314 has ten wires 350; in yet another embodiment, the filter valve has forty filaments 350. Any suitable number of filaments may be used. Preferably, the diameter of the wire is selected in the range of 0.025mm to 0.127mm, although other diameters may be utilized. Preferably, the inclination angle (i.e. the angle of intersection assumed by the braided filaments in the fully open deployed position) is chosen in the range of 100 ° to 150 °, although other inclinations may also be used. Preferably, the young's modulus of the filament is at least 100MPa, and more preferably at least 200 MPa.

The filter valve 314 is selected to have a pore size small enough to trap (filter) embolic agents in the blood stream as the blood passes through the filter valve. In the case of large embolic agents (e.g., 500 μm), it may be possible for the wire alone to act directly as a filter to prevent the embolic agent from passing through the valve (assuming the wire has pores smaller than, e.g., 500 μm). Alternatively, a coating 364 is preferably added to the filaments 350, and more preferably to the formed braided structure, to provide a filtering function. Such a separate polymer filter is particularly useful where a smaller embolic agent is utilized. The polymeric filter may be placed on the woven structure by spraying, spinning, electrospinning, bonding with adhesives, heat fusing, mechanically capturing the weave, melt bonding, dip coating, or any other desired method. The polymer coating 364 can be a material with voids (such as ePTFE), a solid material with added voids (such as polyurethane with laser drilling), or the filter coating can be a mesh of very thin filaments laid onto a braid. In the case where the coating 364 is a network of thin wires, the characteristic pore size of the filter can be determined by attempting to pass beads of different diameters through the filter and finding which diameter of beads is able to pass through the filter in bulk. According to us patent 4,738,740, very thin filaments can be spun onto a rotating mandrel by means of an electrostatic field, or in the absence of an electrostatic field, or both. The filter so formed may be adhered to the braid structure with an adhesive, or the braid may be placed on a mandrel and the filter spun over the braid, or under the braid, or both over and under the braid to substantially capture the braid. The filter 364 may have some porosity formed by spraying or electrospinning followed by a secondary step in which the porosity is laser drilled or formed by a secondary operation. In a preferred embodiment, a material capable of being electrostatically deposited or spun is used to form the filter on the woven fabric, wherein the preferred material is capable of bonding to itself. The filter may be made of polyurethane, thermoplastic polyurethane elastomer (pellethane), polyolefin, polyester, fluoropolymer, acrylic polymer, acrylate, polycarbonate, or other suitable material. The polymer is spun onto the braid in a wet state, and therefore it is desirable that the polymer is soluble in the solvent. In a preferred embodiment, the filter is formed of polyurethane soluble in dimethylacetamide. The polymeric material is spun onto the braid in a liquid state, wherein the preferred solids concentration for the electrospinning process is 5-10% and for the wet spinning process is 15-25%.

According to one aspect of the invention, the filter coating 364 has a characteristic pore size of between 10 μm and 500 μm. More preferably, the filter has a characteristic pore size of between 15 μm and 100 μm. Even more preferably, the filter has a characteristic pore size of less than 40 μm, and more preferably between 20 μm and 40 μm. Most desirably, the filter is provided with a characteristic pore size that will allow the passage of pressurized blood and contrast agent therethrough while preventing the passage of embolic agent therethrough. By allowing the back-flushing blood and contrast agent to pass through the filter in a direction from the distal side of the valve toward the proximal end of the valve, the contrast agent can be used to indicate when the target site is completely embolized and can be used to identify the clinical endpoint of the embolization procedure. Thus, according to one aspect of the invention, the valve allows for the backflow of contrast agent as an indication of the clinical endpoint while simultaneously preventing backflow of embolic agent. Furthermore, by allowing blood to flow back through the filter material, even at relatively low flow rates, the back pressure on the distal side of the valve can be relieved.

The filter valve is also preferably provided with a hydrophilic, hydrophobic, or other coating that affects how proteins in the blood adhere to the filter and in particular within the pores of the filter. More specifically, the coating resists adhesion of blood proteins. One COATING that has been successfully used is ANTI-FOG COATING 7-TS-13 available from Hydromer, inc. of Branchburg, NJ, which can be applied to a filter by, for example, dip COATING, spray COATING, roll COATING, or flow COATING.

By proper design of the pore size and use of a proper coating, the proteins in the blood will almost immediately fill the pores during use. The protein on the coated porous filter acts as a pressure relief valve such that when subjected to an initial fluid pressure greater than the blood vessel pressure, the pores are filled with protein; but at higher pressures, such as a specified threshold pressure, the proteins are displaced from the pores and the pores are open to blood flow. The specified threshold pressure is determined to prevent damage to tissues and organs and to prevent injury to the patient. Thus, the system allows for greater pressure than the vessel pressure while limiting very high pressures that may be unsafe for the patient. Thus, the system provides pressure regulation that is not possible with other occlusion devices that include a balloon. Despite the advantages described above, the present invention does not require that the filter be configured to allow blood or contrast media to pass in the upstream "back flow" direction at any determined pressure.

It is recognized that in the open state, proteins in the blood may quickly fill the pores of the filter valve. However, as discussed above, if the threshold pressure is reached, the filter valve is designed to allow backflow of blood through the pores of the filter valve while still preventing the passage of embolic agents. An exemplary threshold pressure on the distal surface of the filter valve is 180mmHg, although the device may be designed to accommodate other threshold pressures. This may be achieved, at least in part, by using a suitable coating on the filter that facilitates removal of blood proteins from within the pores of the filter when subjected to a threshold pressure. This prevents the vessel into which the device is inserted from being subjected to stresses that might otherwise cause damage. Nevertheless, it is not necessary to allow blood and contrast media to flow back through the valve.

In an embodiment, the filter coating 350 is preferably provided as a homogenous coating of the wire, wherein the proximal portion 346 and the distal portion 348 of the filter valve 314 have a consistent coating configuration. Since the filter valve 314 is provided in the form of a closed shape, with the proximal end 346 of the filter valve 314 fused to the outer catheter 302 and the distal end 348 of the filter valve 314 fused to the inner catheter 308, it will be appreciated that any fluid or agent passing from the blood vessel and through the filter must pass through two similar filter layers; i.e. a layer at the proximal side of the filter valve and a layer at the distal side of the filter valve.

According to one aspect of the invention, the filter valve has a different radial force at its proximal portion relative to its distal portion. This difference in radial force enables a flow-dependent behavior (i.e. valve behavior). Preferably, the distal portion has a lower radial force than the proximal portion, as depicted in fig. 11-16, described below.

Turning now to fig. 11, another filter valve 414 at the distal end of the microvalve device 400 is shown. The filter valve 414 includes a heterogeneous filter coating, wherein the entire filter valve is coated. The coating 450 includes smaller pores at the proximal portion 426 of the filter valve, and larger pores at the distal portion 428. By way of example only, the smaller pores may be up to about 1 micron, while the larger pores may be up to about 30 microns. The difference in pore size may be provided by placing more of the same filamentous coating at the proximal portion and relatively less at the distal portion to provide a greater radial force in the proximal portion than in the distal portion. The difference in radial force allows the filter valve to have different performance in forward flow as compared to reverse flow. In the forward flow, the device remains in a conical shape, allowing fluid to surround it. In reverse flow, the very weak structures collapse inwardly, allowing fluid pressure to seal the device against the vessel wall and reduce reverse flow.

Referring now to fig. 12, yet another embodiment of a filter valve 514 at the distal end of a microvalve device 500 is shown. The filter valve 514 includes a heterogeneous filter coating wherein the entire filter valve is coated. The coating 550 includes a non-porous membrane disposed at the proximal portion 526 of the filter valve, and a porous wire-like coating disposed at the distal portion 528. The non-porous membrane does not allow flow through the membrane, thus increasing the antegrade flow around the device in forward flow. The porous membrane on the distal portion allows flow through the device, which expands the filter valve to the wall in reverse flow to more effectively block the flow of embolic agent back.

Turning now to FIG. 13, another embodiment of a filter valve 614 is shown. The filter valve has a non-porous membrane coating 690 at an inner surface 692 of a proximal portion thereof and a filter coating 650 on an outer surface of at least a distal portion of the filter valve (and preferably the entire filter valve). The combination of both the non-porous membrane and the porous membrane on the proximal portion increases antegrade flow and radial strength in forward flow, while the porous membrane on the distal portion decreases radial strength in reverse flow and allows flow into the filter valve to seal the vessel and prevent backflow of the embolic agent.

Referring now to FIG. 14, another embodiment of a filter valve 714 is shown. The filter valve has a configuration with a variable braid angle; i.e. with different weaving angles at different parts of the filter valve. In the illustrated embodiment, the braid angle is lower at the proximal end and higher at the distal end. The smaller braid angle (e.g., at 792) is preferably in the range of 60-90; and the larger braid angle (e.g., at 794) is preferably greater than 110. A smaller braid angle has more rigidity than a smaller braid angle, again providing a different operational behavior in forward flow than backward flow. The variable braid angle aspect of the device may be used in conjunction with any of the other embodiments described herein.

Turning now to fig. 15, another embodiment of a filter valve 814 is shown, substantially as described above with respect to device 300. The strainer valve 814 differs in having a thicker braid 827 at its proximal portion 826 and a relatively thinner braid 829 at its distal portion 828. The so-called thinner braid 829 may be the result of: the individual thinner braid filaments 831 are in a similar braid-form configuration as in the proximal portion 826; or braid filaments of similar size as in the proximal portion, but which appear in a more dense lattice configuration in the proximal configuration and a wider, less dense lattice configuration across the distal portion of the filter valve; or a combination of these two structural design elements. In addition, the filaments of the proximal and distal portions may be otherwise designed to exert different radial forces (with greater force at the proximal portion). As an example, the filaments of the braid in the proximal portion may be selected to have increased elasticity or spring force, regardless of size or spacing, to operate as desired. The proximal and distal portions 826, 828 are preferably bounded by a circumference around the maximum diameter 833 of the filter valve. The proximal and distal portions 826, 828 may have either a homogeneous filter coating (discussed above with respect to fig. 4 and 5) or a heterogeneous filter coating (discussed above with respect to fig. 11-13), as well as a common (discussed above with respect to fig. 4 and 5) or different braid angles (discussed above with respect to fig. 14).

Referring to fig. 16, another embodiment of a filter valve 914 for the device is shown, generally as described above with respect to 300. The filter valve 914 includes: a proximal filamentous braided portion 926, preferably coated with a polymeric filter material 927; and a distal portion including a polymeric filter material 928. The proximal portion 926 and the distal portion 928 are preferably bounded by a circumference around a maximum diameter 933 of the filter valve. According to the present embodiment, the distal portion 928 is braidless; i.e. not including any self-expanding filamentous structures. The filter valve 914 may be formed by: positioning the filamentous braid for the proximal portion 926 over a mandrel (not shown) and spraying a porous polymer film material over the proximal braid; and also more distally spraying a porous polymer film material over the mandrel (where the braid is not provided) for constructing the braid-free distal portion 928. After curing, the construct is removed from the mandrel. Once the proximal portion 926 of the filter valve 914 is coupled to the outer catheter 904 and the distal portion 928 of the filter valve 914 is coupled to the inner catheter 908, the filter valve has preferred properties. At the distal portion 928, the filter valve 914 is substantially fabric-like in structure. That is, when the inner catheter 908 is advanced relative to the outer catheter 904 and the distal portion 928 is placed under tension, the distal portion 928 of the filter valve 914 is malleable under tension; however, when the inner catheter 908 is retracted relative to the outer catheter 904 and the distal portion 928 is placed in a compressed state, the distal portion of the filter valve is floppy under the compressive force.

Turning now to fig. 17A-18, another embodiment of a filter valve 1014 is shown, generally as described above with respect to the device 300. The filter valve 1014 differs in having a braided structure 1027 of filaments 1027a at its proximal portion 1026 and a non-braided, helically arranged structure 1029 of filaments 1029a at its distal portion 1028, as best seen in fig. 18. Filaments 1027a and 1029a may be of metallic construction, including nitinol, or of polymeric construction. Braided structure 1027 includes filaments 1027a crossing over and under each other (e.g., in a textile configuration) to define crossing angles at intersections of the filaments. As described below, the helical arrangement 1029 includes fewer filaments 1029a than the braided arrangement 1027, wherein such fewer filaments 1029a preferably extend in the distal portion 1028 but do not cross over and under other filaments, such that the distal portion is preferably non-braided for a desired force application. The proximal and distal portions 1026, 1028 are preferably bounded by a circumference that surrounds the maximum diameter 1033 of the filter valve 1014. Each of the braided structure 1027 and the helical arrangement 1029 is provided with a filter coating 1050, preferably as described above with respect to the coating 350 on the device 300. The filaments 1027a, 1029a, including the number of strands in each of the proximal and distal portions, the length of the respective filament, and the diameter of the respective filament, as well as the braiding and helical arrangement of the material of the respective filament, may be individually or collectively optimized for generating the intended applied radial force within the blood vessel. By way of example only, the distal helical arrangement may include three, six, twelve, or twenty helically wound wires. Additionally, the filaments 1029a arranged helically in distal portion 1028 can be evenly circumferentially spaced around the distal portion, i.e., each filament 1029a is equidistantly displaced between the two filaments around it (fig. 18); or may have helically configured filaments 1129a arranged in groups 1131, thereby allowing the filaments to have variable relative displacement between each other or between groups of filaments (fig. 19). By way of example, fig. 19 shows a group 1131 of two filaments, but groups of three, four, and six filaments, or combinations of groups having different numbers of filaments, are also contemplated within the scope of the present disclosure. Also, while a Clockwise (CW) direction helical arrangement is shown in fig. 17A-18, it should be appreciated that the filaments may be configured in a counterclockwise (CCW) configuration; or such that some of the filaments 1129a extend in the CW direction and the remainder of the filaments 1129b extend in the CCW direction, as shown in fig. 19. However, where some filaments extend in each of the CW and CCW directions, such filaments preferably extend between sets or sets of counter-rotation (as shown) in order to prevent interference; or in separate "planes" or layers of the distal portion, whereby the filaments do not cross over and under the filaments in opposite directions.

The filter valve 1014 may be formed by: a braided filamentous tubular construct is provided, and certain filaments are selectively removed and the remaining filaments are helically wound at a distal portion of the braided filamentous tubular construct while leaving the filament structure of the proximal braided portion intact. The resulting filamentous construct is then filter coated. In this configuration, it should be understood that the filaments of the braided structure defining the proximal portion and the filaments of the helically wound structure defining the distal portion may be continuous. Thus, in this configuration, reference herein to a proximal wire should be considered to be a proximal portion of such a wire, while reference herein to a distal wire should be considered to be a distal portion of such the same wire. Alternatively, the filamentary constructions of the proximal and distal portions 1026, 1028 may be separately formed and subsequently joined together and then coated with the filter coating 1050. Other manufacturing processes may also be used.

In use, as described above, with the filter valve 1014 provided on the distal ends of the outer catheter 1004 and the inner catheter 1008, the inner catheter 1008 is distally displaced relative to the outer catheter 1004 to reduce the diameter of the filter valve 104 (as shown in fig. 17A) for insertion into a patient. This configuration facilitates tracking of the location of the therapeutic treatment over the guidewire. The spiral wire configuration of the distal portion 1028 of the filter valve provides a lower profile at the distal end of the device. Once at the treatment site, the guidewire may be removed. Then, in preparation for treatment (fig. 17B), the user begins to displace the inner catheter 1008 proximally relative to the outer catheter 1004 to retract the distal end portion 1028 relative to the proximal braided portion 1026. When the distal portion 1028 is fully retracted, the spiral wire "struts" (strut) "1029 a pushes radially outward, driving the braided section 1028 radially outward in diameter until the circumference reaches its maximum potential diameter 1033 (fig. 17C), i.e., is in contact with the vessel wall. At this point, the spiral wire "struts" begin to reverse in rotational direction and pull generally within the braided proximal portion of the filter valve. Thus, in this embodiment, a hinge point is created at the transition from the spiral to the braid. In addition, the filter valve 1014 has a higher force potential at the braided proximal portion 1026 than at the spiral filament distal portion 1028.

In each of the embodiments of FIGS. 11-19, the distal portion of the filter valve exerts a significantly reduced radial force relative to the proximal portion of the filter valve, which results in optimizing the function of the filter valve as a valve. In the forward (downstream) flow of fluid within the blood vessel, the fluid flows around the filter valve as the fluid contacts the proximal side of the expanded proximal portion. The difference is that in the backward or back (upstream) flow of fluid within the vessel, as the fluid contacts the distal side of the expanded distal portion, the fluid flows into the filter valve, rather than around the filter valve. In this upstream flow, some fluid (i.e., blood) is able to flow through the double layer filter material of the filter valve, while the pores of the filter material are of sufficiently small size to capture embolic and other related therapeutic agents.

In any embodiment, the physician will track and advance the inner catheter of the microvalve device over the guidewire to the target location, and then remove the guidewire. The embolic agent is then infused through the inner catheter to deliver the embolic agent distal to the microvalve, and the device is utilized as intended and according to the particular structural design of the device. Then, after perfusion, when it is desired to remove the device from the patient, the physician has two options to prepare or configure the microvalve device for removal. The inner catheter may be pushed forward relative to the distal end of the outer catheter or otherwise displaced forward to create a collapse of the microvalve, reducing its diameter to facilitate its removal from the body vessel. Alternatively, after infusion of the embolic agent, the inner catheter may be retracted proximally and inverted into the distal end of the outer catheter to retain at least a portion, and preferably all, of the microvalve device within the outer catheter and capture any embolic agent on such portion of the microvalve within the outer catheter during subsequent withdrawal of the device from the patient. The second option is preferred for radioactive embolic agents, where otherwise there may be a potential for the radioactive emboli to spread during removal.

Turning now to fig. 20, another embodiment of a microvalve device 1100 in accordance with the present invention is shown. The device 1100 includes a flexible infusion catheter 1108 having a proximal end 1110 provided with an infusion hub 1116, and a distal end 1112. The irrigation catheter has a lumen in communication with the hub 1116 that leads to a distal port 1158 through which the irrigation can be injected 1158. A filter valve 1114 is coupled to the distal end 1112 of the irrigation catheter 1108. The filter valve 1114 may have a structure similar to that described with respect to the filter valve 1014; having a proximal filter coated braid 1120 and one or more distal struts 1122 preferably arranged in a helical orientation. Braid 1120 and struts 1122 can be made from metals and/or polymers including nitinol. The distal brace 1122 may or may not be filter coated. This configuration results in a radial expansion of the valve structure that is weaker at its distal side than at its proximal side. Alternatively, filter valve 1114 may have any other filter valve configuration described herein. The proximal end 1124 of the filter valve 1114 is secured in place to the outside 1128 of the catheter 1108, such as at a fusion, adhesive or plastic bond, or mechanical crimp or collar. The distal end 1126 of the filter valve 1114 is provided with or defines a movable collar 1130. The collar 1130 is longitudinally displaceable along the outer side 1116 of the conduit 1108, and is preferably free floating and is movable relative to the proximal end 1124 of the filter valve 1114. Collar 1130 is always located proximal to aperture 1158. The radiopaque markers may be provided or defined at the proximal end 1124 of the filter valve, at the collar 1130, and/or adjacent the aperture 1158. An introducer sleeve 1102 is provided over the irrigation conduit 1108 and is longitudinally displaceable relative to the filter valve 1114. The introducer sleeve 1102 is adapted to collapse the filter valve 1114 and introduce the irrigation conduit 1108 and its collapsed filter valve 1114 into a guide conduit (not shown).

Referring to fig. 21, the introducer sleeve 1102 is positioned relative to the irrigation catheter 1108 such that the distal end 1104 of the sleeve 1102 is advanced over the filter valve 1114 to cause the filter valve to collapse against the outer surface 1128 of the irrigation catheter 1108 and to cause the distal end 1126 of the filter valve 1114 to be distally displaced relative to the proximal end 1124 of the filter valve. The infusion catheter 1108 is advanced distally over a guidewire (not shown) relative to the introducer sleeve 1102 and into the patient through the blood vessel to a deployed position. The perfusion catheter 1108 in the open or expanded configuration may be tracked over the guidewire. The filter valve 1114 is adapted to self-center during tracking. In an alternative deployment, the guide catheter may be advanced through the blood vessel with the irrigation catheter to the deployed position, and once in the deployed position, the guide catheter is retracted relative to the filter valve 1114 to allow the filter valve to automatically radially expand in view of the inherent outward bias of the filter valve. Regardless of the manner of advancement and deployment within the vessel, the filter valve distal end 1126 retracts back toward the filter valve proximal end 1124 with the collar 1130 sliding along the outer side 1128 of the catheter 1108. Once released and expanded, the filter valve 1114 dynamically opens and closes based on local fluid pressure conditions relative to the proximal and distal sides of the filter valve 1114.

At rest (shown in fig. 22), the filter valve 1114 will expand into apposition with the vessel wall 1162. In a forward (downstream) flow condition (pressure at the proximal portion 1134 of the filter valve is higher than pressure at the distal portion 1136), the filter valve will automatically partially collapse to allow forward flow fluid to pass through the filter valve. Referring to fig. 23, in a reverse (upstream or reverse) flow state (pressure at the distal portion 1136 of the filter valve is higher than pressure at the proximal portion 1134, as indicated by arrow 1164), the distal portion 1136 of the filter valve will automatically collapse longitudinally toward the proximal portion 1134 and may even be fully or partially inverted and force the filter valve 1114 into a fully open (wide open) configuration across the vessel 1162 so as to form a barrier to flow through the filter valve. This occurs when the infusate 1188 is injected under pressure through the lumen and out of the distal orifice 1158, resulting in a higher pressure condition at the distal portion of the filter valve than at the proximal portion of the filter valve. The distal portion 1136 of the filter valve converges toward the proximal portion 1134 of the filter valve, forcing the filter valve 1114 open wider and capturing any perfusion 1188 that would otherwise flow back upstream through the filter valve.

Turning now to fig. 24, another embodiment of a microvalve device 1200 is shown that is substantially similar to device 1100. The device 1200 includes a flexible infusion catheter 1208, the flexible infusion catheter 1208 having a proximal end 1210 provided with an infusion hub 1216, and a distal end 1212 that opens at an orifice 1258. A filter valve 1214 is coupled to the distal end 1212 of the irrigation catheter 1208. In this embodiment, the filter valve 1214 has a woven construction from its proximal end to its distal end. Braided construct 1120 may be made of metal and/or polymer wires comprising nitinol. The polymer filter is coated on the proximal portion 1234 of the filter valve; preferably, the distal portion 1236 of the braided construct is free of a polymeric filter. As described with respect to the device 1100, the proximal end 1224 of the filter valve 1214 is secured to the outside of the catheter 1208, and the distal end of the filter valve 1214 forms the collar 1230. The collar 1230 is free floating around the outside of the catheter and is longitudinally displaceable relative to the proximal end 1224 of the filter valve 1214. An introducer sleeve (or outer catheter) 1202 may be advanced over the infusion catheter 1208 and the filter valve 1214 to collapse the filter valve (as shown in fig. 24A) to facilitate introduction of the device 1200 through a patient's blood vessel over a guidewire to a deployed position within the blood vessel. Once in the deployed position within the blood vessel 1162, the sleeve 1202 is retracted relative to the filter valve 1214, and the filter valve 1214 is advanced over the guidewire and through a guide catheter (not shown) to a target location within the patient. Upon deployment through the guide catheter, the filter valve 1214 automatically expands radially (fig. 25) in view of the inherent outward spring bias of the filter valve. This also causes the filter valve distal end 1226 to retract back toward the filter valve proximal end 1224, with the collar 1230 sliding proximally along the outside 1216 of the catheter 1208. Once released and expanded, the filter valve 1214 dynamically opens and closes based on local fluid pressure conditions relative to the proximal and distal sides of the filter valve 1214.

At rest, the filter valve 1214 expands toward apposition with the vessel wall 1162 (fig. 25). In a forward (downstream) flow condition (pressure at the proximal portion of the filter valve is higher than pressure at the distal portion), the filter valve will automatically partially collapse to allow forward flow fluid to pass through the filter valve. Referring to fig. 26, in a reverse (upstream or reverse) flow state (i.e., the pressure at the distal portion of the filter valve is higher than the pressure at the proximal portion, as indicated by arrow 1264), the filter coated proximal portion 1234 of the filter valve will fully expand under pressure to a fully open configuration across the blood vessel 1262 so as to form a barrier to upstream flow; such as occurs when the perfusate 1288 is injected under pressure through the lumen and out of the distal orifice 1158.

Turning now to fig. 27, another embodiment of a microvalve device 1300 in accordance with the present invention is shown. The apparatus 1300 includes a flexible infusion catheter 1308 having a proximal end 1310 provided with an infusion hub 1316, and a distal end 1312, and a lumen opening at the distal orifice 1358. A filter valve 1314 is coupled to the distal end 1312 of the irrigation conduit 1308. In this embodiment, the filter valve 1314 may comprise a non-woven construction or a woven multi-strand construction; a non-woven construction is illustrated by way of example only. The strands 1330 making up the filter valve 1314 may be made of metals and/or polymers including nitinol. The strands 1330 each include a proximal portion 1332, an intermediate portion 1334, and a distal portion 1336. The proximal portion 1332 is attached circumferentially around the outer surface 1318 of the conduit 1308 at a location proximal of the aperture 1358, the middle portion 1334 extends radially outward and toward the aperture 1358, and the distal portion 1336 of the strand reverses back into the filter valve 1314 and couples circumferentially around the outer surface 1318 of the conduit 1308. The distal portion 1336 is preferably fixed to the outer surface 1318, but may be coupled to a movable collar that is held over the catheter, as described above with respect to the devices 1100 and 1200. The proximal and intermediate portions 1332, 1334 of the strands are coated with a polymeric filter 1370, the polymeric filter 1370 extending between the strands 1330 and across the strands 1330. Optionally, the distal portion 1336 of the strand may also be coated with a polymer filter, although the illustrated filter valve is provided with an uncoated distal portion.

An introducer sleeve (or outer catheter) 1302 is provided for holding the filter valve 1314 in a collapsed configuration for introducing the irrigation catheter 1308 with the filter valve 1314 into the guide catheter to a target location within the patient.

When the introducer sleeve is retracted over the filter valve 1314 at the target site, the filter valve 1314 expands outward and is adapted to dynamically open and close in response to local fluid pressure conditions around the proximal and distal portions of the filter valve, as described above.

Turning now to fig. 28, another embodiment of a microvalve device 1400 in accordance with the present invention can be seen. Device 1400 includes a flexible irrigation catheter 1408 having a proximal end 1410 provided with an irrigation hub 1416, and a distal end 1412 that opens in an aperture 1458. A filter valve 1414 is coupled to the distal end 1412 of the perfusion catheter 1408. The filter valve 1414 includes a proximal first disk 1434 and a distal second disk 1436, the proximal first disk 1434 and the distal second disk 1436 being coupled together at their peripheral edges (collectively 1435). The discs 1434, 1436 are preferably of a common size. The discs 1434, 1436 are made of a very soft material, such as polyester or polyurethane. The soft material may be a fluid-tight membrane comprising a single porous material, or coated with a filter material having a pore size sufficient to capture embolic agents. The discs may have the same composition as each other, or may be different. For example, the first disk 1434 may be impermeable, while the second disk 1436 may be porous. The discs 1434, 1436 may also incorporate filamentary strands. The filamentary strands may be made of metals and/or polymers including nitinol. The disks 1434, 1436 are secured to the outer surface 1428 of the irrigation conduit 1408 in a closely spaced manner, preferably spaced apart by a distance of between 0-5mm, but may be otherwise spaced relative to one another. In one embodiment, the two discs 1434, 1436 butt up against each other. As described above, an introducer sleeve 1402 is provided for advancement over the perfusion catheter 1408, and for collapsing a filter valve 1414 for introduction over the guidewire and into the guide catheter.

Referring now to fig. 29, when filter valve 1414 is in a target position within a blood vessel, filter valve 1414 is expanded outward to a blood vessel wall 1462 and has an expanded diameter that is greater than the diameter of the blood vessel. For use, distal surface 1436a of second disc 1436 should present a concave surface to stop and capture embolic agent that has perfused through distal orifice 1458, as shown in fig. 29. The configuration of the distal surface 1436a may be tested by injecting contrast agent 1490 through the perfusion catheter 1408. If contrast agent backflow is seen through filter valve 1414, it can be concluded that the orientation is reversed, which will not provide a sufficient barrier to backflow of the pressurized embolic agent. (fig. 30) in this case, the perfusion catheter 1408 may be retracted slightly within the blood vessel to cause the filter valve 1414 to invert and present a concave distal surface 1436a, which concave distal surface 1436a may serve as an effective barrier to the pressurized embolic agent 1488. (FIG. 31).

In any of the embodiments described herein, components of the valve may be coated to reduce friction during deployment and retraction. The components may also be coated to reduce thrombosis along the valve or to be compatible with therapeutic, biological or embolic materials. The member may be coated to increase the binding of the embolic agent such that the embolic agent is removed from the blood vessel during retraction.

According to one aspect of the invention, the catheter body and mesh may be individually marked for easy visualization under fluoroscopy. The catheter body may be marked using any means known in the art; for example, radiopaque materials are incorporated into catheter tubing. The radiopaque material may be barium sulfate, bismuth subcarbonate, or other material. Alternatively or additionally, the radiopaque media may be incorporated into the material of the braid and filter. Alternatively, as previously described, one or more of the wires may be selected to be made of a radiopaque material, such as platinum iridium.

In each of the embodiments, the inner catheter may be a single lumen or a multi-lumen catheter. Preferably, the catheter has at least one lumen for delivering the embolic agent, and, if desired, one or more additional lumens may be provided for passage of a guidewire or other device or for administration of fluids, e.g., for flushing the artery after administration of the embolic agent.

The above-described apparatus and methods have been generally directed to a system that allows for proximal and distal flow of biological fluid (e.g., blood) within a body vessel, and that prevents backflow of perfusate through the valve in a proximal direction. It will be appreciated that the valve may also be optimized to reduce blood flow in the distal direction. In any embodiment, the radial force of the filter valve can be adjusted by adjusting the braid angle. Adjusting the radial force allows reducing blood flow by as much as over 50%. As an example, providing a braid angle greater than 130 ° will significantly reduce blood flow through the valve in the distal direction, with a braid angle of about 150 ° slowing blood flow by 50% to 60%. Other braid angles may provide different reductions in distal blood flow. Reduced distal blood flow may be used in lieu of the "wedge" technique, wherein distal blood flow is reduced for treatment of cerebral and spinal arteriovenous malformations. Once the valve slows down blood flow, a glue such as cyanoacrylate may be applied at the target site.

Although the above description has primarily referred to the use of the device for the infusion of a therapeutic agent, it will be appreciated that the device has significant functionality even when the delivery of the therapeutic agent is not the primary function. As an example, the device may be used to retrieve thrombus and prevent the escape of dislodged embolic particles into the patient's blood. Briefly, a thrombus removal device may be passed through the inner catheter 308 to release and retrieve the thrombus. The filter valve 314 operates to prevent the spray of thrombus and embolic particles from passing over the filter valve and into the blood vessel. Then, in a similar manner to that described above, when the thrombus is captured, the thrombus, along with any embolic particles, may be contained within the filter valve as the filter valve is inverted into the outer catheter for removal from the patient. For this use, the inner catheter may comprise a single lumen or multiple lumens; that is, one lumen is used for a thrombus removal device and one or more lumens are used for additional device or therapeutic agent infusion.

Various embodiments of devices and methods for reducing or preventing backflow of embolic agents in a blood vessel have been described and illustrated herein. While particular embodiments of the present invention have been described, it is not intended that the invention be limited thereto, as it is intended that the invention be as broad in scope as the art will allow and that the specification be read likewise. Thus, while a variety of materials have been listed for the valve wire, valve filter, and inner and outer conduits, it will be appreciated that in each of the various embodiments, other materials may be utilized in combination and without limitation for each of these structures. Moreover, while reference has been made throughout to the infusion of embolic agents, it should be understood that the devices described herein may be used to infuse any other treatment agent, including, but not limited to, drugs targeted to cancer cells and immunotherapeutic agents, including immunomodulators, vaccines, modified cells and checkpoint inhibitors. Furthermore, although the invention has been described in relation to a particular artery of a human being, it will be appreciated that the invention may be applied to any blood vessel of humans and animals, as well as other vessels, including tubes (ducts). In particular, the device may also be used for treating tumors, such as liver cancer, kidney cancer or pancreatic cancer. Additionally, embodiments have been described with respect to their distal ends, as their proximal ends may take any of a variety of forms, including forms well known in the art. For example only, the proximal end may include two handles, one of which is connected to the inner catheter and the other of which is connected to the outer catheter. Movement of one handle relative to the other handle in a first direction may be used to extend the filter valve in an undeployed configuration for advancement to a treatment site, and movement of the handle in a second, opposite direction may be used to deploy the filter valve. Depending on the arrangement of the handles, deployment of the filter valve may occur when the handles are moved away from or toward each other. As is well known, the handles may be arranged to provide linear or rotational movement relative to each other. If desired, the proximal end of the inner catheter may be provided with hash marks or other indications at intervals along the catheter so that movement of the handles relative to each other can be visually calibrated and an indication given as to the extent to which the valve is open. It will thus be appreciated by those skilled in the art that yet other modifications could be made to the provided invention without deviating from its spirit and scope as claimed.