Therapeutic treatment device having a braided microvalve occluder - Patent Application 20070122999

Abstract

A vascular treatment device for use in a blood vessel includes a catheter and a microvalve occluder. The occluder includes a plurality of braided elastic strands, each strand including a proximal portion, a central portion, and a distal portion. The plurality of strands are secured to the outer surface of the catheter. According to one aspect, the distal portion is circumferentially secured to the outer surface of the catheter at a position toward the distal end of the catheter, the central portion extends proximally and radially outward from the distal end, and the proximal portions of the strands are inverted radially within the central portion and circumferentially connected to the outer surface of the catheter at a position proximally offset from the distal portion. The proximal portion of the microvalve is covered with a fluid-impermeable membrane, while the distal portions of the strands are substantially uncovered.

Description

[Technical Field]

[0001] This application claims priority to U.S. Patent Application No. 17 / 969,506, filed October 19, 2022, which is incorporated by reference in its entirety into this disclosure.

[0002] This application is related to commonly owned U.S. Patent Nos. 8,696,698 and 10,588,636, which are incorporated by reference in their entireties into this disclosure.

[0003] The present disclosure relates generally to catheters for introducing therapeutic treatments into blood vessels, and more particularly to catheters having microvalves at their distal ends for increasing penetration of the therapeutic treatment into target blood vessels and reducing backflow of the therapeutic treatment into non-target blood vessels. [Background technology]

[0004] Endovascular treatment procedures are commonly used clinically to treat a wide range of diseases, including endovascular embolization, chemoembolization, and radioembolization, which are used to treat a wide range of diseases, including hypervascular liver tumors, uterine fibroids, secondary cancer metastases to the liver, preoperative treatment for hypervascular meningiomas in the brain, and bronchial artery embolization for hemoptysis.

[0005] Non-targeted delivery of various therapeutic agents can lead to adverse events and morbidity, and non-targeted delivery suggests that the intended delivery target does not receive the full dose of the therapeutic agent.

[0006] Injections using standard infusion microcatheters allow for bidirectional flow. That is, when a microcatheter is used to inject a therapeutic agent, it allows for forward movement of blood and the injected therapeutic agent in addition to backward movement (reflux). Backflow of therapeutic agent can cause non-target damage to surrounding healthy organs. Interventional oncology treatment procedures aim to attack cancerous tumors using either radiation therapy or chemotherapy. Maintaining blood flow throughout the vasculature of the target organ is crucial to delivering therapeutic agents to the distal vasculature where they can be most effective. This challenge is exacerbated in patients with hypovascular tumors or those receiving chemotherapy, as slow blood flow limits the amount of therapeutic agent delivered and may backflow into non-target tissues before the physician has time to deliver the desired amount.

[0007] During a therapeutic agent injection process, intravascular pressure changes at multiple locations in the vasculature. Pressure is initially higher proximally and decreases along the length of the vessel. This pressure drop results in forward flow of the therapeutic agent. Without a pressure drop along the entire length of the vessel, the therapeutic agent will not flow downstream. If pressure is higher at one location, such as a catheter orifice, the therapeutic agent will flow toward the location of lower pressure. If the pressure generated at the injection catheter orifice is greater than the pressure in the vessel proximal to the catheter orifice, some of the injected therapeutic agent will migrate upstream (backflow) and flow into non-target vessels or organs. This phenomenon can occur even in vessels with strong forward flow, provided the injection pressure (pressure at the catheter orifice) is sufficiently high.

[0008] In clinical practice with standard infusion catheters, physicians attempt to inject therapeutic agents at pressures that do not cause backflow. To do this, physicians either slow the infusion rate (and pressure) or stop the infusion entirely. The clinical impact of current infusion catheters and technologies is two-fold: delivery of low doses of therapeutic agents and insufficient distal penetration to the target vessel.

[0009] Furthermore, reflux is a time-sensitive phenomenon. For example, reflux in response to a therapeutic agent injection can occur at a rate (e.g., milliseconds) that is too fast for the operator to react. Furthermore, after a brief period of reflux, forward flow may resume briefly within the vessel, but further reflux may occur.

[0010] Various devices have been proposed to enhance peripheral permeability while preventing backflow. For example, commonly owned U.S. Patent No. 8,696,698 (the contents of which are incorporated herein by reference) describes a microvalve injection system for injecting therapeutic agents, in which a dynamically adjustable filter valve is connected to the distal end of a delivery catheter. The delivery catheter and filter valve self-expand upon deployment from the delivery catheter. The filter valve is naturally spring-loaded by a filamentary element structure to automatically partially expand within the vessel upon deployment from the outer catheter, and is coated with a porous polymer with pores small enough to filter the therapeutic agent. This configuration increases fluid pressure within the filter valve during injection, causing it to open and expand to seal against the vessel, preventing backflow of the injected therapeutic agent. Furthermore, as fluid is pumped through the delivery catheter to the filter valve, downstream pressure within the vessel increases, maximizing uptake of the therapeutically delivered medication into the target tissue. Furthermore, the filter valve responds to local pressure around the valve, thereby controlling the forward flow of blood within the vessel without substantial restriction, reducing or eliminating the backflow (overflow or backflow) of therapeutic agents introduced into the blood.

[0011] However, the device of U.S. Patent No. 8,696,698 has several limitations that make it less advantageous in certain situations. Specifically, while the filter valve device disclosed therein is generally suitable when introducing an occluder into small blood vessels is not a primary requirement, its tracking ability through tortuous, branching vasculature is limited. The distal end of the collapsed, undeployed device is dictated by the size of the deployment catheter. The size of the deployment catheter is significantly larger than the catheter supporting the filter valve and significantly larger than the outer diameter of the guidewire used to guide the microvalve to the target location within the blood vessel. Therefore, it may not be optimal for introducing a filter valve into small branching vessels. Furthermore, once the device is delivered to the treatment site, deployment of the filter valve requires overcoming frictional forces between the filter valve and the outer deployment catheter.

[0012] Commonly owned U.S. Patent No. 10,588,636 (previously incorporated herein) describes a microvalve injection system for injecting therapeutic agents and also mentions device introduction capabilities. Referring to Prior Art FIG. 1, the system 10 includes a flexible injection catheter 12. The flexible injection catheter 12 has a hub 14 at its proximal end 16 and a filter valve occluder 18 connected to its distal end 20. The filter valve occluder 18 has a plurality of elastic strands 22, each of which includes a proximal portion 24, a central portion 26, and a distal portion 28. The proximal portions 24 of the strands are attached to the outer surface 30 of the catheter 12 at a location proximal to a distal catheter aperture 32, and the central portions 26 of the strands extend radially outward and toward the aperture 32. The distal portions 28 of the strands are folded back within the filter valve occluder 18 and circumferentially connected to the outer surface 30 of the catheter 12. The proximal and central portions 24, 26 of the strands 22 are coated with a polymeric filtration coating 34 that extends across and between the strands 18. The distal portions 28 of the strands 22 are uncoated. The microvalve infusion system 10 is manufactured by Trisalus Life Sciences, Inc. of Westminster, Colorado under the trade name TRINAV. (登録商標) It is manufactured and sold as an infusion system. In use, the microvalve injection system can be deployed to the target vascular location through the introducer sleeve 36, but does not require the use of an introducer sleeve. The injection system can be advanced over a guidewire without the introducer sleeve, which in fact provides superior delivery capabilities. Once introduced into the vessel, the filter valve occluder 18 dynamically operates in synchronization with the cardiac cycle, providing the intended retrograde blockage of therapeutic agents while maintaining greater than 70% of antegrade blood flow through the microvalve occluder within the vessel. Furthermore, the design allows for non-traumatic increase in therapeutic agent infusion pressure into locally resistant tumor vessels, enabling deeper perfusion delivery of therapeutic agents. Summary of the Invention

[0013] An infusion device is provided that includes a catheter and a microvalve. The catheter has a proximal end and a distal end, and a lumen extending from the proximal end to the distal end and opening at a distal aperture. The microvalve is coupled to the distal end of the catheter proximal to the aperture.

[0014] The microvalve is formed from a filament structure with a natural spring bias. The filament structure is biased to expand radially and has a proximal end and a distal end. The filament structure includes a plurality of elastic strands forming a braided mesh. Each elastic strand includes a proximal portion, a central portion, and a distal portion. The distal portion of the strand is attached around the outer surface of the catheter proximal to the catheter aperture and toward the distal end. The central portion of the strand extends proximally and radially outward from the distal end. The proximal portion of the strand turns radially within the central portion and extends distally, and is circumferentially bonded around the outer surface of the catheter at a position proximal to the distal portion of the strand. The proximal and central portions of the strand are coated with a polymeric filter or membrane material. The polymeric filter or membrane material extends across and between the strands, rendering that portion of the microvalve liquid-impermeable. Meanwhile, the distal portions of the strands are substantially free of the polymeric filter and are configured to allow fluid to pass between the open strands.

[0015] The microvalve's geometry is axially inverted from known injection microvalves. This provides several advantages. First, the geometry naturally creates a tapered tip for navigation within a blood vessel. This tapered shape significantly reduces resistance to forward navigation along the vessel wall, reducing the risk of vasospasm. Second, the geometry provides a large, bulbous proximal end. This proximal end shape offers significantly higher resistance to forward blood flow than conventional dynamic microvalve devices. This significantly reduces blood flow around the valve, creating a significant pressure drop distal to the valve. This configuration offers unexpected advantages in various therapeutic delivery procedures. For example, for the localized delivery of therapeutic agents to various tumors within organs such as the liver or pancreas, it has been found to be beneficial to reduce vascular flow to the organ prior to and during pressurized delivery of therapeutic agents to these organs.

[0016] According to another aspect of the microvalve, the distal ends of the braided strands are circumferentially attached to the outer surface of the catheter at a location distally and proximal to the catheter's open bore, with the central portions of the braided strands extending proximally and radially outward from the distal ends, and the proximal portions of the braided strands extending radially inward and circumferentially attached to the outer surface of the catheter at a location proximally offset from the distal portions of the braided strands, thereby defining a spherical shape. The length between the proximal and distal ends is fixed. The proximal and central portions of the strands are coated with a polymer filter or membrane material that extends across and between the braided strands, making that region of the microvalve liquid-impermeable. Meanwhile, the distal portions of the braided strands are substantially free of the polymer filter, allowing liquid to pass between the open braided strands. Such a configuration provides lower flow resistance compared to the tapered tip and bulbous proximal end configuration described above, creating higher drag when advancing the microvalve within a blood vessel. [Brief explanation of the drawings]

[0017] [Figure 1] PRIOR ART FIG. 1 is a side elevation view of a prior art microvalve injection system.

[0018] [Figure 2] FIG. 2 is a side elevational view of a microvalve injection system according to an embodiment described herein.

[0019] [Figure 3] FIG. 3 is an enlarged view of the distal end of the microvalve injection system shown in FIG.

[0020] [Figure 4] FIG. 4 is a close-up view of the distal end of another microvalve injection system. DETAILED DESCRIPTION OF THE INVENTION

[0021] In this disclosure, when referring to the human body and to components of devices and systems intended to be manually manipulated by a user, the terms "proximal" and "distal" are defined relative to the user's hand, i.e., unless otherwise specifically indicated, "proximal" means closer to the user's hand and "distal" means farther from the user's hand.

[0022] A first exemplary embodiment of a microvalve device 100 according to the present invention is shown in FIGS. 2 and 3. It should be noted that the system portions shown in these figures are not drawn to scale, with the distal portion being greatly exaggerated for illustrative purposes. As shown in FIG. 2, the device 100 includes a flexible catheter 102 having a proximal end 104 and a distal end 106, a hub 108 coupled to the proximal end 104 of the catheter, and a filter valve vascular occluder 110, described in more detail below, coupled to the distal end 106 of the catheter 102. An infusion lumen extends from the hub 108 to the distal end 106 of the catheter 102 and opens at a distal aperture 112, configured to enable delivery of a therapeutic agent into a target vessel (artery or vein) of the patient from outside the patient's body (not shown). The hub 108 is configured to facilitate advancement of a guidewire through the infusion lumen and / or connection of a syringe for injecting a therapeutic agent through the infusion lumen. Any hub may be utilized that at least facilitates delivery of the therapeutic agent to the infusion lumen.

[0023] One or more radiopaque marker bands 114, 116 are provided on the proximal and / or distal sides of vascular occluder 110. During use of device 100, the location of marker bands 114, 116 in vivo as viewed under fluoroscopy indicates the location of vascular occluder 114 relative to anatomical landmarks.

[0024] The catheter 102 has a length of 2 to 8 feet and an outer diameter of 0.67 to 3 mm (corresponding to a catheter size of 2 to 12 French). It has a liner made of a fluorinated polymer such as polytetrafluoroethylene (PTFE) or fluorinated ethylene propylene (FEP), a braided body made of a metal such as stainless steel or a nickel-titanium alloy, or a polymer such as polyethylene terephthalate (PET) or a liquid crystal polymer, and a Pebax (登録商標)The catheter may be constructed of a tubular or tubular material, and an outer coating may be made of a polyether block amide-based thermoplastic elastomer resin such as a polyurethane, polyamide, polyamide copolymer, polyester, polyester copolymer, fluorinated polymer such as PTFE or FEP, polyimide, polycarbonate, or other suitable material, or other standard or specialty materials used in the manufacture of catheters used in the bloodstream.

[0025] Referring to FIG. 3 , the filter valve occluder 110 is a tubular braided structure comprised of multiple metal (e.g., stainless steel or nickel-titanium alloy) or polymer filaments or strands 120 that are configured to assume a substantially closed configuration upon deployment and resist external forces. When polymer filaments are used, the filaments 120 can be comprised of, for example, PET, polyethylene naphthalate (PEN), liquid crystal polymer, fluorinated polymer, nylon, polyamide, or other suitable polymers. Optionally, when polymer filaments are used, one or more metal filaments may be utilized in conjunction with the polymer filaments. According to one aspect of the present invention, when metal filaments are used, such metal filaments may be comprised of a radiopaque material to facilitate tracking of the filter valve occluder 110 and its configuration within the body. In its expanded diameter configuration, the filter valve occluder 110 is configured to change shape in response to fluid forces. The ends of the filaments 120 are preferably not bonded together to allow the valve to rapidly and automatically adapt to dynamic flow conditions. The filter valve's multiple filaments 120 are preferably braided and configured to allow relative movement between their ends. The filaments are spring-loaded (ie, have "shape memory") to assume a desired cross angle relative to one another so that the bulb can self-assemble into a desired shape.

[0026] 3, the filter valve occluder 110 has a substantially spherical shape with a larger proximal end and a smaller distal end, defined by a tapered shape toward the distal end where it is coupled to the catheter and a proximal inversion such that the distal end where it is coupled to the catheter faces the proximal end.

[0027] More specifically, each filament or strand 120 includes a proximal portion 122, a central portion 124, and a distal portion 126. The distal portion 126 is attached to the outer surface of the catheter at a first location 128 toward the distal end of the catheter 102 and proximal to the catheter's aperture 112. The central portion 124 extends proximally and radially outward from the distal portion 126. The proximal portion 122 of the strand turns radially inward from the central portion 124 and extends distally on the outer surface of the catheter, where it is attached circumferentially to the outer surface of the catheter 108 at a second location 130 proximally offset from the first location 128. The proximal and distal attachment locations 128, 130 are preferably secured to the outer surface of the catheter, for example, by melt bonding or bonding agents. Alternatively, one or both of these attachment locations may be configured as a movable link, for example, by applying a ring-shaped member to the catheter. As described in more detail below, the proximal and central portions 122, 124 of the strands are coated with a polymer filter or membrane material 132 that spans and extends across the strands 120, rendering that region of the microvalve fluid impermeable, while the distal portion 126 of the fibers 120 is substantially free of the polymer filter coating, allowing fluid to pass between open fiber spaces 134 from the exterior to the interior 136 of the filter valve occluder 110.

[0028] 2, an introducer sleeve (or outer catheter) 140 may be provided to hold the filter valve occluder 110 in a collapsed configuration while the infusion catheter 102 with occluder 110 is advanced to a target location within the patient. When the introducer sleeve 140 is retracted over the filter valve occluder 110 at the target location, the filter valve occluder 110 expands outward and is configured to undergo limited dynamic movement (radial expansion and contraction) in response to local fluid pressure conditions proximal and distal to the filter valve occluder. Alternatively, the system can be guided to the target location without the sleeve 140.

[0029] As noted above, as described in U.S. Patent No. 8,696,698, previously incorporated herein, there are three parameters that help define the performance and properties of a deployed filter valve occluder 110: the radial (outward) force of the filter valve occluder, the time constant for the filter valve occluder to change from a closed to an open configuration, and (if applicable) the porous pore size of the filter valve occluder.

[0030] According to a preferred embodiment, as the filter valve occluder 110 advances within a blood vessel, it expands to a deployed configuration. Once the filter valve is deployed, if the pressure at the distal opening of the catheter is greater than blood pressure, the filter valve will fully expand to the vessel wall (i.e., be in an open configuration). Alternatively, if blood is flowing from proximal to distal with sufficient force at a pressure greater than the pressure at the catheter opening, the filter valve occluder will be deployed but in a closed configuration (i.e., the filter valve occluder is separated from the vessel wall). Furthermore, if the radial expansion force on the filter valve occluder (i.e., the force due to distal intravascular pressure on the distal surface area of ​​the filter valve occluder in addition to the expansion force of the filter valve occluder itself) is greater than the radial compression force on the filter valve occluder (i.e., the force on the proximal surface area of ​​the filter valve occluder due to proximal vascular pressure), the filter valve occluder will fully expand and be in the open configuration. That is, the radial force at which the filter valve occluder expands can be set low (as described in more detail below) to prevent normal downstream distal blood flow from opening the deployed filter valve occluder, or the radial force can be set high enough so that the filter valve occluder remains substantially fully open under normal blood flow.

[0031] The radial expansion force of a braid was reported by Jedwab and Clerc (Journal of Applied Biomaterials, Vol. 4, 77-85, 1993) and later updated by DeBeule (DeBeule et al., Computer Methods in Biomechanics and Biomedical Engineering, 2005) as follows:

[0032] [ka]

[0033] where K1, K2, and K3 are constants defined by:

[0034] [ka]

[0035] Additionally, I and Ip are the surface and polar moments of inertia of the braided filaments, E is the Young's modulus of the filaments, and G is the shear modulus of the filaments. These material properties, the initial braid angle (β), the final braid angle (β), the stent diameter (D), and the number of filaments (n) affect the radial force of the braided valve.

[0036] According to one exemplary embodiment, the filter valve occluder 110 is constructed from 24 polyethylene terephthalate (PET) filaments 120. Each filament has a diameter of 0.1 mm and is preformed onto an 8 mm diameter mandrel with a braid angle of 130° (i.e., the filaments are spring-loaded or have shape memory, forming a 130° angle with respect to each other when the valve is fully deployed and open to a frustum shape). The Young's modulus of the filaments 120 is preferably greater than 200 MPa, and the filter valve occluder 110 preferably has a radial force of less than 40 mN when in the fully deployed position (i.e., when the filaments have reached their shape memory state). More preferably, the filter valve occluder 110 has a radial force of less than 20 mN when in the fully deployed position, and even more preferably, the filter valve has a radial force of approximately 10 mN when in the deployed position (as used in this disclosure, the term "approximately" is defined to mean ±20%).

[0037] According to one embodiment, when subjected to infusion pressure at the distal opening 112 of the catheter, the filter valve occluder 110 moves between a deployed (closed) position that allows downstream fluid passage and a deployed (open) position that prevents fluid passage in 0.067 seconds when using a static fluid (e.g., glycerin) with a viscosity approximately equal to that of blood (i.e., approximately 3.2 cP). For purposes of this disclosure, the time required to move from the closed position to the open position with a static fluid is referred to as the "time constant." Furthermore, according to certain aspects of the present invention, the filter valve occluder 110 is configured such that its time constant is between 0.01 and 1.00 seconds when using a fluid with the same viscosity as blood. More preferably, the filter valve occluder 110 is configured such that its time constant is between 0.05 and 0.50 seconds when using a fluid with the same viscosity as blood. The time constant of the filter valve occluder 110 can be adjusted by varying one or more of the parameters mentioned above (eg, number of filaments, modulus of elasticity of the filaments, diameter of the filaments, etc.).

[0038] According to one aspect of the present invention, the deployed filter valve opens and closes quickly enough to achieve high therapeutic agent capture efficiency even in the presence of rapidly changing pressure conditions. More specifically, when the pressure at the distal aperture 112 exceeds the intravascular pressure, a tight seal is formed between the filter valve periphery and the vessel wall, thereby preventing backflow of the therapeutic agent. Importantly, pressure is transmitted through the blood throughout the vascular system at the speed of sound (1540 m / s), causing the valve to open and close in response to pressure changes within the vessel. Because the expandable filter valve responds to pressure changes, it responds much faster than the flow velocity of emboli in the blood (0.1 m / s), thereby preventing backflow of emboli.

[0039] As one skilled in the art will appreciate, the braid geometry and material properties of the filaments 120 are closely related to the radial force and time constant of the filter valve. Therefore, according to one aspect of the present invention, a filter valve is useful in a variety of vessels with different diameters and flow conditions, allowing for unique optimization for each embodiment. For example, in one embodiment, the filter valve occluder 110 has 10 filaments 120, while in another embodiment, the filter valve has 40 filaments 120. Any suitable number of filaments can be used. The filament diameter is preferably selected from the range of 0.025 to 0.127 mm, although other diameters are also possible. The pitch angle (i.e., the crossing angle of the braided filaments in the fully open, deployed position) is preferably selected from the range of 100 to 150°, although other pitch angles are also possible.

[0040] The proximal and central portions of the braid of the filter valve occluder 110 have a polymer coating. The polymer can be coated onto the braid to form a filter in several ways, including spraying, spinning, electrospinning, adhesive bonding, heat sealing, mechanical entrapment, melt bonding, dip coating, or any other desired method to form the coating. Filter materials can include porous materials such as ePTFE, laser-drilled holes in a solid material such as polyurethane, or a mesh of very fine filaments layered over the braid.

[0041] When a thin filament mesh is used as the polymer filter 132, the characteristic pore size of the filter can be determined by passing beads of different diameters through the filter and determining which diameters pass through the filter in large quantities. According to U.S. Patent No. 4,738,740, very thin filaments can be wound around a rotating mandrel with the aid of an electrostatic field, in the absence of an electrostatic field, or both. The filter thus formed can be attached to a braided structure with an adhesive, or the braid can be placed on a mandrel and the filter wrapped over, under, or on both sides of the braid, essentially trapping the filter. The filter may have pores formed by spraying or electrospinning, or the pores may be subsequently formed by laser drilling or a secondary process. According to one embodiment, materials capable of electrostatic deposition or spinning are used to form the filter on the braid. Materials that can be bonded to themselves are particularly preferred. Filter materials include polyurethane, pelletane, and the like. (登録商標) Examples of suitable polymers include thermoplastic urethanes such as urethane foam, polyolefins, polyesters, fluororesins, acrylic polymers, acrylates, polycarbonates, or other suitable materials. Because the polymer is wound around the braided body in a wet state, a solvent-soluble polymer is preferred. According to one embodiment, the filter is formed from a solution of polyurethane in dimethylacetamide (DMA) and tetrahydrofuran (THF). The polymer concentration in the solution during spinning is preferably 5-10% solids for electrostatic spinning and 15-25% solids for wet spinning.

[0042] As an alternative to the polymer coating 132, the braid can be dip-coated to form a filter. The braid is placed on a mandrel with an outer diameter equal to the inner diameter of the fully expanded braid. The mandrel is preferably made of polytetrafluoroethylene (PTFE)-coated steel. PTFE also serves as a release surface. Alternatively, an uncoated mandrel can be used. When placing the braid on the mandrel, it is important to ensure there is no gap between the inner diameter of the braid and the outer diameter of the mandrel. That is, the diameters should preferably be the same within a tolerance of ±0.065 mm. Having the entire inside of the braid in contact with the mandrel ensures uniform coating of the filaments with the polymer, as described below, and ensures uniform expansion of the filter valve after the polymer dries. Alternatively, the braid can be placed on an oversized mandrel (larger than the inner diameter of the braid), but this will increase the braid angle of the filaments, altering the size of the filter valve and affecting expansion force. Alternatively, the braid can be placed inside a tubular mandrel that is the same size as the braid's outer diameter and has tolerances similar to those mentioned above. Yet another option is to place the braid inside a smaller tubular mandrel (with an inner diameter smaller than the braid's outer diameter), but this reduces the filament braid angle, which also changes the size of the filter valve and affects the expansion force. The type of mandrel (solid or tubular) and the braid's location (external or internal) affect the distribution of the polymer on the braid (solid mandrels provide a smooth inner-coated filter valve for external installations, while tubular mandrels provide a smooth outer-coated filter valve for internal installations). This changes the lubricity zone of the finished filter valve.

[0043] After the braid is securely placed over (or within) the mandrel, it is immersed in a polymer solution at a controlled, constant rate. This solution can be prepared by dissolving an elastomeric thermoplastic polymer in a solvent system with a boiling point between 30 and 200°C, resulting in a solution with a dynamic viscosity ranging from 50 to 10,000 cP. Suitable rise and fall speeds are inversely proportional to the viscosity of the solution and range from 1 to 100 mm / sec. This speed is important to ensure that the polymer uniformly coats the braid, wetting the entire surface of the braid, even where the braid filaments are in contact with the mandrel, penetrating the polymer coating, especially onto the surface in contact with the mandrel, and releasing any air bubbles trapped during the immersion process. One example is a thermoplastic urethane solution (pelletane). (登録商標) In one embodiment, the braid is immersed in a solution of the polymer in dimethylacetamide (DMA) and tetrahydrofuran (THF) solvents at a rate that results in a residence time of 16 seconds for a 6-inch (135 mm) braid. This rate is also preferably such that the polymer flows down the entire length of the braid as it is withdrawn from the solution. This limits the coating thickness, prevents binding of the braid filaments, and / or controls the smoothness of the polymer coating, so the braid is immersed in the solution only once. Speed ​​control can be achieved by connecting the mandrel to a mechanical device that dips and withdraws the braid from the polymer solution at a steady, controlled rate.

[0044] After the braid is drawn from the polymer solution, the solvent is evaporated over a time frame and temperature range corresponding to the boiling point of the solvent. Higher temperatures and longer periods are used for higher-boiling solvents. A preferred polymer solution uses some DMA to control the uniformity of the coating thickness. THF may be used to control the rate of solvent evaporation. The ratio of a high-boiling solvent, such as DMA, to a low-boiling solvent, such as THF, can control the rate of conversion from a low-viscosity, high-solvent polymer solution to a high-viscosity, low-solvent polymer solution and then to a solvent-free solid material, thereby adjusting the quality of the polymer film. According to one method, the solvent is released in an oven heated to a temperature above the boiling point of DMA (165°C), resulting in rapid release of the DMA. A preferred heating time at this temperature is 5 minutes, which is sufficient to fully release the DMA. It will be appreciated that THF has a substantially lower boiling point (66°C) and will evaporate quickly without such extensive heating. Alternatively, heating the polymer-coated braided body in an oven at a temperature below the boiling point of DMA, e.g., 80°C to 100°C, will release DMA from the coated braided body, but at a slower rate than heating above the boiling point of DMA. This temperature allows for rapid expulsion of DMA while maintaining the integrity of the coated braided body. A preferred heating time at this temperature is 10 minutes, which allows for sufficient release of DMA. Alternatively, the polymer-coated braided body can be dried at ambient temperature, which will result in a slower release rate of DMA than the methods described above.

[0045] After the solvent is released from the polymer-coated braid, the coated braid is cooled below the glass transition temperature of the polymer on the braid. After cooling, the coated braid is removed from the mandrel. If the mandrel is coated with PTFE, the braid will naturally separate from the mandrel or can be easily removed. If the mandrel is not coated, a release agent such as isopropyl alcohol (IPA) can be used to facilitate removal of the coated braid from the mandrel. The elastomeric membrane filter formed on the braid can be elastically deformed in the elongation range of 100 to 1000%. The membrane is made of pelletane. (登録商標) In addition, but not limited to, other polyether-based aromatic thermoplastic urethanes, polyether-based aliphatic thermoplastic urethanes (e.g., Tecoflex (登録商標) ), polyether block amide (e.g., Pebax (登録商標) They are made from polymers such as styrene-isoprene-butadiene-styrene (SIBS), silicones, and other polymers. These polymers can be made into a fluid by dissolving them in an appropriate solvent or by heating them to their melting point.

[0046] Depending on the polymer and coating technology, the coating may be liquid-impermeable or porous. If porous, the coating may have a characteristic pore size of 10 μm to 500 μm, more preferably 15 μm to 100 μm, even more preferably less than 40 μm, and even more preferably 20 μm to 40 μm. The filter valve may be configured to allow the retrograde flow of contrast media through the valve opening as a clinical endpoint indicator while preventing the retrograde flow of therapeutic agents. Furthermore, allowing blood to retrogradely flow through the filter material, even at a relatively slow rate, can alleviate backpressure on the distal side of the valve, if such functionality is desired.

[0047] According to yet another aspect, the coating on the filament braid may be non-polymeric and may be applied by any suitable method. As one example, the coating may include a metal mesh. As another example, the coating may include a biological tissue material. Such a coating material is configured to form a barrier to the passage of a therapeutic agent on the resulting occluder when the therapeutic agent is applied to the filament braid.

[0048] The filter valve occluder 110 preferably includes a hydrophilic coating, a hydrophobic coating, or other coating that affects the adhesion of blood proteins to the filter. More specifically, such coatings are resistant to blood protein adhesion. Suitable coatings include ANTI-FOG COATING 7-TS-13 from Hydromer, Inc., Branchburg, New Jersey, and SERENE COATING from Surmodics, Inc., Eden Prairie, Minnesota. These and other coatings can be applied to the filter by, for example, dipping, spraying, or roll or flow coating.

[0049] The filter valve occluder 110 offers several advantages over conventional vascular occluders. First, its shape naturally creates a tapered tip for navigation within a blood vessel. This tapered shape significantly reduces resistance to navigation within a blood vessel and contact with the vessel wall, thereby reducing the likelihood of vasospasm. Second, its shape creates a large, bulbous proximal end that offers significantly higher resistance to blood flow than conventional dynamic microvalve devices. This results in a greater reduction in vascular blood flow at the valve site and a significant pressure drop distal to the valve site. This is advantageous in various therapeutic drug delivery procedures. For example, for localized delivery of therapeutic drugs to various tumors within organs, such as the liver or pancreas, it is desirable to reduce vascular blood flow to the organ before and during pressurized delivery of the therapeutic drug to the organ. Furthermore, the filter valve occluder offers the advantage of being a dynamic valve that can dynamically change shape in response to pressure changes proximal and distal to the occluder, thereby regulating downstream pressure and dynamically preventing backflow.

[0050] 4, there is shown an alternative filter valve occluder 210 (like parts are numbered in increments of 100) constructed from a tubular braid of multifilamentary elastic filaments as described above, wherein a distal end 226 of the braid 220 is circumferentially attached to the outer surface of the catheter 212 at a first location 228d distal to and proximal to the catheter aperture 212, a central portion 224 of the braid 220 extends proximally and radially outward from the first location 228d, and a proximal portion 222 of the braid extends radially inward and is circumferentially attached to the outer surface of the catheter 212 at a second location 230 displaced proximally from the first location 228d, such that the braid defines a spherical shape. The length between the first and second positions 228, 230 is preferably fixed, although one of the first and second positions 228, 230 can be a tubular member that is movable relative to the outer surface of the catheter. The proximal and central portions 222, 224 of the strands are covered with a polymer filter or membrane material 232 that spans and crosses the braids, making that region of the microvalve fluid-impermeable, while the distal portion 226 of the braid is substantially free of the polymer filter and is configured to allow fluid to pass between the open braids. This configuration provides lower flow resistance and greater drag when advancing the microvalve within a vessel compared to the tapered tip and bulbous proximal end configurations described above.

[0051] In embodiments described herein, the components of the filter valve occluder may be coated to reduce friction during deployment and retraction. Such components may also be coated to further reduce vasospasm, reduce thrombus formation along the valve, or enhance compatibility with therapeutic agents, biologics, or embolic materials. Such components may also be coated to enhance embolic material binding and removal of embolic material from the blood vessel during withdrawal of the therapeutic treatment device.

[0052] Additionally, the catheter and braid may be separately labeled for easy visualization under fluoroscopy. Catheter labeling can be accomplished by any means known in the art. Examples include incorporating a radiopaque material into the catheter tubing. Radiopaque materials include barium sulfate, bismuth carbonate, or other materials. Alternatively, or in addition, a radiopaque medium may be incorporated into the braid and filter material. Alternatively, as previously discussed, one or more filaments may be selected and formed from a radiopaque material, such as platinum-iridium.

[0053] In each embodiment, the catheter may be a single-lumen catheter or a multi-lumen catheter, preferably having at least one lumen used for delivering a therapeutic agent, and optionally including one or more additional lumens for passage of a guidewire or other device, or for administering, for example, a vascular flushing fluid after administration of a therapeutic agent.

[0054] The above-described devices and methods are primarily directed to therapeutic devices capable of allowing biological fluids (e.g., blood) to flow proximally and distally within a body vessel while preventing the backflow of injected therapeutic agents past the valve in the proximal direction. Furthermore, in some embodiments, the microvalve occluder configuration is optimized to reduce blood flow from proximal to distal through the occluder. Such microvalves may be configured to adjust the radial force of the occluder to further reduce blood flow within the vessel. For example, in all embodiments, the radial force of the filter valve can be adjusted by adjusting the braid angle. Adjusting the radial force can reduce blood flow by up to 50% or more. By way of example, braid angles greater than 130° significantly reduce blood flow distally through the valve. A braid angle of approximately 150° slows blood flow by 50-60%. Other braid angles reduce distal blood flow by different amounts.

[0055] Although the above description is directed to the use of such devices primarily for injecting therapeutic agents, it is understood that the devices have functionality even when therapeutic agent delivery is not their primary function.

[0056] This disclosure has described and illustrated embodiments of devices and methods for reducing or preventing backflow of therapeutic agents within blood vessels. While specific embodiments have been described, the invention is not limited thereto. The invention is intended to be as broad as technically possible, and the specification should be construed accordingly. That is, while various materials are listed for the microvalve filaments, valve coatings, and catheters, it will be understood that each material in each of the various embodiments can be used in combination with other materials. Furthermore, while reference is made throughout this disclosure to the infusion of therapeutic agents, this term should be broadly interpreted to include any therapeutic agent, including, but not limited to, cancer cell-targeted drugs and immunotherapeutic agents, such as immunomodulators, vaccines, modified cells, checkpoint inhibitors, and the like, as well as agents that assist in the delivery of therapeutic agents, such as, but not limited to, imaging agents. Furthermore, while the invention has been described with respect to specific human arteries, it will be understood that the invention is broadly applicable to blood vessels and other vessels (including tubular tissues) in humans and animals. In particular, the device can be used to treat tumors, such as liver, kidney, or pancreatic cancer. Furthermore, although these aspects have been described with respect to the distal end, the proximal end may take a variety of forms known in the art. Accordingly, those skilled in the art will recognize that further modifications may be made to the present invention without departing from the scope of the claims.

Claims

1. A therapeutic device for delivering a therapeutic agent into a blood vessel during vascular surgery in a patient, the blood vessel having a vascular wall, the therapeutic device including a flexible catheter and a filamentous structure; a) the flexible catheter has a size that allows it to be introduced into the blood vessel, and has a proximal end, a distal end, an outer surface, and an inner lumen extending between the proximal end and the distal end and opening into a distal opening; b) the filamentary structure is attached to the outer surface of the catheter adjacent the distal end of the catheter and comprises a plurality of elastic filamentary strands and a material; i) the plurality of elastic filamentary strands form a tubular braid and have a proximal portion, a central portion, and a distal portion; the distal portion is fixed at a first position proximal to the aperture along a longitudinal direction relative to the outer surface of the catheter; the central portion extends proximally from the distal portion and is biased to extend radially outward from the outer surface of the catheter; the proximal portion is everted radially from the central portion toward the interior of the central portion and everted distally toward the exterior surface, and the proximal portion is circumferentially connected to a second location proximally spaced from the first location around the exterior surface of the catheter; ii) the material is provided over the proximal portion of the strand and at least a portion of the central portion of the strand and forms a barrier to the passage of a therapeutic agent; treatment equipment.

2. The treatment device of claim 1 , wherein the proximal portions of the strands are longitudinally fixed at the first location.

3. The therapeutic device of claim 1 , wherein the strands are movable relatively and independently between the proximal and distal ends.

4. The therapeutic device of claim 1 , wherein the strands are made of a nickel-titanium alloy.

5. The therapeutic device of claim 1 , wherein the proximal and central portions of the strands are coated with the polymeric material.

6. The therapeutic device of claim 1 , wherein the polymeric material is a fluid-impermeable membrane.

7. The treatment device of claim 1 , wherein the polymeric material extends across and between the strands.

8. The therapeutic device of claim 1 , wherein the material is a polymer.

9. The therapeutic device of claim 8 , wherein the polymer is a thermoplastic urethane.

10. 10. The therapeutic device of claim 1, wherein the filamentary structure defines spaces between the distal portions of the strands, the spaces providing fluid communication to the interior of the filamentary structure.

11. A therapeutic device for delivering a therapeutic agent into a blood vessel during vascular surgery in a patient, the blood vessel having a vascular wall, the therapeutic device including a flexible catheter and a filamentous structure; a) the flexible catheter has a size that allows it to be introduced into the blood vessel, and has a proximal end, a distal end, an outer surface, and an inner lumen extending between the proximal end and the distal end and opening into a distal opening; b) the filamentary structure is attached to the outer surface of the catheter adjacent the distal end of the catheter and comprises a plurality of elastic filamentary strands and a fluid-impermeable material; i) the plurality of elastic filamentary strands form a tubular braid and have a proximal portion, a central portion, and a distal portion; the distal section is fixed at a first position proximal to the aperture along the longitudinal direction of the outer surface of the catheter; the proximal portion is fixed at a second location proximal to the first location along the longitudinal direction of the outer surface of the catheter; the central portion extends radially from the catheter; ii) the fluid impermeable material is provided over at least the proximal portions of the strands and at least a portion of the central portions of the strands and forms a barrier to the passage of a therapeutic agent; treatment equipment.

12. The therapeutic device of claim 11 , wherein the strands are independently movable relative to one another between the proximal and distal ends.

13. The therapeutic device of claim 11 , wherein the strands are made of a nickel-titanium alloy.

14. The therapeutic device of claim 11 , wherein the proximal and central portions of the strands are coated with the polymeric material.

15. The therapeutic device of claim 11 , wherein the polymeric material is a membrane.

16. The treatment device of claim 11 , wherein the polymeric material extends across and between the strands.

17. The therapeutic device of claim 11 , wherein the material is a polymer.

18. 18. The therapeutic device of claim 17, wherein the polymer is a thermoplastic urethane.

19. 12. The therapeutic device of claim 11, wherein the filamentary structure defines spaces between the distal portions of the strands, the spaces providing fluid communication to the interior of the filamentary structure.

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