Therapeutic treatment device having a braided microvalve occluder with a foldable cover - Patent Application 20070122997

Abstract

The therapeutic device for use in blood vessels includes a catheter and a microvalve. A flexible, low-friction, reconfigurable cover is attached to or near the distal end of the microvalve. The cover is deployed between the occluder and the vessel wall and intervenes between the occluder and the vessel wall as the occluder moves relative to the vessel wall, reducing the occurrence of vascular spasm.

Description

[Technical Field]

[0001] This application claims priority to U.S. Patent Application No. 17 / 970,329, filed October 20, 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 features that may not be 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 device in its collapsed, undeployed state is determined 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.

[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 not coated with a polymeric filter. One variation of this microvalve infusion system 10 is available from Trisalus Life Sciences, Inc. of Westminster, Colorado, under the tradename 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] It has been observed that some microvalve occluders, when moved longitudinally within a blood vessel, create significant resistance to advancing the microvalve occluder within the blood vessel, especially if the occluder is large in size. As the microvalve occluder advances, it deforms, increasing its surface area in contact with the vessel wall. Drag is generated at the interface between the occluder surface and the vessel wall. Thus, the greater the surface area in contact with the vessel wall, the greater the drag generated.

[0014] Such resistance can traumatize and irritate the artery, potentially leading to vasospasm. Vasospasm is a condition in which the smooth muscle of the artery constricts. This can occur locally or can cause a chain reaction along the length of the vessel. This constriction significantly reduces blood flow within the vessel, resulting in a drop in pressure distal to the vessel. If this occurs proximally to the microvalve occluder, antegrade blood flow is lost, preventing downstream blood flow after injection, creating an effect similar to that of an occlusion balloon. If spasm occurs distal to the microvalve occluder, distal blood flow is significantly reduced, inhibiting therapeutic drug delivery. Furthermore, tracking the microvalve occluder back and forth through the spasm can result in further damage to the device and vessel injury.

[0015] An infusion device is provided that includes a catheter and an occluder. The catheter has a proximal end, a distal end having a distal tip, and a lumen extending from the proximal end to the distal tip and opening through the distal tip into a distal opening. The occluder may be a microvalve.

[0016] Depending on the side of the injection device, a flexible cover is attached to or near the distal end of the microvalve. The flexible cover can be formed from a smooth, lubricious sheet material. The flexible cover is interposed between the occluder and the patient's vessel wall, providing a low-friction surface against the vessel wall as the occluder advances through the vessel. The cover reduces or prevents the occurrence of vessel spasm during tracking and guidance of the device.

[0017] The cover preferably deploys in response to resistance to advancement of the occluder through the vessel, and then, when movement stops, the force of antegrade blood flow within the vessel disengages the cover from the occluder, allowing the occluder to function as intended. [Brief explanation of the drawings]

[0018] [Figure 1] PRIOR ART FIG. 1 is a side elevation view of a prior art injection system.

[0019] [Figure 2] FIG. 2 is a side elevational view of an injection system according to an embodiment described herein.

[0020] [Figure 3] FIG. 3 is an enlarged view of the distal end of the injection system shown in FIG.

[0021] [Figure 4-6] 4 to 6 are diagrams showing the operation of the injection device within a blood vessel, showing the device moving forward within the blood vessel (FIG. 4), the device at rest receiving antegrade fluid flow (FIG. 5), and the device injecting a therapeutic agent (FIG. 6).

[0022] [Figure 7-9] 7 to 9 are diagrams showing the operation of a modified injection device within a blood vessel, depicting the device moving forward within the blood vessel (FIG. 7), the device at rest receiving antegrade fluid flow (FIG. 8), and the injection of a therapeutic agent by the injection device (FIG. 9).

[0023] [Figure 10-12] 10 to 12 are diagrams showing the operation of a modified injection device within a blood vessel, depicting the device moving forward within the blood vessel (FIG. 10), the device at rest receiving antegrade fluid flow (FIG. 11), and the device injecting a therapeutic agent (FIG. 12). DETAILED DESCRIPTION OF THE INVENTION

[0024] 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.

[0025] A first exemplary embodiment of an injection device 110 according to the present invention is shown in Figures 2 and 3. It should be noted that the portions of the system shown in these figures are not drawn to scale, with the distal portion being greatly exaggerated for illustrative purposes. As shown in Figure 2, the injection device 110 includes a flexible catheter 112 having a proximal end 116 and a distal end 120, a hub 114 coupled to the proximal end 116 of the catheter, and a vascular occluder 118, described in more detail below, coupled to the distal end 120 of the catheter 112. In accordance with one aspect of the injection system, a deployable cover 124, described in more detail below, is provided to protect the patient's vessel wall from the outer surface of the vascular occluder 118 while the injection device 110 is tracked along a guidewire and / or navigated to a target location within the patient's vessel.

[0026] The catheter 112 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). The catheter 112 is made of 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.

[0027] The hub 116 may include a luer connector or other standardized connector. The infusion lumen extends from the hub 116 to the distal tip 122 of the catheter and opens at a distal opening 132 of the catheter, with the hub 116 configured to deliver a therapeutic agent from outside the patient's body to a target blood vessel (artery or vein). The hub 116 is preferably configured to facilitate the advancement of a guidewire through the infusion lumen and / or the connection of a syringe to the infusion lumen for infusion of the therapeutic agent. Any hub suitable for at least facilitating delivery of a therapeutic agent to the infusion lumen may be utilized.

[0028] The occluder 118 is preferably a dynamic microvalve fabricated as follows. Referring to FIG. 3, multiple strands are fabricated or provided as a tubular braid 142. The tubular braid is a tubular braided structure comprised of multiple metal (e.g., stainless steel or nickel-titanium alloy) or polymer filaments or strands 142 that, when deployed, assume a substantially closed configuration and are not subject to external forces. When polymer filaments are used, the filaments 142 may 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. In accordance with one aspect of the present invention, when metal filaments are used, the metal filaments may be comprised of a radiopaque material to facilitate tracking of the filter valve occluder 118 and its configuration within the body. The filaments 142 are not bonded end-to-end to allow for relative movement between the ends. The filter valve's multiple filaments 120 are preferably braided and configured. The filaments are spring-loaded (i.e., have "shape memory") to assume a desired crossing angle relative to one another so that the bulb can self-assemble into a desired shape. Diamond-shaped gaps 144 are formed between adjacent pairs of crossing filaments, with the intersections of the filaments forming the apexes of the diamond-shaped gaps. The specific shape and size of the diamond-shaped gaps are determined by the braid angle between the crossing filaments in the tubular braid.

[0029] The filament diameter is selected in the range of 0.025 to 0.127 mm, although other diameters can be used. The pitch angle (i.e., the crossing angle of the braided filaments in the fully open, deployed position) is preferably selected in the range of 100 to 150°, although other pitch angles can be used.

[0030] In accordance with one aspect of the infusion device, the strands 142 of the tubular braid are primed to promote adhesion of the polymer coating described below and to maintain the stability of the polymer on the filaments to prevent degradation over time. An example of a primer is Tecoflex (登録商標) These include polyether polyurethanes, polyamic acids, and parylenes.

[0031] A polymer coating 160 is then applied onto the elastic strands 142 and into the diamond-shaped interstices 144 formed between the strands. The braid can be coated with the polymer 160 by any of several methods, including spraying, spinning, electrospinning, adhesive bonding, heat sealing, mechanical entrapment, melt bonding, dip coating, or any other desired method to form a coating suitable for use as a filter. 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 a braid.

[0032] When a thin filament mesh is used as the polymer filter 160, 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) Suitable polymers include polyolefins, polyesters, fluororesins, acrylic polymers, acrylates, polycarbonates, silicones, and / or other suitable materials. Because the polymer is wrapped around the braid 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.

[0033] As an alternative to polymer coating, 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 can be polytetrafluoroethylene (PTFE)-coated steel. The 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. Contacting the entire inside of the braid with the mandrel ensures uniform polymer coating of the filaments, as described below, and ensures uniform expansion of the filter valve after the polymer dries. Alternatively, a cylindrical 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.

[0034] After the braid 140 is securely placed over (or within) the mandrel, it is dipped into a polymer solution at a controlled, constant speed. This solution may consist of an elastomeric thermoplastic polymer dissolved 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 all surfaces of the braid, even those filaments 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 dipping 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.

[0035] After the braid 140 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 point solvents. A preferred polymer solution uses some DMA to control the uniformity of the coating thickness. THF may also 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 driven off 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.

[0036] 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.

[0037] Depending on the polymer and coating technique, the coating may be liquid impermeable or porous, and if porous, 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.

[0038] According to various embodiments, polymer coating 160 is located in areas of thicker primer (region 152a), thinner primer (region 152b), and / or primer-free (region 152c) on strands 142. According to one embodiment, the polymer coating is applied non-uniformly between the proximal and distal ends of the tubular form of the braid.

[0039] 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.

[0040] The polymer-coated braid preferably comprises 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.

[0041] After being coated with the polymer, the tubular braid is assembled into a catheter 112. The multiple strands 142, tubular primer, and polymer filter 160 that make up the braid have an inner and outer surface. According to one embodiment, a first end 170 of the tubular form is secured to the catheter at a first location 172 proximal to the distal tip 122 of the catheter 112. The tubular form is then reformed by inverting the tubular form and bending it so that the previously inner surface of the catheter's second end 174 faces the exterior of the tubular form. The second end is then bonded to the catheter at a second location 176 proximally spaced from the first location, thereby defining a shape that flares outward from the proximal to distal direction and reaches a maximum diameter at a central portion 178.

[0042] In one embodiment, the polymer coating is removed or perforated from the portion of the occluder distal to its maximum expanded diameter. The resulting opening in the occluder is critical to the operation of the occluder of this embodiment. This removal or perforation of the coating exposes the strands of the braid.

[0043] The resulting microvalve occluder dynamically responds to local pressure around the occluder. That is, when the fluid pressure on the proximal side of the occluder exceeds the fluid pressure on the distal side of the occluder by a predetermined level, the occluder automatically transitions to a smaller diameter contracted (or partially contracted) configuration (closed position), allowing forward flow of blood around the occluder and through the vessel. Conversely, when the fluid pressure on the distal side of the occluder exceeds the fluid pressure on the proximal side by a predetermined level, for example, when a therapeutic agent is injected through the distal opening through the infusion lumen, the occluder automatically transitions to a larger diameter expanded configuration (open position), contacting the occluder with the vessel wall and preventing backflow of the therapeutic agent (retrograde inflow). The pressure differential between the proximal and distal sides of the microvalve occluder during dynamic operation is based, at least in part, on the radial expansion force of the braid, as described above.

[0044] As discussed above, the deployable cover 124 is provided to shield a portion of the occluder 118 from the patient's vessel wall while the occluder 118 is moving relative to the vessel wall, e.g., during tracking and guidance of the occluder to a target location, to reduce or prevent vessel spasm prior to therapy delivery. The cover is preferably constructed from a thin, strong, lubricious, and flexible polymer. Exemplary polymers include silicone rubber, natural rubber, and synthetic rubber, as well as pellets, Tecoflex, and the like. (登録商標) and Corothane (登録商標) Aliphatic polyether polyurethanes such as Santoprene (登録商標)Examples of suitable materials include thermoplastic vulcanizates, such as styrene-isobutane-styrene (SIBS), and elastomers, such as styrene-isobutane-styrene (SIBS). Other materials include polyethylene terephthalate (PET), nylon, and polyimide. Additionally, the cover can be constructed from spun polymer fibers. Examples of spun polymer fabrics include pellets and polytetrafluoroethylene (PTFE). The cover can be impermeable, semi-permeable, or permeable; however, it is preferred that the cover shield at least the exposed distal portion of the braid, since the braid is configured to create the most friction against the vessel wall.

[0045] In one aspect, portion 180 of cover 124 is attached to the catheter by sandwiching the portion of the cover between an outer surface 182 of catheter 112 and the braid of occluder 118. More specifically, cover portion 180 is attached between first end 170 of the occluder and first location 172 on the catheter. Cover 124 is immersed in blood or a fluid having substantially the same properties as blood and is configured to have a slight bias or memory such that cover 124 is biased toward the distal portion of occluder 118 and in a generally open direction. Further, with reference to FIG. 4 , as occluder 118 is advanced within a patient's blood vessel 190 in the direction of arrow 192, fluid pressure on distal surface 184 of cover 124 overcomes the force on the cover due to antegrade fluid flow 194, forcing the cover against the distal portion of the occluder, particularly the portion that would otherwise contact the vessel wall. Because the cover 124 has much greater lubricity than the occluder itself, friction between the occluder and the vessel wall is significantly reduced during advancement of the occluder. Referring to FIG. 5, when forward movement stops, fluid pressure within the vessel 190 due to antegrade flow 194 partially contracts the occluder, creating a space between the exterior of the occluder and the vessel wall, overcoming the expansive force of the cover 124 and extending the cover distally from the occluder. Thus, the cover does not interfere with the occluder while it is stationary within the vessel. Next, referring to FIG. 6, when a drug 196 is injected through the catheter's infusion lumen and flows out the distal opening 132, vortex and turbulent flow 198 is generated near the catheter's distal tip 122. However, the increased fluid pressure from the injection causes the occluder 118 to fully expand and contact the vessel wall 190, preventing fluid from passing through the occluder. Thus, although the cover 124 may flutter in the turbulent flow, it again does not interfere with the operation of the occluder. Once the injection has stopped, the occluder 118 with cover 124 again operates as described with respect to FIG.

[0046] 7-9, another embodiment of infusion device 210 is shown, substantially similar to infusion device 110 (like parts are numbered in increments of 100). Infusion device 210 includes a cover 224 attached to catheter 212 at a location displaced from occluder 218. By way of example, cover 224 may be attached to the catheter at a location between occluder 218 and distal aperture 232. Cover 224 may be attached with crimp band 202 and / or adhesive or bonding agent. Cover 224 is configured to extend rearward toward the distal portion of the occluder. Referring to FIG. 7 , as the occluder 218 moves forward within the patient's blood vessel, the distal end 218a of the occluder 218 contacts the distal end 232 of the blood vessel, and as the occluder moves forward within the blood vessel in the direction of arrow 292, the fluid pressure on the distal surface 284 of the cover overcomes the force on the cover from the antegrade fluid 294, maintaining the cover 224 in intimate contact with the distal portion of the occluder 218, particularly the portion that contacts the blood vessel wall 290. Referring to FIG. 8 , when advancement is halted, the fluid pressure from the antegrade flow 294 moves the occluder 218, separating the cover 224 from the occluder 218. The cover 224 may be partially retracted or even everted, as shown. In this manner, the cover 224 does not impede the occluder 218 and fluid flow within the blood vessel while the occluder is stationary within the blood vessel. 9, as therapeutic agent 296 is infused through the infusion lumen of the catheter and through distal aperture 232, the higher pressure at the distal aperture than at the proximal side 206 of occluder 218 causes the occluder to expand, blocking fluid flow within blood vessel 290 past occluder 218, and cover 224 re-extends distally of occluder 218. When infusion stops, the covered occluder resumes operation as described with respect to FIG. 8. Once the therapeutic agent has been infused and the intravascular procedure is complete, infusion device 210 is removed from the patient.

[0047] 10-12, another embodiment of an infusion device 310 is shown, substantially similar to the infusion device 110 shown in FIGS. 4-6 (similar parts are numbered with the addition of 200). The infusion device 310 includes an occluder 318 attached to a catheter 320, with a cover 324 to reduce friction as the occluder advances through a blood vessel. The catheter 320 is provided with a plurality of side holes 400 extending through the wall of the catheter, with the occluder 318 located in the portion of the catheter 320 containing the side holes 400. The side holes are preferably radially oriented. The side holes are preferably equally spaced circumferentially. By way of example, between four and twelve catheter side holes 400 may be spaced along the portion of the catheter 320 within the occluder. The catheter 320 further includes a distal opening 332. The catheter 320 preferably includes a fluid pressure sensor 402 at the distal end 382 of the catheter, adjacent the distal opening 332.

[0048] The occluder 318 advances through the patient's blood vessel 390 in the direction of arrow 392, with the cover 324 operating as previously described. Once movement within the vessel ceases, the cover 324 on the device operates as previously described, specifically disengaging from the occluder 318 when a pressure differential across the occluder allows forward flow of the occluder, as shown in FIG. 11 . Referring now to FIG. 12 , during infusion of a drug through the catheter's infusion lumen, a portion of the drug 404 exits the catheter's holes 400 in the occluder 318, creating pressure within the occluder and forcing the cover 324 out of the occluder. The holes 400 are sized and numbered to have a larger surface area than the distal opening holes 332. This ensures that the flow rate 406 at the distal opening holes 332 is always greater than the flow rate due to infusion through the side holes 400, preventing the cover 324 from blocking the occluder 318.

[0049] Furthermore, end-port injection devices typically experience significant turbulence and Venturi effects near the distal port. Such turbulence can cause localized pressure drops and lead to erroneous pressure measurements within the vessel. However, by providing and positioning the side port 400, i.e., by placing it away from the pressure sensor and on the cover 324 opposite the sensor 402, as shown in FIG. 12, the pressure sensor 402 can be more stable, providing pressure measurements that are less susceptible to artifacts caused by localized turbulence. This benefit is also achieved when the cover is omitted from this embodiment. The present disclosure contemplates that implementing this embodiment with or without the cover will provide the benefits of the side port, including reduced turbulence at the distal port and reduced turbulence-related errors in measurements from the pressure sensor at the distal end of the catheter.

[0050] 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.

[0051] This disclosure has described and illustrated aspects of devices and methods for reducing vascular spasm during the infusion of therapeutic agents or other vascular procedures using an infusion device equipped with an occluder. While specific aspects have been described, the invention is not limited thereto. The invention is intended to be as broad as technically possible, and this specification should be construed accordingly. That is, while various materials are described for the cover, microvalve filament, valve coating, and catheter, it will be understood that each material in each of the various aspects can be used in combination with other materials. While an occluder is described as a preferred microvalve, the cover can also be used with other occluders, including static occluders such as balloons and malecots. 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 agents and immunotherapeutics, such as immunomodulators, vaccines, modified cells, and checkpoint inhibitors, as well as agents that assist in the delivery of the therapeutic agent, such as, but not limited to, contrast media. Also, while the present invention has been described with reference to specific human blood vessels, it will be understood that the present invention has broad application 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 embodiments have been described with reference to the distal end, this is merely because the proximal end can take a variety of forms known in the art. Accordingly, those skilled in the art will recognize that further modifications can be made to the present invention without departing from the scope of the claims.

Claims

1. 1. A therapeutic device for delivering a therapeutic agent into a blood vessel of a patient, the blood vessel having a vascular wall, the device comprising: a) a catheter having a proximal end and a distal end; b) a vascular occluder attached to the catheter adjacent the distal end; c) a flexible cover connected to the catheter, extending between a portion of the occluder and the vessel wall as the occluder advances through the vessel, and configured to automatically separate from the occluder when a predetermined pressure condition within the vessel is met; including, therapeutic devices.

2. The treatment device of claim 1 , wherein a portion of the cover is sandwiched between an outer surface of the catheter and a distal end of the occluder.

3. The treatment device of claim 1 , wherein the cover is secured to the catheter at a location distal to the distal end of the occluder.

4. The treatment device of claim 1 , wherein the cover is self-expanding.

5. The treatment device of claim 1 , wherein the cover is made of a lubricious material.

6. The treatment device of claim 1 , wherein the cover is impermeable.

7. The treatment device of claim 1 , wherein the cover is semi-permeable.

8. The treatment device of claim 1 , wherein the cover is made of an elastomeric material.

9. The treatment device of claim 1 , wherein the cover is made of a polymeric material.

10. The polymer is pellethane （登録商標） and polytetrafluoroethylene.

11. The treatment device of claim 1 , wherein the catheter has a distal opening and a plurality of side holes proximal to the distal opening, and the occluder extends over the side holes.

12. The treatment device of claim 11 further comprising a pressure sensor at the distal end of the catheter.

13. The treatment device of claim 12 , wherein the cover is positioned between the side hole and the pressure sensor.

14. 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, an occluder, and a flexible cover; 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 occluder is attached to the catheter adjacent the distal end, has a proximal side and a distal side, and dynamically changes shape in response to relative fluid pressure between the proximal side and the distal side; Under a first fluid pressure condition within the blood vessel, where the fluid pressure is higher on the distal side than on the proximal side, the occluder transitions to a first configuration having a first diameter that allows blood to flow around the occluder and within the blood vessel from the proximal side to the distal side; under a second fluid pressure condition within the blood vessel, where the fluid pressure is higher on the proximal side than on the distal side, the occluder is configured to transition to a second configuration having a relatively larger second diameter so as to contact the blood vessel wall and prevent passage of fluid through the blood vessel; c) The flexible cover is attached to the catheter and configured to extend between a portion of the occluder and the blood vessel wall as the occluder advances within the blood vessel, but to move away from the occluder when the second fluid pressure condition exists.

15. the occluder comprises a plurality of elastic filamentary strands and a polymeric 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 the first position longitudinally relative to an outer surface of the catheter; the proximal portion is fixed at the second position longitudinally relative to an outer surface of the catheter; the central portion is biased radially outward from the outer surface between the proximal portion and the distal portion; ii) the polymeric material coats the filamentary strands, thereby forming a barrier to passage of the therapeutic agent.

16. 16. The therapeutic device of claim 15, wherein the polymeric material coats at least a portion of the proximal and central portions of the strands, while the distal portions of the strands are free of the polymeric material coating to the extent that the therapeutic agent can pass between the distal portions and within the occluder.

17. 16. The treatment device of claim 15, wherein the distal portions of the strands are inverted to lie at least partially radially within the central portions of the strands.

18. 16. The therapeutic device of claim 15, wherein the strands are made of a nickel-titanium alloy.

19. 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 an occluder; a) the flexible catheter has a size that allows it to be introduced into the blood vessel, and has a proximal end and 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 hole and a plurality of side holes proximal to the distal opening hole; b) the occluder is attached to the catheter adjacent the distal end, has a proximal side and a distal side, extends over the side hole, and dynamically changes shape in response to relative fluid pressure between the proximal side and the distal side; Under a first fluid pressure condition within the blood vessel, where the fluid pressure is higher on the distal side than on the proximal side, the occluder transitions to a first configuration having a first diameter that allows blood to flow around the occluder and within the blood vessel from the proximal side to the distal side; and wherein under a second fluid pressure condition within the blood vessel, where the fluid pressure is higher on the proximal side than on the distal side, the occluder is configured to transition to a second configuration having a relatively larger second diameter so as to contact the blood vessel wall and prevent the passage of fluid through the blood vessel.

20. 20. The treatment device of claim 19, further comprising a pressure sensor at the distal end of the catheter.

21. 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 an occluder; a) the flexible catheter has a size that allows it to be introduced into the blood vessel, and has a proximal end and 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 hole and a plurality of side holes proximal to the distal opening hole; b) The occluder is attached adjacent to the distal end of the catheter and has a maximum diameter and a proximal fluid-impermeable surface and a distal fluid-permeable surface located opposite the maximum diameter, the occluder extending over the side hole and configured to dynamically change shape in response to relative fluid pressures on the proximal and distal sides.

22. 22. The treatment device of claim 21, further comprising a pressure sensor at the distal end of the catheter.

23. 23. The treatment device of claim 22, wherein the pressure sensor is located distal to the occluder.

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