Therapeutic Treatment Device Comprising a Braided Wire Microvalve Occluder with a Modified Filter Coating - Patent application

Abstract

The treatment device includes a catheter and a temporary vascular occluder. The vascular occluder has a plurality of elastic strands extending in a tubular arrangement from a first end to a second end, a primer on the strands, and a polymer filter coating on the primer. The primer is non-uniformly distributed among the plurality of elastic strands. A coated filter is applied over the primer and onto the strands. A portion of the polymer coating may be removed.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Patent Application No. 17 / 992,433, filed November 22, 2022, the entire contents of which are incorporated herein by reference.

[0002] This application is related to commonly owned US Pat. Nos. 8,696,698 and 10,588,636, which are incorporated herein by reference in their entireties.

[0003] 1Technical field The present disclosure relates generally to an infusion catheter for delivering a therapeutic treatment agent into a blood vessel, and more particularly to an infusion catheter having a microvalve at its distal end for increasing penetration of the therapeutic treatment agent into a target blood vessel and reducing backflow of the therapeutic treatment agent into a non-target blood vessel. [Background technology]

[0004] 2. Conventional Technology Intravascular therapeutic agents are often delivered clinically to treat a variety of diseases. For example, endovascular embolization, chemoembolization, and radioembolization therapy have been used to treat a variety of diseases, including hypervascular liver tumors, uterine fibroids, secondary cancer metastases to the liver, preoperative treatment of 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 complications. In addition, non-targeted delivery suggests that the intended delivery target does not receive the full amount of the therapeutic agent.

[0006] Infusion using a standard infusion microcatheter allows for bidirectional flow. That is, the use of a microcatheter to infuse therapeutic agents allows blood and infused therapeutic agents to move forward as well as backflow (reflux). Backflow of therapeutic agents can cause non-target damage to surrounding healthy organs. In interventional tumor treatment procedures, the goal is to attack cancerous tumors with either radiation or chemotherapy. Maintaining forward flow throughout the vascular tree of the target organ is crucial to delivering therapeutic agents to the distal vasculature where they will be most effective. This problem is exacerbated in patients with low-perfusion tumors or undergoing chemotherapy, where slow blood flow limits the amount of therapeutic agent delivered and can result in backflow of the agent to non-target tissues long before the physician can deliver the desired dose.

[0007] During a therapeutic infusion procedure, pressure changes within the blood vessel at multiple locations in the vascular tree. Initially, pressure is higher proximally and decreases along the length of the blood vessel. Forward flow of therapeutic agent occurs when there is a pressure drop. If pressure does not drop along the length of the blood vessel, the therapeutic agent will not flow downstream. If pressure is higher at a location, such as at the orifice of the catheter, the therapeutic agent will flow in the direction of lower pressure. If the pressure generated at the orifice of the infusion catheter is greater than the pressure within the blood vessel proximal to the catheter orifice, some portion of the infused therapeutic agent will flow upstream (reflux) and enter non-target vessels and non-target organs. This phenomenon can occur even in vessels with strong forward flow if the infusion pressure (pressure at the catheter orifice) is sufficiently high.

[0008] In clinical practice with standard infusion catheters, physicians strive to infuse therapeutic agents at pressures that do not induce backflow. To do this, physicians slow the infusion rate (and infusion pressure) or stop the infusion entirely. The clinical impact of current infusion catheters and infusion techniques is twofold: low therapeutic agent doses are delivered and insufficient distal penetration into the target vessel.

[0009] Additionally, reflux can be a time-sensitive phenomenon. Sometimes, reflux occurs in response to the injection of a therapeutic agent, and in this case, reflux occurs rapidly (e.g., on the order of milliseconds), which is too fast for a human operator to react. Alternatively, reflux may occur momentarily, followed by a brief resumption of forward flow within the vessel, after which additional reflux may occur.

[0010] Various devices have been proposed to increase distal penetration while preventing backflow. For example, commonly owned U.S. Patent No. 8,696,698, incorporated herein by reference, describes a microvalve infusion system for infusing a therapeutic agent, which includes a dynamically adjustable filter valve 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 due to its structure of filamentous elements and, upon deployment from an outer catheter, automatically partially expands within the blood vessel and is coated with a porous polymer coating with a pore size small enough to filter or block the therapeutic agent. This structure allows fluid pressure within the filter valve to increase during infusion, thereby opening the filter valve and extending across the blood vessel, thereby preventing backflow of the infused therapeutic agent. In addition, as fluid is pressurized and passes through the delivery catheter and into the filter valve, downstream pressure within the blood vessel increases, thereby promoting maximum absorption of the delivered therapeutic agent into the target tissue. Additionally, the filter valve responds to local pressure around the valve, which thereby allows nearly unrestricted forward flow of blood within the blood vessel and reduces or stops backflow (reverse or backward flow) of therapeutic agents introduced into the blood.

[0011] However, the device in U.S. Patent No. 8,696,698 has certain design features that may not necessarily be advantageous in a given situation. The disclosed filter valve device is generally well-suited when tracking the occluder into small vessels is not a critical requirement, and its trackability in tortuous, branching vasculature may be limited. The distal end of the device in its collapsed, undeployed state is defined by the size of the deployment catheter through which the occluder must be advanced into the vessel, which may be 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 vessel. As a result, tracking the filter valve down to smaller branch vessels may not be optimal. Additionally, once the device is tracked to the treatment location, deployment of the filter valve requires overcoming frictional forces between the filter valve and the outer deployment catheter.

[0012] Co-owned U.S. Patent No. 10,588,636, previously incorporated herein, describes a microvalve infusion system for infusing therapeutic agents, which system addresses device trackability. Referring to Prior Art FIG. 1, the system 10 includes a flexible infusion catheter 12 having 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 includes a braided elastic wire 22, each of which includes a proximal portion 24, a central portion 26, and a distal portion 28. The proximal portion 24 is circumferentially attached around the outer surface 30 of the catheter 12 proximal to a distal orifice 32 of the catheter, the central portion 26 extends radially outward of and toward the orifice 32, and the distal portion 28 of the wire is everted back into the filter valve occluder 18 and circumferentially connected around the outer surface 30 of the catheter 12. The proximal and central portions 24, 26 of the strands 22 are coated with a polymeric filter coating 34 that extends between and across the strands 18. The distal portions 28 of the strands 22 are not coated with a polymeric filter coating. Summary of the Invention [Problem to be solved by the invention]

[0013] An infusion device is provided that includes a catheter having a proximal end, a distal end having a distal tip, a lumen extending from the proximal end to the distal tip, through the distal tip and opening at a distal orifice, and a microvalve including a braided multi-strand structure coupled to the distal end of the catheter proximal to the orifice. [Means for solving the problem]

[0014] The braided multi-strand structure is initially formed as a tube. According to one embodiment of the infusion device, the primer is unevenly distributed along the strands as a result of primer application or post-application treatment. The uneven application can include applying different thicknesses of primer over different areas during the initial primer application, or post-treatment to remove the primer from selected regions of the strands after the initial, preferably consistent, primer application. The post-treatment can include partially or completely removing the primer from selected areas of the elastic strands. Then, after the uneven primer application, a polymeric filter coating is applied over the elastic strands and across the diamond-shaped gaps formed between the braided strands. While the primer is intended to increase the adhesion of the filter coating, the uneven distribution of the primer over the elastic strands alters, particularly reducing, such adhesion of the filter coating to the strands in locations where the primer is reduced or eliminated.

[0015] The braided multi-strand structure is naturally biased to expand radially outward and has a proximal end and a distal end. The inside of a first end of the braided structure is coupled to a catheter at a first location proximally adjacent to the catheter's distal tip, and the braid is then everted and bent backward so that the surface formed as the outside of the braided structure is coupled to the catheter at a second location proximally displaced from the first location. The occluder has a shape that expands outward in a proximal-to-distal direction and maximizes to its largest diameter. When the occluder is placed in a blood vessel, antegrade (downstream) pressure from the flow deforms the occluder to close, allowing flow around the occluder. Then, when a therapeutic agent is infused through the catheter, retrograde pressure (in a distal-to-proximal direction) on the occluder opens the occluder and pushes it into contact with the patient's vessel wall, blocking retrograde flow within the vessel. With reduced adhesive forces, the elastic strands within the braid are less constrained to one another by the filter coating, resulting in less force required to move the strands relative to one another, and therefore the strands can more easily and quickly reconfigure to allow the occluder to move between open and closed states.

[0016] According to another embodiment of the infusion device, the primer may be uniformly or non-uniformly distributed between the elastic strands and the filter coating. The filter coating is then selectively removed down to the elastic strands while the braid is in its tubular configuration. The filter coating is preferably removed by laser ablation. In one embodiment, removal is preferably limited to an area distal to where the braid will later be reshaped to have the maximum diameter of the occluder. In other embodiments, the filter coating may be ablated from the tubular braid, with the remaining coating located at the distal portion of the occluder or removed from the maximum diameter of the occluder. After the coating is removed from selected areas, the tubular braid is then reshaped to form the occluder and attached to the catheter. As a result of the selective removal in the tubular configuration, a precise transition is created between the coated and uncoated portions of the braid. This allows the infusion device to operate with consistent filter valve occluder performance when subjected to force.

[0017] The aspects of non-uniform primer distribution and ablation of the filter coating from the tubular braid can be used individually or together, however, each aspect operates to improve the performance of the filter valve occluder. [Brief explanation of the drawings]

[0018] [Figure 1] FIG. 1 is a side view of a prior art microvalve infusion system. [Figure 2] FIG. 1 is a side view of a microvalve infusion system according to an embodiment described herein. [Figure 3] FIG. 3 is a schematic diagram of a tubular braided structure for use in fabricating an occluder for the microvalve infusion system shown in FIG. 2. [Figure 4] FIG. 1 is a schematic illustration of the reconfiguration of a pixel of a tubular braid by a microvalve occluder as described herein. [Figure 5]FIG. 1 is a schematic illustration of pixel reconstruction of a tubular braid by a microvalve occluder as described herein. [Figure 6] FIG. 1 is a schematic illustration of pixel reconstruction of a tubular braid by a microvalve occluder as described herein. [Figure 7] FIG. 1 is a schematic illustration of the reconfiguration of a tubular braid with a microvalve occluder as described herein. [Figure 8] FIG. 1 is a schematic illustration of the reconfiguration of a tubular braid with a microvalve occluder as described herein. [Figure 9] FIG. 4 is a schematic diagram of the tubular braided structure of FIG. 3 coated with a primer in accordance with the teachings herein. [Figure 10] FIG. 10 is a schematic illustration of the tubular braided structure of FIG. 9 coated with a polymeric filter coating in accordance with the teachings herein. [Figure 11] 1 illustrates the fabrication of a microvalve occluder on a catheter from a polymer-coated braid that is dip-coated onto the inside of a tubular mandrel. [Figure 12] 1 illustrates the fabrication of a microvalve occluder on a catheter from a polymer-coated braid that is dip-coated onto the inside of a tubular mandrel. [Figure 13] FIG. 10 is a partial cross-sectional view of a polymer-coated braided structure attached to a catheter in the manufacture of an occluder for a microvalve infusion system. [Figure 14] FIG. 14 is a view similar to FIG. 13, but showing the polymer coating removed from the distal portion of the occluder after attachment to the catheter. [Figure 15] FIG. 11 is a view similar to FIG. 10 showing a portion of the polymer coating removed from the tubular braided structure by laser ablation. [Figure 16] 16 is a partial cross-sectional view of the polymer-coated braided structure of FIG. 15 attached to a catheter in the manufacture of an occluder for a microvalve infusion system. DETAILED DESCRIPTION OF THE INVENTION

[0019] As used herein, when referring to components of the human body and devices and systems intended to be operated by a user's hand, the terms "proximal" and "distal" are defined relative to the user's hand, with the term "proximal" being closer to the user's hand and the term "distal" being farther from the user's hand, unless otherwise defined.

[0020] 2, an infusion device 110 is provided that includes a catheter 112 and a microvalve occluder 118. The catheter 112 has a proximal end 116, a distal end 142 having a distal tip 122, and an infusion lumen extending from the proximal end to the distal tip, through the distal tip, and opening at a distal orifice 132. The microvalve occluder 118, described in detail below, is formed from a polymer-coated, braided, multi-strand tubular structure that, in a preferred manner, is coupled to the catheter's distal end 142 proximal to the orifice 132.

[0021] The catheter 112 is 2 to 8 feet long and has an outer diameter of 0.67 mm to 3 mm (corresponding to a catheter size of 2 French to 12 French), and is made from a liner made from a fluorinated polymer, such as polytetrafluoroethylene (PTFE) or fluorinated ethylene propylene (FEP), a braid made from a metal, such as stainless steel or a nickel-titanium alloy, or an outer coating made from a polymer, such as polyethylene terephthalate (PET) or liquid crystal polymer, and a polyether block amide thermoplastic elastomer resin, such as Pebax®, polyurethane, polyamide, copolymers of polyamide, polyester, copolymers of polyester, fluorinated polymers, such as PTFE, FEP, polyimide, polycarbonate, or any other suitable material, or any other standard or specialty material used in making catheters used in the bloodstream.

[0022] A hub 114 is preferably coupled to the proximal end 116 of the catheter 112. The hub 114 may include a Luer connector or other standardized connector. An infusion lumen extends within the hub 114, such that the hub is adapted to deliver a therapeutic agent from outside the patient's body (not shown) to a target blood vessel (artery or vein) of the patient. The hub 108 is also preferably adapted to facilitate advancement of a guidewire through the infusion lumen and / or connection of a syringe for infusion of a therapeutic agent through the infusion lumen. Any hub suitable for at least facilitating delivery of a therapeutic agent to the infusion lumen may be utilized.

[0023] The microvalve occluder 118 is preferably fabricated as follows. Referring to FIG. 3, a multi-strand braid 140 in a tubular configuration is created or provided. The tubular braid 140 is composed of multiple metal (e.g., stainless steel or nickel-titanium alloy) or polymer filaments or strands 142 within a tubular braided structure that forms a substantially closed shape when deployed and is not subject to external forces. If polymer filaments are utilized, the filaments 142 may be composed of PET, polyethylene naphthalate (PEN), liquid crystal polymer, fluorinated polymer, nylon, polyamide, or any other suitable polymer. Optionally, if polymer filaments are utilized, one or more metal filaments may be utilized in combination with the polymer filaments. According to one aspect of the present invention, if metal filaments are utilized, they may be composed of a radiopaque material to facilitate tracking of the filter valve occluder 110 and its components within the body. The filaments 142 are not joined to one another between their ends to allow them to move relative to one another. The filaments are spring-loaded (i.e., the filaments have "shape memory") to assume the desired crossing angle with respect to one another. Between each two adjacent pairs of crossing filaments, a diamond-shaped gap, or pixel 144, is formed, with the crossing of the filaments defining the pixel vertices 146. The specific shape and size of the pixel is determined by the braid angle between the crossing filaments in the tubular braid.

[0024] The diameter of the filaments 142 is selected in the range of 0.025 mm to 0.127 mm, although other diameters may be utilized. Preferably, the pitch angle (i.e., the crossing angle taken by the braided filaments in the fully open, deployed position) is selected in the range of 100° to 150°, although other pitch angles may be used.

[0025] More specifically, the tubular braid 140 operates to radially expand and contract as it is displaced longitudinally. The radial force exerted by the braid is related to the bending strength of the filaments 142 comprising the braided structure and the crossing angle at which the braided filaments intersect at vertices 146. The more longitudinally oriented the filaments 142 are within the braided structure, the greater the radial force they exert. As the tubular braid 140 is displaced laterally (from expansion to compression), the vertices 146 of the pixels 144 can move, but the side length (X) of each pixel 144 remains fixed. See Figure 4 (pixels 144 of an expanded tubular braid), Figure 5 (pixels of a tubular braid in a neutral state), and Figure 6 (pixels of a compressed tubular braid).

[0026] Referring to FIG. 7, in one example, a pixel 144 is defined in a tubular braid 140 with a braid angle of 120°. The vertical axis of pixel 144 has a length of 1.732*X, calculated as 2*sin(120 / 2)*X, and the horizontal axis of pixel 144 has a length of 1*X, calculated as 2*sin((180-120) / 2)*X. When the tubular braid 140 is then stretched lengthwise to reduce the diameter of the construct, such as when the braid is introduced through a thin catheter, the pixel is stretched along its horizontal axis and compressed in the direction of its vertical axis, as shown in FIG. 8. The vertical length is reduced to 0.1743*X, calculated as 2*sin(10 / 2)*X, and the horizontal length is stretched to 1.992*X, calculated as 2*sin((180-10) / 2)*X. This is roughly a 10x compression in the longitudinal length, calculated as 1.732 / .1743 = 9.93, and roughly a 2x increase in elongation in the transverse axis, calculated as 1.992 / 1 = 1.992. Any materials and material coating processes used on the braid and within the pixel must be able to tolerate this degree of simultaneous elongation or compression without failure.

[0027] The radial force associated with the expansion of a tubular braid was described 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) and is expressed as follows:

[0028]

number

[0029] Here, K1, K2, and K3 are constants given by the following equations:

[0030]

number

[0031] Also I and I p are the moment of inertia and polar moment of inertia of the braided filament, E is the Young's modulus of elasticity of the filament, and G is the shear modulus of the filament. These material properties, along with the initial braid angle (β), final braid angle (β), tubular braid diameter (D), and number of filaments or strands (n), affect the radial force of the braided bulb.

[0032] As will be appreciated by those skilled in the art, the braid geometry and material properties of the filaments 142 are closely related to the radial force and time constant of the filter valve. Because the filter valve is useful in a variety of vessels with different diameters and flow conditions, each implementation can have its own optimization.

[0033] In one exemplary embodiment, the braid uses 24 strands 142: 12 nickel titanium strands 142 having a diameter of approximately 0.02 mm (0.0008 inches) and 12 nickel titanium strands 142 having a diameter of approximately 0.032 mm (0.00125 inches). This produces a tubular braid 140 with approximately 34-38 pixels per linear inch and a braid angle of 120°-130° when the diameter of the tubular braid 140 is set at 4.5 mm.

[0034] In another exemplary embodiment, the braid uses 24 strands 142: 12 nickel titanium strands 142 having a diameter of approximately 0.025 mm (0.001 inch) and 12 nickel titanium strands 142 having a diameter of approximately 0.038 mm (0.0015 inch). This produces a tubular braid 140 with approximately 27-31 pixels per linear inch and a braid angle of 120°-130° when the diameter of the tubular braid 140 is set at 6 mm.

[0035] According to one embodiment of the infusion device and method, and referring to FIG. 9 , primer 150 is unevenly distributed among the strands 142 of the tubular braid 140. The uneven distribution of primer can include applying different thicknesses of primer onto different areas of the tubular braid during initial application, or during post-processing after initial, preferably consistent, application, and removing the primer from selected regions of the strands while the braid is in the tubular form. The different applied thicknesses can include reducing the thickness of the primer along one or more portions of the braid. The different applied thicknesses can include completely removing the primer along one or more portions of the braid.

[0036] The primer may be applied by spray coating, dip coating, brushing, or any other suitable application method. If the initial application is uneven, thicker or multiple coats of primer may be applied to selected areas, while fewer or even no coatings may be applied to other selected areas. FIG. 9 illustrates an area 152a where a thicker application of primer 150 is applied to the strands 142, an area 152b where a thinner application of primer is applied to the strands, and an area 152c where no primer is applied to the strands. While tubular braid 140 does not necessarily have all such areas, according to this embodiment, it has area 152a and at least one of areas 152b and 152c.

[0037] Post-treatment can include partially or completely removing the primer from selected areas of the elastic strands. In the case of uneven distribution via post-treatment, the thickness of the primer can be mechanically removed completely or partially from over the selected areas. Mechanical removal can include scraping. The primer can alternatively or additionally be removed by non-mechanical means such as laser ablation or heating and peeling. Any other suitable means for reducing, partially removing, or completely removing the primer from selected areas of the tubular braid after the primer has already been applied can be utilized.

[0038] Referring now to FIG. 10 , after the primer 150 has been modified to reduce primer thickness in selected areas, a polymer filter coating 160 is applied over the primed and / or remaining uncoated elastic strands 142, as well as over the pixels 144 formed between the strands. The braid is preferably set in a neutral position to receive the coating 160; that is, the braid is neither compressed nor stretched longitudinally. The polymer 160 can be coated onto the braid by any of several methods, including spraying, spinning, electrospinning, adhesive bonding, heat fusing, mechanically entrapment of the braid, melt bonding, dip coating, or any other desired method, to form a coating suitable for use as a filter. The filter can be a porous material such as ePTFE, a solid material with added pores such as laser-drilled polyurethane, or the filter can be a web of very fine filaments laid over the braid.

[0039] If the polymer filter 160 is a web of thin filaments, the characteristic pore size of the filter can be determined by attempting to pass beads of different diameters through the filter and determining which diameters pass through the filter in large quantities. Ultrafine filaments can be spun onto a rotating mandrel with the aid of an electrostatic field, or without an electrostatic field, or both, according to U.S. Patent No. 4,738,740. The filter thus formed can be attached to a braided structure using an adhesive, or the braid can be placed on a mandrel and the filter spun over, under, or both over and under the braid to substantially capture the braid. The filter can have some pores formed from spraying or electrospinning, followed by a secondary step in which pores are laser-drilled or formed by a secondary operation. In one embodiment, a material capable of being electrostatically deposited or spun is used to form the filter on the braid; preferred materials can be bonded to themselves. The filter may be made from polyurethane, thermoplastic urethane, such as Pellethane®, polyolefin, polyester, fluoropolymer, acrylic polymer, acrylate, polycarbonate, silicone, or other suitable material. The polymer is spun onto the braid in a wet state; therefore, it is desirable that the polymer be soluble in a solvent. In a preferred embodiment, the filter is formed from polyurethane in a solution of dimethylacetamide (DMA) and tetrahydrofuran (THF). The polymer in solution is spun at a preferred concentration of 5-10% solids for the electrospinning process and 15-25% solids for the wet spinning process.

[0040] As another alternative to the polymer coating 160 on the braid, the braid can be dip-coated to form a filter on the braid. The braid is mounted on a mandrel having an outer diameter equal to the inner diameter of the fully expanded braid. The mandrel can be polytetrafluoroethylene (PTFE)-coated steel, where the PTFE acts as a release surface. Alternatively, an uncoated mandrel can be used. When the braid is mounted on the mandrel, it is important that the inner diameter of the braid and the outer diameter of the mandrel do not separate from each other. Therefore, these diameters are preferably consistent within a tolerance of ±0.065 mm. Keeping the entire inner braid in contact with the mandrel ensures that the filaments are uniformly coated with polymer, as described below, which results in a uniform expansion of the filter valve after the polymer dries. Alternatively, the tubular braid 140 can be mounted on an oversized mandrel (larger than the inner diameter of the braid), which increases the braid angle of the filaments, thereby changing the size of the filter valve and affecting its expansion force. In an alternative arrangement, the braid may be mounted within a tubular mandrel having the same size as the outer diameter of the braid and provided with the same tolerances described above. As yet another alternative, the braid may be mounted within a smaller tubular mandrel (having an inner diameter smaller than the outer diameter of the braid), which would result in a reduced braid angle of the filaments, thereby also changing the size of the filter valve and affecting its expansion force.

[0041] The type of mandrel (solid or tubular) and the placement of the braid relative to the mandrel affect the localization of the polymer on the braid. For example, if a braid is attached to the exterior of a mandrel and dip-coated, the braid will have a resulting polymer coating with a smooth interior surface (the surface previously facing the mandrel) and a rough exterior surface. Conversely, if a braid is attached to the interior surface of a tubular mandrel and dip-coated, the braid will have a resulting polymer coating with a smooth exterior surface (the surface previously facing the mandrel) and a rough interior surface. Generally, smooth surfaces provide improved sealing against the vessel surface, while rough surfaces defined by peaks (high points of the filamentous structure) and valleys (low points between filaments with gaps in the polymer) represent reduced friction against the vessel wall. Specifically, rougher, lower-friction surfaces have improved lubricity and are better suited to occluders that require contact with and translate against the vessel wall. For further illustration, see the coated tubular braid shaped into an occluder described below with reference to FIGS.

[0042] Once the braid 140 is securely mounted on (or within) the mandrel, it is dip-coated into the polymer solution at a controlled, constant speed. The solution is an elastic thermoplastic polymer dissolved in a solvent system with a boiling point between 30 and 200°C to produce a solution with a kinematic viscosity ranging from 50 to 10,000 cP. The descending and ascending speeds are inversely proportional to the viscosity of the solution and range from 1 to 100 mm / sec. This speed is important to provide a uniform coating of polymer on the braid, to wet the entire surface of the braid, even where the braid filaments contact the mandrel, and thereby allow the polymer coating to wick into the braid, particularly to the surface that contacts the mandrel, and to release any air bubbles that may have become trapped during the dip process. By way of example, in one embodiment of a method for immersion in a thermoplastic urethane solution (e.g., Pellethane® dissolved in dimethylacetamide (DMA) and tetrahydrofuran (THF) solvent), the speed is such that a 135 mm (6 inch) braid has a residence time of 16 seconds. The speed is also preferably such that the polymer wicks along the entire length of the braid while the braid is being withdrawn from the solution. The braid is immersed in the solution only once to limit the thickness of the coating, thereby preventing binding of the braid filaments, and / or to control the smoothness of the polymer coating film. The controlled speed can be controlled by connecting the mandrel to a mechanical device that dips and withdraws the braid on the mandrel into the polymer solution at a constant and controlled speed.

[0043] After the braid 140 is drawn from the polymer solution, the solvent evaporates over a time frame and temperature range corresponding to the boiling point of the solvent; higher temperatures and longer periods are utilized for higher-boiling solvents. All preferred polymer solutions use some DMA to control the uniformity of the coating thickness, and 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, allows for control of the rate of transition from a low-viscosity, high-solvent content polymer solution to a high-viscosity, low-solvent content polymer solution to a solid solvent-free material, affecting the quality of the polymer film. In one method, the solvent is released in an oven heated to a temperature above the boiling point of DMA (165°C) to rapidly release the DMA. The preferred heating time at this temperature is 5 minutes, which is sufficient to release the DMA. It is understood that THF has a fairly low boiling point (66°C) and evaporates quickly without such significant heating. Alternatively, the polymer-coated braid can be oven-heated at a temperature below the boiling point of DMA, e.g., 80°C to 100°C, which releases DMA from the coated braid, but at a slower rate than occurs above the boiling point of DMA. This temperature promotes rapid removal of DMA while maintaining the integrity of the coated braid. The preferred time for heating at this temperature is 10 minutes, which is sufficient to release the DMA. As yet another alternative, the polymer-coated braid can be dried at room temperature, resulting in the release of DMA at a slower rate than each of the above.

[0044] After the solvent is released from the polymer-coated braid, the coated braid is cooled. Once cooled, the coated braid is released from the mandrel. If the mandrel is PTFE-coated, the braid may self-release or be easily released from the mandrel. If the mandrel is uncoated, a release agent such as isopropyl alcohol (IPA) may be used to facilitate removal of the coated braid from the mandrel. The elastomeric membrane filter formed on the braid can elastically deform over a range of 100 to 1000% elongation. In addition to Pellethane®, membranes may be formed from other polyether-based aromatic thermoplastic urethanes, polyether-based aliphatic thermoplastic urethanes (e.g., Tecoflex®), polyether block amides (e.g., Pebax®), styrene-isoprene-butadiene-styrene (SIBS), silicones, and other polymers. These polymers may be dissolved in an appropriate solvent or heated to their melting point to form a fluid.

[0045] The coating 160 material should have elasticity that allows it to fully recover from a 2-3x stretch and a 10x compression. The coating thickness should be minimized so that the material volume does not significantly affect the braided structure when compressed. If the coating is too thick, it will bunch excessively when compressed. The strain required to stretch the coating should be low enough so that the braided filaments do not bend significantly upon stretching. If the stretching force is greater than the flexural strength of the braid, the structure will bend and fold rather than change radial diameter upon stretching.

[0046] In an exemplary embodiment, coating 160 is a thermoplastic elastomer with a Shore hardness of 80A, which has a tensile modulus of 6.10 MPa at 100 percent elongation and 10.3 MPa at 300 percent elongation, can be elongated at least 500 percent before breaking, and is applied to produce a coating thickness of 5 μm to 20 μm. An exemplary coating can be a polyether-based aromatic thermoplastic urethane, such as Pellethane®. These coating parameters can be used in combination with each of the exemplary braided structure embodiments described above, without limitation.

[0047] It is further preferred that the coating 160 is adapted to withstand a Kv / h ratio greater than 3, where Kv / h is the ratio of longitudinal compression to transverse elongation, where the longitudinal compression (v) is at least 10 and the transverse elongation (h) is at least 3.

[0048] It is also preferred that the coating 160 be adapted to have a Kb / m ratio of 1 to 6, where Kb / m is the ratio of the strand diameter (b) to the coating thickness (m), with preferred strand thicknesses being 20 to 40 μm and preferred coating thicknesses being 5 to 20 μm.

[0049] Depending on the polymer and coating technique, the coating can be fluid-impermeable or porous. If porous, the coating can 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, or even more preferably 20 μm to 40 μm.

[0050] According to various embodiments, polymer coating 160 is located on strands 142 having a greater primer thickness (area 152a), strands 142 having a lesser primer thickness (area 152b), and / or no primer (area 152c). According to embodiments, the polymer coating is applied non-uniformly between the proximal and distal ends of the braided tubular form.

[0051] The polymer-coated braid may also be provided with a hydrophilic coating, a hydrophobic coating, or other coating that affects how blood proteins adhere to the filter. More specifically, the coating is resistant to blood protein adhesion. Suitable coatings include ANTI-FOG COATING 7-TS-13 from Hydromer, Inc. of Branchburg, New Jersey, and SERENE COATING from Surmodics, Inc. of Eden Prairie, Minnesota. These and other coatings may be applied to the filter by, for example, dipping, spraying, or rolling or flow coating.

[0052] Given that the primer is unevenly distributed on the elastic filamentary strands, adhesion of the filter coating to the strands is altered compared to known coatings on braids. Specifically, the primer is intended to increase the adhesion of the filter coating, but in areas with reduced or no primer, the braid can move more easily under the coating. In such locations, the force required to deform the filter coating is reduced. As a result, a lower change in intravascular pressure is required to change the shape of the braided structure in such locations to allow the intended passage of fluids or quickly prevent the unintended passage of fluids and infusions.

[0053] Areas with reduced primers dynamically behave more consistently with tubular braids without any coating. On the other hand, areas of the braid with a primer coating are affected by the properties of the coating: its location, the stiffness of the particular coating, and the thickness of the applied / remaining coating. For example, a primer made of a rigid material stiffens the length of each individual filament and binds the intersections of intersecting filaments on the braid. The force required to bend a filament is then related to the bending force of the filament over a length equal to the side length of the pixel. Stiffer materials include primer coatings such as polyamide and parylene, while more elastic primer coatings, such as polyether-based aromatic and aliphatic thermoplastic urethanes, have a reduced effect on bending force. Additionally, the thinner the coating for a given primer, the less impact the primer has on braid properties.

[0054] Referring now to FIG. 11 , after the tubular braid 140 has been coated with a polymer, it is ready for assembly into a catheter 112. More specifically, the polymer filter 160 in tubular form 140 has a plurality of braided strands 142, a primer 150, and an initially roughened surface 162 facing inward and an initially smoother surface 164 facing outward. A first end 170 of the tubular form 140 is secured to the catheter 112 at a first location 172 proximally adjacent the distal tip 122 of the catheter, with the roughened surface 162 attached to the catheter facing inward and the smooth surface 164 facing outward. Then, referring to FIGS. 12 and 13 , the tubular form 140 is reshaped by inverting and bending the tubular form back so that the smooth surface 164 faces inward and the roughened surface 162 faces outward. A second end 174 of the tubular form 140 is then coupled to the catheter at a second position 176 displaced proximally from the first position 172 to define a shape that flares outward in a proximal-to-distal direction, maximizing to a largest diameter at a central portion 178. In the flared configuration, the braided strands or filaments define pixels of different sizes. The pixels 144 at the proximal end of the filter valve are elongated and have a lower radial force, while the pixels in the larger diameter portion are longitudinally compressed and have a higher radial force, i.e., an increased radial force where the microvalve occluder attempts to seal against the vessel wall.

[0055] 14, once the tubular form is attached to the catheter 112 in the shape of an occluder, the polymer coating 160 is preferably removed from the distal portion 180 of the occluder to open the occluder between the strands 142 in that location. This allows fluid to flow through and into the occluder at open pixels (gaps) 144 in at least a portion of the distal portion. Removal of the polymer 160 from the occluder is preferably by solvent, laser ablation, or mechanical means. However, due to the shape of the occluder on the catheter and the catheter extending through the occluder, some roughness may be present around the periphery of the removed polymer coating.

[0056] According to embodiments, primer 150 beneath polymer coating 160 is thicker at the proximal end of the occluder and thinner or absent beneath the distal end of the occluder. According to embodiments, primer 150 beneath polymer coating 160 is thicker proximal to the maximum diameter of occluder 118 and thinner distal to the maximum diameter of the occluder.

[0057] When the occluder 118 is placed within a blood vessel, antegrade (downstream) pressure from the flow deforms the occluder closed, allowing flow around the occluder. Then, when a therapeutic agent is infused through the infusion lumen and exits the distal orifice 132 of the catheter 112, retrograde pressure (in the distal-to-proximal direction) on the occluder 118 pushes the occluder 118 open and into contact with the patient's vessel wall, blocking retrograde flow within the vessel. With reduced adhesive forces from the modified primer application, the elastic strands 142 within the braid are less constrained to each other by the filter coating 160. As a result, the force required to move the strands 142 relative to each other is reduced, and therefore the strands can more easily and quickly reconfigure, allowing the occluder to move between open and closed states.

[0058] More specifically, upon application of infusion pressure at distal orifice 132 of catheter 112, filter valve occluder 118 moves between a (closed) deployed position that allows downstream fluid passage and an (open) deployed position that prevents fluid passage in 0.067 seconds in a quiescent fluid (e.g., glycerin) having a viscosity approximately equal to that of blood (i.e., approximately 3.2 cP). The time it takes to move from the closed position to the open position in a quiescent fluid is referred to herein as the "time constant." According to another aspect of the present invention, filter valve 118 is positioned such that the time constant of filter valve occluder 118 in a fluid having the viscosity of blood is between 0.01 and 1.00 seconds. More preferably, filter valve occluder 118 is positioned such that the time constant of filter valve occluder 118 in a fluid having the viscosity of blood is between 0.05 and 0.50 seconds. The time constant of the filter valve occluder 118 may be adjusted by varying one or more of the parameters described above (eg, number of filaments, modulus of elasticity of the filaments, diameter of the filaments, etc.).

[0059] The deployed filter valve 118 opens and closes quickly enough to achieve high capture efficiency of the therapeutic agent under rapidly changing pressure conditions. More specifically, as the pressure at the distal orifice 132 increases above the pressure within the blood vessel, the seal between the filter valve's outer periphery and the vessel wall increases, thereby blocking backflow of the therapeutic agent. It is important to note that pressure propagates throughout the blood vessel at the speed of sound in blood (1540 m / s), and the valve opens and closes in response to pressure changes within the blood vessel. Because the expandable filter valve responds to pressure changes, it does so much faster than the flow velocity of the therapeutic agent in the blood (0.1 m / s), thereby preventing any backflow of the therapeutic agent.

[0060] 15 and 16, according to another embodiment, primer 250 may be applied to braided strands 242, either in a regular, uniform coating over the elastic strands or in the non-uniform coating described above. A filter coating 260 is then applied according to any suitable method described herein. After applying the filter coating to the strands, portions of filter coating 260 are then selectively removed down to elastic strands 242 while the braid is still in tubular form 240. In one embodiment, the filter coating is removed from an area of ​​the tubular braid distal to where the braid will assume its maximum diameter when reshaped as an occluder. Tubular form 240 defines a circular circumference 290, and in one embodiment, polymer coating 260 is removed along one side of the circumference. In another embodiment, the polymer coating may be removed within an area defined between two circumferences displaced along the tubular form. In another embodiment, the polymer coating is removed on one side of a ring of apexes 246 extending around the circumference of the tubular form, with the boundary between the polymer coating and the removed coating extending through the apexes. In another embodiment, the polymer coating is removed along a curve extending around the circumference of the tubular form. The filter coating is preferably removed by laser ablation, thereby providing a sharp, clean boundary between the polymer coated and uncoated areas on the braid.

[0061] Then, after the coating 260 has been ablated from only selected portions of the braided tubular form 240, the tubular braid is reshaped to form the occluder 218 and attached to the catheter 212 as described above. As a result of the selective removal of the polymer coating 260 while the braided strands 242 are in their tubular form, a precise transition 294 is created between the polymer-coated and uncoated portions of the final occluder 218. Such precision is possible because the coating is ablated while the braid is in its regular tubular form and away from the catheter for better handling. This allows the resulting infusion device to operate with consistent filter valve occluder performance.

[0062] Additionally, removing the polymeric filter coating via laser ablation while in a tubular configuration may be effective for occluders or even other devices having final shapes other than those shown. Furthermore, depending on the application, the polymeric filter coating may be removed at the proximal end of the device rather than at the distal end.

[0063] This specification describes and illustrates embodiments of devices and methods for manufacturing devices for use in delivering therapeutic agents within blood vessels. While specific embodiments of the invention have been described, the invention is not intended to be limited to these embodiments; the invention is intended to be as broad as the art will permit, and the specification is intended to be interpreted accordingly. Thus, while various materials have been listed for the microvalve filaments, polymer coatings, and catheters, it will be understood that other materials can be utilized for each, without limitation, in combination with each of the various embodiments. While partial primer removal and partial polymer coating removal are described with respect to an exemplary occluder having a portion of the occluder inverted / inverted, these concepts are applicable to multi-strand occluders of any shape in which the coating can be removed from any portion of the occluder. Additionally, while these concepts are described with respect to a braided occluder, the concepts of partial primer removal and polymer coating removal prior to shaping the occluder are also applicable to multi-strand elastic occluders having a partially unbraided structure, such as the distal portion, or a completely unbraided structure. Also, while various methods for partial primer removal and partial coating removal are described, such methods are not intended to be an exhaustive list, but rather exemplary. Also, while the present invention is described with respect to use in combination with a vascular treatment device for delivering therapeutic agents to a patient's blood vessels, the manner in which the primer application is controlled and the polymer coating is modified prior to occluder formation may be useful for other medical treatment and implantable devices, as well as other therapeutic applications, and are considered to be within the scope of the present invention. Additionally, while several examples of braided tubular structures for use in fabricating microvalve occluders are disclosed, it will be understood that other structures may be utilized that differ in one or more of the structure's material, dimensions, filament count, braid angle, and overall dimensions.As used herein, when the terms "approximately" or "substantially" are used to modify a numerical value, such terms mean within 10 percent of the modified numerical value. Thus, those skilled in the art will appreciate that other modifications can be made to the provided invention without departing from the scope of the claims.

Claims

1. 1. A therapeutic device for delivering a therapeutic agent into a patient's blood vessel during an intravascular procedure, comprising: a) a catheter having a proximal end, a distal end having a distal tip, and an infusion lumen extending from the proximal end to the distal end; b) an occluder coupled to the distal end of the catheter, the occluder having a first end and a second end, the occluder comprising: i) a plurality of strands extending in a tubular arrangement from the first end to the second end; ii) a primer of a first polymer distributed non-uniformly over the plurality of elastic strands; iii) a second polymer, different from the first polymer, provided as a coating on at least a portion of the elastic wires and extending between the wires.

2. The treatment device of claim 1 , wherein the plurality of elastic strands extending in the tubular arrangement include braided strands that intersect to define diamond-shaped gaps in the spaces between the braided strands.

3. The therapeutic device of claim 2 , wherein the primer is distributed at different thicknesses over different portions of the braided strands.

4. 3. The therapeutic device of claim 2, wherein the primer is completely absent from at least a first portion of the braided strand, and the first and second polymers are provided as a coating on the first portion.

5. 10. The treatment device of claim 1, wherein the occluder has a proximal portion, a distal portion, and a maximum diameter between the proximal portion and the distal portion, and wherein a polymer primer is non-uniformly distributed among the plurality of elastic strands between the proximal portion and the distal portion.

6. 2. The treatment device of claim 1, wherein the occluder has a proximal portion, a distal portion, and a portion having a maximum diameter between the proximal portion and the distal portion, and the primers are non-uniformly distributed among the plurality of elastic strands between the proximal portion and the portion having the maximum diameter.

7. 3. The treatment device of claim 2, wherein the braided strands, primer, and coating are in a tubular form having an inner surface and an outer surface, the tubular form being secured to the catheter at a first location proximally adjacent the distal tip of the catheter, everted so that the inner surface forms the exterior of the occluder, and coupled to the catheter at a second location proximally displaced from the first location to define a shape that flares outward in a proximal-to-distal direction.

8. The treatment device of claim 7 , wherein the coating is removed from a distal portion of the tubular form.

9. 1. A method of manufacturing an occluder for a therapeutic device for temporary use within a patient's blood vessel during an endovascular procedure, the method comprising: a) obtaining a tubular arrangement of a plurality of elastic wires, the tubular arrangement having a first end and a second end and defining diamond-shaped gaps in the spaces between the braided wires; b) applying a primer to the tubular arrangement of elastic wires to obtain a primed tubular arrangement of elastic wires, the primer being unevenly distributed between the first end and the second end; c) coating the primed tubular arrangement with a polymer coating to obtain a polymer coated tubular arrangement of the plurality of elastic strands, the polymer coating extending across the gap; d) then coupling the polymer coated tubular arrangement of elastic wires to a catheter, the catheter having a proximal end, a distal end, a lumen extending from the proximal end to the distal end, and an outer surface, the tubular arrangement of elastic wires being attached to the outer surface at the distal end such that the tubular arrangement of elastic wires forms the occluder, the occluder being adapted to expand into contact with the blood vessel of the patient during use.

10. 10. The method of claim 9, further comprising removing a portion of the polymer coating from the coated multi-strand braid after coating and before joining.

11. The method of claim 10, wherein the tubular form has a circumference and the removal occurs along the circumference and on one side of the circumference.

12. The method of claim 10 , wherein the removal is performed by laser ablation.

13. The method of claim 10, wherein the occluder has a maximum diameter and all of the removal occurs distal to the maximum diameter.

14. The method of claim 10 , wherein the catheter includes a hub at its proximal end for attaching a source of therapeutic agent in fluid communication with the infusion lumen.

15. 1. A method of manufacturing an occluder for a therapeutic device for temporary use within a patient's blood vessel during an endovascular procedure, the method comprising: a) obtaining a multi-strand braid in a tubular form, said tubular form having a first end and a second end; b) coating said multi-filament braid with a polymer coating to obtain a coated multi-filament braid; c) removing a portion of the polymer coating from the coated multi-filament braid while the coated multi-filament braid is in tubular form; d) then coupling the coated multi-strand braid to an infusion catheter having a proximal end, a distal end, an infusion lumen extending from the proximal end to the distal end, and an outer surface, the coated multi-strand braid being attached and reshaped to the outer surface at the distal end so that the multi-strand braid forms the occluder, the occluder being adapted to expand into contact with the patient's blood vessel during use.

16. 16. The method of claim 15, wherein the tubular form has a circumference and the removal occurs along the circumference and on one side of the circumference.

17. The method of claim 16 , wherein the removal is performed by laser ablation.

18. 16. The method of claim 15, wherein the occluder has a maximum diameter and all of the removal occurs distal to the maximum diameter.

19. 17. The method of claim 16, wherein the infusion catheter includes a hub coupled at the proximal end for connecting a source of therapeutic agent in fluid communication with the infusion lumen.

20. 1. A therapeutic device for delivering a therapeutic agent into a patient's blood vessel during an intravascular procedure, comprising: a) a catheter having a proximal end, a distal end having a distal tip, and an infusion lumen extending from the proximal end to the distal end; b) an occluder coupled to the distal end of the catheter, the occluder having a first end and a second end, the occluder comprising: i) twelve nickel titanium elastic wires having a diameter of approximately 0.025 mm and twelve nickel titanium strands having a diameter of approximately 0.038 mm, said elastic wires being formed into a tubular braid having approximately 27 to 31 pixels per linear inch and a braid angle of 120° to 130° when said diameter of the tubular braid is approximately 6 mm; ii) a coating on at least a portion of said elastic wire.

21. 21. The treatment device of claim 20, wherein the tubular braid has an inner surface and an outer surface, the tubular form being secured to the catheter at a first location proximally adjacent the distal tip of the catheter, the inner surface being everted to form the exterior of the occluder, and coupled to the catheter at a second location proximally displaced from the first location to define a shape that flares outward in a proximal to distal direction, the exterior of the occluder having a rougher surface than the interior of the occluder.

22. 22. The treatment device of claim 21, wherein the exterior of the occluder has more surface peaks and valleys than the interior of the occluder.

23. 22. The therapeutic device of claim 21, wherein the coating is a polymeric coating.

24. The therapeutic device of claim 23, wherein the coating has a thickness of 5 to 20 μm.

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