BR112020008852B1 - MICROCATHETER FOR EMBOLIZATION FOR THE DISTRIBUTION OF EMBOLIZATION PARTICLES INTO A TARGET AREA - Google Patents

Abstract

This is an embolization microcatheter that is configured to deliver embolization particles to a target area and minimize or prevent embolization of a non-target area. The microcatheter includes a section, located between the distal and proximal ends of the microcatheter, that has a frame formed by braided wires and a polymeric layer intercalated and/or superimposed on the frame. This section includes a plurality of axial slits, each slit having a smaller cross-sectional dimension configured to prevent efflux of the embolization particles.

Description

FIELD OF TECHNIQUE

[0001] The present disclosure relates generally to the field of microcatheters for embolization, specifically for local embolization of blood vessels supplying a target tissue (e.g., cancerous tissue), while preventing or minimizing non-target embolization.

BACKGROUND

[0002] Transarterial embolization therapy, tumor embolization, or transcatheter arterial embolization (TAE) involves the administration of embolization material (which may include chemotherapeutics and/or radiotherapeutics) directly to a tumor (e.g., liver tumors) via a microcatheter.

[0003] Tumor embolization is typically performed using microcatheters due to the need to selectively affect the tumor while avoiding, as much as possible, damage to healthy tissue. A major problem associated with embolization is “non-target embolization” in which the embolic material travels to blood vessels other than those directly supplying the target tumor or tumor region, thereby damaging healthy tissue, resulting in undesirable and even dangerous consequences. Possible scenarios include gastric ulcers caused by hepatic embolization, as well as cases in which the embolic material refluxes past the microcatheter, reaching the stomach wall, possibly causing ischemia and ulceration. Another phenomenon, which is abundant especially in advanced liver cancer, is non-target embolization via arterioportal shunting.

[0004] A microcatheter is typically passed through a larger lumen catheter, which is placed in the proximal portion of a vessel, such as the celiac or hepatic artery, and the microcatheter is then advanced through it toward the tumor until a target site is reached. In some scenarios, it is advantageous to use a diagnostic catheter as the delivery medium for the microcatheter. This procedure obviates the need to replace one catheter with another, thus saving substantial time.

[0005] Another reason why microcatheters are routinely used in embolization procedures is the size of the feeding vessels that carry blood directly to the organ or tumor. In order to reach as close to the tumor as possible, the embolization catheter is advanced through smaller and sometimes tortuous vessels. Access to these vessels is difficult, if not impossible, with a larger and often more rigid catheter. Furthermore, blood vessels in the body tend to spasm when manipulated, causing ineffective delivery of the embolic material, so flexible microsized catheters are an absolute necessity.

[0006] A major disadvantage of transcatheter embolization is that the embolization material, which is typically invisible, can reflux into and damage non-target tissues. Furthermore, reflux of embolization material can negatively affect the distribution of embolization material to the target tissue and thus impair treatment efficacy and clinical outcome.

SUMMARY OF THE INVENTION

[0007] The present disclosure relates to an embolization microcatheter for delivering embolization particles to a target area while preventing or minimizing non-target embolization. The microcatheter is comprised of a frame formed by braided wires, a polymeric layer intercalated in and/or on the frame, a distal end opening sized and shaped to allow delivery of a suspension (the suspension includes a suspended fluid and the embolization particles), and a plurality of axial slits formed proximal to the distal end opening and at a predetermined distance therefrom. These axial slits of the microcatheter disclosed herein are sized and shaped to prevent passage of the embolization particles while allowing efflux of the suspended fluid. This ensures delivery of optimal treatment doses and prevents non-target embolization.

[0008] In one aspect of the present disclosure, the microcatheter includes three or more sections, namely, a delivery section at a proximal end of the catheter, a fluid barrier section, and a flow restriction section at the distal end of the catheter. The delivery section of the microcatheter (which constitutes the majority of the microcatheter) is relatively rigid to allow the physician to push the microcatheter to its target site. In contrast, the fluid barrier section and the flow restriction section are extremely flexible (compared to the delivery section) to allow the microcatheter to make the necessary twists and turns during navigation through the complicated vasculature without kinking. Although the plurality of slits are located in a part of the catheter that is highly flexible, and although the slits are cut through the braided wires that constitute the frame of the microcatheter, the tensile force of the microcatheter exceeds 5 N (Newton) and thus meets the requirement of ISO 10555.

[0009] Furthermore, since the axial slits are non-selective, (i.e. formed through the braided wires of the frame), the slits are essentially braid-free. This significantly reduces the risk of thrombosis, while also greatly simplifying the production of the microcatheter.

[0010] As an additional advantage, the microcatheter disclosed herein provides effective protection against backflow, which requires a relatively high slit density/relatively large open area, while also ensuring a small kink-free radius and tensile strength.

[0011] Furthermore, the size and shape of the axial slits, as well as their position relative to the distal end opening, may obviate the need for a tapered internal lumen distal to the axial slits. This is due to the controlled flow of the suspension fluid through the axial slits, which is sufficient to create the fluid barrier and to reduce the flow velocity of the suspension at the distal end opening. Furthermore, the flow velocity may be further reduced as a result of the axial slits being positioned at a predetermined distance from the distal end opening, such that the section of the microcatheter between the axial slits and the distal end opening may serve as a restrictor without including lumen narrowing features (e.g., without having a tapered internal surface). The fluid barrier created by the microcatheter enables essentially “reflow-free” delivery of embolization particles at injection rates much higher than those possible using standard microcatheters, thus enabling a significant shortening of the procedure duration.

[0012] According to some embodiments, the inner cross-sectional dimension of the axial openings is smaller than the outer cross-sectional dimension which prevents embolization particles from exiting through the axial slits while also causing minimal restriction to the flow of suspended fluid therethrough. This again ensures that the flow of suspended fluid through the axial slits creates a fluid barrier which hinders the retrograde flow of embolization particles delivered through the distal end opening.

[0013] According to some embodiments, the distal end of the microcatheter may be an integral part of the microcatheter. This significantly simplifies the production of the microcatheter and ensures that no fixation is required, which would constitute a weak link and could potentially result in dismemberment, presenting a safety hazard.

[0014] According to some embodiments, the microcatheter may be suitable for soft embolization, chemoembolization, radioembolization, or any combination thereof.

[0015] According to some embodiments, the microcatheter may be suitable for embolization of tumors such as hepatocellular carcinoma (HCC), uterine fibroid tumors, renal tumors, lung tumors, prostate tumors, and the like.

[0016] According to some embodiments, an embolization microcatheter is provided for delivering embolization particles to a target area, the microcatheter comprising a first section located at a proximal end of the microcatheter and configured to deliver the microcatheter to a target site. The microcatheter also includes a second section located at a distal end of the microcatheter and configured to restrict flow therethrough, the second section comprising a distal end opening sized and shaped to allow delivery of a suspension flowing through the microcatheter. The suspension includes a suspended fluid and the embolization particles. The microcatheter further includes a third section located between the first and second sections. The third section comprises a plurality of axial slits formed proximal to the distal end opening and at a predetermined distance therefrom. Each of the plurality of axial slits has a smaller cross-sectional dimension configured to prevent efflux therethrough of embolization particles while permitting efflux of suspended fluid. The plurality of slits are sized and shaped to permit flow of particles downstream of the filter section at a volumetric flow rate that permits delivery of substantially all of the particles in the suspension through the distal end opening while preventing backflow thereof. Additionally, the third section is formed of a material having greater flexibility than the first section, and the embolization microcatheter has a tensile strength of at least about 5 N.

[0017] According to some embodiments, the frame is formed of braided wires and a polymeric layer interspersed and/or superimposed on the frame. The braided wire of the frame and the polymeric layer are cut, thereby forming the plurality of axial slits.

[0018] According to some embodiments, each of the plurality of axial slits has a greater width on its outer surface compared to its inner surface slits, such that embolization particles are prevented from entering the plurality of axial slits from the interior of the microcatheter, while causing minimal restriction to the efflux of suspended fluid therethrough.

[0019] According to some embodiments, the third section further comprises a hydrophilic coating overlying the outer surface of the microcatheter, and the plurality of axial slits are formed through the hydrophilic coating.

[0020] According to some embodiments, the plurality of axial slots are formed through the inner layer. According to some embodiments, the inner layer comprises polytetrafluoroethylene (PTFE).

[0021] According to some embodiments, the width of each of the plurality of axial slots is in the range of about 15 to 100 microns. According to some embodiments, the width of each of the plurality of axial slots is approximately/about 50 microns.

[0022] According to some embodiments, the first section has a flexural stiffness of 0.00021 to 0.0007 kg/cm2 (0.003 to 0.01 lbs/in2). According to some embodiments, the third section has a flexural stiffness of about 0.000007 to 0.00014 kg/cm2 (0.0001 to 0.002 lbs/in2).

[0023] According to some embodiments, the second section has a tapered inner surface. According to some embodiments, the second section has a non-tapered inner surface.

[0024] According to some embodiments, the second section has an inner lumen diameter in the range of about 0.2 to 0.75 mm.

[0025] According to some embodiments, the total open area of the plurality of slots of the third section is in the range of 0.2 to 1 mm2. According to some embodiments, the total open area of the plurality of slots of the third section is in the range of 0.2 to 0.6 mm2. According to some embodiments, at least 5 to 30% of the third section is open area formed by the plurality of slots.

[0026] According to some embodiments, the polymeric layer has a maximum tensile strength of 62,052.82 to 68,947.57 kPa (9,000 to 10,000 psi) and a maximum elongation of 350 to 450%. According to some embodiments, the polymeric layer has a maximum tensile strength of approximately/about 66,189.67 kPa (9,600 psi) and a maximum elongation of approximately/about 400%.

[0027] According to some embodiments, the polymeric layer comprises a polycarbonate-based thermoplastic polyurethane.

[0028] According to some embodiments, the plurality of axial fenders are formed by laser cutting the braided wires.

[0029] According to some embodiments, an embolization microcatheter is provided for delivering embolization particles to a target area. The microcatheter includes a first section located at a proximal end of the microcatheter and configured to deliver the microcatheter to a target site. The microcatheter also includes a second and a third section. The second section is located at a distal end of the microcatheter and configured to restrict flow therethrough. The second section comprises a distal end opening sized and shaped to allow delivery of a suspension flowing through the microcatheter (the suspension comprising a suspended fluid and the embolization particles). The third section is located between the first and second sections and includes a frame formed of braided or coiled wires, a polymeric layer interspersed and/or overlapping the frame, and a plurality of axial openings formed proximal to the distal end opening and at a predetermined distance therefrom. Each of the axial openings selectively traverses the polymer layer while leaving the scaffold intact. Additionally, each of the plurality of axial openings has a greater width on its outer surface compared to its inner surface slits so that embolization particles are prevented from entering the plurality of axial openings from the interior of the microcatheter while causing minimal restriction to the efflux of suspended fluid through the plurality of axial openings.

[0030] Certain embodiments of the present disclosure may include some, all, or none of the above features. One or more advantages of the technique may be readily apparent to those skilled in the art from the figures, descriptions, and claims included herein. Furthermore, although specific features have been enumerated above, various embodiments may include all, some, or none of the enumerated features.

[0031] In addition to the exemplary aspects and modalities described above, additional aspects and modalities will be further explored in the figures and detailed descriptions below.

BRIEF DESCRIPTION OF THE FIGURES

[0032] The features, nature and advantages of the present disclosure will become more apparent from the description set forth below taken in conjunction with the drawings in which like reference characters are correspondingly identified. Identical structures, elements or parts appearing in more than one figure are generally identified by the same number in all of the figures in which they appear. Alternatively, elements or parts appearing in more than one figure may be identified by different numbers in the different figures in which they appear. The dimensions of the components and features in the figures have been chosen for convenience and clarity of presentation and are not necessarily shown to scale. The figures are listed below.

[0033] Figure 1 schematically illustrates a microcatheter for embolization in accordance with aspects of the present disclosure.

[0034] Figure 2 schematically illustrates the distal end of the microcatheter for embolization having a wall formed by a braided frame and a polymeric layer intercalated and/or covering the frame and having axial openings formed by non-selective laser cutting of the frame and the polymeric layer of the microcatheter wall, according to some embodiments.

[0035] Figure 3 is a representative image of a distal end of a microcatheter for embolization having a wall formed by a braided frame and a polymeric layer interspersed and/or covering the frame and having axial openings formed by non-selective laser cutting of the frame and the polymeric layer of the microcatheter wall, according to some embodiments.

[0036] Figure 4 schematically illustrates the distal end of a microcatheter for embolization that has a wall formed by a spiral frame and polymeric layers intercalated and/or covering the frame and that has selective axial openings, according to some embodiments.

[0037] Figure 5 is a representative image of a distal end of an embolization microcatheter having a wall formed by a spiral frame and a polymeric layer intercalated and/or covering the frame and having axial openings formed by selective laser cutting of the polymeric layer of the microcatheter wall; according to some embodiments.

[0038] Figure 6A illustratively depicts a cross-sectional perspective view of the fluid barrier-forming section of a microcatheter; according to some embodiments.

[0039] Figure 6B illustratively depicts a cross-sectional front view of the fluid barrier-forming section of a microcatheter; according to some embodiments.

[0040] Figure 6C illustratively depicts a cross-sectional front view of the fluid barrier-forming section of a microcatheter; according to some embodiments.

[0041] Figure 7A schematically illustrates a 0.93 mm (2.8 Fr) embolization microcatheter with a fluid barrier forming section; according to some embodiments.

[0042] Figure 7B schematically illustrates an enlarged and partially exposed view of the distal end of the microcatheter of Figure 7A.

[0043] Figure 7C schematically illustrates an enlarged and partially exposed view of the distal tip of the microcatheter of Figure 7A.

[0044] Figure 7D schematically illustrates the slit pattern of the microcatheter of Figure 7A.

[0045] Figure 8A schematically illustrates a 0.9 mm (2.7 Fr) embolization microcatheter with a fluid barrier section; according to some embodiments.

[0046] Figure 8B schematically illustrates an enlarged and partially exposed view of the distal end of the microcatheter of Figure 8A.

[0047] Figure 8C schematically illustrates an enlarged and partially exposed view of the distal tip of the microcatheter of Figure 8A.

[0048] Figure 8D schematically illustrates the slit pattern of the microcatheter of Figure 8A.

[0049] Figure 9A schematically illustrates a 0.8 mm (2.4 Fr) embolization microcatheter with a fluid barrier section; according to some embodiments.

[0050] Figure 9B schematically illustrates an enlarged and partially exposed view of the distal end of the microcatheter of Figure 9A.

[0051] Figure 9C schematically illustrates an enlarged and partially exposed view of the distal tip of the microcatheter of Figure 9A.

[0052] Figure 9D schematically illustrates the slit pattern of the microcatheter of Figure 9A.

[0053] Figure 10 shows representative images captured at various time points while monitoring the reflux of fluorescent beads when using the microcatheter for embolization disclosed herein (panel A) compared to standard microcatheters (panel B); according to some embodiments.

[0054] Figure 11 shows representative images captured at various time points during monitoring of the administration dose of fluorescent beads when using the microcatheter for embolization disclosed herein (panel A) compared to standard microcatheters (panel B); according to some embodiments.

[0055] Figure 12 shows comparative results obtained during the evaluation of the reflux-free distribution of embolization beads as a function of the injection rate, when using the embolization microcatheter disclosed herein (right column) and standard embolization microcatheters (left column), according to some embodiments.

[0056] Figure 13 shows representative images obtained during evaluation of the kink-free curvature of the embolization microcatheter disclosed herein (panel A) and of an embolization microcatheter having a different structural configuration (panel B), according to some embodiments.

DETAILED DESCRIPTION OF THE INVENTION

[0057] The detailed description presented below, in connection with the accompanying drawings, is intended to describe various embodiments and is not intended to represent only those embodiments in which the concepts described herein may be practiced. The detailed description includes specific details for the purpose of providing a thorough understanding of the various concepts. However, it will also be apparent to one skilled in the art that these concepts may be practiced without the specific details being presented herein. In some cases, well-known features may be omitted or simplified in order to avoid obscuring the disclosure.

[0058] Aspects of the present disclosure relate to an embolization microcatheter for delivering embolization particles to a target area, while also preventing or minimizing the occurrence of non-target embolization. The microcatheter includes a plurality of axial slits specifically positioned in a section of the microcatheter. The plurality of slits are configured to prevent efflux of the embolization particles through the slits, but allow efflux of the suspended fluid. The slits are sized and shaped so as to allow flow of particles downstream of the filter section at a volumetric flow rate that allows delivery of essentially all of the particles in the suspension through the distal end opening, while also preventing backflow thereof.

[0059] According to some embodiments, an embolization microcatheter is provided for delivering embolization particles to a target area. The microcatheter comprises three or more sections, including a delivery section at a proximal end of the catheter, a fluid barrier section, and a flow restriction section. The fluid barrier section and/or the flow restriction section have greater flexibility than the flexibility of the delivery/navigation section.

[0060] As used herein, the terms “embolization,” “transcatheter embolization,” “transcatheter arterial embolization,” and “TAE” may be used interchangeably and refer to the passage and lodgement of an embolus in the bloodstream for therapeutic purposes, for example, as a hemostatic treatment of bleeding or as a treatment for some types of cancer by deliberately blocking blood vessels to starve tumor cells.

[0061] As used herein, the term “microcatheter” may refer to catheters that have an outer diameter of less than 5 mm, less than 2 mm, less than 1 mm, less than 0.75 mm, less than 0.60 mm, less than 0.5 mm, or any other diameter in the range of 0.5 mm to 5 mm. Each possibility is a separate embodiment. According to some embodiments, the microcatheter may be 0.57 mm (1.7 French) or 0.67 mm (2 French). In a non-limiting example, when the internal lumen of the diagnostic catheter is very small, such as compatible with devices that have an outer diameter of 0.889 mm and up to 0.9652 mm, the microcatheter may have an outer diameter of less than 1 mm.

[0062] According to some embodiments, the terms “axial openings” and “axial slits” may refer to the elliptical shaped slit or opening positioned such that the longitudinal axis of the slit is parallel to the longitudinal axis of the microcatheter. According to some embodiments, the plurality of axial slits may be formed through all layers of the wall of the microcatheters.

[0063] According to some embodiments, the radial distance between the centers of each pair of slits may be in the range of 200 to 600 microns, 250 to 500 microns, 300 to 500 microns, or any other suitable distance in the range of 200 to 600 microns. According to some embodiments, each slit may be separated from its adjacent slit by approximately 470 microns. As used herein, the term approximately with reference to the distance between adjacent openings may refer to +/-10%, or +/-5%, or +/-2%. Each possibility is a separate embodiment.

[0064] Reference will now be made to Figure 1, which schematically illustrates an embolization microcatheter 100 and an enlarged view thereof, respectively, in accordance with some aspects of the present disclosure. The embolization microcatheter 100 includes an elongated body 101 having an outer diameter of 1 mm or less. The elongated body 101 includes three sections, namely, a delivery section (also referred to as a “first section”) 110, a fluid barrier section (also referred to as a “third section”) 120, and a flow restriction section (also referred to as a “second section”) 130, the latter of which terminates in a delivery opening (also referred to as a “distal end opening”) 132. In one aspect, the fluid barrier section 120 and/or the flow restriction section 130 are more flexible than the delivery section 110.

[0065] The delivery section 110 is configured for delivering a suspension that includes embolization particles suspended in a fluid suspension, as substantially described herein. As used herein, the term “delivery section” may refer to the portion of the microcatheter necessary to push and/or direct the microcatheter through the vasculature to the target region. The term is interchangeable with the term “first section.” As used herein, the terms “fluid barrier section,” “filter section,” “side filter section,” and “third section” may be used interchangeably and refer to the portion of the microcatheter 100 formed at the distal portion of the microcatheter at a predetermined distance from its distal exit (e.g., section 120). The fluid barrier section 120 is configured to allow lateral efflux of a suspended fluid while blocking the passage of beads/particles (i.e., embolization particles) flowing therein, as disclosed herein. According to some embodiments, 20 to 75% of the fluid injected into the catheter exits the filter section.

[0066] As used herein, the term “distal end” of the microcatheter may refer to the portion of the microcatheter 100 that extends between the most proximal of the axial slits and the opening of the distal end of the microcatheter. This may also be referred to as the predetermined distance between the axial slit and the opening of the distal end. According to some embodiments, the distal end may refer to the distal 100 mm, 50 mm, 30 mm, 20 mm, 15 mm, 10 mm, 5 mm, or 2 mm of the microcatheter 100. Each possibility is a separate embodiment.

[0067] The fluid barrier-forming section 120 may be integrally formed with the delivery section 110 and the flow restriction section 130. The fluid barrier-forming section 120 and the flow restriction section 130 may be collectively referred to as the distal end 125 of the microcatheter 100. According to some embodiments, the portion of the fluid barrier-forming section 120 including the plurality of slits may extend along a length of 0.3 mm to 20 mm, such as 1 mm to 10 mm, 1 mm to 5 mm, 1.5 mm to 5 mm, 2 mm to 5 mm, or any other suitable length therebetween. Each possibility is a separate embodiment.

[0068] As used herein, the term “flow restriction section” may refer to the distal end of the microcatheter that extends between the fluid barrier section and the distal outlet opening (e.g., second section 130). Flow restriction section 130 may be configured to restrict and/or prevent flow and/or to modify the flow of the suspension so as to decrease the horizontal velocity of the particles along the longitudinal axis of microcatheter 100. The term is interchangeable with the term “second section.”

[0069] According to some embodiments, the flow restriction section 130 may have a tapered inner surface. According to some embodiments, the flow restriction section 130 may have both tapered inner and outer surfaces. According to some embodiments, the flow restriction section 130 may have an essentially non-tapered inner surface. According to some embodiments, the length of the flow restriction section 130 may be in the range of 2 to 15 mm, 3 to 12 m, 5 to 10 mm, 5 to 8 mm, or any other suitable length in the range of 2 to 20 mm. According to some embodiments, the length of the flow restriction section 130 may be approximately 7 mm. As used herein, the term “approximately” with respect to the length of the flow restriction section 130 may refer to +/-10%, or +/-5%, or +/-2%. Each possibility is a separate modality.

[0070] The flow restriction section 130 terminates in a delivery opening (also referred to as a “distal end opening”) 132. As used herein, the term “distal end opening” refers to the opening at the end of the microcatheter that leads to its lumen. According to some embodiments, the distal end opening 132 defines the termination of the microcatheter at its distal end. According to some embodiments, the distal end opening 132 may have an inner diameter essentially equal to the inner diameter of the lumen of the microcatheter. According to some embodiments, the distal end opening 132 may be an inner diameter that is smaller than the inner diameter of the lumen of the microcatheter that leads to a narrowing of the lumen toward the end thereof.

[0071] The delivery section 110 extends along the majority of the length of the elongated body 101. The delivery section 110 may be relatively rigid compared to the relatively flexible fluid barrier section 120 and, optionally, the flow restriction section 130, enabling smooth and efficient delivery of the microcatheter 100 to a target region (not shown), such as using a pusher mechanism (not shown) of a handle 102.

[0072] According to some embodiments, the three or more sections of the microcatheter 100 (e.g., sections 110, 120, and 130) may be formed integrally or as one piece. Such a configuration advantageously facilitates production of the microcatheter and may ensure that no fastening is required, which typically constitutes a weak link and thus may result in dismemberment. However, the sections may also be formed as separate elements assembled to form the microcatheter 100.

[0073] According to some embodiments, the delivery section 110 of the microcatheter 100 may be made from a thermoplastic elastomer, such as, but not limited to, thermoplastic polyurethane (such as TPU Pellethane™ from Lubrizol Corporation, OH, USA) or polyether block amide (such as TPE Pebax™ from Arkema Group, Colombes, France), nylon, polyimide, silicone, or any combination thereof. Each possibility is a separate embodiment. According to some embodiments, the fluid barrier section 120 and/or the flow restriction section 130 of the microcatheter 100 may be made from a thermoplastic elastomer, such as, but not limited to, thermoplastic polyurethane (such as TPU Pellethane™ from Lubrizol Corporation, OH, USA) or polyether block amide (such as TPE Pebax™ from Arkema Group, Colombes, France), nylon, polyimide, silicone, or any combination thereof. Each possibility is a separate embodiment.

[0074] In some embodiments, the stiffness of the application section 110 is greater than that of the fluid barrier section 120 and, optionally, the flow restriction section 130 by at least 1.1 times, 1.2 times, 1.3 times, 1.4 times, 1.5 times, 2 times, 3 times, or 4 times. Each possibility represents a separate embodiment. For example, according to some embodiments, the application section 110 may have a flexural stiffness (bending stiffness) of at least about 0.00021 (0.003). For example, about 0.00021 to about 0.0007 [km/cm2] (about 0.003 to about 0.01 [lbs/in2]), such as 0.00021 to 0.00042 [kg/cmf] (0.003 to 0.006 [lbs/in2]) or 0.00028 to 0.00035 [kg/cm2] (0.004 to 0.005 [lbs/in2]), or any flexural stiffness therebetween. According to an exemplary embodiment, application section 110 may have a flexural stiffness of about 0.00031 [kg/cm2] (0.0045 [lbs/in2]).

[0075] According to some embodiments, the fluid barrier forming section 120 may have a flexural stiffness of at least about 0.000007 [kg/cm2] (0.0001 [lbs/in2]). For example, about 0.000007 to 0.00014 [kg/cm2] (about 0.0001 to 0.002 [lbs/in2]), such as 0.000035 to 0.00014 [kg/cm2] (0.0005 to 0.002 [lbs/in2]) or 0.000049 to 0.00007 [kg/cm2] (0.0007 to 0.001 [lbs/in2]), or any flexural stiffness therein, for example, 0.000063 [kg/cm2] (0.0009 [lbs/in2]).

[0076] According to some embodiments, the fluid barrier section 120 and/or the flow restriction section 130 may have a flexural stiffness at least 5 times lower, 4 times lower, 3 times lower, or 2 times lower than that of the application section 110. Each possibility is a separate embodiment.

[0077] As used herein, the term “flexural rigidity” refers to the flexural modulus of each layer of the catheter, i.e., its ability to flex, as well as the moment of inertia of each layer of the catheter. According to some embodiments, the term “flexural rigidity” may refer to the resistance offered by a structure while subjected to flexion.

[0078] If one sticks to theory, the flexural rigidity of the fluid barrier section 120 and the application section 110 may be determined by the material from which the sections are formed, the thickness of the material, the presence or geometries of cracks and their number, size and/or configuration, and any combination thereof.

[0079] According to some embodiments, the application section 110 may have a gradually decreasing stiffness towards the distal end thereof.

[0080] According to some embodiments, the flow restriction section 130 may be made from the same material or a less rigid and softer material than the fluid barrier forming section 120.

[0081] The circumferential lines (a, b, c, and d) indicate sections made from different materials that have unique flexibility and/or tensile strength, as essentially described herein. A distal portion of the delivery section 110 may include a first proximal marker 112. The proximal marker 112 may be made from a polymeric material configured to ensure the tensile strength of the microcatheter 100. Similarly, a distal end of the flow restriction section 130 may include a second distal marker section 114. The distal marker section 114 may include a metal marker. According to some embodiments, the microcatheter 100 may include one or more radiopaque markers, such as, for example, two radiopaque markers. According to some embodiments, the microcatheter 100 may include a first marker at the proximal end of the filter section and a second marker at the distal end of the filter section. According to some embodiments, the first marker may be a polymeric marker and the second marker may be a metallic marker. This may, on the one hand, ensure that the catheter withstands a force of at least 5 N and, on the other hand, prevent dismantling of the braid. Advantageously, due to the difference in radiopacity, the markers may serve as indications of the proximal/distal end of the filter section when traveling through curved vasculature.

[0082] The distal end 125, on the other hand, is configured to be elastic/flexible so as to allow for bending without kinking thereof, as essentially described herein. The fluid barrier forming section 120 includes a plurality of axial slits 122 formed proximally to the distal outlet 132 and at a predetermined distance therefrom. The slits 122 are sized and shaped so as to permit efflux of the suspended fluid while blocking the passage of the embolization particles. As a result of the efflux of the suspended fluid, a fluid barrier is formed around a portion of the elongated body 101 proximally to the distal outlet 132; the fluid barrier preventing backflow of the embolization particles (as illustrated in Figure 8 below herein). The wall 124 of the fluid barrier section 120 includes or is manufactured from a frame sandwiched or covered with a polymeric layer, and the slits 122 may pass through (i.e., laser cut) the wall 124 of the fluid barrier section 120 (as best seen in Figure 2) or be formed by selectively cutting the polymeric layer that leaves the frame 426 intact (as best seen in Figure 4).

[0083] In order to obtain a desired flow distribution of the flux between the axial slots 122 and the distal outlet 132, the number of slots, the total open area formed by the slots, their minimum cross-sectional dimension, their width, the length spacing, the distance from the distal outlet 132, or any other dimensions or geometries may be adjusted according to the size of the beads used, as essentially described herein, while ensuring a bend-free radius of about 0.5 to 1.5 mm and a tensile strength of at least about 5 N.

[0084] The fluid barrier forming section 120 may have a length of between about 5 and about 15 mm, as substantially described herein. The size and shape of the slits 122 may be as substantially described herein (e.g., the width of the slits 122 may be approximately 50 microns and their length may be approximately 320 microns).

[0085] According to some embodiments, the fluid barrier section may have a total open area, formed by the slits, in the range of 0.2 to 1 mm2, 0.2 to 0.6 mm2, 0.3 to 1 mm2, 0.3 to 0.5 mm2, 0.4 to 0.6 mm2, 0.5 to 1.5 mm2, 1.0 to 3.5 mm2, 1.5 to 4 mm2, 2.0 to 3.5 mm2, or any other suitable area in the range of 0.1 to 4 mm2. Each possibility is a separate embodiment. According to some embodiments, at least 5%, at least 10%, at least 15% of the fluid barrier section is open area formed by the slits. According to some embodiments, 5% to 30%, at least 7% to 25%, 7% to 20%, 5% to 15% of the fluid barrier section is open area formed by the slits. Each possibility is a separate embodiment. As used herein, the term approximately with reference to the open area of the fluid barrier section may refer to +/-10%, or +/-5%, or +/-2%. Each possibility is a separate embodiment.

[0086] Advantageously, the fluid barrier forming section 120 may be configured for bending without bending despite the plurality of slits formed in the wall thereof. According to some embodiments, the flexibility of the fluid barrier forming section 120 together with the number of slits 122, their minimum cross-sectional dimension, their width, length spacing, geometry, distal outlet distance, etc., as essentially described herein, may enable bending without bending thereof.

[0087] As used herein, the term “kink-free bending” may refer to a bending of the fluid barrier-forming section 120 that does not impede flow therethrough. According to some embodiments, the fluid barrier-forming section 120 may be configured to kink-free bend at an angle of about 180 degrees. According to some embodiments, the fluid barrier-forming section 120 may be configured to kink-free bend at a minimum bending radius in the range of about 0.5 to 1.5 mm, e.g., 0.5 to 1.2, 0.5 to 1 mm, or any radius therebetween.

[0088] As an additional advantage, the microcatheter disclosed herein 100, including the fluid barrier-forming section 120, provides effective protection against backflow, which requires a relatively high slit density/relatively large open area, while ensuring a small free bend radius (e.g., in the range of 0.5 to 1.5 mm) and tensile strength of at least 5 N. This can be achieved due to the unique size, shape, density, and/or distribution of the plurality of slits. According to some embodiments, the fluid barrier forming section 120 may include 5 to 8 spaced circumferential sections, each section including 5 to 8 axial slots (e.g., 6 slots in each circumferential section), each circumferential section being separated by 0.2 to 0.5 mm (e.g., about 0.3 mm) from at least one of its adjacent sections, the slots in at least some of the circumferential sections being separated by 0.4 to 0.6 mm from its adjacent slot in the same section, and each of the plurality of axial slots having a length of 0.2 to 0.6 mm or 0.2 to 0.4 mm (e.g., about 0.35 mm) and a width of 30 to 50 microns (inside diameter). According to some embodiments, the length of the fluid barrier-forming section 120 (as measured from the most distal to the most proximal circumferential section) can be in the range of 2 to 10 mm, 2 to 5 mm, or 3 to 4 mm. According to some embodiments, some of the circumferential sections can be separated by a first distance (e.g., by 0.2 to 0.5 mm), while others are separated by a second distance (e.g., by 1 to 5 mm, 2 to 4 mm, or by 3 to 3.5 mm), thereby providing two areas of fluid efflux, each area including a plurality of circumferential sections (e.g., 2 to 4 circumferential sections).

[0089] According to some embodiments, the catheter may have a length of at least 50 cm, at least 60 cm, at least 75 cm, or at least 1 m. Each possibility is a separate embodiment. According to some embodiments, the delivery section 110 may constitute the majority of the microcatheter 100, such as at least 50% of its length, at least 75% of its length, at least 80% of its length, or at least 90% of its length. Each possibility is a separate embodiment.

[0090] According to some embodiments, the outer wall of the microcatheter 100 or at least the delivery section 110 and/or the fluid barrier forming section 120 thereof may be essentially non-tapered along its entire length.

[0091] Reference will now be made to Figure 2 which shows the distal end 225 of an embolization microcatheter. The distal end 225 is essentially similar to the distal end 125 of the embolization microcatheter 100 and includes a frame 226. The frame 226 of the fluid barrier forming section 220 is illustratively shown. The fluid barrier forming section 220 includes or is formed from a frame 226 made from braided yarns (which optionally extend around a length of the microcatheter) sandwiched between or covered by a polymeric layer 228 (partially removed for illustrative purposes). Slits 222 traverse (i.e., laser cut) the frame 226 and the polymeric layer 228 to form frame-free slits. Advantageously, the use of a braid for the frame 226 allows for the formation of non-selectively cut slits without compromising the microcatheter's tensile strength, which exceeds 5 N. This is in contrast to microcatheters that utilize a coil for the frame 226, as demonstrated in the experiment described below herein. Furthermore, by having slits 222 formed as non-selective cutouts through both the polymeric layer 228 and the frame 226, the risk of thrombosis formation is significantly reduced.

[0092] As used herein, the terms “braid” and “braided frame” may refer to a structural element, such as a tubular element formed by a plurality of intertwined wires. According to some embodiments, the braid may be formed by at least three intertwined wires that form a tube. According to some embodiments, the braid may include 8 to 48 wires or 12 to 32 wires. As a non-limiting example, the braid may include 16 wires. Each possibility is a separate element. According to some embodiments, the wires forming the braid may have a diameter in the range of 10 to 60 microns, such as 15 to 40 microns or 20 to 30 microns or any other suitable diameter in the range of 10 to 60 microns. Each possibility is a separate embodiment. As a non-limiting example, the wires forming the braid may have a diameter of 25 microns. According to some embodiments, the frame 226 may extend along essentially the entire length of the catheter. According to some embodiments, the frame 226 may extend along only the filter section or along only the filter section and the flow restriction section. Each possibility is a separate embodiment.

[0093] As used herein, the terms “coil” and “spiral frame” may refer to a structural element, such as a tubular element formed by a single wound wire or by a plurality of wound wires, such as two, three or four wound wires. Each possibility is a separate element. According to some embodiments, the wires forming the coil may have a diameter in the range of 10 to 120 microns, such as 15 to 80 microns or 20 to 60 microns or any other suitable diameter in the range of 10 to 120 microns. Each possibility is a separate embodiment.

[0094] According to some embodiments, the braided or wound frame may be made from or include a metal coil, such as, but not limited to, tungsten, stainless steel, nickel-titanium (also called Nitinol), nitinol, cobalt-chromium, platinum-iridium, nylon, or any combination thereof. Each possibility is a separate embodiment.

[0095] Reference will now be made to Figure 3 which is a representative image of the distal end 325 of an embolization catheter (formed as illustrated in Figure 2) having a wall formed by a braided frame (not visible) and a polymeric layer 328 interspersed with and/or covering the frame. The slits 322 are generated by non-selective laser cutting of the frame and polymeric layer 328, thus forming an aperture free of frame elements. The slits 322 are formed along the longitudinal axis of the microcatheter 100. Accordingly, the term “slit” may be used interchangeably with the terms “axial slit” and “axial opening” to refer to through holes positioned such that the longitudinal axis of the slit (or opening) is parallel to the longitudinal axis of the microcatheter 100. According to some embodiments, the slits 322 may have an optionally elongated rectangular, elliptical, or oval shape. According to some embodiments, the length of the opening (which defines the major diameter thereof) is formed along the longitudinal axis of the microcatheter 100. According to some embodiments, the slits 322 may be formed by non-selective cutting through the braided wires (e.g., using a laser and/or chemical photoetching). Unexpectedly, it was found that the use of braided wires allows cutting through the microcatheter frame, while retaining both the strength and flexibility of the microcatheter required by regulatory authorities. Advantageously, by having the slits 322 formed as cutouts through both the polymer layer and the frame, the risk of thrombosis formation is significantly reduced.

[0096] According to some embodiments, each of the axial slots may have a length in the range of 50 to 400 microns, 50 to 350 microns, 100 to 500 microns, in a range of 200 to 400 microns, in a range of 250 to 350 microns, or any other suitable range in the range of 100 to 500 or 100 to 1,000 microns. Each possibility is a separate embodiment.

[0097] According to some embodiments, each of the axial openings may have a length of approximately 300 microns. As used herein, the term approximately with reference to the length of the axial openings may refer to +/-10%, or +/-5%, or +/-2%. Each possibility is a separate embodiment.

[0098] According to some embodiments, each of the plurality of axial slits may have an inner cross-sectional dimension on an inner surface of the microcatheter that is smaller than an outer cross-sectional dimension on an outer surface of the microcatheter; thereby preventing embolization particles from entering the plurality of axial slits from the interior of the microcatheter, while causing minimal restriction to the flow of suspended fluid through the plurality of axial slits, such that the flow of suspended fluid through the plurality of axial slits hinders retrograde flow of embolization particles delivered through the distal end opening.

[0099] According to some embodiments, the width of each of the plurality of axial slits in the inner surface of the microcatheter can be in the range of 10 to 80 microns, in the range of 10 to 25 microns, in the range of 15 to 20 microns, in the range of 20 to 70 microns, in the range of 30 to 60 microns, in the range of 40 to 60 microns, or any other suitable range in the range of 10 to 80 microns. Each possibility is a separate embodiment.

[00100] According to some embodiments, the axial slits may have a width of approximately 50 microns on the inner surface of the microcatheter. According to some embodiments, the axial slits may have a width of approximately 20 microns on the inner surface of the microcatheter. According to some embodiments, the axial slits may have a width of approximately 15 microns on the inner surface of the microcatheter. As used herein, the term approximately with reference to the width of the axial slits may refer to +/-10%, or +/-5%, or +/-2%. Each possibility is a separate embodiment.

[00101] According to some embodiments, the width of each of the plurality of axial openings in the outer surface of the microcatheter is in the range of 40 to 170 microns, 50 to 130 microns, 60 to 90 microns, or any other suitable range in the range of 40 to 170 microns. Each possibility is a separate embodiment. According to some embodiments, the diameter of the opening in the outer surface of the microcatheter is about 20 to 40 microns larger, e.g., 30 microns larger, than the diameter of the opening in the inner surface of the microcatheter.

[00102] According to some embodiments, each of the axial slits may have a width of approximately 100 microns on an outer surface of the microcatheter. As used herein, the term approximately with reference to the smallest outer diameter of the axial openings may refer to +/-10%, or +/-5%, or +/-2%. Each possibility is a separate embodiment.

[00103] Alternatively, according to some embodiments, the axial slots may be formed so as to overlap the armature windings or between the armature windings.

[00104] Optionally, according to some embodiments, the microcatheter may include radial slits in addition to or instead of the axial slits.

[00105] According to some embodiments, the slits may be essentially trapezoidal in shape (i.e., angled relative to the outer wall of the microcatheter). According to some embodiments, the slit angle may be in the range of 90° to 145° or between 95° to 135°. Each possibility is a separate embodiment.

[00106] According to some embodiments, the term “plurality” with reference to axial slots may refer to 10 or more, 15 or more, 20 or more, or 25 or more axial slots. Each possibility is a separate embodiment. According to some embodiments, the plurality of axial slots may refer to 10 to 100, 10 to 50, 15 to 40, 20 to 30 axial slots, or any other suitable number of axial slots in the range of 10 to 100 axial slots, e.g., 27 axial slots.

[00107] Reference will now be made to Figure 4 which shows the distal end 425 of an embolization microcatheter and an enlarged view thereof, respectively, according to some embodiments. The distal end 425 is essentially similar to the distal end 125 of the embolization microcatheter 100 of Figure 1, featuring the frame 426 of the fluid barrier section 420 (shown illustratively in Figure 4). The distal end 425 includes or is formed from a frame 426 (which optionally extends along the length of the microcatheter) made from a coiled wire sandwiched or covered by a polymeric layer 428 (partially removed in Figure 4 for illustrative purposes). However, the frame may also be formed of braided or otherwise interwoven wires (option not shown). The slits 422 are formed by selectively cutting the polymer layer 428 so as to form slits that expose the uncut frame 426. The selective cutting allows a tensile force of at least about 5 N to be maintained.

[00108] As used herein, the term “polymeric layer” may include one or more polymeric layers, such as 1, 2, 3, 4, 5 or more polymeric layers. According to some embodiments, the polymeric layers may be arranged one on top of the other. Additionally or alternatively, the one or more layers may be arranged sequentially along the length of the microcatheter for embolization. According to some embodiments, the one or more layers may be the same or different. For example, according to some embodiments, the one or more polymeric layers may include a sequence of polymeric layers arranged along the length of the microcatheter, with each layer including a different polymer or combination of polymers. According to some embodiments, different polymeric layers may contribute to different characteristics of the layer and thus the microcatheter. For example, the different polymer layers may contribute to the elasticity, flexibility, extensibility, toughness, rigidity, ultimate tensile strength, elongation or any other characteristic of the layer and thus of the microcatheter. Each possibility is a separate embodiment.

[00109] According to some embodiments, the polymeric layer 428 can be made from or include a thermoplastic elastomer, such as, but not limited to, thermoplastic polyurethane (such as TPU Pellethane™ from The Lubrizol Corporation, OH, USA) or polyether block amide (such as TPE Pebax™ from Arkema group, Colombes, France), nylon, polyimide, silicone, or any combination thereof. Each possibility is a separate embodiment. According to some embodiments, the polymeric layer can be or include TPU Carbothane® (Lubrizol).

[00110] According to some embodiments, the polymeric layer 428 has a maximum tensile in the range of 20,684.27 to 68,947.57 kPa (3,000 to 10,000 psi), 27,579.03 to 68,947.57 (4,000 to 10,000); 51,710.68 to 68,947.57 (7,500 to 10,000), 62,052.82 to 68,947.57 kPa (9,000 to 10,000 psi), or any other range in the range of 13,789.51 to 68,947.57 kPa (2,000 to 10,000 psi), such as, but not limited to, a maximum tensile of approximately 66,189.67 kPa (9,600 psi). Each possibility is a separate embodiment. Additionally or alternatively, the polymeric layer 428 may have a maximum elongation of 350 to 450%, such as, but not limited to, a maximum elongation of approximately 400%. As used herein, the term approximately with reference to ultimate tensile strength and ultimate elongation may refer to +/-10%, or +/-5%, or +/-2%. Each possibility is a separate embodiment.

[00111] According to some embodiments, the polymeric layer 428 can be or include a thermoplastic polyurethane. According to some embodiments, the polymeric layer 428 can be or include a polycarbonate-based thermoplastic polyurethane. According to some embodiments, the polymeric layer 428 can be or include TPU Carbothane® PC- (Lubrizol).

[00112] As used herein, the terms “ultimate tensile strength” and “tensile strength” may be used interchangeably and refer to the maximum stress that a material can withstand while being stretched or distended before rupture. According to some embodiments, the microcatheter 100 has a tensile strength of at least 4 N, at least 5 N, at least 7 N, or at least 10 N, when tested as described in Example 4 herein.

[00113] As used herein, when reciting polymeric layer 428 as being “intercalated and/or on” frame 426, this may refer to polymeric layer 428 covering frame 426, surrounding wires of the frame, formed on top of and between wires of frame 426, or any other suitable form of partially or fully covering frame 426. Each possibility is a separate embodiment. According to some embodiments, polymeric layer 428 may coat frame 426.

[00114] Reference will now be made to Figure 5 which is a representative image of the distal end 525 of an embolization catheter (formed as illustrated in Figure 4) having a wall formed by a spiral frame 526 and a polymeric layer 528 interspersed with and/or covering the frame 526. The slits 522 may be generated essentially by selective laser cutting of the polymeric layer 528, thereby forming an opening exposing the frame 526.

[00115] Reference will now be made to Figures 6A-6C which illustratively depict a cross-sectional perspective view (Figure 6A) and front views (Figures 6B and 6C) of the fluid barrier-forming section 620 of a microcatheter, such as the microcatheter 100 of Figure 1, according to some embodiments. As shown, the slits 622 may essentially have a trapezoidal-like shape comprising an angle 622a with respect to the outer surface 623 of the wall 624. The angle 622a may be about 90° or greater. In an exemplary non-limiting embodiment, and as shown in Figure 6B, the angle 622b is about 135°. In a further exemplary non-limiting embodiment, and as shown in Figure 6C, the angle 622c is about 90°. As a result, the slits 622 obtain an inner cross-sectional dimension 627 on an inner surface 621 of the wall 624 that is smaller than an outer cross-sectional dimension 629 on an outer surface 623 of the wall 624. The trapezoidal-like shape ensures that the entry of embolizing particles into the slits 622 is prevented (and thus blockage thereof), while causing minimal restriction to the flow of suspended fluid therethrough.

[00116] Reference will now be made to Figures 7A-7C which schematically illustrate an embolization microcatheter 700 and enlarged/exposed views of portions thereof, as well as to Figure 7D which schematically illustrates the slit pattern of the embolization microcatheter 700. The embolization microcatheter 700 is a 0.93 mm (2.8 Fr) microcatheter comprising an elongated body 701 having an outer diameter of 1 mm or less and an outer layer including a plurality of sections optionally produced from different polymeric materials.

[00117] The proximal end of the microcatheter 700 includes a hub 702 that is molded into or otherwise attached to the microcatheter 700. The hub 702 is configured to allow access to the lumen of the microcatheter 700 for a variety of functions, such as injection of fluids or drugs or introduction of guidewires. The central portion 702 includes a strain relief 712, preferably mechanically coupled to the central portion 702. The strain relief 712 may be made from a polymeric material and may, as illustrated, be tapered at its distal end and be configured to provide structural support to the microcatheter 700, thereby preventing/minimizing kinking of the microcatheter 700. The proximal end of the microcatheter 700 may optionally have an outer layer made from a high shore hardness material, for example, a polyether block amide having a shore hardness of about 70 D and/or a flexural modulus of about 510,212.04 kPa (74,000 psi) (such as, but not limited to, Pebax® 7233). According to some embodiments, the proximal end may have a length of 800 to 1,200 mm (e.g., about 1,000 mm). Optionally, part of the outer layer may include a heat shrinkable material 734 that covers the joint between the strain relief 712 and the elongated body 701.

[00118] An intermediate portion of the microcatheter 700 may include sections having an outer layer made from a material having a lower shore hardness than the proximal end, for example, a section made from a polyether block amide having a shore hardness of about 60 D and/or a flexural modulus of about 282,685.05 kPa (41,000 psi) (such as, but not limited to, Pebax® 6333), a section made from a polyether block amide having a shore hardness of about 55 D and/or a flexural modulus of about 172,368.93 kPa (25,000 psi) (such as, but not limited to, Pebax® 5533), and/or a section made from a polyether block amide having a shore hardness of about 40 D and/or a flexural modulus of about 75,842.33 kPa (11,000 psi) (such as, but not limited to, Pebax® 4033). The outer layer of the distal end 750 of the microcatheter 700 can be produced from sections of low shore hardness materials, for example, polycarbonate-based thermoplastic polyurethane having a shore hardness of about 80 A and/or a flexural modulus of about 10,342.14 kPa (1,500 psi) (such as, but not limited to, Carbothane PC-3585-A) and/or polycarbonate-based thermoplastic polyurethane having a shore hardness of about 90 A and/or a flexural modulus of about 44,126.45 kPa (6,400 psi) (such as, but not limited to, Carbothane PC-3595-A). The distal end 750 includes a proximal marker 760 (seen in Figure 7B ) and a distal marker 762 (also seen in Figure 7B ). According to some embodiments, the distal end 750 may have a length of 175 to 200 mm. According to some embodiments, the proximal marker 760 may be a radiopaque powder incorporated into the outer layer. According to some embodiments, the proximal marker 760 may be positioned approximately 5 to 15 mm from the opening of the distal end 780. According to some embodiments, the distal marker 762 may be a radiopaque alloy submerged in the outer layer. According to some embodiments, the distal marker 762 may be positioned approximately 1 mm proximal to the opening of the distal end 780. According to some embodiments, the outer layers of the microcatheter 700 may have an overall thickness of approximately 0.08 mm to 0.1 mm.

[00119] Reference will now be made to Figure 7B which schematically illustrates a partially exposed view of the distal end 750 of the microcatheter 700 shown (with the portion of the distal end 750 extending between the proximal marker 760 and the distal marker 762 being exposed). As seen in the partially exposed view, below the outer layer is a braid 790. According to some embodiments, the braid 790 extends along the entire length of the elongated body 701. Alternatively, the braid 790 extends along only a portion of the elongated body 701, such as only along the distal end 750. Preferably, the braid 790 has a weave per inch (PPI) that ensures that, in combination with a polymer of low hardness, a flexible distal end is achieved, and, in combination with a polymer having a higher hardness, a relatively rigid proximal end is provided (e.g., 130 PPI). Below the braid 790 is an inner layer (also referred to as a “liner” or “inner liner” - not shown) that may be made from polytetrafluoroethylene (PTFE). According to some embodiments, the inner layer may have a thickness of 0.0381 mm (0.0015 inch) or less.

[00120] The distal end 750 includes a fluid barrier-forming section 720 (also referred to as a “second section”) that terminates at the distal end opening 780 configured for dispensing a suspension that includes embolization particles suspended in a suspension fluid, as essentially described herein. The fluid barrier-forming section 720 includes a plurality of axial slits 722 formed proximal to the distal end opening 780 and at a predetermined distance therefrom. The slits 722 have a length of about 350 microns (SL) and a width of 30 to 50 microns (SW - as measured across the inner diameter of the microcatheter) to allow efflux of the suspension fluid while blocking the passage of the embolization particles. As a result of the efflux of the suspended fluid, a fluid barrier is formed around a portion of the elongated body 701 proximal to the distal end opening 780, the fluid barrier preventing backflow of the embolization particles. Slits 722 traverse (i.e., laser cut) all layers of the wall of the microcatheter 700, including the braid 790.

[00121] According to some embodiments, the axial slits may be positioned in circumferential sections spaced along the longitudinal axis of the microcatheter. According to some embodiments, each circumferential section may include at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, or at least 8 longitudinal axial slits. According to some embodiments, each circumferential section may include 1 to 60 axial slits. According to some embodiments, each slit may be longitudinally separated from its adjacent slit by at least 100 microns, at least 200 microns, at least 250 microns, or at least 300 microns. Each possibility is a separate embodiment. According to some embodiments, each slit may be separated from its adjacent slit in the same row by 200 to 400 microns, by 250 to 300 microns, by 300 to 330 microns, or any other suitable range in the range of 200 to 400 microns. Each possibility is a separate embodiment. According to some embodiments, each slit may be separated from its adjacent slit in the same row by approximately 320 microns. According to some embodiments, each slit may be separated from its adjacent slit in a different row by at least 200 microns, by at least 250 microns, or by at least 300 microns. Each possibility is a separate embodiment. According to some embodiments, each slit may be separated from its adjacent slit in a different row by 200 to 400 microns, by 250 to 300 microns, by 300 to 330 microns, or any other suitable range in the range of 200 to 400 microns. Each possibility is a separate embodiment. According to some embodiments, each slit may be separated from its adjacent slit in a different row by approximately 320 microns. As used herein, the term approximately with reference to the distance between adjacent slits may refer to +/-10%, or +/-5%, or +/-2%. Each possibility is a separate embodiment.

[00122] According to some embodiments, the rows of slits may be circumferentially distributed around the filter section of the microcatheter. According to some embodiments, the number of axial slits in each row may be equal. As a non-limiting example, each row may include 6 axial slits. According to some embodiments, the number of axial slits in the row may be different. As a non-limiting example, some (e.g., 4) rows may include 6 axial slits, while others (e.g., 1) may include 3 axial slits.

[00123] According to some embodiments, the slits may be positioned in the same longitudinal position or in a different longitudinal position. Each possibility is a separate embodiment. According to some embodiments, the distribution of the slits may be staggered, zigzag, or any other suitable uniform or uneven distribution.

[00124] According to some embodiments, the embolization catheter may include more than 1 longitudinally spaced barrier-forming section, such as 2, 3, 4, or more barrier-forming sections. Each possibility is a separate embodiment. According to some embodiments, each barrier-forming section may include a plurality of rows, each row including a plurality of slits (e.g., 2, 3, 4, or more slits per row), as essentially described herein. According to some embodiments, each barrier-forming section may be spaced from its adjacent barrier-forming section by at least 2 mm, at least 4 mm, at least 5 mm, or at least 10 mm, or any other suitable distance in the range of 1 to 20 mm. According to some embodiments, the section separating two adjacent barrier-forming sections may serve as a flow restriction section, in a manner similar to the flow restriction section disclosed herein. As a non-limiting example, the spacer section may have a tapered and/or restricted inner diameter or have an inner diameter equal to that of the remainder of the embolization catheter, in which case flow restriction is determined by the length of the section.

[00125] Referring now to Figure 7B and Figure 7D, the slots 722 of the microcatheter 700 are arranged in the pattern such that 5 circumferential sections are spaced apart, three distal circumferential sections 724 spaced apart by approximately 350 microns (L1), and two proximal circumferential sections 726 also spaced apart by approximately 350 microns (L1). The distal circumferential sections 724 and the proximal circumferential sections 726 are spaced apart by approximately 3.25 mm (L6). The distal circumferential sections 724 each include 4 axial slots spaced apart by about 0.66 mm (L4). The proximal circumferential sections 726 each include 6 axial slots spaced apart by about 0.42 mm (L5). The most distal section of the circumferential sections 724 is located approximately 3.5 mm proximal to the distal end opening 780 (L2), while the most distal section of the circumferential sections 726 is located approximately 8.5 mm proximal to the distal end opening 780 (L3).

[00126] Reference will now be made to Figures 8A-8C which schematically illustrate an embolization microcatheter 800 and enlarged/exposed views of portions thereof, as well as to Figure 8D which schematically illustrates the slit pattern of the embolization microcatheter 800. The embolization microcatheter 800 is a 0.93 mm (2.7 Fr) microcatheter comprising an elongated body 801 having an outer diameter of 1 mm or less and an outer layer including a plurality of sections optionally produced from different polymeric materials.

[00127] The proximal end of the microcatheter 800 includes a hub 802 that is molded over or otherwise attached to the microcatheter 800. The hub 802 is configured to allow access to the lumen of the microcatheter 800 for a variety of functions, such as injection of fluids or drugs or introduction of guidewires. The central portion 802 includes a strain relief 812, preferably mechanically coupled to the central portion 802. The strain relief 812 may be made from a polymeric material and may, as illustrated, be tapered at its distal end and be configured to provide structural support to the microcatheter 800, thereby preventing/minimizing kinking of the microcatheter 800. The proximal end of the microcatheter 800 may optionally have an outer layer made from a high shore hardness material, for example, a polyether block amide having a shore hardness of about 70 D and/or a flexural modulus of about 510,212.04 kPa (74,000 psi) (such as, but not limited to, Pebax® 7233). According to some embodiments, the proximal end may have a length of 800 to 1,200 mm (e.g., about 1,000 mm). Optionally, part of the outer layer may include a heat shrinkable material 834 that covers the joint between the strain relief 812 and the elongated body 801.

[00128] An intermediate portion of the microcatheter 800 may include sections having an outer layer made from a material having a lower shore hardness than the proximal end, for example, a section made from a polyether block amide having a shore hardness of about 60 D and/or a flexural modulus of about 282,685.05 kPa (41,000 psi) (such as, but not limited to, Pebax® 6333), a section made from a polyether block amide having a shore hardness of about 55 D and/or a flexural modulus of about 172,368.93 kPa (25,000 psi) (such as, but not limited to, Pebax® 5533), and/or a section made from a polyether block amide having a shore hardness of about 40 D and/or a flexural modulus of about 75,842.33 kPa (11,000 psi) (such as, but not limited to, Pebax® 4033). The outer layer of the distal end 850 of the microcatheter 800 can be produced from sections of low shore hardness materials, for example, polycarbonate-based thermoplastic polyurethane having a shore hardness of about 80 A and/or a flexural modulus of about 10,342.14 kPa (1,500 psi) (such as, but not limited to, Carbothane PC-3585-A) and/or polycarbonate-based thermoplastic polyurethane having a shore hardness of about 90 A and/or a flexural modulus of about 44,126.45 kPa (6,400 psi) (such as, but not limited to, Carbothane PC-3595-A). The distal end 850 includes a proximal marker 860 (seen in Figure 8B ) and a distal marker 862 (also seen in Figure 8B ). According to some embodiments, the distal end 850 may have a length of 175 to 200 mm. According to some embodiments, the proximal marker 860 may be a radiopaque powder incorporated into the outer layer. According to some embodiments, the proximal marker 860 may be positioned approximately 5 to 15 mm from the opening of the distal end 880. According to some embodiments, the distal marker 862 may be a radiopaque alloy submerged in the outer layer. According to some embodiments, the distal marker 862 may be positioned approximately 1 mm proximal to the opening of the distal end 880. According to some embodiments, the outer layers of the microcatheter 800 may have an overall thickness of approximately 0.08 mm to 0.1 mm.

[00129] Reference will now be made to Figure 8B which schematically illustrates a partially exposed view of the distal end 850 of the microcatheter 800 shown (with the portion of the distal end 850 extending between the proximal marker 860 and the distal marker 862 being exposed). As seen in the partially exposed view, below the outer layer is a braid 890. According to some embodiments, the braid 890 extends along the entire length of the elongated body 801. Alternatively, the braid 890 extends along only a portion of the elongated body 801, such as only along the distal end 850. Preferably, the braid 890 has a weave per inch (PPI) that ensures that, in combination with a polymer of low hardness, a flexible distal end is achieved, and, in combination with a polymer having a higher hardness, a relatively rigid proximal end is provided (e.g., 130 PPI). Below the braid 890 is an inner layer (also referred to as a “liner” or “inner liner” - not shown) that may be made from polytetrafluoroethylene (PTFE). According to some embodiments, the inner layer may have a thickness of 0.0381 mm (0.0015 inch) or less.

[00130] The distal end 850 includes a fluid barrier section 820 (also referred to as a “second section”) configured for dispensing a suspension that includes embolization particles suspended in a suspending fluid, as essentially described herein. The fluid barrier section 820 includes a plurality of axial slits 822 formed proximal to the opening of the distal end 880 and at a predetermined distance therefrom. The slits 822 have a length of about 350 microns (SL) and a width of 30 to 50 microns (SW - as measured across the inner diameter of the microcatheter) to allow efflux of the suspending fluid while blocking the passage of the embolization particles. As a result of the efflux of the suspended fluid, a fluid barrier is formed around a portion of the elongated body 801 proximal to the distal end opening 880, the fluid barrier preventing backflow of the embolization particles. Slits 822 traverse (i.e., laser cut) all layers of the wall of the microcatheter 800, including the braid 890.

[00131] The slits 822 of the microcatheter 800 are arranged in the pattern shown in Figure 8D, including 5 spaced circumferential sections separated from each other by approximately 350 microns (L1). The most distal circumferential section includes 3 axial slits spaced by about 0.88 mm (L4), while the remaining circumferential sections each include 6 axial slits spaced by about 0.4 mm (L5). The most distal circumferential section is located approximately 7.0 mm proximal to the distal end opening 880 (L2).

[00132] Reference will now be made to Figures 9A-9C which schematically illustrate an embolization microcatheter 900 and enlarged/exposed views of portions thereof, as well as to Figure 9D which schematically illustrates the slit pattern of the embolization microcatheter 900. The embolization microcatheter 900 is a 0.93 mm (2.4 Fr) microcatheter comprising an elongated body 901 having an outer diameter of 1 mm or less and an outer layer including a plurality of sections optionally produced from different polymeric materials.

[00133] The proximal end of the microcatheter 900 includes a hub 902 that is molded over or otherwise attached to the microcatheter 900. The hub 902 is configured to allow access to the lumen of the microcatheter 900 for a variety of functions, such as injection of fluids or drugs or introduction of guidewires. The central portion 902 includes a strain relief 912, preferably mechanically coupled to the central portion 902. The strain relief 912 may be made from a polymeric material and may, as illustrated, be tapered at its distal end and be configured to provide structural support to the microcatheter 900, thereby preventing/minimizing kinking of the microcatheter 900. The proximal end of the microcatheter 900 may optionally have an outer layer made from a high shore hardness material, for example, a polyether block amide having a shore hardness of about 70 D and/or a flexural modulus of about 510,212.04 kPa (74,000 psi) (such as, but not limited to, Pebax® 7233). According to some embodiments, the proximal end may have a length of 800 to 1,200 mm (e.g., about 1,000 mm). Optionally, part of the outer layer may include a heat shrinkable material 934 that covers the joint between the strain relief 912 and the elongated body 901.

[00134] An intermediate portion of the microcatheter 900 may include sections having an outer layer made from a material having a lower shore hardness than the proximal end, for example, a section made from a polyether block amide having a shore hardness of about 60 D and/or a flexural modulus of about 282,685.05 kPa (41,000 psi) (such as, but not limited to, Pebax® 6333), a section made from a polyether block amide having a shore hardness of about 55 D and/or a flexural modulus of about 172,368.93 kPa (25,000 psi) (such as, but not limited to, Pebax® 5533), and/or a section made from a polyether block amide having a shore hardness of about 40 D and/or a flexural modulus of about 75,842.33 kPa (11,000 psi) (such as, but not limited to, Pebax® 4033). The outer layer of the distal end 950 of the microcatheter 900 can be produced from sections of low shore hardness materials, for example, polycarbonate-based thermoplastic polyurethane having a shore hardness of about 80 A and/or a flexural modulus of about 10,342.14 kPa (1,500 psi) (such as, but not limited to, Carbothane PC-3585-A) and/or polycarbonate-based thermoplastic polyurethane having a shore hardness of about 90 A and/or a flexural modulus of about 44,126.45 kPa (6,400 psi) (such as, but not limited to, Carbothane PC-3595-A). The distal end 950 includes a proximal marker 960 (seen in Figure 9B ) and a distal marker 962 (also seen in Figure 9B ). According to some embodiments, the distal end 950 may have a length of 175 to 200 mm. According to some embodiments, the proximal marker 960 may be a radiopaque powder incorporated into the outer layer. According to some embodiments, the proximal marker 960 may be positioned approximately 5 to 15 mm from the opening of the distal end 980. According to some embodiments, the distal marker 962 may be a radiopaque alloy submerged in the outer layer. According to some embodiments, the distal marker 962 may be positioned approximately 1 mm proximal to the opening of the distal end 980. According to some embodiments, the outer layers of the microcatheter 900 may have an overall thickness of approximately 0.08 mm to 0.1 mm.

[00135] Reference will now be made to Figure 9B which schematically illustrates a partially exposed view of the distal end 950 of the microcatheter 900 shown (with the portion of the distal end 950 extending between the proximal marker 960 and the distal marker 962 being exposed). As seen in the partially exposed view, below the outer layer is a braid 990. According to some embodiments, the braid 990 extends along the entire length of the elongated body 901. Alternatively, the braid 990 extends along only a portion of the elongated body 901, such as only along the distal end 950. Preferably, the braid 990 has a weave per inch (PPI) that ensures that, in combination with a polymer of low hardness, a flexible distal end is obtained, and, in combination with a polymer having a higher hardness, a relatively rigid proximal end is provided (e.g., 130 PPI). Below the braid 990 is an inner layer (also referred to as a “liner” or “inner liner” - not shown) that may be made from polytetrafluoroethylene (PTFE). According to some embodiments, the inner layer may have a thickness of 0.0381 mm (0.0015 inch) or less.

[00136] The distal end 950 includes a fluid barrier section 920 (also referred to as a “second section”) configured for dispensing a suspension that includes embolization particles suspended in a suspending fluid, as essentially described herein. The fluid barrier section 920 includes a plurality of axial slits 922 formed proximal to the opening of the distal end 980 and at a predetermined distance therefrom. The slits 922 have a length of about 350 microns (SL) and a width of 30 to 50 microns (SW - as measured across the inner diameter of the microcatheter) to allow efflux of the suspending fluid while blocking the passage of the embolization particles. As a result of the efflux of the suspended fluid, a fluid barrier is formed around a portion of the elongated body 901 proximal to the distal end opening 980, the fluid barrier preventing backflow of the embolization particles. Slits 922 traverse (i.e., laser cut) all layers of the wall of the microcatheter 900, including the braid 990.

[00137] The slits 922 of the microcatheter 900 are arranged in the pattern shown in Figure 9D, including 8 spaced circumferential sections separated from each other by approximately 350 or 400 microns (L1). Each circumferential section includes 6 axial slits spaced by approximately 0.37 mm (L4). The most distal circumferential section is located approximately 2.9 mm proximal to the distal end opening 980 (L2).

[00138] According to some embodiments, the microcatheter and/or the distal end thereof (including the fluid barrier section and the flow restriction section) may further include a hydrophilic coating, such as a hydrophilic lubricant coating, formed on the outer surface of the microcatheter. According to some embodiments, the coating may be configured to reduce the coefficient of friction (COF) of the microcatheter to about 0.03.

[00139] According to some embodiments, the plurality of slits may extend through the coating layer. According to some embodiments, the plurality of axial slits may be formed after coating the microcatheter, thereby ensuring that the slits are devoid of coating material and that their size is not affected by the coating material (as opposed to when coating is performed after formation of the slits).

[00140] According to some embodiments, the microcatheter may further include an inner layer that lines the inner surface of the microcatheter. According to some embodiments, the inner layer may include or be polytetrafluoroethylene (PTFE). According to some embodiments, the plurality of slits may extend through the inner layer. According to some embodiments, the microcatheter may include an inner layer of PTFE or similar material, on top of this, braiding, and then jackets of the different polymers.

[00141] According to some embodiments, the suspension fluid may include a contrast agent/medium. Non-limiting examples of suitable contrast agents include iodixanol, iohexol, among many other suitable types and varieties of contrast media. According to some embodiments, the contrast agent may be diluted to a certain degree, such as with saline.

[00142] According to some embodiments, the embolization particles may include or be beads and/or microspheres. According to some embodiments, the beads may be embolic beads, chemotherapeutic beads, radioactive beads, radiopaque beads, drug eluting beads, or any combination thereof. According to some embodiments, the suspension fluid may include or be in the form of lipiodol mixed with chemotherapeutic agents and embolic beads and/or chemotherapeutic drug eluting beads (e.g., doxorubicin-loaded polyvinyl alcohol microspheres, doxorubicin-loaded superabsorbent polymeric microspheres, or cisplatin-loaded gelatin microspheres) for chemoembolization. Optionally, alternatively, or additionally, the infusion suspension may include the infusion agent suspended in the form of radioactive pellets for radioembolization. When used for the treatment of cancers, the embolus, in addition to blocking the blood supply to the tumor, often also includes an ingredient to attack the tumor chemically or with radiation. When the embolus carries a chemotherapeutic drug, the process is called chemoembolization. When the embolus carries a radiopharmaceutical for unsealed source radiation therapy, the process is called radioembolization.

[00143] In order to obtain a desired flow, the flow distribution between the plurality of axial slots and the distal outlet, the number of slots, their minimum cross-sectional dimension, their width, the length spacing, the distance from the distal outlet, etc. can be adjusted according to the size of the beads.

[00144] As a non-limiting example, microcatheters for delivering embolization particles of 70 to 700 microns (e.g., 250 micron embolization particles) may include 5 to 100, 10 to 50, 15 to 30, 20 to 30, or any other suitable number of slits in the range of 5 to 100 slits (e.g., 27 slits). According to some embodiments, the slits may have a width in the range of 25 to 75 microns (e.g., about 50 microns) and a length in the range of 400 to 800 microns (e.g., about 600 microns). Additionally or alternatively, microcatheters for delivery of 70 to 700 micron embolization particles may have a lumen diameter at the distal end section that is essentially equal to (or similar to) the lumen diameter at the proximal end section (i.e., without restriction). Additionally or alternatively, microcatheters for delivery of 70 to 700 micron embolization particles may have a distal end section length of 5 to 10 mm (e.g., about 7 mm). It is understood that such proportions may ensure that the flow of the suspension fluid through the through ports is sufficient to generate a fluid flow barrier that prevents backflow of particles delivered through the suspension delivery opening, while retaining sufficient flow for optimal delivery of embolization particles through the suspension delivery opening.

[00145] As another non-limiting example, microcatheters for delivering 20-200 micron embolization particles (e.g., 40 micron embolization particles) may include 5-100, 10-75, 20-60, 25-50, or any other suitable number of slits in the range of 5-100 slits (e.g., 50 slits). According to some embodiments, the slits may have a width in the range of 10-30 microns (e.g., about 18 microns) and a length in the range of 200-800 microns (e.g., about 800 microns). Additionally or alternatively, microcatheters for delivering 20 to 200 micron embolization particles may have a lumen diameter at the distal end section that (at least along part of its length) is smaller than the lumen diameter at the proximal end section (also referred to herein as a “restricted lumen” or “restrictor section”). Additionally or alternatively, the length of the distal end section of microcatheters for delivering 20 to 200 micron embolization particles may be in the range of 4 mm to 10 mm, 2 mm to 20 mm. According to some embodiments, the length of the distal end section of microcatheters for delivering 20 to 200 micron embolization particles may be about 7 mm or more (e.g., about 10 mm or about 15 mm). As set forth above, it is understood that such proportions can ensure that the flow of the suspension fluid through the through holes is sufficient to generate a fluid flow barrier that prevents the backflow of particles distributed through the suspension distribution opening, while retaining sufficient flow for the optimal distribution of embolization particles through the suspension distribution opening.

[00146] As another non-limiting example, microcatheters for delivering embolization particles of 500 to 900 microns (e.g., 700 micron embolization particles) may include 5 to 50, 10 to 40, or any other number of slits in the range of 5 to 50 slits having a width in the range of 50 to 100 microns and a length in the range of 200 to 800 microns (e.g., about 600 microns). Additionally or alternatively, microcatheters for delivering embolization particles of 500 to 900 microns may have a lumen diameter at the distal end section essentially equal to (or similar to) the lumen diameter at the proximal end section (i.e., without restriction). Additionally or alternatively, microcatheters for delivery of 500 to 900 micron embolization particles may have a distal end section length in the range of 4 mm to 10 mm, or optionally a length of less than 7 mm. As set forth above, it is understood that such proportions may ensure that the flow of the suspension fluid through the through ports is sufficient to generate a fluid flow barrier that prevents backflow of particles delivered through the suspension delivery opening, while retaining sufficient flow for optimal delivery of embolization particles through the suspension delivery opening.

[00147] According to some embodiments, an embolization microcatheter is provided for delivering embolization particles to a target area; the microcatheter comprising three or more sections, including a delivery section at a proximal end of the catheter, a fluid barrier section, and a flow restriction section, the fluid barrier section and the flow restriction section having greater flexibility than the delivery/navigation section, as substantially described herein. The flow restriction section terminates in a distal end opening sized and shaped to allow delivery of a suspension, the suspension comprising a suspended fluid and embolization particles. The fluid barrier section of the catheter includes: a frame formed of braided or coiled wires; a polymeric layer interspersed with and/or coating the frame; and a plurality of axial slits formed proximal to and at a predetermined distance from the distal end opening. The slits are sized and shaped to allow efflux of suspended fluid while blocking the passage of embolization particles. As a result of the efflux of suspended fluid, a fluid barrier is formed around the microcatheter proximal to its distal exit, and the fluid barrier prevents reflux of embolization particles.

[00148] According to some embodiments, each of the axial slits selectively cuts through the polymer layer while leaving the scaffold intact. Selectively cutting through the polymer layer while leaving the scaffold intact enables the use of scaffolds formed from braided wires or a coiled wire, since the integrity of the wire remains intact. Unexpectedly, the selectively formed axial openings have no significant impact on the efflux of suspended fluid and its ability to serve as a fluid barrier to the reflux of embolization particles.

[00149] According to some embodiments, the microcatheter has a traction force of at least 4 N, at least 5 N, at least 7 N, or at least 10 N.

[00150] According to some embodiments, each of the plurality of axial openings has an inner dimension of the cross-section on the inner surface of the microcatheter that is smaller than the outer dimension of the cross-section on the outer surface of the microcatheter, thereby preventing embolization particles from passing through the smaller inner diameter while causing minimal restriction to the flow of suspended fluid therethrough, such that the flow of suspended fluid through the plurality of axial openings hinders the retrograde flow of embolization particles delivered through the distal end opening.

[00151] According to some embodiments, a method is provided for producing the microcatheters for embolization disclosed herein.

[00152] According to some embodiments, the method includes: providing a mandrel; threading a braid or coil onto the mandrel; threading one or more polymeric sleeves (or coatings) onto the braid; threading a heat-shrinkable sleeve onto the polymeric layer; applying heat and/or pressure to the heat-shrinkable layer, thereby causing the one or more polymeric layers to interleave onto and/or into the braid; peeling the heat-shrinkable sleeve; removing the mandrel and cutting (e.g., by laser cutting) slits through the outer coating, the polymeric layer, the inner liner, and preferably the frame (in the case of a braided frame) to obtain the micro embolization catheter described herein.

[00153] According to some embodiments, the mandrel may be coated with polytetrafluoroethylene (PTFE) (e.g., Teflon®) or other non-stick material that allows for removal of the mandrel. According to some embodiments, the PTFE or other non-stick material may remain on the braid (or coil) due to the applied heat and/or pressure, thereby forming an internal coating facing the lumen of the microcatheter. According to some embodiments, the one or more polymeric sleeves/coatings may be threaded sequentially such that a sequence of polymeric elements is placed along the braid (or coil), as essentially described herein. According to some embodiments, the polymeric layers or elements may be the same or different, as essentially described herein. According to some embodiments, the method further includes applying an external coating facing the outside of the microcatheter. In some embodiments, the outer coating may be made from or include a hydrophilic material, as essentially described herein.

[00154] According to some embodiments, cutting through the frame may be performed before and after applying a hydrophilic coating. According to some embodiments, the method may further include masking the slits.

[00155] According to some embodiments, cutting the frame may cause deformation of the catheter. Therefore, according to some embodiments, the method may further include annealing. According to some embodiments, annealing may include heating the distal end of the frame prior to adding the polymer. According to some embodiments, the slits retain their shape when cut.

[00156] According to some embodiments, the sequence of the method steps may be modified, and such modifications are within the scope of this disclosure. For example, according to some embodiments, the mandrel may be removed prior to peeling the heat shrink sleeve. As another example, the hydrophilic coating may be applied prior to removal of the mandrel.

[00157] According to some embodiments, a method is provided for embolizing a vascular structure (e.g., a blood vessel) using the microcatheters disclosed herein.

[00158] According to some embodiments, a kit is provided that includes microcatheters, as disclosed herein, and embolization particles.

EXAMPLES

[00159] Example 1 - Preventing Backflow of Embolization Particles. Backflow of fluorescent beads using the microcatheter disclosed herein formed as disclosed herein was compared to backflow using a standard microcatheter under the same test conditions. The tested microcatheter comprises a fluid barrier with a braided frame, 5 spaced circumferential sections, each section including 6 axial slits, each circumferential section being spaced by about 0.3 mm from its adjacent section (or adjacent sections), and the slits in the same circumferential section being spaced by about 0.5 mm from their adjacent slits in the same section, and each of the plurality of axial slits having a length of about 0.35 mm and a width of 30 to 50 microns (as measured at the inner diameter of the microcatheter). Each microcatheter was inserted into a tube connected at its distal end to a syringe consisting of a large mesh to collect the injected beads and a flow regulator that maintained a constant flow rate of 5 cm3/min in the tube. Fluorescent beads were injected at a constant flow rate of 8 cm3/min using a syringe pump, and the injection was recorded. The time between the start of injection and the onset of reflux was measured for each microcatheter.

[00160] When using a standard microcatheter, reflux began less than 4 seconds after the start of injection, whereas when using the microcatheter disclosed herein, no reflux was observed.

[00161] Figure 10 shows representative images captured at various time points while monitoring the reflux of fluorescent beads using the embolization microcatheter disclosed herein (panel A) and standard microcatheters (panel B). It can be clearly seen that reflux is significantly prevented by the formation of a fluid barrier (arrow 1001) when using the embolization microcatheter disclosed herein, as compared to standard microcatheters (refluxed beads are indicated by arrows 1002 and 1003).

EXAMPLE 2 - DOSE DISTRIBUTION

[00162] The dose distribution of fluorescent beads using the microcatheter disclosed herein was compared to the dose distribution of a standard microcatheter. The microcatheter disclosed herein was formed as disclosed herein and comprises a fluid barrier with a braided frame, 5 spaced circumferential sections, each section including 6 axial slits, each circumferential section being spaced by about 0.3 mm from its adjacent section (or adjacent sections), and the slits in the same circumferential section being spaced by about 0.5 mm from their adjacent slits in the same section, and each of the plurality of axial slits having a length of about 0.35 mm and a width of 30 to 50 microns (as measured across the inner diameter of the microcatheter).

[00163] Each microcatheter was inserted into a tube consisting of a mesh filter with a pore size of 20 microns that collected the fluorescent beads. The fluorescent beads were injected at a constant flow rate of 8 cm3/min using a syringe pump. The injection was stopped once backflow of beads was observed, and the volume of fluorescent beads accumulated on the mesh filter was measured.

[00164] Figure 11 shows representative images captured at various time points during monitoring of a delivery dose of fluorescent beads. The figure shows that when using the embolization microcatheter disclosed herein (panel A) and comparing it to standard microcatheters (panel B), a significantly higher delivery dose (as indicated by reference numeral 1101) can be delivered compared to the standard microcatheter (as indicated by reference numeral 1102) without causing backflow. Significant backflow was observed for the standard microcatheter even at small delivery doses, as indicated by arrow 1103.

EXAMPLE 3 - INJECTION RATE

[00165] The injection rate of the microcatheter disclosed herein formed as disclosed herein was compared to that of a standard microcatheter.

[00166] The tested microcatheter includes a fluid barrier with a braided frame and 5 spaced circumferential sections. Each section of the circumferential sections includes 6 axial slits, wherein each circumferential section is spaced by about 0.3 mm from its adjacent section (or adjacent sections), and wherein the slits in the same circumferential section are spaced by about 0.5 mm from their adjacent slits in the same section, and wherein each of the plurality of axial slits has a length of about 0.35 mm and a width of 30 to 50 microns (as measured across the inner diameter of the microcatheter).

[00167] Each microcatheter was separately tested, under the same conditions, inside an in vitro anatomical-physiological model, with the distal tip of the microcatheter being placed approximately 3 cm after the vessel bifurcation. The flow rate inside the tubing was adjusted to 4 ± 2 cm3/min, and the automatic injection flow rate was initially adjusted to 4 cm3/min and activated for 3 seconds. If there was no reflux of beads, the injection flow rate was increased by 1 cm3/min until there was reflux of the embolic beads. The experiment was then repeated in an identical manner with the second microcatheter, and the results were compared.

[00168] The disclosed microcatheter demonstrated the ability to inject at a higher flow rate before backflow occurred compared to a standard microcatheter. The ratio of the injection flow rate at which backflow occurred using the disclosed microcatheter to a standard microcatheter was between 1.15 and 3. Performance varied based on the size range of the embolic beads injected. Thus, in one or more embodiments, the microcatheter disclosed herein exhibits backflow-free delivery even at a higher injection flow rate compared to the standard microcatheter. In one or more embodiments, the microcatheter disclosed herein exhibits backflow-free delivery at a higher flow rate by at least about 1.15 times compared to the standard microcatheter. In one or more embodiments, the microcatheter disclosed herein exhibits reflux-free delivery at a flow rate higher by at least about 1.15 to 3 times compared to a standard microcatheter.

[00169] As seen in Figure 12 which compares the reflux-free delivery of embolization beads using the microcatheter for embolization disclosed herein (right column) and standard microcatheters for embolization (left column), as a function of injection rate. Reflux-free delivery was possible at twice the injection rates (2Q, column C) using the microcatheter disclosed herein, compared to standard microcatheters for embolization (Q, column B), here 10 ml/min compared to 5 ml/min, respectively. Above the injection rate Q, reflux of the delivered beads was observed for the standard microcatheter (column A). Advantageously, this result emphasizes that the use of the microcatheter for embolization disclosed in the present document enables a reflux-free delivery of embolization particles at higher injection rates, thus significantly shortening the length of the procedure and, as a result, increasing patient comfort as well as hospital efficiency, for example, by enabling additional procedures to be performed at a given time.

EXAMPLE 4 - TENSILE STRENGTH

[00170] The disclosed microcatheter formed as disclosed herein, herein having a fluid barrier with a braided frame, 5 spaced circumferential sections, each section including 6 axial slots, each circumferential section being spaced by about 0.3 mm from its adjacent section (or adjacent sections), and the slots in the same circumferential section being spaced by about 0.5 mm from their adjacent slots in the same section, and each of the plurality of axial slots having a length of about 0.35 mm and a width of 30 to 50 microns (as measured across the inner diameter of the microcatheter), was tensile tested in accordance with ISO 10555-1. The tested specimens were cut into smaller sections so that each joint in the microcatheter assembly could be tested. The sections were placed in a 37 °C water bath prior to testing and were removed one by one for testing, thus minimizing heat loss as much as possible.

[00171] Each section was then fixed in position within the tensile testing machine and tested at a working length of 20 mm and a tensile rate of 400 mm/min until the pipe ruptured or the joint separated. All sections exceeded the lower limit of 5 N, and even reached tensile strengths of up to 11 N.

EXAMPLE 5 - BENDING WITHOUT FOLDING

[00172] The bend radius of a microcatheter is defined as the smallest radius to which it can be bent without kinking. In order to determine the bend radius of various microcatheters according to embodiments of the invention, a fixture was created with pins of different radii. The microcatheter was carefully looped around each pin, starting with the largest, so that the proximal and distal ends were at 180° to each other. The ends are then pulled so that the microcatheter is tight around the pin. The microcatheter is tested on each pin until kinking occurs. The smallest pin to which the microcatheter can be wrapped without kinking is recorded. The results demonstrated that a bend radius using a standard microcatheter was 1.5 mm, advantageously, the bend radius using the microcatheter disclosed herein was 0.9 mm.

[00173] As can be seen in Figure 13, certain characteristics of a microcatheter can contribute to the bend radius. Panel A of Figure 13 shows the kink-free bending of a microcatheter formed as disclosed herein so as to ensure its effectiveness in preventing backflow of particles while ensuring a kink-free radius of 0.5 to 1.5 mm and a tensile strength of 5 N. Here, the fluid barrier was formed having 5 spaced circumferential sections, each section including 6 axial slits, each circumferential section being spaced by about 0.3 mm from its adjacent section (or adjacent sections), and the slits in the same circumferential section being spaced by about 0.5 mm from their adjacent slits in the same section, and each of the plurality of axial slits having a length of about 0.35 mm and a width of about 30 to 50 microns (as measured across the inner diameter of the microcatheter).

[00174] As shown in Panel B, increasing the length of the slits above 500 microns negatively affected the bend radius and caused further distortion of the slit configuration, which may detrimentally result in particle efflux therethrough. Thus, in one or more embodiments, the slits have a length below about 500 microns. For example, the slits have a length of about 350 microns or less.

[00175] The flow restriction section terminates in a distal end opening sized and shaped to permit delivery of a suspension, the suspension comprising a suspended fluid and embolization particles. The fluid barrier section of the catheter includes: a frame formed of braided wires; a polymeric layer interspersed and/or overlapping the frame; and a plurality of axial slits formed proximally to the distal end opening and at a predetermined distance therefrom. The slits are sized and shaped to permit efflux of the suspended fluid while blocking the passage of the embolization particles. As a result of the efflux of the suspended fluid, a fluid barrier is formed around the microcatheter proximally to its distal exit, the fluid barrier preventing backflow of the embolization particles. Advantageously, each of the plurality of axial slits can pass through and/or can be formed (i.e., by laser cutting) through the frame and the polymer layer without compromising the tensile strength of the microcatheter exceeding about 5 N. As an additional advantage, the size, shape, and density of the plurality of slits are configured to ensure effective protection against backflow while ensuring a free bending radius in the range of about 0.5 mm to about 1.5 mm and a tensile strength of about 5 N.

[00176] According to some embodiments, the three or more sections of the microcatheter may be formed integrally or as one piece. Such a configuration advantageously facilitates production of the microcatheter and may ensure that no clamping is required, which typically constitutes a weak link and thus may result in dismemberment. However, the sections may also be formed as separate elements assembled to form the microcatheter.

[00177] The terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting. As used herein, the singular forms “a,” “an,” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will further be understood that the terms “comprise” or “comprise,” when used in this specification, specify the presence of indicated features, integers, steps, operations, elements, or components, but do not preclude or rule out the presence or addition of one or more features, integers, steps, operations, elements, components, or groups thereof. According to some embodiments, the term “comprise” may be replaced by the term “consist essentially of” or “consist of.”

[00178] The term “about” refers to a reasonable variation of an indicated amount that retains the ability to achieve one or more functional effects to substantially the same extent as the indicated amount. The term may also refer, herein, to a value of plus or minus 10% of the indicated amount; or plus or minus 5%, or plus or minus 1%, or plus or minus 0.5%, or plus or minus 0.1%, or any percentage therebetween.

[00179] While various exemplary aspects and embodiments have been discussed above, those skilled in the art will contemplate certain modifications, additions, and subcombinations thereof. Accordingly, it is intended that the claims appended hereto and future claims be construed to include all such modifications, additions, and subcombinations that are within the true spirit and scope thereof.

Claims (14)

1. An embolization microcatheter (100) for delivering embolization particles to a target area, the microcatheter comprising: a first section (110) located at a proximal end of the microcatheter (100) and configured for delivering the microcatheter to a target site; a second section (130) located at a distal end of the microcatheter (100) and configured to restrict flow therethrough; the second section (130) comprising an opening (132) of the distal end sized and shaped to allow delivery of a suspension flowing through the microcatheter (100), the suspension comprising a suspended fluid and the embolization particles; and a third section (120) located between the first (110) and second (130) sections; the third section (120) comprising: a plurality of axial slits (122) formed proximally to the distal end opening (132) and at a predetermined distance therefrom, each axial slit being spaced from its adjacent slit by 200 to 600 microns, and wherein each of the plurality of axial slits (122) has a smaller cross-sectional dimension configured to prevent efflux of the embolizing particles therethrough while permitting efflux of the suspended fluid; and wherein the plurality of slits (122) are sized and shaped to permit flow of the particles downstream of the third section (120) at a volumetric flow rate that permits delivery of essentially all of the particles in the suspension through the distal end opening while preventing backflow thereof; characterized in that the third section (120) is formed of a material having greater flexibility than the first section (110); and wherein the embolization microcatheter (100) has a tensile strength of at least 5 N. 2. Microcatheter for embolization (100), according to claim 1, characterized by the fact that a frame (226) is formed by braided wires; and a polymeric layer (228) intercalated and/or superimposed on the frame (226), and in which the braided wires of the frame (226) and the polymeric layer (228) are cut, thus forming the plurality of axial slits (122) that is essentially free of the frame (226) and/or the polymeric layer (228). 3. The microcatheter for embolization (100) of claim 2, wherein the polymeric layer (228) has a maximum tensile strength of 62,052.82 to 68,947.57 kPa (9,000 to 10,000 psi) and a maximum elongation of 350% to 450%, preferably wherein the polymeric layer (228) has a maximum tensile strength of 66,189.67 kPa (9,600 psi) and a maximum elongation of 400%. 4. Microcatheter for embolization (100), according to claim 2 or 3, characterized by the fact that the polymeric layer (228) comprises a polycarbonate-based thermoplastic polyurethane. 5. Microcatheter for embolization (100), according to any one of claims 2 to 4, characterized by the fact that a plurality of axial slits (122) are formed by laser cutting of the braided wires. 6. The microcatheter for embolization (100) of any one of claims 1 to 5, wherein each of the plurality of axial slits (122) has a greater width on its outer surface compared to its inner surface slits; such that embolization particles are prevented from entering the plurality of axial slits (122) from the interior of the microcatheter (100), while causing minimal restriction to the efflux of suspended fluid therethrough. 7. Microcatheter for embolization (100), according to any one of claims 1 to 6, characterized by the fact that the third section (120) additionally comprises a hydrophilic coating superimposed on the external surface of the microcatheter (100), and in which the plurality of axial slits (122) is formed through the hydrophilic coating. 8. Microcatheter for embolization (100), according to any one of claims 1 to 7, characterized by the fact that the third section (120) additionally comprises an inner layer that lines the inner surface of the microcatheter (100), in which the plurality of axial slits (122) are formed through the inner layer, preferably in which the inner coating comprises polytetrafluoroethylene (PTFE). 9. Microcatheter for embolization (100), according to any one of claims 1 to 8, characterized by the fact that the width of each of the plurality of axial slits (122) is in the range of 15 to 100 microns, preferably in which the width of each of the plurality of axial slits (122) is 50 microns. 10. The microcatheter for embolization (100) of any one of claims 1 to 9, wherein the first section (110) has a flexural stiffness of 0.00021 to 0.0007 kg/cm2 (0.003 to 0.01 lbs/in2). 11. The microcatheter for embolization (100) of any one of claims 1 to 10, wherein the third section (120) has a flexural stiffness of 0.000007 to 0.00014 kg/cm2 (0.0001 to 0.002 lbs/in2). 12. Microcatheter for embolization (100), according to any one of claims 1 to 11, characterized by the fact that the second section (130) has an internal lumen diameter in the range of 0.2 to 0.75 mm. 13. Microcatheter for embolization (100), according to any one of claims 1 to 12, characterized by the fact that a total open area of the plurality of slits (122) of the third section (120) is in the range of 0.2 to 1 mm2. 14. Microcatheter for embolization (100), according to any one of claims 1 to 13, characterized by the fact that a total open area of the plurality of slits (122) of the third section (120) is in the range of 0.2 to 0.6 mm2, or in which at least 5% to 30% of the third section (120) is an open area formed by the plurality of slits (122).