Patent Description:
Ureteric stents are thin tubes inserted into the ureter in order to allow for urine drainage in the presence of a ureteric obstruction. They are typically <NUM> to <NUM> long and have multiple circular holes across the stent wall, which permit flow exchange between the central bore of the stent and the surrounding environment.

Ureteric stents are largely employed in the clinics to retrieve urine drainage in either cases of externally- or internally-induced occlusion of the ureter lumen, for example caused by a tumour mass or a kidney stone. The stent provides a pathway for urine flow to bypass the occlusion, lowering the static pressure within the kidneys and reducing the risk of renal tissue damage.

The use of ureteric stents is, however, associated with a range of side effects and complications. The most common source of stent dysfunction is the deposition and growth of encrusting and bacterial deposits over the stent surface, which can cause blockage of the side holes and the bore of the stent. This compromises urine drainage and can result in increased renal pelvic pressure, which may have severe consequences for the patient, and often requires surgical re-intervention or pharmaceutical treatment, with significant impact on healthcare costs and patients' quality of life.

Although different strategies have been proposed to reduce the impact of encrustation on stent lifetime, with the majority focusing on the introduction of novel bulk materials and surface coatings, encrustation of ureteric stents is still recognised as a major cause of stent failure and associated side effects on patients.

There is currently a move towards the use of metallic stents as a more reliable product against encrustation and erosion (particularly for long-term placement). However, metallic stents are more expensive to fabricate than the more commonly used polymer-or silicone-based stents.

Other approaches against encrustation have focussed on surface coatings, such as heparin (<NPL>) and carbon-based (<NPL>) coatings, which have demonstrated success in reducing the rate of encrustation.

Notably, the introduction of new material or coating strategies into the industrial and clinical environments is often hindered by high associated costs and technological complexity. For instance, metal stents have been proposed since the late `<NUM> as a means to reduce the occurrence of mineralogical encrustation (as opposed to the more common polymer- or silicone-based stents), but they have not yet become a widespread practice in the clinic.

It has been observed that encrustation of stents can be more pronounced at the location of the side holes. Consequently, it has been suggested that side holes represent one of the initial anchoring sites for encrusting material.

Tong et al. have reported a computational fluid dynamics (CFD) study on a new side hole design, which comprises tubular extrusions of the side holes with the purpose of providing more efficient urine drainage (<NPL>). This design has the potential disadvantage of increasing patient discomfort due to the contact between the extrusions and the inner ureter wall. The extrusions are also more prone to mechanical breakage, which is potentially made worse by encrustation or other chemical factors. Such stents are also relatively complicated to fabricate.

There is therefore a need for a stent design that effectively reduces encrustation without significantly impacting on production complexity or costs, which is independent of the bulk material from which the stent is made or of any surface treatments or coatings, and which mitigates against the disadvantages of currently known stents.

<CIT> describes an implantable catheter, consisting of an elongate, cylindrical element with an axial interior and with radially extending openings.

<CIT> describes catheters with bevelled drainage holes and a method and a device for forming holes through a lateral wall of a catheter. The method comprises the steps of providing a section of the catheter between a pair of tubular punching members, driving at least one of said pair of tubular punching members towards the other in order to punch through said lateral wall of the catheter and thereby sever one pair of oppositely located hole pieces from the lateral wall, actuating an ejection unit, in order to force said severed hole pieces away from the catheter via said internal lumen of the tubular punching members, withdrawing said pair of tubular punching members.

<CIT> describes a urethral prosthesis comprising a flexible tube being delimited by a wall comprising openings. Each opening constitutes a whistle-type notch, whose median plane is oblique with respect to the axis of the tube in the zone of the opening.

<CIT> describes a plastic tubing having holes and a process for producing the same.

<CIT> describes devices, apparatuses, systems, and methods for improved clog resistant orifices in medical devices and tubes. The clog resistant orifices have an outwardly flared orifice wall so as to minimize the occurrence of clogging.

Any embodiments or examples described herein are not necessarily in accordance with the invention unless they fall within the scope of the claims.

The invention provides a stent according to claim <NUM>.

Each side hole may be defined by a surrounding side hole wall that extends between the inner and outer surfaces of the stent wall. Each side hole has an upstream end and a downstream end, spaced apart in the direction of, or along, the longitudinal axis of the stent, and the stent wall tapers so that it decreases in thickness in a direction towards the side hole at the upstream and/or downstream end of at least one of the side holes.

The stent wall may taper away from both the inner surface and the outer surface of the stent wall at the upstream and/or downstream end of the side hole.

The stent wall may taper in thickness (for example, as viewed in cross-section in any of the planes described herein) to form a vertex located between, and offset in the radial direction of the stent from, both the inner surface and the outer surface of the stent wall. For example, the stent wall may taper symmetrically so that the vertex is located half way between the inner surface and outer surface of the stent wall. Alternatively, the stent wall may taper asymmetrically so that the vertex is offset in the radial direction from the midpoint between the inner and outer surfaces of the stent wall. The vertex may have an internal angle of <NUM> to <NUM>°, <NUM> to <NUM>°, <NUM> to <NUM>°, <NUM> to <NUM>°, for example about <NUM>°.

The stent wall may taper away from the inner surface of the stent wall but not taper away from the outer surface of the stent wall at the upstream end of the at least one of the side holes. Alternatively, the stent wall may taper away from the outer surface of the stent wall but not taper away from the inner surface of the stent wall at the upstream end of the at least one of the side holes. The side hole wall may meet the inner or outer surface of the stent wall to form a non-perpendicular vertex.

The stent wall may taper away from the inner surface of the stent wall but does not taper away from the outer surface of the stent wall at the downstream end of at the at least one of the side holes. Alternatively, the stent wall may taper away from the outer surface of the stent wall but not taper away from the inner surface of the stent wall at the downstream end of at the at least one of the side holes. The side hole wall may meet the inner or outer surface of the stent wall to form a non-perpendicular vertex.

The stent wall may be tapered in a direction towards the side hole around the entire perimeter of the side hole. Alternatively, the stent wall may be tapered only at the upstream and/or downstream end regions of the side hole, or in the vicinity of the upstream and downstream end regions of the side hole. For example, the stent wall may be tapered at an angle of ±<NUM>°, ±<NUM>°, or ±<NUM>° either side of the upstream and/or downstream end of the side hole. Alternatively, the side hole may be tapered only at the extreme upstream and/or downstream ends of the side hole.

The side hole may extend through the stent wall at an oblique angle relative to the longitudinal axis of the stent. The side hole may extend through the stent wall at an angle of <NUM> to <NUM>°, <NUM> to <NUM>°, <NUM> to <NUM>°, <NUM> to <NUM>°, <NUM> to <NUM>°, <NUM> to <NUM>°, for example about <NUM>° relative to the longitudinal axis of the stent. For example, the longitudinal axis of the side hole may extend through the stent wall at an oblique angle to the longitudinal axis of the stent.

The stent may have an upstream plurality of side holes in an upstream portion of the stent and a downstream plurality of side holes in a downstream portion of the stent, wherein the upstream plurality of side holes extend through the stent wall at an acute angle relative to the longitudinal axis of the stent when measured from the upstream direction, and wherein the downstream plurality of side holes extend through the stent wall at an obtuse angle relative to the longitudinal axis of the stent when measured from the upstream direction. More generally, the upstream plurality of side holes may be arranged to direct fluid into the central bore of the stent, and the downstream plurality of side holes may be arranged to direct fluid out from the central bore of the stent.

The side holes in which the stent wall tapers in thickness in a direction towards the side hole at the upstream and/or downstream end of the side holes may be confined to the upstream end of the stent.

The stent wall may taper in a linear manner. For example, the stent wall may taper at an approximately constant rate in a direction towards the side hole.

The stent wall may taper at a non-constant rate. For example, the stent wall may taper to form a convex side hole wall when viewed in cross-section.

Each of the plurality of side holes may have a minimum diameter in the direction of the longitudinal axis of the stent of <NUM> to <NUM>, <NUM> to <NUM>, <NUM> to <NUM>, or <NUM> to <NUM>, in particular about <NUM>.

The main, non-tapered part of the stent wall may have a thickness of <NUM> to <NUM>, or <NUM> to <NUM>, in particular about <NUM>.

The invention also provides a method of making a side hole in a stent wall, wherein the method comprises cutting a side hole in the stent wall by milling, in particular by micro-milling.

The side hole may be milled in a stepwise process using a milling tool. The milling tool may be removed from the stent between each step.

One (a first) step of the stepwise process may form one (a first) portion of the stent side hole (e.g. a portion of the side hole side wall) and another (second or further) step of the stepwise process may form a different (second or further) portion of the side hole (e.g. a portion of the side hole side wall).

Each step of the stepwise process may comprise moving the stent and/or the milling tool to cause relative rotation of the milling tool about the longitudinal (central) axis of the resulting side hole.

The longitudinal axis of the resulting side hole may be substantially perpendicular to the longitudinal axis of the portion of the stent in which the side hole is formed.

The method may further comprise inserting a support or support material into the central bore of the stent. The support may support the stent wall during the milling (or cutting) of the side hole.

The method may further comprise cooling the stent prior to milling, for example to a temperature of -<NUM> or less, or -<NUM> or less, for example to about -<NUM>. The stent may be cooled sufficiently to prevent the stent from flexing when milled. For example, the stent may be cooled to ensure that the stent material has a Young's modulus of at least <NUM> GPa, at least <NUM> GPa, at least <NUM> GPa, or at least <NUM> GPa, for example about <NUM> GPa, when milled.

The stent may be cooled using liquid nitrogen. For example, the stent may be cooled by immersion in liquid nitrogen.

The invention also provides a method of making a stent having side holes, wherein the method comprises making the stent by injection moulding using a mould shaped to form a stent with side holes.

The mould used in the injection moulding process may be an aluminium mould. The mould may also be an iron, magnesium, or a copper mould.

The injection moulding method may comprise the step of removing the stent from the mould by dissolving the mould in acid. The acid may be hydrochloric acid and/or nitric acid.

The mould may be formed by 3D printing. The mould may be 3D printed from a polymer and then subsequently coated in aluminium. Alternatively, the mould may be 3D printed directly from aluminium.

The stent may be made from silicone or a silicone-based material. Alternatively, the stent may be made from a polymer or from a metal.

The stent may be a ureteric stent. Alternatively, the stent may be suitable for use in other parts of the body, such as the brain, the biliary, or pancreatic system. Alternatively, the invention may apply to a catheter instead of a stent.

The following description and examples are intended to illustrate a number of nonlimiting embodiments of the invention. Unless otherwise stated, any of the features disclosed herein may be combined insofar as the relevant features are compatible. The disclosure of certain features in combination in reference to the specific examples described herein does not imply that all of the features in question must necessarily be present together.

Referring to <FIG>, the stent <NUM> comprises a stent wall <NUM> having an inner <NUM> surface and an outer surface <NUM>. The inner surface <NUM> of the stent wall <NUM> defines a central bore <NUM> of the stent <NUM>, through which fluid, such as urine, may flow. The stent <NUM> comprises a plurality of side holes <NUM> that extend through the stent wall <NUM> from the inner surface <NUM> to the outer surface <NUM> to provide fluid communication between the central bore <NUM> of the stent <NUM> and the surrounding environment <NUM>. Each side hole is defined by a surrounding side hole wall <NUM> that extends between the inner <NUM> and the outer <NUM> surfaces of the stent wall <NUM>. The stent wall <NUM> tapers in thickness in a direction towards the side hole <NUM> at the upstream end <NUM> and the downstream end <NUM> of the side hole <NUM>. The thickness of the stent wall <NUM> is the distance between the innermost and the outermost surfaces of the stent wall (e.g. the inner <NUM> and outer <NUM> surfaces of the stent wall <NUM>) in a direction perpendicular to the longitudinal axis of the stent <NUM>. The thickness is typically measured in a radial direction from the longitudinal axis of the stent <NUM>. The stent wall <NUM> may taper to reduce in thickness in a direction towards the centre of the side hole <NUM> or generally towards the side hole <NUM> when viewed in the relevant cross-section plane, parallel to a radial direction from the longitudinal axis of the stent <NUM>. In other words, the stent wall <NUM> tapers immediately adjacent to the side hole <NUM>. In this way, the surface of the tapered portion of the stent wall <NUM> defines at least a portion of the side hole wall <NUM>.

As used herein, the upstream end is the end from which fluid (e.g. urine) flows, and the downstream end is the end towards which the fluid flows when the stent <NUM> is in use.

The upstream end and the downstream end of the stent or of the side holes <NUM> may be identical in structure and will therefore be indistinguishable and interchangeable, as in <FIG>. Alternatively, the upstream <NUM> and the downstream <NUM> ends of the side holes <NUM> may be structurally distinct. The stent <NUM> has a longitudinal axis, which extends along the centre of the central bore <NUM> from the upstream end of the stent to the downstream end of the stent when the stent is arranged in a linear configuration.

The cross-section of the part of the stent wall <NUM> that defines the upstream <NUM> or downstream <NUM> end of the side hole <NUM> may taper, to become progressively narrower, in a direction towards the centre of the side hole <NUM>. The cross-section may be taken in a plane defined by the longitudinal axis of the side hole <NUM> (i.e. along the central axis of the side hole <NUM>) and the longitudinal direction of the stent <NUM>, i.e. the longitudinal axis of the side hole <NUM> lies in the cross-section plane and the cross-section plane is parallel to the longitudinal axis of the stent <NUM>. At least a portion of the side hole wall <NUM> (e.g. when viewed in this cross-section plane) at the upstream <NUM> and/or downstream <NUM> ends of the side hole <NUM> may be at an oblique angle to the longitudinal axis of the stent <NUM>.

Referring to <FIG>, the side hole <NUM> extends through the stent wall <NUM> to form an internal opening <NUM> in the inner surface of the stent wall and an external opening <NUM> in the outer surface of the stent wall <NUM>. Each of the internal <NUM> and external <NUM> openings may have a point around its perimeter <NUM>, <NUM> that is the closest to the upstream end of the stent, i.e. the extreme upstream point <NUM>, <NUM> of the opening <NUM>, <NUM>. Similarly, each of the internal <NUM> and external <NUM> openings may have a point around its perimeter <NUM>, <NUM> that is the closest to the downstream end of the stent, i.e. the extreme downstream point <NUM>, <NUM> of the opening <NUM>, <NUM>.

Typically, the side hole <NUM> will be symmetrical with respect to reflection in a plane defined by (i.e. containing) a radial direction from the longitudinal axis and the longitudinal axis itself, as shown in <FIG>. In this case, the extreme upstream <NUM>, <NUM> and downstream <NUM>, <NUM> points of the internal <NUM> and external <NUM> openings will lie in this plane. However, this may not be so, for example the internal <NUM> and external <NUM> openings may be offset around the circumference of the stent wall <NUM>, as shown in <FIG>. In this case, it is useful to consider a different frame of reference.

For example, at least a portion of the side hole wall <NUM> at the downstream end of the side hole <NUM> may be at an oblique angle to the longitudinal axis of the stent <NUM> when viewed in cross-section in a plane defined by: i) the vector that connects the extreme downstream points <NUM>, <NUM> of the internal <NUM> and external <NUM> openings, and ii) the longitudinal direction of the stent <NUM>. In other words, the vector that connects the extreme downstream points <NUM>, <NUM> of the internal <NUM> and external <NUM> openings lies in the cross-section plane and the cross-section plane is parallel to the longitudinal axis of the stent <NUM>.

Similarly, at least a portion of the side hole wall <NUM> at the upstream end of the side hole <NUM> may be at an oblique angle to the longitudinal axis of the stent <NUM> when viewed in cross-section in a plane defined by: i) the vector that connects the extreme upstream points <NUM>, <NUM> of the internal <NUM> and external <NUM> openings, and ii) the longitudinal direction of the stent <NUM>. In other words, the vector that connects the extreme upstream points <NUM>, <NUM> of the internal <NUM> and external <NUM> openings lies in the cross-section plane and the cross-section plane is parallel to the longitudinal axis of the stent <NUM>.

The oblique angle of the stent wall may be <NUM> to <NUM>°, <NUM> to <NUM>°, <NUM> to <NUM>°, <NUM> to <NUM>°, <NUM> to <NUM>°, <NUM> to <NUM>°, for example about <NUM>° relative to the longitudinal axis of the stent <NUM>. Substantially all of the side hole wall <NUM> at the upstream and/or downstream end of the side hole may be at an oblique angle relative to the longitudinal axis of the stent <NUM>. Alternatively, at least <NUM>%, at least <NUM>%, at least <NUM>%, at least <NUM>%, at least <NUM>%, at least <NUM>%, at least <NUM>%, at least <NUM>%, at least <NUM>%, or the entire height of the side hole wall <NUM>, as measured in the direction perpendicular to the longitudinal axis of the stent <NUM> in the relevant cross-section plane, may be at an oblique angle to the longitudinal axis of the stent <NUM>.

Returning to <FIG>, the stent wall <NUM> may taper inwardly away from both the inner surface <NUM> and the outer surface <NUM> of the stent wall <NUM> at the upstream <NUM> and downstream <NUM> ends of a side hole <NUM>, as illustrated in <FIG>. In this context, inwardly away from means radially towards the opposing surface of the stent wall <NUM>. For example, the outer surface <NUM> of the stent wall <NUM> may deflect towards the inner surface <NUM> of the stent wall <NUM> to form the side hole wall <NUM>, and vice versa.

The stent wall <NUM> may taper in thickness to form a vertex <NUM> located between, and offset in the radial direction from, both the inner surface <NUM> and the outer surface <NUM> of the stent wall <NUM>. The vertex <NUM> may be located half way between the inner surface <NUM> and outer surface <NUM> of the stent wall <NUM>. The vertex <NUM> may have an internal angle, defined as the angle between the converging portions of the side hole wall <NUM> that form the vertex <NUM>, of <NUM> to <NUM>°, <NUM> to <NUM>°, <NUM> to <NUM>°, <NUM> to <NUM>°, for example about <NUM>°, which has been found to be advantageous for reducing encrustation.

The stent wall <NUM> may taper inwardly away from both the inner <NUM> and the outer <NUM> surfaces to an equal extent. For example, the cross-section of the side hole wall <NUM> may be symmetrical with respect to reflection about the line defining the mid-point between the inner <NUM> and outer <NUM> surfaces of the stent wall <NUM>. For example, the tapered section of the stent wall <NUM> may form an isosceles or equilateral triangle in cross-section, wherein the base of the triangle faces away from the side hole <NUM>.

Alternatively, the stent wall <NUM> may taper asymmetrically so that the vertex <NUM> is offset in the radial direction from the midpoint between the inner <NUM> and outer <NUM> surfaces of the stent wall <NUM>. For example, the tapered section of the stent wall <NUM> may form an acute scalene triangle in cross-section.

Instead of forming a vertex <NUM>, the portions of the side hole wall <NUM> that lie at an oblique angle to the longitudinal axis of the stent <NUM> due to the tapering of the stent wall <NUM> may be joined by a portion of the side hole wall <NUM> that is perpendicular to the longitudinal axis of the stent <NUM>.

When in use, for example when inserted into the ureter of a patient, the stent <NUM> provides a fluid pathway around an occlusion, such as a kidney stone or caused by a cancerous growth. The stent <NUM> typically has side holes <NUM> located along its length and located either side of the occlusion when in use. On the upstream side of the occlusion, fluid may pass into the central bore <NUM> of the stent <NUM> from the surrounding environment <NUM>. In the case of a ureteric stent the surrounding environment <NUM> is the intraluminal region of the ureter. The occlusion blocks or obstructs the passage of urine through the ureter, which results in an increase in pressure within the intraluminal region of the ureter. This causes fluid to pass into the central bore <NUM> of the stent <NUM> through the side holes <NUM> that are in close proximity to the occlusion on the upstream side of the occlusion. The urine bypasses the occlusion through the central bore <NUM> of the stent. Once the urine has passed the occlusion, the increased pressure within the central bore <NUM> of the stent <NUM> causes urine to flow out of the central bore <NUM> of the stent <NUM> through the side holes <NUM> that are on the downstream side of the occlusion.

As a result, only relatively few of the side holes <NUM> are active in transferring fluid between the central bore <NUM> of the stent <NUM> and the surrounding environment <NUM>, these being the side holes <NUM> in close proximity to the occlusion. The majority of the side holes <NUM> experience relatively small amounts of fluid exchange, which results in regions of flow stagnation within the side holes <NUM>. This flow stagnation causes the build-up of encrusting deposits within the side holes <NUM>, such as bacterial or crystal deposits, which results in the blockage or obstruction of the side holes <NUM> and provides anchor points, or nucleation points, for further encrustation or biofilm formation.

Referring to <FIG>, conventional ureteric stents have side holes <NUM> that are punched through the side walls <NUM> in a perpendicular direction to the longitudinal axis of the stent. This results in the side holes <NUM> having side hole walls <NUM> that are perpendicular to the longitudinal axis of the stent when viewed in cross-section. The grayscale shading surrounding the stent wall in <FIG> illustrates the flow velocity: the darker the shading the slower the flow velocity. As can be seen, the region within the side hole <NUM> experiences substantially reduced flow velocity and stagnation compared to the fluid in the central bore <NUM> of the stent and the surrounding environment <NUM>. This allows the accumulation of encrusting deposits within the side hole <NUM>, ultimately leading to blockage of the side hole <NUM> and failure of the stent.

As can be seen in <FIG>, the stents according to the present invention reduce the flow stagnation due to the more streamlined shape of the side holes <NUM> in the flow direction resulting from the tapered profile of the stent wall <NUM> at the upstream <NUM> and/or downstream <NUM> ends of the side holes <NUM>.

Referring to <FIG>, the side hole walls <NUM> may instead taper to form a rounded, or convex, profile when viewed in cross-section. This is one example of the stent wall <NUM> tapering at a non-constant rate.

Referring to <FIG>, the stent wall <NUM> may taper away from the inner surface <NUM> of the stent wall <NUM> but not taper away from the outer surface <NUM> of the stent wall <NUM> at the upstream end <NUM> of the side hole <NUM> and may taper away from the outer surface <NUM> of the stent wall <NUM> but not taper away from the inner surface <NUM> of the stent wall <NUM> at the downstream end <NUM> of the at side hole <NUM>. In this way, fluid that flows in a downstream direction is directed from the central bore <NUM> of the stent <NUM> to the surrounding environment <NUM>, e.g. the intraluminal region of the ureter.

Alternatively, referring to <FIG> the stent wall <NUM> may taper away from the outer surface <NUM> of the stent wall <NUM> but not taper away from the inner surface <NUM> of the stent wall <NUM> at the upstream end <NUM> of the side hole <NUM> and may taper away from the inner surface <NUM> of the stent wall <NUM> but not taper away from the outer surface <NUM> of the stent wall <NUM> at the downstream end <NUM> of at the side hole <NUM>. In this way, fluid that flows in a downstream direction is directed from the surrounding environment <NUM>, e.g. the intraluminal region of the ureter, into the central bore <NUM> of the stent <NUM>.

The upstream <NUM> and the downstream <NUM> ends of the side hole wall <NUM> may be parallel to each other, as illustrated in <FIG>.

One or more of the side holes <NUM> may extend through the stent wall <NUM> at an oblique angle relative to the longitudinal axis of the stent <NUM>. This would result in a cross-section of the sort illustrated in <FIG>. For example, the side hole <NUM> may extend through the stent wall at an angle of <NUM> to <NUM>°, <NUM> to <NUM>°, <NUM> to <NUM>°, <NUM> to <NUM>°, <NUM> to <NUM>°, <NUM> to <NUM>°, for example about <NUM>° relative to the longitudinal axis of the stent <NUM>. For example, the longitudinal axis of the side hole <NUM> may extend through the stent wall <NUM> at an oblique angle to the longitudinal axis of the stent <NUM>. The side hole <NUM> may be tubular and may have a substantially circular cross-section when viewed along its longitudinal axis (i.e. along its length).

Referring to <FIG>, the stent wall <NUM> may taper away from the inner surface <NUM> of the stent wall <NUM> but not taper away from the outer surface <NUM> of the stent wall <NUM> at both the upstream <NUM> and downstream <NUM> ends of the side hole <NUM>. Alternatively, referring to <FIG>, the stent wall <NUM> may taper away from the outer surface <NUM> of the stent wall <NUM> but not taper away from the inner surface <NUM> of the stent wall <NUM> at both the upstream <NUM> and downstream <NUM> ends of the side hole <NUM>.

It should also be noted that, in general, it is not necessary for both the upstream <NUM> and the downstream <NUM> ends to both taper. For example, one or the other of the upstream <NUM> or downstream <NUM> ends of the side holes <NUM> may not taper.

The portion of the side hole wall <NUM> that is at an oblique angle to the longitudinal axis of the stent <NUM> may meet the inner <NUM> or outer surface <NUM> of the stent wall <NUM> to form a vertex <NUM>. Alternatively, the oblique portion of the side hole wall <NUM> may be joined to either the inner <NUM> or the outer <NUM> surface of the stent wall <NUM> by an untapered portion, for example that is perpendicular to the longitudinal axis of the stent <NUM>.

The stent wall <NUM> may be tapered in a direction towards the side hole <NUM>, for example in a direction towards the centre of the side hole <NUM>, around the entire perimeter of the side hole <NUM>. Alternatively, the stent wall <NUM> may be tapered only at the upstream and/or downstream end regions of the side hole <NUM>, or in the vicinity of the upstream and downstream end regions of the side hole <NUM>. For example, the stent wall may be tapered at an angle of ±<NUM>°, ±<NUM>°, or ±<NUM>° either side of the upstream <NUM> and/or downstream <NUM> end of the side hole <NUM>. Alternatively, the side hole <NUM> may be tapered only at the extreme upstream <NUM> and/or downstream <NUM> ends of the side hole <NUM>.

The side hole wall <NUM> at the upstream <NUM> and/or downstream <NUM> end of the side hole <NUM> may be at an oblique angle to the longitudinal axis of the stent <NUM> (due to the tapering of the stent wall <NUM>) along its entire height, or along at least <NUM>%, at least <NUM>%, at least <NUM>%, at least <NUM>%, at least <NUM>%, at least <NUM>%, at least <NUM>%, at least <NUM>%, at least <NUM>% of its height, where the height of the side hole <NUM> is the distance between the inner <NUM> and outer <NUM> surfaces of the stent wall <NUM> and is in a direction perpendicular to the longitudinal axis of the stent <NUM>. Generally, this will be in a radial direction.

The stent wall <NUM> may taper at the upstream <NUM> and/or downsteam <NUM> end of the side hole over a length that is at least <NUM>%, at least <NUM>%, at least <NUM>%, or at least <NUM>% of the thickness of the main, non-tapered portion of the stent wall <NUM>. The length is measured parallel to the longitudinal axis of the stent <NUM>.

Each of the plurality of side holes <NUM> may have a minimum diameter in the direction of the longitudinal axis of the stent <NUM> of <NUM> to <NUM>, <NUM> to <NUM>, <NUM> to <NUM>, or <NUM> to <NUM>, in particular about <NUM>. For example, the side holes <NUM> may have a diameter (for example a minimum or maximum diameter, e.g. in the direction of the longitudinal axis of the stent) of less than <NUM>, or of less than <NUM> (i.e. sub-millimetre, or micron-sized). The diameter in question may be, for example, the diameter of the internal or external opening. For example, the side holes <NUM> may have a diameter in the range of about <NUM> to about <NUM>.

The stent wall <NUM> may have a thickness of <NUM> to <NUM>, or <NUM> to <NUM>, for example about <NUM> in the non-tapered regions.

The side holes <NUM> may all be of the same type or may have the same cross-section. For example, each of the plurality side holes <NUM> may have a cross-section as shown in <FIG>. Alternatively, the stent may comprise a number of side holes <NUM> of different geometries. For example, the stent <NUM> may comprise an approximately equal number of the side holes <NUM> illustrated in <FIG>. For example, the ratio of the two different types of side hole <NUM> may be at most <NUM>:<NUM>, or at most <NUM>:<NUM>. The two different types of side hole <NUM> projecting in opposite directions along the longitudinal axis of the stent <NUM> may alternate along the length of the stent <NUM> to equalise the exchange of fluid between the central bore <NUM> of the stent <NUM> and the surrounding environment <NUM>. Alternatively, the upstream portion of the stent may have side holes <NUM> as illustrated in <FIG> (i.e. directing fluid into the central bore <NUM> of the stent) and the downstream portion of the stent <NUM> may have side holes <NUM> as illustrated in <FIG> (i.e. directing fluid out from the central bore <NUM> of the stent <NUM>). Preferably, the side holes <NUM> illustrated in <FIG> will be located on the upstream side of the occlusion when the stent <NUM> is in use, for example in the upstream half of the stent <NUM>, and the side holes <NUM> illustrated in <FIG> will be located on the downstream side of the occlusion, for example in the downstream half of the stent <NUM>. The transition point along the length of the stent <NUM> at which the side holes <NUM> change from being those illustrated in <FIG> to those illustrated in <FIG> may be the mid-point along the length of the stent <NUM>. Alternatively, the location of the occlusion may be determined and the transition point may be selected so that the side holes <NUM> illustrated in <FIG> will be located on the upstream side of the occlusion when the stent <NUM> is in use, and the side holes <NUM> illustrated in <FIG> will be located on the downstream side of the occlusion.

The tapered side holes <NUM> may be distributed along the entire length of the stent <NUM>. Alternatively, the tapered side holes <NUM> may be located only along the part of the stent <NUM> that will be located in the upper or proximal part of the ureter when the stent <NUM> is in use, i.e. the upstream portion of the stent. For example, the tapered side holes <NUM> may be confined to one end of the stent <NUM>, preferably the upstream end of the stent <NUM> that is located in the proximal part of the ureter when in use. The proximal part of the ureter has a larger diameter, which reduces the flow velocity. The upstream end of the stent <NUM> is therefore more prone to the deposition of encrusting deposits. The use of streamlined side holes <NUM> in the upstream part of the stent <NUM> is therefore particularly advantageous. Limiting the extent of the streamlined side holes <NUM> to only the upstream part of the stent <NUM> simplifies the manufacture of the stent <NUM> and reduces its cost, while maintaining a significant benefit. The streamlined side holes <NUM> may be located within a region extending no further from one end of the stent <NUM> (preferably the upstream end of the stent <NUM> if the upstream and downstream ends of the stent <NUM> are structurally distinct) than <NUM>%, <NUM>%, or <NUM>% of the total length of the stent <NUM>. For example, the streamlined side holes <NUM> may be located within a region extending no further than <NUM>, <NUM>, or <NUM> along the length of the stent <NUM> from one of its ends, preferably the upstream end of the stent <NUM>.

Stents <NUM> in accordance with the present invention may be formed from any suitable material because it is the streamlined shape of the side holes <NUM> that results in the reduction in encrustation, not any specific material or coating properties. For example, the stent <NUM> may be made from silicone or a polymer-based material, for example polyurethane or polyethylene. Alternatively, the stents <NUM> could be made from a metal, such as a nickel-cobalt-chromium-molybdenum alloy.

The side holes <NUM> may be formed in the stent wall <NUM> by milling, in particular by micro-milling. Micro-milling may involve milling using milling tools having micron-sized cutting surfaces, for example to form micron-sized features, such as micron-sized side holes <NUM>. Computer numerical control (CNC) milling is particularly advantageous due to its accuracy and ability to form complex shapes. Side holes <NUM> other than those of the present invention (i.e. those without tapered side walls <NUM>) may also be formed by milling.

Typically, stent side holes <NUM> are punched into the stent wall <NUM>. However, it is difficult to accurately control the shape and profile of the side holes <NUM> by punching. Furthermore, the side holes <NUM> may have a diameter on the micrometre or millimetre scale. For example, the side holes <NUM> may have a diameter (for example a minimum or maximum diameter) of less than <NUM>, or of less than <NUM> (i.e. sub-millimetre, or micron-sized). The diameter in question may be, for example, the diameter of the internal or external opening. For example, the side holes <NUM> may have a diameter in the range of about <NUM> to about <NUM>. However, punching does not provide the level of control or resolution required to manufacture sub-millimetre side holes <NUM> accurately.

Various other methods of fabricating stents <NUM> having side holes <NUM> are possible, such as laser cutting, water-jet cutting, and micro-milling. However, micro-milling has been found to be the most suitable, accurate and reliable method for forming micron-sized side holes <NUM> in stents <NUM>. For example, laser cutting was found to cause undesirable deformation of the cut zone and melting of surrounding material, precluding the formation of carefully shaped side holes <NUM>. Water-jet cutting was found to require additional drilling steps prior to the water-jet cutting in order to cut holes <NUM> with diameters smaller than the substrate (i.e. stent wall <NUM>) thickness.

Various shaped milling tools may be used to form the various shaped side holes <NUM>, <NUM> according to the present invention. For example, an end mill <NUM>, such as the cylindrical end mill <NUM> illustrated in profile in <FIG>, may be used to bore side holes <NUM> through the stent wall <NUM> at an oblique angle to the longitudinal axis of the stent <NUM>, thereby forming side holes <NUM> having cross sections such as those illustrated in <FIG>. An end mill <NUM> may also be used to mill side holes <NUM>, <NUM> with cross-sections as illustrated in <FIG>, <FIG> if the end mill <NUM> is used to cut into the stent wall <NUM>, <NUM> at a second oblique angle relative to the longitudinal axis of the stent <NUM>, <NUM> in addition to the first, where the first oblique angle is an acute angle and the second oblique angle is an obtuse angle when measured from the same direction along the longitudinal axis of the stent <NUM>, <NUM>. End mills <NUM> (or milling tools) having other profiles may also be used to mill side holes <NUM> in these ways.

Alternatively, specialist milling tools with more complex cutting edges may be employed to cut the side holes <NUM>, <NUM>. For example, the triangular-shaped milling tool <NUM> illustrated in <FIG> could be used to form side holes <NUM>, <NUM> having cross-sections such as those illustrated in <FIG>, <FIG>. The triangular-shaped milling tool <NUM> has an upward-facing cutting edge <NUM> and a downward-facing cutting edge <NUM>, with both the upward- and downward-facing cutting edges <NUM>, <NUM> being at an oblique angle to the longitudinal axis of the milling tool <NUM>. The downward-facing cutting edge <NUM> is able to form the portions of the side hole walls <NUM> that are at an oblique angle to the longitudinal axis of the stent <NUM> and which face away from the central bore <NUM> of the stent <NUM>, and the upward-facing cutting edge <NUM> is able to form the portions of the side hole walls <NUM> that are at an oblique angle to the longitudinal axis of the stent <NUM> and which face toward the central bore <NUM> of the stent <NUM>. The upward- and downward- facing cutting edges <NUM>, <NUM> of the triangular-shaped milling tool may be straight, as shown in <FIG>, or they may be concave, as shown in <FIG>, which allows the cutting of convex side hole walls, such as those illustrated in <FIG>.

Referring now to <FIG>, the side holes <NUM> may be formed by inserting the milling tool <NUM> into or through the wall <NUM> of the stent so that the milling tool <NUM> (in particular the longitudinal axis <NUM> of the milling tool <NUM>) is arranged at an oblique angle to the longitudinal (or central) axis <NUM> of the side hole <NUM> that is being milled (i.e. the longitudinal axis <NUM> of the completed or resulting side hole <NUM>) and moving the milling tool <NUM> and/or the stent <NUM> to cause the milling tool <NUM> to rotate (or precess) about the longitudinal axis <NUM> of the side hole <NUM> being milled, in particular so that the longitudinal axis <NUM> of the milling tool <NUM> rotates or precesses about the longitudinal axis <NUM> of the resulting side hole <NUM>. This may be achieved either by moving or rotating (e.g. precessing) the milling tool <NUM> or the stent <NUM>, or a combination of both. For example, the longitudinal axis <NUM> of the milling tool <NUM> may remain stationary, while the stent <NUM> is moved or rotated to effect the relative movement of the stent <NUM> and the milling tool <NUM> that is required. For example, the stent <NUM> or a portion of the stent <NUM> may be rotated about an axis substantially perpendicular to its longitudinal axis <NUM>. In particular, the stent <NUM> (or a portion of the stent <NUM> within which the side hole <NUM> is being milled) may be rotated in a plane arranged at an oblique angle to the longitudinal axis <NUM> of the milling tool <NUM>, which provides the required relative rotation or precession of the longitudinal axis <NUM> of the milling tool <NUM> about the longitudinal axis <NUM> of the side hole <NUM> that is being milled. This process may result in a side hole <NUM> having a waist or vertex <NUM> located between the inner <NUM> and outer <NUM> surfaces of the stent <NUM>.

The longitudinal axis <NUM> of the side hole <NUM> being milled (i.e. the resulting side hole) is generally substantially perpendicular to the longitudinal axis <NUM> of the stent <NUM> (or the portion of the stent <NUM> in which the side hole <NUM> is formed). Therefore, references to the longitudinal (or central) axis <NUM> of the side hole should be understood to be interchangeable with references to a rotational axis <NUM> that may be substantially perpendicular to the longitudinal axis <NUM> of the stent <NUM>.

As shown in <FIG>, the stent <NUM> may be held by a stent holder <NUM> such that the stent <NUM>, or a portion of the stent held by the stent holder <NUM>, may be rotated in a plane that lies at an oblique angle (α) to the milling tool <NUM>, in particular to the longitudinal axis of the milling tool <NUM>. As such, once the milling tool <NUM> is inserted into the stent wall, the stent <NUM> (or portion thereof) may be rotated (as indicated by the arrow) in the oblique plane to form a side hole in accordance with the invention (i.e. with tapered side walls).

Referring again to <FIG>, preferably, the stent <NUM> and/or the milling tool <NUM> are moved such that the longitudinal axis <NUM> of the milling tool <NUM> rotates or precesses in the same direction or sense as the milling tool <NUM> rotates about its longitudinal axis <NUM>. For example, the stent <NUM> may be rotated in a direction counter to the direction in which the milling tool <NUM> rotates about its longitudinal axis <NUM>. This improves the accuracy of the milling and provides neater and more accurate side holes <NUM> with a more uniform profile.

The milling tool <NUM> may be rotated (or may precess) entirely (e.g. by <NUM>° or more) about the longitudinal axis <NUM> of the side hole <NUM> being milled without removing the milling tool <NUM> from the stent <NUM>. For example, the milling tool <NUM> may be rotated entirely about the longitudinal axis <NUM> of the side hole <NUM> in one movement. However, preferably the stent side hole <NUM> is milled progressively in steps of less than <NUM>°, with the milling tool <NUM> removed between each step. For example, the milling tool <NUM> may be inserted into the stent <NUM> and rotated about the longitudinal axis <NUM> of the resulting side hole <NUM> by a first amount, which is less than <NUM>°, for example, about <NUM>° or about <NUM>° and then removed from the stent <NUM>. In this first step, the milling tool <NUM> may be rotated about the longitudinal axis of the side hole <NUM> between a first angle and a second angle through a first angular range. During this first rotational movement, the milling tool <NUM> forms or mills a first portion of the side hole wall <NUM>, for example the first half or quarter. The milling tool <NUM> may then be reinserted into the stent <NUM> and rotated about the longitudinal axis <NUM> of the side hole <NUM> by a second, or further, amount, for example by another <NUM>° or <NUM>°. In this second, or subsequent, step, the milling tool <NUM> may be rotated about the longitudinal axis <NUM> of the side hole <NUM> between a third angle and a fourth angle through a second angular range, the second angular range preferably being different to the first angular range. For example, the first angular range may be from <NUM>° to <NUM>° and the second angular range may be from <NUM>° to <NUM>° or from <NUM>° to <NUM>°. During this second rotational movement or step, the milling tool <NUM> forms or mills a second portion of the side hole wall <NUM>, for example the second half or quarter. The milling tool <NUM> may then again be removed from the stent <NUM>. This process may be repeated until the side hole <NUM> is fully formed or milled, with all portions of the side wall <NUM> formed or milled. In this way, the side hole <NUM> is milled in a stepwise manner with different portions of the side hole wall <NUM> being initially milled during different steps, the milling tool <NUM> being removed from the stent <NUM> between each step. Thus different steps of the stepwise process form different portions of the stent side hole side wall <NUM>.

In each subsequent step, portions of the side hole wall <NUM> that were formed in previous steps may be re-milled. In other words, in subsequent steps the milling tool <NUM> may rotate through angles already covered or milled during previous steps and may also cover additional portions or angles not previously milled. For example, a first portion (e.g. quarter or half) of the side hole wall <NUM> may be milled in the first step and the second step may involve re-milling the first portion and optionally also newly or initially milling a second portion (e.g. the next or adjacent quarter or half) of the side hole wall <NUM>. This improves the quality of the finish by repeatedly milling portions of the side hole wall <NUM>. Preferably all portions of the side hole wall <NUM> are milled at least twice. This may be achieved by performing a final complete (i.e. at least <NUM>°) rotation or precession of the milling tool <NUM> about the longitudinal axis <NUM> of the stent side hole <NUM> once all portions of the side hole wall <NUM> have been milled at least once.

Surprisingly, the stepwise process described above results in more accurately formed side holes <NUM> than simply milling the side holes <NUM> in a single step without removing the milling tool <NUM> from the stent <NUM> during the milling process. This is demonstrated by the data presented in <FIG>. In each of samples <NUM> to <NUM> side holes <NUM> were milled into the side wall of a stent at a cutting angle (α) of <NUM>° to the longitudinal axis <NUM> of the resulting side hole <NUM> (i.e. <NUM>° from the rotational axis <NUM>) to form side holes <NUM> having a waist vertex angle (θ) of <NUM>° located between the inner <NUM> and outer <NUM> surfaces of the stent wall <NUM>. The side holes <NUM> of samples <NUM> and <NUM> were milled in a single step (a single round or rotation), whereas the side holes <NUM> of samples <NUM> and <NUM> were milled using two <NUM>° milling steps (two half rounds or rotations) and four <NUM>° milling steps (four quarter rounds or rotations), respectively, removing the milling tool <NUM> from the stent <NUM> between steps. Once the side holes <NUM> were formed, the cutting angle (α) and the vertex angle (θ) were then calculated by measuring various dimensions of the side hole <NUM>, specifically the internal opening diameter, external opening diameter, and waist diameters of the holes. As can be seen from <FIG>, the measured cutting (α) and vertex angles (θ) for samples <NUM> and <NUM> are in very close agreement with the actual (original) cutting angle (α) and the intended (original) vertex angle (θ) (dashed horizontal lines), whereas samples <NUM> and <NUM> show significant deviations from the target values, thus demonstrating that the stepwise method produces superior results.

<FIG> also demonstrates the superior quality of finish provided by the stepwise process. The side holes of samples <NUM> and <NUM> (<FIG>) are clearly more misshapen and include an increased number of defects (such as the debris, fractures, and bumps highlighted by the dashed boxes) compared to those of samples <NUM> and <NUM> (<FIG>).

In general, the side holes <NUM> may be formed either before or after the central bore <NUM> of the stent <NUM> is formed.

Many materials from which stents <NUM> are fabricated, such as polymers and silicone-based materials are flexible. This makes the accurate milling of side holes <NUM> difficult to achieve. The milling process may therefore further involve cooling the stent <NUM> prior to milling, for example to a temperature of -<NUM> or less, or -<NUM> or less, for example to about -<NUM>. For example, the stent <NUM> may be cooled sufficiently to prevent the stent <NUM> from flexing when milled, which facilitates the accurate milling of side holes <NUM>. For example, the stent <NUM> may be cooled to ensure that the stent <NUM> material has a Young's modulus of at least <NUM> GPa, at least <NUM> GPa, at least <NUM> GPa, or at least <NUM> GPa, for example about <NUM> GPa, when milled when milled (measured by tensile testing, for example using standard test method ASTM D638, for example at a strain rate of <NUM>/min on a <NUM> kN capacity servohydraulic testing machine under displacement control).

The stent <NUM> may be continuously cooled during the milling process, or may be milled a sufficiently short time after cooling so as to ensure that the stiffening of the stent <NUM> due to cooling is sufficient to allow accurate milling of the side holes <NUM>. For example, the stent <NUM> may be milled within <NUM> minutes, <NUM> minutes, <NUM> minute, <NUM> seconds, or <NUM> seconds of the end of the cooling process.

The stent <NUM> may be cooled using liquid nitrogen. For example, the stent <NUM> may be cooled by immersion in liquid nitrogen.

Another way of facilitating the accurate milling of side holes <NUM> in flexible stents <NUM> is to insert a support into the central lumen or bore <NUM> of the stent <NUM> to provide rigidity to the stent <NUM>. The support is inserted into the stent <NUM> before milling is performed, and is removed once the milling is complete. The support may be in the form of a cylindrical core which provides mechanical support to the stent wall <NUM> during milling and prevents or reduces deformation of the stent wall <NUM>. The support may be formed from a polymer, such as PVC, or other material suitable for milling.

Alternatively, the stents <NUM> according to the present invention may be formed by an injection moulding process. The mould used in the injection moulding process is shaped to form a stent <NUM> with side holes <NUM>. Stents <NUM> having side holes <NUM> other than those of the present invention (i.e. those without tapered side walls <NUM>) may also be formed by the injection moulding process of the present invention. Like milling, injection moulding provides a more accurate method of forming side holes <NUM> than the conventional method of punching the side holes <NUM> in the stent wall <NUM> once the stent <NUM> is already formed. It is also more time-efficient as a separate punching process is not required.

The injection moulding method may comprise the step of removing the stent <NUM> from the mould by dissolving the mould in acid. The mould may contain aluminium. For example, the mould may be formed of at least <NUM>%, at least <NUM>%, or at least <NUM>% aluminium, or may be formed entirely from aluminium. The acid may be hydrochloric acid, which will not dissolve the stent <NUM> if it is formed from silicone or a polymer-based material. Alternatively or additionally, nitric acid may be used.

Claim 1:
A stent (<NUM>) comprising a stent wall (<NUM>) having an inner surface (<NUM>) and an outer surface (<NUM>), wherein the inner surface of the stent wall defines a central bore (<NUM>), and wherein the stent wall has a plurality of side holes (<NUM>) extending therethrough, and wherein each side hole has an upstream end (<NUM>) and a downstream end (<NUM>), and wherein the stent wall tapers in thickness in a direction towards the side hole at the upstream and/or downstream end of at least one of the side holes;
characterised in that:
the stent wall tapers away from both the inner surface and the outer surface of the stent wall at the upstream and/or downstream end of the at least one of the side holes; or
the stent wall tapers away from the inner surface of the stent wall but does not taper away from the outer surface of the stent wall at the downstream end of the at least one of the side holes; or
the at least one of the side holes extends through the stent wall at an oblique angle relative to the longitudinal axis of the stent and has a substantially circular cross-section when viewed along its longitudinal axis.