WO2009101472A2

WO2009101472A2 - Stent coated with aligned nanofiber by electrospinning

Info

Publication number: WO2009101472A2
Application number: PCT/IB2008/003867
Authority: WO
Inventors: Kwan-Ho Chan; Yixiang Dong; Wee Eong Teo; Seeram Ramakrishna
Original assignee: National University Of Singapore
Priority date: 2007-11-02
Filing date: 2008-11-03
Publication date: 2009-08-20
Also published as: WO2009101472A3

Abstract

A stent is covered with a coating that comprises nanofibers that are substantially aligned with the longitudinal axis of the stent's tubular body. The nanofibers may be deposited on the stent using an electrospinning process, which may deposit aligned nanofibers onto a collector and then transfer the aligned nanofibers to the stent, or deposit aligned nanofibers directly onto the stent.

Description

STENT COATED WITH ALIGNED NANOFIBER BY ELECTROSPINNING

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 60/984,803, filed November 2, 2007, which is incorporated by reference in its entirety.

BACKGROUND

[0002] This invention relates generally to medical devices and their manufacture, and in particular to the application of nanofibers to improve the efficacy of stents in patients. [0003] Coronary artery disease (CAD) is the most common cause of morbidity and mortality in the United States. According to the American Heart Association, in 1997 there were 466,101 deaths attributed to CAD. This disease accounts for the largest health expenditure in the United States. Around the world, CAD is quickly becoming the most common cause of morbidity and mortality.

[0004] CAD occurs when the coronary arteries become hardened and narrowed. Other than the hardening that occurs naturally due to aging, more severe hardening and narrowing is, more often than not, due to buildup of plaque material on the vessel inner walls. This process is known as atherosclerosis. Plaque is made up of fat, cholesterol, calcium, and other substances from the blood. Traditional methods of treating CAD include invasive surgery and percutaneous transluminal coronary angioplasty (PTCA). A common approach of PTCA is to insert a metal stent into the vessel to reopen the blocking area. [0005] A major drawback of coronary artery bare metal stents, however, is in-stent restenosis (ISR). In ISR, vessel tissue grows through stent and narrows the target area of the vessel again. With an ISR rate of 10-50%, approximately 250,000 ISR cases have to be managed worldwide per year. To overcome ISR, extensive efforts have been made for restenosis-resistant stents. A breakthrough in stenting technology was the introduction of drug-eluting stents (DESs), traditional metal stent coated with a thin layer of drugs. DESs were very successful clinically, able to reduce ISR rate from 30-60% to less than 10%. Since their approval in April 2003, DESs have revolutionized the practice of interventional cardiology. Currently, more than 85% of all coronary interventions in the United States are performed with DESs.

[0006] Disadvantageously, the drug coating delays healing around the stent and creates a risk of clots forming, which can trigger a heart attack. Despite of the widespread use of DESs, there are increasing concerns and doubt reported about the superiority of DES. It has been stated that previous clinical trials have overestimated the clinical benefits of DES, underestimated the adverse events (e.g., stent thrombosis), and neglected the "hard" clinical outcomes (e.g., mortality, major adverse cardiac event, and target vessel failure). In spite of the use of prolonged double antiplatelet therapy, patients are still experiencing higher rate of thrombosis with DES than with bare metal stents. Scientists have argued that DES may increase the risk of potentially fatal blood clots, and a meta analysis of results from past clinical trials of first-generation, drug-coated stents showed these patients had a greater risk of heart attack or death than patients given a bare metal stent. This research follows an earlier study that found the rate of heart attacks and deaths was more than three times higher in patients with drug-coated stents who stopped taking blood-thinning drugs than those who had bare-metal ones. Therefore, the problem of restenosis remains unsolved. [0007] Another use of stents is for treatment of aneurysms, which affect the aorta, the body's largest artery. The aorta carries blood away from the heart and runs from the heart through the chest and abdomen. The normal diameter of the aorta in the abdomen is about 2 cm, or a little less than 1 in. An aneurysm forms if the aorta grows to more than VA to 2 times its normal diameter. Aortic aneurysms are potentially serious health problems, since a burst aorta results in massive internal bleeding that can be fatal unless treated rapidly by an experienced emergency medical team. Endovascular stent graft repair is designed to help prevent an aneurysm from bursting.

[0008] An endovascular stent graft is a tube composed of fabric supported by a metal mesh called a stent. It can be used for a variety of conditions involving the blood vessels, but most commonly to reinforce a weak spot in an artery called an aneurysm. Over time, blood pressure and other factors can cause this weak area to bulge like a balloon and eventually enlarge and rupture. The stent graft works by creating a tight seal with the artery above and below the aneurysm. The graft is stronger than the weakened artery and allows blood to pass through it without pushing on the bulge. Physicians typically use endovascular stent grafting to treat abdominal aortic aneurysms (AAAs), but they also use it to treat thoracic aortic aneurysms (TAAs) and, less commonly, aneurysms in other locations. [0009] Traditional stent grafts use non-degradable fabrics, such as polytetrafluoroethylene (PTFE). These kinds of materials stay permanently in the artery, which can induce thrombosis and inflammation. However, other more biocompatible materials have been suggested, such as polymeric nanofibers. Manufactured using a process known as electrospinning, biodegradable polymeric nanofibers have been chosen to minimize future complications, especially for medical implants. The biomimetic morphology of their nanofibrous structure has been shown to favor cellular adhesion and tissue proliferation. [0010] Due to the relative ease of producing nanofibers from different polymers and the biomimetic morphology of the resultant deposited nanofibers, electrospinning has been used to deposit nanofibers on stents. But the nanofibers deposited in these previous approaches were randomly oriented, which may lead to failure during the deployment of the stent inside a patient's body. The failure may occur if the nanofibers can break, which occurs even under small compliance of the stent, or if the randomly deposited nanofibers are so strong that they obstruct expansion of the stent. These failures could be disastrous, as further surgery would be needed to remove the malfunctioned stent. Accordingly, there is a need for a highly expandable cover for a stent, which is resistant to breakage when the stent is expanded during deployment.

SUMMARY

[0011] To retain the biological benefits of a stent covered with nano fibers, while avoiding the problems of previous approaches, embodiments of the invention produce nanofiber-covered stents in which the nanofibers are substantially aligned with the longitudinal axis of the stent's tubular body. The nanofibers may be deposited on the stent using an electrospinning process, and a number of different embodiments of an apparatus for covering the stents by electrospinning are possible.

[0012] In one embodiment, a stent covered with aligned nanofibers is fabricated by electrospinning aligned nanofibers onto a moving collector. The collector may comprise a pair of collector plates, which collect the electrospun nanofibers and rotate to move the nanofibers to a target stent. The stent is located in the path of the collected nanofibers so that the nanofibers are deposited onto the stent. The stent may also rotate so that nanofibers are deposited around the entire surface of the stent to create an even coating over it. In another embodiment, a stent covered with aligned nanofibers is fabricated by electrospinning nanofibers directly onto the stent, which may be affixed for example on the edge of a spinning plate. The electrospun nanofibers are aligned by virtue of the stent moving quickly across the target where the nanofibers are being deposited. As above, the stent may also rotate so that nanofibers are deposited around the entire surface of the stent to create an even coating over it. These are just a few examples of fabrication techniques for making a stent coated with aligned nanofibers, and many variations on these techniques are possible. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] FIG. 1 is a diagram of a dual-plate apparatus for making a covered stent, in accordance with an embodiment of the invention.

[0014] FIG. 2 is a diagram of a single -plate apparatus for making a covered stent, in accordance with an embodiment of the invention.

[0015] FIG. 3 is a scanning electron microscopy image of a coating for a stent, showing the aligned nanofibers in the coating.

[0016] FIG. 4 is a photograph of a stent coated with aligned nanofibers in an expanded state.

[0017] FIG. 5 is a scanning electron microscopy image of a stent coated with aligned nanofibers in an expanded state.

[0018] The figures depict various embodiments of the present invention for purposes of illustration only. One skilled in the art will readily recognize from the following discussion that alternative embodiments of the structures and methods illustrated herein may be employed without departing from the principles of the invention described herein.

DETAILED DESCRIPTION

[0019] Embodiments of the invention provide a nano fiber-covered stent, in which aligned nanofibers are deposited longitudinally along a traditional bare metal stent, which may be expandable but in an unexpanded state. The alignment of the nanofibers allows for the stent's expansion during deployment while maintaining the nanofiber covering intact. Various mechanical and biological advantages may be achieved by stents having aligned nanofiber coatings. The stents may be used in patients to treat various medical conditions, including coronary artery disease, aortic aneurysm, and brain aneurysm. The nanofibrous structure of the coating generally increases the stent's biocompatibility. [0020] The nanofϊbers may be generated using a known process called electrospinning. In the electrospinning process, a liquid polymer is ejected from a jet and typically solidifies in the air before being deposited at a collector. According to embodiments of the invention, the nanofibers that are deposited are substantially aligned. These aligned nanofibers may be transferred from the collector to a stent, or they may be deposited directly onto a stent that is located at the collector. One or more layers may be deposited onto a stent in this fashion. Moreover, the stent may include one or more layers that are not substantially aligned, in addition to the one or more layers that are substantially aligned, as desired. [0021] In one embodiment, one or more layer of the coating may be incorporated with drugs (e.g., drugs having anti-thrombosis, anti-inflammation, anti-proliferation functions) or other therapeutic agents before being deployed in the body. In particular, biomolecules and drugs may be blended with the polymer during the electrospinning. Biomolecules include various growth factors such as EGF, Elastin, Adhesin, and the like. Drugs that might be beneficial in preventing ISR including taxol and other antifibrotic drugs or anti-proliferative drugs. The controlled release kinetics of the drugs and biomolecules may be tailored by the blending ration as well as by type of polymer used. Biomolecules and drugs may also be coated on the surface nanofiber with or without surface modification. [0022] FIG. 1 illustrates one embodiment of a setup for fabrication of a covered stent with aligned nanofibers. The apparatus for making the covered stent comprises a liquid outlet 10, which is fed liquid by a pump 20. Acting as a collector for the nanofibers, a pair of rotatable plates 30 fixed on an axle 40 are located below the liquid outlet 10. In one embodiment, the height difference between the bottom of the liquid outlet 10 and the top of the plates 30 is about 5 cm, and the distance between the plates is about 8 cm. A high voltage generator 50 is coupled between the liquid outlet 10 and the rotatable plates 30, possibly via the axle 40. In addition, a stent 60 is mounted on a flexible rotary wire 70 and places between the plates 30. [0023] In operation, the nanofibers are generated from the liquid outlet 10. A polymer solution or melt is fed by the pump 20 to the liquid outlet 10, which may comprises a needle of about 18 to about 30 gauge. The liquid may comprise a polymer, and the choice of polymer can be various from non-degradable to degradable polymers. Biocompatible degradable polymers may be desired for vascular applications, such as coronary stents. In one embodiment, the polymer is p(LL A-CL) in HPF 13% (w/v). In one embodiment, the feeding rate of the fluid provided from the pump 20 to the outlet 10 is about 2 ml per hour. [0024] Polymeric nanofibers are generated from the liquid outlet 10 by electrospinning. In the electrospinning process, a high voltage is applied between the liquid outlet and the collector, which in this setup comprises the pair of plates 30. The voltage provided by the high- voltage generator 50 may be in the range of about 5 kV to about 25 kV, and more specifically may be about 10 kV, where the plates 30 are held at ground. The high voltage between the outlet 10 and the plates 30 draws the liquid polymer into a nano fibrous structure, which may solidify in the air before it reaches the collector plates 30 or soon thereafter. The morphology of the generated nanofibers can be optimized by adjusting the polymer concentration, the feeding rate of liquid, the voltage, and the distance between the outlet 10 and the collector plates 30.

[0025] As described, in this setup the collector for the electrospinning process comprises the pair of plates 30. In operation, electrospun nanofibers 80 will tend to deposit between the plates 30, where the nanofibers 80 are substantially aligned with each other and are generally perpendicular to the plates 30. Due to the nature of this process, some variations in the alignment among the nanofibers 80 are expected, and the degree of this variation is expected to depend in part on the process conditions of the electrospinning and other particulars of the apparatus. As nanofibers 80 are deposited between the plates 30 during the electrospinning, the collector plates 30 are rotated at a relatively slow rate. In one embodiment, the collector plates 30 rotate at about 60 rpm. The rotation of the plates 30 makes moves the collected nanofϊbers 80 to make room for newly collected nanofϊbers 80 to form. [0026] The rotation of the plates 30 also moves the collected nanofϊbers 80 towards a stent 60 so that the nanofϊbers 80 can be deposited onto the stent 60. As illustrated, the stent 60 is mounted on a flexible rotary wire 70, and may further be mounted on a balloon coupled to the rotary wire 70. The stent 60 and rotary wire 70 are located between the collector plates 30 and oriented perpendicularly between the plates 30 and in parallel with the collected nanofϊbers 80. In this way, the stent 60 is in the path of the collected nanofϊbers 80 as the plates 30 are rotating them away from the top location where the new nanofϊbers 80 are being formed.

[0027] As the collected nanofϊbers 80 reach the stent 60, they are deposited onto the stent 60 such that they are aligned longitudinally with the stent 60. As used herein, the longitudinal direction is parallel with the length of the tubular body of the stent 60 and perpendicular to its radii. As the process proceeds, the deposited nanofϊbers 80 form a covering around the stent 60. The flexible rotary wire 70 rotates, thereby causing the stent 60 to rotate and expose its entire outside surface to the incoming collected nanofϊbers 80. In one embodiment, the flexible rotary wire 70 rotates at about 80 rpm. In this way, the nanofϊbers 80 tend to deposit over the stent 60 to form a substantially even coating. After a desired amount of nanofϊbers 80 are coated onto the stent 60 or the desired thickness is achieved, the covered stent 60 is collected. As the nanofϊbers 80 will tend to extend beyond the length of the stent 60, the redundant nanofϊbers 80 at both ends of the stent 60 may be trimmed. [0028] In an alternative process, the stent 60 may be placed between the plates 30 at a small crossing angle with respect to the aligned nanofϊbers 80 that have been collected on the stent 60. By adjusting the angle between the stent 60 and the nanofϊbers 80, the aligned nanofϊbers can be deposited onto the stent in a helical arrangement in the covering. By depositing different layers at different angles, a coating with nanofϊbers of various weaves can be created. This may be desirable, in some embodiments, to strengthen the coating and/or to keep the longitudinally aligned nano fibers attached to the stent 60. [0029] In another embodiment, the collector plates 30 are substituted with rings that collect the nano fibers. One benefit of rings is that the nano fibers collected by rings will form at a more predictable radius (i.e., the radius of the rings) than when using plates 30 to collect the nanofibers. Other structures for the collector apparatus are possible, and the collector may move in a fashion other than rotation. For example, instead of using rotating plates 30, the collector structure may comprise opposing conductors that move along a belt or track to transport the collected nanofibers to the stent 60, where they are deposited. The collector apparatus could simply comprise a pair of opposing wires that are moving relative to the liquid outlet 10, where the wires collect the nanofibers and move them towards a stent, where they are deposited. Lastly, the collector, whether rotating plates 30 or otherwise, may be metallic and may be coated with any desired coating.

[0030] FIG. 2 illustrates another embodiment of a setup for fabrication of a covered stent with aligned nanofibers. Like the setup in FIG. 1, the embodiment illustrated in FIG. 2 also comprises a liquid outlet 10 fed by a pump 20 and a high voltage generator 50 coupled between the liquid outlet 10 and a rotating axle 40. In this embodiment, however, the collector comprises a single rotating plate 90. The stent 60 is affixed at an edge of the rotating plate 90 so that as the rotating plate 90 rotates during the electrospinning process, the nanofibers are deposited directly onto the stent 60 in a substantially aligned orientation along the stent's longitudinal axis. In one embodiment, the plate 90 rotates at a relatively fast speed, for example about 1000 rpm, and the height difference between the liquid outlet 10 and the top of the plate 90 is about 15 cm.

[0031] The stent 60 may also be rotated around its longitudinal axis so that the longitudinally aligned nanofibers are deposited evenly over the stent's outer surface area. In one embodiment, the stent is incrementally rotated around its longitudinal axis using a coupled mechanism in which the stent 60 rotates by a predetermined amount (e.g., 1 degree) for each complete rotation of the plate 90. This automated mechanism for rotating the stent 60 facilitates manufacture of the coated stent 60. In another embodiment, the stent 60 is rotated manually, for example, by stopping the electrospinning process every 5 minutes and rotating the stent, for example, by 60 degrees, for about 1 hour. Once the stent has been covered, the excess nano fibers may be trimmed at the edge of the stent. [0032] In embodiments in which the stent 60 is automatically rotated around its longitudinal axis while the rotating plate 90 is moving, continuous nanofibers may be deposited on the stent 60 and onto the edge of the plate 90. This may cause twisting of the nanofibers when the stent 60 is rotated relative to the edge of the plate 90. Accordingly, in one embodiment, the fabrication apparatus includes a device to trim the nanofibers at predetermined locations so that the stent 60 can be rotated around its axis, relative to the edge of the plate 90, without disruption of the nano fiber alignment while the rotation of the plate 90 is maintained. Preferably, this automated cutting mechanism trims the nanofibers at the edge of the stent 60 before the stent 60 is further rotated about its axis. In one embodiment, a laser cutting system may be configured to trim the nanofibers just beyond the edges of the stent 60 as the stent 60 is being rotated on the plate 90. The device to trim the nanofibers may alternatively comprise a blade cutting system, which may be geared or otherwise coupled to the rotating plate 90 so that the cutting system is synchronized with the rotation of the stent 60.

[0033] The dual-plate and single-plate configurations described above are examples of apparatuses for fabricating a stent coated with substantially aligned nanofibers, and various other techniques are possible. For example, nanofibers may be deposited onto a target surface to create a fabric composed of substantially aligned nanofibers. This may be accomplished using a rapidly moving target surface, using a dual-plate mechanism such as the one described in FIG. 1, or by any other suitable means. Once the aligned nanofiber fabric is constructed, it may then be wrapped over the circumference of a stent so that the aligned nano fibers are parallel with the longitudinal axis of the stent.

[0034] FIG. 3 is a scanning electron microscopy image of a coating for a stent composed substantially of aligned nanofibers. As the images shows, the nanofibers are substantially aligned, although due to the irregularities of a typical electrospinning process the coating includes some number of nanofibers that are not aligned with the general alignment direction. Some of the benefits of the aligned nanofibers in the stent coating, as compared to a coating with randomly deposited nanofibers, are that the aligned nanofiber coating requires less force to expand, allows for greater expansion (e.g., about 200% to 400% compliance), avoids rupture of the membrane when expanded, and does not contract axially when expanded. FIG. 4 is a photograph of a stent coated with aligned nanofibers in an expanded state, and FIG. 5 is a scanning electron microscopy image of a stent coated with aligned nanofibers in an expanded state.

[0035] It is also suspected that stents coated with aligned nanofibers, in accordance with embodiments of the invention, have a number of biological advantages over stents coated with randomly oriented nanofibers. For example, aligned nanofibers may encourage cell alignment and migration in the direction of the nanofiber alignment. Moreover, aligned nanofibers may beneficially reduce the turbulence of the fluid flow through the stent. [0036] Other general benefits of the nanofiber covered stents are that they may reduce in-stent restenosis, possibly allowing drug-free or reduced drug loading of the stent. The nanotopography of the nanofiber sleeve around the stent may also provide a high effective surface area for endothelialization. The nanofiber sleeve may also reduce stent-induced vessel injury and reduce friction during insertion of the stent in the body. The gradual degradation profile of the nanofibers may reduce the inflammatory effect of the stent. Also, embodiments using p(LLA-CL) in the nanofiber composition may favor SMC long term growth and thus enhance stent healing, and may exhibit low thrombogenicity. [0037] The foregoing description of the embodiments of the invention has been presented for the purpose of illustration; it is not intended to be exhaustive or to limit the invention to the precise forms disclosed. Persons skilled in the relevant art can appreciate that many modifications and variations are possible in light of the above disclosure. The language used in the specification has been principally selected for readability and instructional purposes, and it may not have been selected to delineate or circumscribe the inventive subject matter. It is therefore intended that the scope of the invention be limited not by this detailed description, but rather by any claims that issue on an application based hereon. Accordingly, the disclosure of the embodiments of the invention is intended to be illustrative, but not limiting, of the scope of the invention, which is set forth in the following claims.

Claims

What is claimed is:

1. A method for making a stent covered with substantially aligned nano fibers, the method comprising: applying an electrical voltage between a liquid outlet and a collector apparatus; ejecting a polymer liquid from the liquid outlet to form electrospun nano fibers from the polymer liquid; collecting the electrospun nano fibers in a substantially aligned orientation onto the collector apparatus; and depositing the nanofibers onto a tubular stent to form a coating around the stent, the coating comprising nanofibers substantially aligned with a longitudinal axis of the stent.

2. The method of claim 1, wherein the collector apparatus comprises a pair of rotating plates, and the collected nanofibers are formed between the pair of rotating plates.

3. The method of claim 2, wherein the stent is located between the rotating plates so that the nanofibers are deposited onto the stent as the plates are being rotated.

4. The method of claim 3, wherein the stent is rotating to deposit the nanofibers evenly over the surface of the stent.

5. The method of claim 1, wherein the collector apparatus comprises a rotating plate and the nanofibers are collected along an edge of the rotating plate.

6. The method of claim 5, wherein the stent is located on the edge of the rotating plate so that the nanofibers are deposited directly onto the stent.

7. The method of claim 6, wherein the stent is rotating to deposit the nanofibers evenly over the surface of the stent.

8. The method of claim 1, wherein the nanofibers collected onto the collector apparatus as a fabric, and depositing the nanofibers onto the stent comprises wrapping the nanofiber fabric over the stent.

9. The method of claim 1 , wherein the stent comprises a metal mesh body that is expandable upon application of an internal pressure.

10. The method of claim 1 , wherein the liquid polymer comprises p(LL A-CL).

11. A method for making a stent covered with substantially aligned nanofibers, the method comprising: applying a high electric voltage to a liquid outlet and a low electrical voltage to a pair of opposing conductors; electrospinning polymer nanofibers from the liquid outlet towards the pair of conductors; collecting the electrospun nanofibers in a substantially parallel arrangement between the pair of opposing conductors; moving the pair of conductors in a continuous fashion towards a tubular stent, the stent located in a path between the pair of conductors; and depositing the nanofibers onto the target stent to form a coating around the stent, the coating comprising nanofibers substantially aligned with a longitudinal axis of the stent.

12. The method of claim 11 , wherein the opposing conductors comprise a pair of rotating plates.

13. The method of claim 11 , wherein the stent is rotating to deposit the nano fibers evenly over the surface of the stent.

14. The method of claim 11 , wherein the stent comprises a metal mesh body that is expandable upon application of an internal pressure.

15. A method for making a stent covered with substantially aligned nano fibers, the method comprising: electrospinning polymer nanofibers from an outlet port over a target area; repeatedly moving a stent though the target area at a sufficient rate to deposit nanofibers onto the stent, the nanofibers substantially aligned with a longitudinal axis of the stent; and rotating the stent around its longitudinal axis to deposit the nanofibers evenly over the surface of the stent.

16. The method of claim 15, wherein the stent is coupled to an edge of a rotating plate, and the nanofibers are collected along an edge of the rotating plate substantially parallel thereto.

17. The method of 15, wherein the stent is continuously rotating while being moved through the target area.

18. The method of 17, further comprising: trimming nano fibers near one or both ends of the stent while the stent is moving and between instances of being moved through the target area.

19. The method of 15, wherein the stent is manually rotated between instances of being moved through the target area.

20. The method of claim 15, wherein the stent comprises a metal mesh body that is expandable upon application of an internal pressure.

21. A stent comprising : a metal mesh tubular body, capable of expanding in a radial direction upon application of an internal pressure; a coating covering the tubular body, the coating comprising nanofibers substantially aligned with a longitudinal axis of the stent.

22. The stent of claim 21 , wherein the nanofibers comprise p(LL A-CL).

23. The stent of claim 21 , wherein coating comprises a plurality of layers.

24. The stent of claim 23, wherein at least one layer of the coating contains nanofibers that are not substantially aligned with the longitudinal axis of the stent.

25. The stent of claim 21, wherein coating carries one or more therapeutic agents.