AU2004203857A1 - Expandable medical device for delivery of beneficial agent - Google Patents

Description

AUSTRALIA

Patents Act COMPLETE SPECIFICATION

(ORIGINAL)

Class Int. Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority Related Art: Name of Applicant: Conor Medsystems, Inc.

Actual Inventor(s): John F Shanley, Neil L Eigler, Kinam Park, Elazer R Edelman Address for Service and Correspondence: PHILLIPS ORMONDE FITZPATRICK Patent and Trade Mark Attorneys 367 Collins Street Melbourne 3000 AUSTRALIA Invention Title: EXPANDABLE MEDICAL DEVICE FOR DELIVERY OF BENEFICIAL AGENT Our Ref 725877 POF Code: 453857/453857 The following statement is a full description of this invention, including the best method of performing it known to applicant(s): -1oo0eq EXPANDABLE MEDICAL DEVICE FOR DELIVERY OF BENEFICIAL AGENT BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to tissue-supporting medical devices, and more particularly to expandable, non-removable devices that are implanted within a bodily lumen of a living animal or human to support the organ and maintain patency, and that can deliver a beneficial agent to the intervention site.

2. Summary of the Related Art In the past, permanent or biodegradable devices have been developed for implantation within a body passageway to maintain patency of the passageway.

These devices are typically introduced percutaneously, and transported transluminally until positioned at a desired location. These devices are then expanded either mechanically, such as by the expansion of a mandrel or balloon positioned inside the device, or expand themselves by releasing stored energy upon actuation within the body. Once expanded within the lumen, these devices, called stents, become encapsulated within the body tissue and remain a permanent implant.

Known stent designs include monofilament wire coil stents Pat. No.

4,969,458); welded metal cages Pat. Nos. 4,733,665 and 4,776,337); and, most prominently, thin-walled metal cylinders with axial slots formed around the circumference Pat. Nos. 4,733,665; 4,739,762; and 4,776,337). Known construction materials for use in stents include polymers, organic fabrics and biocompatible metals, such as, stainless steel, gold, silver, tantalum, titanium, and shape memory alloys such as Nitinol.

U.S. Pat. Nos. 4,733,665; 4,739,762; and 4,776,337 disclose expandable and deformable interluminal vascular grafts in the form of thin-walled tubular members with axial slots allowing the members to be expanded radially outwardly into -3contact with a body passageway. After insertion, the tubular members are mechanically expanded beyond their elastic limit and thus permanently fixed within the body. U.S. Pat. No. 5,545,210 discloses a thin-walled tubular stent geometrically similar to those discussed above, but constructed of a nickel-titanium shape memory alloy ("Nitinol"), which can be permanently fixed within the body without exceeding its elastic limit. All of these stents share a critical design property: in each design, the features that undergo permanent deformation during stent expansion are prismatic, the cross sections of these features remain constant or change very gradually along their entire active length. These prismatic structures are ideally suited to providing large amounts of elastic deformation before permanent deformation commences, which in turn leads to sub-optimal device performance in important properties including stent expansion force, stent recoil, strut element stability, stent securement on delivery catheters, and radiopacity.

U.S. Pat. No. 6,241,762, which is incorporated herein by reference in its entirety, discloses a non-prismatic stent design which remedies the above mentioned performance deficiencies of previous stents. In addition, preferred embodiments of this patent provide a stent with large, non-deforming strut and link elements, which can contain holes without compromising the mechanical properties of the strut or link elements, or the device as a whole. Further, these holes may serve as large, protected reservoirs for delivering various beneficial agents to the device implantation site.

Of the many problems that may be addressed through stent-based local delivery of beneficial agents, one of the most important is restenosis. Restenosis is a major complication that can arise following vascular interventions such as angioplasty and the implantation of stents. Simply defined, restenosis is a wound healing process that reduces the vessel lumen diameter by extracellular matrix deposition and vascular smooth muscle cell proliferation, and which may ultimately result in renarrowing or even reocclusion of the lumen. Despite the introduction of improved surgical techniques, devices and pharmaceutical agents, the overall restenosis rate is still reported in the range of 25% to 50% within six to twelve months after an angioplasty procedure. To treat this condition, additional revascularization procedures are frequently required, thereby increasing trauma and risk to the patient.

Some of the techniques under development to address the problem of restenosis include irradiation of the injury site and the use of conventional stents to deliver a variety of beneficial or pharmaceutical agents to the wall of the traumatized vessel. In the latter case, a conventional stent is frequently surfacecoated with a beneficial agent (often a drug-impregnated polymer) and implanted at the angioplasty site. Alternatively, an external drug-impregnated polymer sheath is mounted over the stent and co-deployed in the vessel.

While acute outcomes from radiation therapies appeared promising initially, long term beneficial outcomes have been limited to reduction in restenosis occurring within a previously implanted stent, so-called 'in-stent' restenosis. Radiation therapies have not been effective for preventing restenosis in de novo lesions.

Polymer sheaths that span stent struts have also proven problematic in human clinical trials due to the danger of blocking flow to branch arteries, incomplete apposition of stent struts to arterial walls and other problems. Unacceptably high levels of MACE (Major Adverse Cardiac Events that include death, heart attack, or the need for a repeat angioplasty or coronary artery bypass surgery) have resulted in early termination of clinical trials for sheath covered stents.

Conventional stents with surface coatings of various beneficial agents, by contrast, have shown promising early results. U.S. Pat. No. 5,716,981, for example, discloses a stent that is surface-coated with a composition comprising a polymer carrier and paclitaxel (a well-known compound that is commonly used in the treatment of cancerous tumors). The patent offers detailed descriptions of methods for coating stent surfaces, such as spraying and dipping, as well as the desired character of the coating itself: it should "coat the stent smoothly and evenly" and "provide a uniform, predictable, prolonged release of the anti-angiogenic factor." Surface coatings, however, can provide little actual control over the release kinetics of beneficial agents. These coatings are necessarily very thin, typically 5 to 8

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microns deep. The surface area of the stent, by comparison is very large, so that the entire volume of the beneficial agent has a very short diffusion path to discharge into the surrounding tissue.

Increasing the thickness of the surface coating has the beneficial effects of improving drug release kinetics including the ability to control drug release and to allow increased drug loading. However, the increased coating thickness results in increased overall thickness of the stent wall. This is undesirable for a number of reasons, including increased trauma to the vessel wall during implantation, reduced flow cross-section of the lumen after implantation, and increased vulnerability of the coating to mechanical failure or damage during expansion and implantation.

Coating thickness is one of several factors that affect the release kinetics of the beneficial agent, and limitations on thickness thereby limit the range of release rates, durations, and the like that can be achieved.

In addition to sub-optimal release profiles, there are further problems with surface coated stents. The fixed matrix polymer carriers frequently used in the device coatings typically retain approximately 30% of the beneficial agent in the coating indefinitely. Since these beneficial agents are frequently highly cytotoxic, sub-acute and chronic problems such as chronic inflammation, late thrombosis, and late or incomplete healing of the vessel wall may occur. Additionally, the carrier polymers themselves are often highly inflammatory to the tissue of the vessel wall.

On the other hand, use of bio-degradable polymer carriers on stent surfaces can result in the creation of "virtual spaces" or voids between the stent and tissue of the vessel wall after the polymer carrier has degraded, which permits differential motion between the stent and adjacent tissue. Resulting problems include micro-abrasion and inflammation, stent drift, and failure to re-endothelialize the vessel wall.

Another significant problem is that expansion of the stent may stress the overlying polymeric coating causing the coating to plastically deform or even to rupture, which may therefore effect drug release kinetics or have other untoward effects. Further, expansion of such a coated stent in an atherosclerotic blood vessel will place circumferential shear forces on the polymeric coating, which may cause the coating to separate from the underlying stent surface. Such separation may again have untoward effects including embolization of coating fragments causing vascular obstruction.

Recent research described in a paper titled "Physiological Transport Forces Govern Drug Distribution for Stent-Based Delivery" by Chao-Wei Hwang et al.

has revealed an important interrelationship between the spatial and temporal drug distribution properties of drug eluting stents, and cellular drug transport mechanisms. In pursuit of enhanced mechanical performance and structural properties stent designs have evolved to more complex geometries with inherent inhomogeneity in the circumferential and longitudinal distribution of stent struts.

Examples of this trend are the typical commercially available stents which expand to a roughly diamond or hexagonal shape when deployed in a bodily lumen. Both have been used to deliver a beneficial agent in the form of a surface coating.

Studies have shown that lumen tissue portions immediately adjacent to the struts acquire much higher concentrations of drug than more remote tissue portions, such as those located in the middle of the "diamond" shaped strut cells.

Significantly, this concentration gradient of drug within the lumen wall remains higher over time for hydrophobic beneficial agents, such as paclitaxel or rapamycin, which have proven to be the most effective anti-proliferatives to date.

Because local drug concentrations and gradients are inextricably linked to biological effect, the initial spatial distribution of the beneficial agent sources (the stent struts) is key to efficacy.

U.S. Pat. No. 5,843,120 discloses an expandable device comprising two groups of deformable elements. The first groups comprise a cylindrical arrays of generally parallel struts connected at alternating strut ends, or junctions, which accommodate radial (circumferential) expansion of the device. Even and odd first groups of struts are specified such that odd first groups are shifted circumferentially so as to be "180 degrees out of phase" with even first groups, with strut junctions of even first groups directly opposed to strut junctions of odd first groups. The second groups of elements are generally flexible bridging elements that connect the junctions of even and odd first groups. This configuration gives rise to the common "diamond" pattern of struts in stent expansion. One frequently used index of the distance of the most distant lumen tissue portions from the nearest drug-eluting element is the "inscribed circle." This is simply the largest circle that can be inscribed in the open cell area bordered by a given set of strut elements, for example, the largest circle that could be inscribed in the diamond pattern cell described above. Smaller inscribed circles, indicating shorter drug diffusion paths and correspondingly lower concentration variations, are more desirable.

A central feature of U.S. Pat. No. 5,843,120 is that the bridging elements (second group elements) are configured to expand along the longitudinal axis of the device to compensate for the longitudinal contraction that occurs in the first groups of struts when the device is expanded radially, so that the device does not undergo overall longitudinal contraction during radial expansion. This property of the device leads to further inhomogeneity in the spatial distribution of the beneficial agent. The bridging elements generally have a substantially smaller width (for flexibility) than the first groups of struts, and have a correspondingly smaller surface area for conveying beneficial agents in the form of coatings.

During device expansion the even and odd first groups of struts, with their relatively high surface area, contract longitudinally, further concentrating drug in smaller annular slices of tissue. Conversely, the low surface area bridging elements expand longitudinally during expansion, effectively reducing the amount of beneficial agent deliver at the larger annular slices of tissue adjacent the bridging elements. The net effect of the longitudinally contracting first group of struts and longitudinally expanding bridging elements is to increase tissue concentration variations of the beneficial agent.

The discussion of the background to the invention herein is included to explain the context of the invention. This is not to be taken as an admission that any of the material referred to was published, known or part of the common general knowledge in Australia as at the priority date of any of the claims.

SUMMARY OF THE INVENTION According to a first aspect of the invention there is provided an expandable medical device including: a plurality of substantially cylindrical tissue supporting bodies which are each expandable from a cylinder having a first diameter to a cylinder having a second diameter; a plurality of flexible bridging members connecting the substantially cylindrical tissue supporting bodies to form an expandable device; and a plurality of openings formed in the flexible bridging members, the openings containing a beneficial agent for delivery to tissue.

According to a second aspect of the invention there is provided an expandable medical device including: a plurality of elongated struts; a plurality of ductile hinges connecting the plurality of struts together in a substantially cylindrical medical device which is expandable from a cylinder having a first diameter to a cylinder having a second diameter, wherein the plurality of ductile hinges are tapered with the taper oriented to achieve uniform strain along the ductile hinge during expansion of the cylinder from the first diameter to the second diameter.

BRIEF DESCRIPTION OF THE DRAWINGS The invention will now be described in greater detail with reference to the preferred embodiments illustrated in the accompanying drawings, in which like elements bear like reference numerals, and wherein: FIG. 1 is a perspective view of a tissue supporting device in accordance with a first preferred embodiment of the present invention;

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FIG. 2 is an enlarged side view of a portion of the device of FIG. 1; FIG. 3 is an enlarged side view of a tissue supporting device in accordance with a further preferred embodiment of the present invention; FIG. 4 is an enlarged side view of a portion of the stent shown in FIG. 3; FIG. 5 is an enlarged cross section of an opening; FIG. 6 is an enlarged cross section of an opening illustrating beneficial agent loaded into the opening; FIG. 7 is an enlarged cross section of an opening illustrating a beneficial agent loaded into the opening and a thin coating of a beneficial agent; FIG. 8 is an enlarged cross section of an opening illustrating a beneficial agent loaded into the opening and thin coatings of different beneficial agents on different surfaces of the device; FIG. 9 is an enlarged cross section of an opening illustrating a beneficial agent provided in a plurality of layers; FIG. 10 is an enlarged cross section of an opening illustrating a beneficial agent and a barrier layer loaded into the opening in layers; FIG. 11A is an enlarged cross section of an opening illustrating a beneficial agent, a biodegradable carrier, and a barrier layer loaded into the opening in layers; FIG. 1 1B is a graph of the release kinetics of the device of FIG. 1 1A; FIG. 12 is an enlarged cross section of an opening illustrating different beneficial agents, carrier, and barrier layers loaded into the opening; FIG. 13 is an enlarged cross section of an opening illustrating a beneficial agent loaded into the opening in layers of different concentrations; FIG. 14 is an enlarged cross section of an opening illustrating a beneficial agent loaded into the opening in layers of microspheres of different sizes; FIG. 15A is an enlarged cross section of a tapered opening illustrating a beneficial agent loaded into the opening; FIG. 15B is an enlarged cross section of the tapered opening of FIG. with the beneficial agent partially degraded; FIG. 15C is a graph of the release kinetics of the device of FIGS. 15A and FIG. 16A is an enlarged cross section of an opening illustrating a beneficial agent loaded into the opening in a shape configured to achieve a desired agent delivery profile; FIG. 16B is an enlarged cross section of the opening of FIG. 16A with the beneficial agent partially degraded; FIG. 16C is a graph of the release kinetics of the device of FIGS. 16A and 16B; FIG. 17A is an enlarged cross section of an opening illustrating the beneficial agent loaded into the opening and a spherical shape; FIG. 17B is a graph of the release kinetics of the device of FIG. 17A; FIG. 18A is an enlarged cross section of an opening illustrating a plurality of beneficial agent layers and a barrier layer with an opening for achieving a desired agent delivery profile; FIG. 18B is an enlarged cross section of the opening of FIG. 18A with the agent layers beginning to degraded; FIG. 18C is an enlarged cross section of the opening of FIG. 18A with the agent layers further degraded; FIG. 19 is an enlarged cross section of an opening illustrating a plurality of cylindrical beneficial agent layers; FIG. 20 is an enlarged side view of a portion of tissue-supporting device in accordance with a first preferred embodiment of the present invention; FIG. 21 is a schematic side view of a portion of the device of FIG. 20 in an unexpanded configuration; FIG. 22 is a schematic side view of a portion of the device of FIG. 20 in a partially expanded configuration; FIG. 23 is a schematic side view of a portion of the device of FIG. 20 in a fully expanded configuration; FIG. 24 is an enlarged side view of a portion of a tissue supporting device in a partially expanded configuration; FIG. 25 is a diagram of the change in longitudinal length of the long leg of the L-shaped strut element during radial expansion; FIG. 26 is a diagram of the change in longitudinal length of the short leg of the L-shaped strut element during radial expansion; FIG. 27 is a simple moment diagram showing the variation in a bend moment along the horizontal axis of a strut and ductile hinge; FIG. 28 is an enlarged side view of a portion of an expanded device according to the present invention having a constant width ductile hinge; and FIG. 29 is an enlarged side view of a portion of an unexpanded device according to the present invention having a tapered ductile hinge.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Referring to FIGS. 1 and 2, a tissue supporting device in accordance with one preferred embodiment of the present invention is shown generally by reference numeral 10. The tissue supporting device 10 includes a plurality of cylindrical tubes 12 connected by S-shaped bridging elements 14. The bridging elements 14 allow the tissue supporting device to bend axially when passing through the tortuous path of the vasculature to the deployment site and allow the device to bend when necessary to match the curvature of a vessel wall to be supported. Each of the cylindrical tubes 12 has a plurality of axial slots 16 extending from an end surface of the cylindrical tube toward an opposite end surface.

Formed between the slots 16 is a network of axial struts 18 and links 22.

The struts 18 and links 22 are provided with openings for receiving and delivering a beneficial agent. As will be described below with respect to FIGS. 9-17, the beneficial agent is loaded into the openings in layers or other configurations which provide control over the temporal release kinetics of the agent.

Each individual strut 18 is preferably linked to the rest of the structure through a pair of reduced sections 20, one at each end, which act as stress/strain concentration features. The reduced sections 20 of the struts function as hinges in -12the cylindrical structure. Since the stress/strain concentration features are designed to operate into the plastic deformation range of generally ductile materials, they are referred to as ductile hinges 20. The ductile hinges 20 are described in further detail in U.S. Patent No. 6,241,762, which has been incorporated herein by reference.

With reference to the drawings and the discussion, the width of any feature is defined as its dimension in the circumferential direction of the cylinder. The length of any feature is defined as its dimension in the axial direction of the cylinder. The thickness of any feature is defined as the wall thickness of the cylinder.

The presence of the ductile hinges 20 allows all of the remaining features in the tissue supporting device to be increased in width or the circumferentially oriented component of their respective rectangular moments of inertia thus greatly increasing the strength and rigidity of these features. The net result is that elastic, and then plastic deformation commence and propagate in the ductile hinges before other structural elements of the device undergo any significant elastic deformation. The force required to expand the tissue supporting device 10 becomes a function of the geometry of the ductile hinges 20, rather than the device structure as a whole, and arbitrarily small expansion forces can be specified by changing hinge geometry for virtually any material wall thickness. The ability to increase the width and thickness of the struts 18 and links 22 provides additional area and depth for the beneficial agent receiving openings.

In the various described preferred embodiments, it is desirable to increase the width of the individual struts 18 between the ductile hinges 20 to the maximum width that is geometrically possible for a given diameter and a given number of struts arrayed around that diameter. The only geometric limitation on strut width is the minimum practical width of the slots 16 which is about 0.002 inches (0.0508 mm) for laser machining. Lateral stiffness of the struts 18 increases as the cube of strut width, so that relatively small increases in strut width significantly increase strut stiffness. The net result of inserting ductile hinges 20 and increasing strut width is that the struts 18 no longer act as flexible leaf springs, but act as essentially rigid beams between the ductile hinges. All radial expansion or compression of the

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-13cylindrical tissue supporting device 10 is accommodated by mechanical strain in the hinge features 20, and yield in the hinge commences at very small overall radial expansion or compression.

The ductile hinge 20 illustrated in the various Figures illustrating the preferred embodiments is exemplary of a preferred structure that will function as a stress/strain concentrator. Many other stress/strain concentrator configurations may also be used as the ductile hinges in the present invention, as shown and described by way of example in U.S. Pat. No. 6,241,762, the entire contents of which are incoportated herein by reference. The geometric details of the stress/strain concentration features or ductile hinges 20 can be varied greatly to tailor the exact mechanical expansion properties to those required in a specific application.

As shown in the Figures of the preferred embodiments of the invention, at least one and more preferably a series of openings (24 of Figures 1-4 and 30 of Figures 20-24) are formed by laser drilling or any other means known to one skilled in the art at intervals along the neutral axis of the struts 18. Similarly, at least one and preferably a series of openings (26 of Figures 1-4 and 32 of Figures 20-24) are formed at selected locations in the links 22 (or bridging elements 14 of Figure 24).

Although the use of openings in both the struts 18 and links 22 (or bridging elements 14 of Figure 24) is preferred, it should be clear to one skilled in the art that openings could be formed in only one of the struts and links (or bridging elements 14 of Figure 24). Openings may also be formed in the bridging elements 14. In the illustrated embodiment, the openings are circular in nature and form cylindrical holes extending through the width of the tissue supporting device 10. It should be apparent to one skilled in the art, however, that openings of any geometrical shape or configuration could of course be used without departing from the scope of the present invention. In addition, openings or recesses having a depth less than the thickness of the device may also be used.

The behavior of the struts 18 in bending is analogous to the behavior of an Ibeam or truss. The outer edge elements 32 of the struts 18, shown in FIG. 2, correspond to the I-beam flange and carry the tensile and compressive stresses, whereas the inner elements 34 or edges of the struts 18 correspond to the web of an I-beam which carries the shear and helps to prevent buckling and wrinkling of the faces. Since most of the bending load is carried by the outer edge elements 32 or edges of the struts 18, a concentration of as much material as possible away from the neutral axis results in the most efficient sections for resisting strut flexure. As a result, material can be judiciously removed along the axis of the strut so as to form openings (24, 26 of Figures 1-4 and 30 of Figures 20-24) without adversely impacting the strength and rigidity of the strut. Since the struts 18, links and bridging elements thus formed remain essentially rigid during stent expansion, the openings are also non-deforming.

The openings in the struts 18 may promote the healing of the intervention site by promoting regrowth of the endothelial cells. By providing the openings in the struts 18 and in the bridging elements 14 of the embodiments shown in Figures 20-29, the cross section of the strut is effectively reduced without decreasing the strength and integrity of the strut, as described above. As a result, the overall distance across which endothelial cell regrowth must occur is also reduced to approximately 0.0025 0.0035 inches, which is approximately one-half of the thickness of a conventional stent. It is further believed that during insertion of the expandable medical device, cells from the endothelial layer may be scraped from the inner wall of the vessel by the openings and remain therein after implantation. The presence of such endothelial cells would thus provide a basis for the healing of the vessel wall.

At least some of the openings (See 24, 26 of Figures 1-19 and 30, 32 of Figures 20-29) are loaded with an agent, most preferably a beneficial agent, for delivery to the vessel wall which the tissue supporting device 10 is supporting.

The terms "agent" and "beneficial agent" as used herein are intended to have their broadest possible interpretation and are used to include any therapeutic agent or drug, as well as inactive agents such as barrier layers or carrier layers. The terms "drug" and "therapeutic agent" are used interchangeably to refer to any therapeutically active substance that is delivered to a bodily conduit of a living being to produce a desired, usually beneficial, effect. The present invention is particularly well suited for the delivery of antiproliferatives (anti-restenosis agents) such as paclitaxel and rapamycin for example, and antithrombins such as heparin, for example.

The beneficial agents used in the present invention include classical small molecular weight therapeutic agents commonly referred to as drugs including all classes of action as exemplified by, but not limited to: antiproliferatives, antithrombins, antiplatelet, antilipid, anti-inflammatory, and anti-angiogenic, vitamins, ACE inhibitors, vasoactive substances, antimitotics, metello-proteinase inhibitors, NO donors, estradiols, anti-sclerosing agents, alone or in combination.

Beneficial agent also includes larger molecular weight substances with drug like effects on target tissue sometimes called biologic agents including but not limited to: peptides, lipids, protein drugs, enzymes, oligonucleotides, ribozymes, genetic material, prions, virus, bacteria, and eucaryotic cells such as endothelial cells, monocyte/macrophages or vascular smooth muscle cells to name but a few examples. Other beneficial agents may include but not be limited to physical agents such as microspheres, microbubbles, liposomes, radioactive isotopes, or agents activated by some other form of energy such as light or ultrasonic energy, or by other circulating molecules that can be systemically administered.

The embodiment of the invention shown in FIGS. 1 and 2 can be further refined by using Finite Element Analysis and other techniques to optimize the deployment of the beneficial agent within the openings of the struts and links.

Basically, the shape and location of the openings 24, 26 can be modified to maximize the volume of the voids while preserving the relatively high strength and rigidity of the struts 18 with respect to the ductile hinges FIG. 3 illustrates a further preferred embodiment of the present invention, wherein like reference numerals have been used to indicate like components. The tissue supporting device 100 includes a plurality of cylindrical tubes 12 connected by S-shaped bridging elements 14. Each of the cylindrical tubes 12 has a plurality of axial slots 16 extending from an end surface of the cylindrical tube toward an opposite end surface. Formed between the slots 16 is a network of axial struts 18 and links 22. Each individual strut 18 is linked to the rest of the structure through a pair of ductile hinges 20, one at each end, which act as stress/strain concentration features. Each of the ductile hinges 20 is formed between an arc surface 28 and a concave notch surface 29.

At intervals along the neutral axis of the struts 18, at least one and more preferably a series of openings 24' are formed by laser drilling or any other means known to one skilled in the art. Similarly, at least one and preferably a series of openings 26' are formed at selected locations in the links 22. Although the use of openings 24', 26' in both the struts 18 and links 22 is preferred, it should be clear to one skilled in the art that openings could be formed in only one of the struts and links. In the illustrated embodiment, the openings 24' in the struts 18 are generally rectangular whereas the openings 26' in the links 22 are polygonal. It should be apparent to one skilled in the art, however, that openings of any geometrical shape or configuration could of course be used, and that the shape of openings 24, 24' may be the same or different from the shape of openings 26, 26', without departing from the scope of the present invention. As described in detail above, the openings 24', 26' may be loaded with an agent, most preferably a beneficial agent, for delivery to the vessel in which the tissue support device 100 is deployed. Although the openings 24', 26' are preferably through openings, they may also be recesses extending only partially through the thickness of the struts and links.

The relatively large, protected openings 24, 24', 26, 26', as described above, make the expandable medical device of the present invention particularly suitable for delivering agents having more esoteric larger molecules or genetic or cellular agents, such as, for example, protein drugs, enzymes, antibodies, antisense oligonucleotides, ribozymes, gene/vector constructs, and cells (including but not limited to cultures of a patient's own endothelial cells). Many of these types of agents are biodegradable or fragile, have a very short or no shelf life, must be prepared at the time of use, or cannot be pre-loaded into delivery devices such as stents during the manufacture thereof for some other reason. The large through- -17openings in the expandable device of the present invention form protected areas or receptors to facilitate the loading of such an agent either at the time of use or prior to use, and to protect the agent from abrasion and extrusion during delivery and implantation.

The volume of beneficial agent that can be delivered using through openings is about 3 to 10 times greater than the volume of a 5 micron coating covering a stent with the same stent/vessel wall coverage ratio. This much larger beneficial agent capacity provides several advantages. The larger capacity can be used to deliver multi-drug combinations, each with independent release profiles, for improved efficacy. Also, larger capacity can be used to provide larger quantities of less aggressive drugs and to achieve clinical efficacy without the undesirable side-effects of more potent drugs, such as retarded healing of the endothelial layer.

Through openings also decrease the surface area of the beneficial agent bearing compounds to which the vessel wall surface is exposed. For typical devices with beneficial agent openings, this exposure decreases by a factors ranging from about 6:1 to 8:1, by comparison with surface coated stents. This dramatically reduces the exposure of vessel wall tissue to polymer carriers and other agents that can cause inflammation, while simultaneously increasing the quantity of beneficial agent delivered, and improving control of release kinetics.

FIG. 4 shows an enlarged view of one of the struts 18 of device 100 disposed between a pair of ductile hinges 20 having a plurality of openings 24'. FIG. illustrates a cross section of one of the openings 24' shown in FIG. 4. FIG. 6 illustrates the same cross section when a beneficial agent 36 has been loaded into the opening 24' of the strut 18. Optionally, after loading the opening 24' and/or the opening 26' with a beneficial agent 36, the entire exterior surface of the stent can be coated with a thin layer of a beneficial agent 38, which may be the same as or different from the beneficial agent 36, as schematically shown in FIG. 7. Still further, another variation of the present invention would coat the outwardly facing surfaces of the stent with a first beneficial agent 38 while coating the inwardly facing surfaces of the stent with a different beneficial agent 39, as illustrated in FIG.

8. The inwardly facing surface of the stent would be defined as at least the surface of the stent which, after expansion, forms the inner passage of the vessel. The outwardly facing surface of the stent would be defined as at least the surface of the stent which, after expansion, is in contact with and directly supports the inner wall of the vessel. The beneficial agent 39 coated on the inner surfaces may be a barrier layer which prevents the beneficial agent 36 from passing into the lumen of the blood vessel and being washed away in the blood stream.

FIG. 9 shows a cross section of an opening 24 in which one or more beneficial agents have been loaded into the opening 24 in discrete layers 50. One method of creating such layers is to deliver a solution comprising beneficial agent, polymer carrier, and a solvent into the opening and evaporating the solvent to create a thin solid layer of beneficial agent in the carrier. Other methods of delivering the beneficial agent can also be used to create layers. According to another method for creating layers, a beneficial agent may be loaded into the openings alone if the agent is structurally viable without the need for a carrier. The process can then be repeated until each opening is partially or entirely filled.

In a typical embodiment, the total depth of the opening 24 is about 125 to about 140 microns, and the typical layer thickness would be about 2 to about microns, preferably about 12 microns. Each typical layer is thus individually about twice as thick as the typical coating applied to surface-coated stents. There would be at least two and preferably about ten to twelve such layers in a typical opening, with a total beneficial agent thickness about 25 to 28 times greater than a typical surface coating. According to one preferred embodiment of the present invention, the openings have an area of at least 5 x 10.6 square inches, and preferably at least 7 x 10.6 square inches.

Since each layer is created independently, individual chemical compositions and pharmacokinetic properties can be imparted to each layer. Numerous useful arrangements of such layers can be formed, some of which will be described below.

Each of the layers may include one or more agents in the same or different -19proportions from layer to layer. The layers may be solid, porous, or filled with other drugs or excipients.

FIG. 9 shows the simplest arrangement of layers including identical layers that together form a uniform, homogeneous distribution of beneficial agent. If the carrier polymer were comprised of a biodegradable material, then erosion of the beneficial agent containing carrier would occur on both faces of the opening at the same time, and beneficial agent would be released at an approximately linear rate over time corresponding to the erosion rate of the carrier. This linear or constant release rate is referred to as a zero order delivery profile. Use of biodegradable carriers in combination with through openings is especially useful, to guarantee 100% discharge of the beneficial agent within a desired time without creating virtual spaces or voids between the radially outermost surface of the stent and tissue of the vessel wall. When the biodegradable material in the through openings is removed, the openings may provide a communication between the strut-covered vessel wall and the blood stream. Such communication may accelerate vessel healing and allow the ingrowth of cells and extracellular components that more thoroughly lock the stent in contact with the vessel wall. Alternatively, some through-openings may be loaded with beneficial agent while others are left unloaded. The unloaded holes could provide an immediate nidus for the ingrowth of cells and extracellular components to lock the stent into place, while loaded openings dispense the beneficial agent.

The advantage of complete erosion using the through openings over surface coated stents opens up new possibilities for stent-based therapies. In the treatment of cardiac arrhythmias, such as atrial fibrillation both sustained and paroxysmal, sustained ventricular tachycardia, super ventricular tachycardia including reentrant and ectopic, and sinus tachycardia, a number of techniques under development attempt to ablate tissue in the pulmonary veins or some other critical location using various energy sources, e.g. microwaves, generally referred to as radio-frequency ablation, to create a barrier to the propagation of undesired electrical signals in the form of scar tissue. These techniques have proven difficult to control accurately. A stent based therapy using through openings, biodegradable carriers, and associated techniques described herein could be used to deliver a chemically ablative agent in a specific, precise pattern to a specific area for treatment of atrial fibrillation, while guaranteeing that none of the inherently cytotoxic ablating agent could be permanently trapped in contact with the tissue of the vessel wall.

If, on the other hand, the goal of a particular therapy is to provide a long term effect, beneficial agents located in openings provide an equally dramatic advantage over surface coated devices. In this case, a composition comprising a beneficial agent and a non-biodegradable carrier would be loaded into the through openings, preferably in combination with a diffusion barrier layer as described below. To continue the cardiac arrhythmias example, it might be desirable to introduce a long-term anti-arrhythmic drug near the ostia of the pulmonary veins or some other critical location. The transient diffusion behavior of a beneficial agent through a non-biodegradable carrier matrix can be generally described by Fick's second law: a C [D aCt] I ac Where C is the concentration of beneficial agent at cross section x, x is either the thickness of a surface coating or depth of a through opening, D is the diffusion coefficient and t is time. The solution of this partial differential equation for a through opening with a barrier layer will have the form of a normalized probability integral or Gaussian Error Function, the argument of which will contain

X

2,FD7 the term -21- To compare the time intervals over which a given level of therapy can be sustained for surface coatings vs. through openings, we can use Fick's Second Law to compare the times required to achieve equal concentrations at the most inward surfaces of the coating and opening respectively, i.e. the values of x and t for which the arguments of the Error Function are equal: The ratio of diffusion times to achieve comparable concentrations thus varies as the square of the ratio of depths. A typical opening depth is about 140 microns while a 2 Xl X2 Xi tl 2 2,FD3t 2 Df32 X2 t2 typical coating thickness is about 5 micron; the square of this ratio is 784, meaning that the effective duration of therapy for through openings is potentially almost three orders of magnitude greater for through openings than for surface coatings of the same composition. The inherent non-linearity of such release profiles can in part be compensated for in the case of through openings, but not in thin surface coatings, by varying the beneficial agent concentration of layers in a through opening as described below. It will be recalled that, in addition to this great advantage in beneficial agent delivery duration, through openings are capable of delivering a 3 to times greater quantity of beneficial agent, providing a decisive overall advantage in sustained therapies. The diffusion example above illustrates the general relationship between depth and diffusion time that is characteristic of a wider class of solid state transport mechanisms.

Beneficial agent that is released to the radially innermost or inwardly facing surface known as the lumen facing surface of an expanded device may be rapidly carried away from the targeted area, for example by the bloodstream, and thus lost.

Up to half of the total agent loaded in such situations may have no therapeutic effect due to being carried away by the bloodstream. This is probably the case for all surface coated stents as well as the through opening device of FIG. 9.

FIG. 10 shows a device in which the first layer 52 is loaded into a through opening 24 such that the inner surface of the layer is substantially co-planar with the inwardly facing surface 54 of the cylindrical device. The first layer 52 is comprised of a material called a barrier material which blocks or retards biodegradation of subsequent layers in the inwardly facing direction toward the vessel lumen, and/or blocks or retards diffusion of the beneficial agent in that direction. Biodegradation of other layers or beneficial agent diffusion can then proceed only in the direction of the outwardly facing surface 56 of the device, which is in direct contact with the targeted tissue of the vessel wall. The barrier layer 52 may also function to prevent hydration of inner layers of beneficial agent and thus prevent swelling of the inner layers when such layers are formed of hygroscopic materials. The barrier layer 52 may further be comprised of a biodegradable material that degrades at a much slower rate than the biodegradable material in the other layers, so that the opening will eventually be entirely cleared. Providing a barrier layer 52 in the most inwardly facing surface of a through-opening thus guarantees that the entire load of beneficial agent is delivered to the target area in the vessel wall. It should be noted that providing a barrier layer on the inwardly facing surface of a surface-coated stent without openings does not have the same effect; since the beneficial agent in such a coating cannot migrate through the metal stent to the target area on the outer surface, it simply remains trapped on the inner diameter of the device, again having no therapeutic effect.

Barrier layers can be used to control beneficial agent release kinetics in more sophisticated ways. A barrier layer 52 with a pre-determined degradation time could be used to deliberately terminate the beneficial agent therapy at a pre-determined time, by exposing the underlying layers to more rapid bio-degradation from both sides. Barrier layers can also be formulated to be activated by a separate, systemically applied agent. Such systemically applied agent could change the porosity of the barrier layer and/or change the rate of bio-degradation of the barrier layer or the bulk beneficial agent carrier. In each case, release of the beneficial agent could be activated by the physician at will by delivery of the systemically

I

applied agent. A further embodiment of physician activated therapy would utilize a beneficial agent encapsulated in micro-bubbles and loaded into device openings.

Application of ultrasonic energy from an exterior of the body could be used to collapse the bubbles at a desired time, releasing the beneficial agent to diffuse to the outwardly facing surface of the reservoirs. These activation techniques can be used in conjunction with the release kinetics control techniques described herein to achieve a desired drug release profile that can be activated and/or terminated at selectable points in time.

FIG. 11A shows an arrangement of layers provided in a through opening in which layers 50 of a beneficial agent in a biodegradable carrier material, are alternated with layers 58 of the biodegradable carrier material alone, with no active agent loaded, and a barrier layer 52 is provided at the inwardly facing surface. As shown in the release kinetics plot of FIG. 11 B, such an arrangement releases beneficial agent in three programmable bursts or waves achieving a stepped or pulsatile delivery profile. The use of carrier material layers without active agent creates the potential for synchronization of drug release with cellular biochemical processes for enhanced efficacy.

Alternatively, different layers could be comprised of different beneficial agents altogether, creating the ability to release different beneficial agents at different points in time, as shown in FIG. 12. For example, in FIG. 12, a layer 60 of anti-thrombotic agent could be deposited at the inwardly facing surface of the stent, followed by a barrier layer 52 and alternating layers of anti-proliferatives 62 and anti-inflamatories 64. This configuration could provide an initial release of antithrombotic agent into the bloodstream while simultaneously providing a gradual release of anti-proliferatives interspersed with programmed bursts of antiinflammatory agents to the vessel wall. The configurations of these layers can be designed to achieve the agent delivery bursts at particular points in time coordinated with the body's various natural healing processes.

A further alternative is illustrated in FIG. 13. Here the concentration of the same beneficial agent is varied from layer to layer, creating the ability to generate release profiles of arbitrary shape. Progressively increasing the concentration of agent in the layers 66 with increasing distance from the outwardly facing surface 56, for example, produces a release profile with a progressively increasing release rate, which would be impossible to produce in a thin surface coating.

Another general method for controlling beneficial agent release kinetics is to alter the beneficial agent flux by changing the surface area of drug elution sources as a function of time. This follows from Fick's First Law, which states that the instantaneous molecular flux is proportional to surface area, among other factors: ac aN ac J=D -=AD- &x at Where aN/at is the number of molecules per unit time, A is the instantaneous drug eluting surface area, D is the diffusivity, and C is the concentration. The drug eluting surface area of a surface coated stent is simply the surface area of the stent itself. Since this area is fixed, this method of controlling release kinetics is not available to surface coated devices. Through openings, however, present several possibilities for varying surface area as a function of time.

In the embodiment of FIG. 14, beneficial agent is provided in the openings 24 in the form of microspheres, particles or the like. Individual layers 70 can then be created that contain these particles. Further, the particle size can be varied from layer to layer. For a given layer volume, smaller particle sizes increase the total particle surface area in that layer, which has the effect of varying the total surface area of the beneficial agent from layer to layer. Since the flux of drug molecules is proportional to surface area, the total drug flux can be adjusted from layer to layer by changing the particle size, and the net effect is control of release kinetics by varying particle sizes within layers.

A second general method for varying drug eluting surface area as a function of time is to change the shape or cross-sectional area of the drug-bearing element along the axis of the opening. FIG. 15A shows an opening 70 having a conical shape cut into the material of the stent itself. The opening 70 may then be filled with beneficial agent 72 in layers as described above or in another manner. In this embodiment, a barrier layer 74 may be provided on the inwardly facing side of the opening 70 to prevent the beneficial agent 72 from passing into the blood stream. In this example, the drug eluting surface area At would continuously diminish (from FIG. 15A to FIG. 15B) as the bio-degradable carrier material erodes, yielding the elution pattern of FIG. FIG. 16A shows a simple cylindrical through-opening 80 in which a preformed, inverted cone 82 of beneficial agent has been inserted. The rest of the through opening 80 is then back-filled with a biodegradable substance 84 with a much slower rate of degradation or a non-biodegradable substance, and the inwardly facing opening of the through opening is sealed with a barrier layer 86. This technique yields the opposite behavior to the previous example. The drug-eluting surface area At continuously increases with time between FIG. 16A and 16B, yielding the elution pattern of FIG. 16C.

The changing cross section openings 70 of FIG. 15A and the nonbiodegradable backfilling techniques of FIG. 16A may be combined with any of the layered agent embodiments of FIGS. 9-14 to achieve desired release profiles. For example, the embodiment of FIG. 15A may use the varying agent concentration layers of FIG. 13 to more accurately tailor a release curve to a desired profile.

The process of preforming the beneficial agent plug 82 to a special shape, inserting in a through opening, and back-filling with a second material can yield more complex release kinetics as well. FIG. 17A shows a through opening 90 in which a spherical beneficial agent plug 92 has been inserted. The resulting biodegradation of the sphere, in which the cross sectional surface area varies as a sinusoidal function of depth, produces a flux density which is roughly a sinusoidal function of time, FIG. 17B. Other results are of course possible with other profiles, but none of these more complex behaviors could be generated in a thin, fixed-area surface coating.

An alternative embodiment of FIGS. 18A-18C use a barrier layer 52' with an opening 96 to achieve the increasing agent release profile of FIG. 16C. As shown in FIG. 18A, the opening 24 is provided with an inner barrier layer 52 and multiple beneficial agent layers 50 as in the embodiment of FIG. 10. An additional outer barrier layer 52' is provided with a small hole 96 for delivery of the agent to the vessel wall. As shown in FIGS. 18B and 18C, the beneficial agent containing layers 50 degrade in a hemispherical pattern resulting in increasing surface area for agent delivery over time and thus, an increasing agent release profile.

FIG. 19 illustrates an alternative embodiment in which an opening in the tissue supporting device is loaded with cylindrical layers of beneficial agent.

According to one method of forming the device of FIG. 19, the entire device is coated with sequential layers 100, 102, 104, 106 of beneficial agent. The interior surface 54 and exterior surface 56 of the device are then stripped to remove the beneficial agent on these surfaces leaving the cylindrical layers of beneficial agent in the openings. In this embodiment, a central opening remains after the coating layers have been deposited which allows communication between the outer surface 56 and inner surface 54 of the tissue supporting device.

In the embodiment of FIG. 19, the cylindrical layers are eroded sequentially.

This can be used for pulsatile delivery of different beneficial agents, delivery of different concentrations of beneficial agents, or delivery of the same agent. As shown in FIG. 19, the ends of the cylindrical layers 100, 102, 104, 106 are exposed.

This results in a low level of erosion of the underlying layers during erosion of an exposed layer. Alternatively, the ends of the cylindrical layers may be covered by a barrier layer to prevent this low level continuous erosion. Erosion rates of the cylindrical layers may be further controlled by contouring the surfaces of the layers.

For example, a ribbed or star-shaped pattern may be provided on the radially inner layers to provide a uniform surface area or uniform erosion rate between the radially inner layers and the radially outer layers. Contouring of the surfaces of layers may 1 also be used in other embodiments to provide an additional variable for controlling the erosion rates.

Although a tissue supporting device configuration has been illustrated in FIG. 1 which includes ductile hinges, it should be understood that the beneficial agent may be contained in openings in stents having a variety of designs including, for example, the designs illustrated in U.S. Provisional Patent Application Serial No.

60/314,360, filed on August 20, 2001 which are incorporated herein by reference.

The present invention incorporating beneficial agent openings may also be used with other known stent designs.

FIG. 20 illustrates a portion of a cylindrical tissue supporting device according to an embodiment of the present invention which improves the spatial distribution of beneficial agent delivered to tissue by the tissue supporting device.

The tissue supporting device 10 includes a strut arrangement which decreases the mean and maximum distances between lumen tissue portions and agent-eluting elements of the devices, while staying within the desirable range of ratios of device area to lumen tissue area and allowing side branch perfusion. The tissue supporting device 10 achieves the improved spatial distribution with a strut arrangement which expands to substantially parallelogram shaped cells. The tissue supporting device is preferably provided with a beneficial agent loaded in a plurality of openings in the device. Alternatively, the beneficial agent for delivery to the lumen tissue may be coated on the device The tissue supporting device 10 is shown in Figures 20 to 24 in an unrolled flat view of a portion of the device for ease of illustration. The device 10 is preferably cut from a tube of material to form a cylindrical expandable device. The tissue supporting device 10 includes a plurality of sections forming cylindrical tubes 12 connected by bridging elements 14. The bridging elements 14 allow the tissue supporting device to bend axially when passing through the tortuous path of the vasculature to the deployment site and allow the device to bend when necessary to match the curvature of a lumen to be supported. Each of the cylindrical tubes 12 has -28a plurality of axial slots 16 extending from each end surface of the cylindrical tube toward an opposite end surface.

Formed between the slots 16 is a network of elongated struts 18. Preferably, the elongated struts 18 are L-shaped struts each having a long leg 22 and a short leg 24. Each individual elongated strut 18 is preferably linked to an adjacent strut through reduced sections called ductile hinges 20, one at each end, which act as stress/strain concentration features. The ductile hinges 20 of the struts function as hinges in the cylindrical structure. The ductile hinges 20 are stress/strain concentration features designed to operate into the plastic deformation range of generally ductile materials. Such features are also commonly referred to as "Notch Hinges" or "Notch Springs" in ultra-precision mechanism design, where they are used exclusively in the elastic range.

Although the elongated struts 18 have been shown as L-shaped, other shaped struts may also be used as long as the struts are connected to the ductile hinges and the bridging elements 18 with the same spatial arrangement. For example, struts having J-shapes or amorphous shapes may also be used.

The ductile hinges 20 may be symmetrical or asymmetric ductile hinges.

The ductile hinges 20 essentially take the form of a small, prismatic strut having a substantially constant cross section or a tapering cross section, as will be discussed below. As the cylindrical tubes 12 are expanded, bending or plastic deformation occurs in the ductile hinges 20, and the elongated struts 18 are not plastically deformed.

In the preferred embodiment of FIG. 20, it is desirable to increase the width of the individual struts 18 between the ductile hinges 20 to the maximum width that is geometrically possible for a given diameter and a given number of struts arrayed around that diameter. The only geometric limitation on strut width is the minimum practical width of the slots 16 which is about 0.002 inches (0.0508 mm) for laser machining. Lateral stiffness of the struts 18 increases as the cube of strut width, so that relatively small increases in strut width significantly increase strut stiffness.

The net result of inserting ductile hinges 20 and increasing strut width is that the -29struts 18 no longer act as flexible leaf springs, but act as essentially rigid struts between the ductile hinges. All radial expansion or compression of the cylindrical tissue supporting device 10 is accommodated by mechanical strain in the hinge features 20, and yield in the hinge commences at very small overall radial expansion or compression.

The embodiment of the invention shown in FIG. 20 can be further refined by using Finite Element Analysis and other techniques to optimize the deployment of the beneficial agent within the openings of the struts 18 and bridging elements 14.

Basically, the shape and location of the openings 30, 32 can be modified to maximize the volume of the voids while preserving the relatively high strength and rigidity of the struts 18 with respect to the ductile hinges 20. According to one preferred embodiment of the present invention, the openings have an area of at least x 10- 6 square inches, and preferably at least 7 x 10 6 square inches.

Examples of the ways in which the agent may be loaded in the openings 32 are described in U.S. Provisional Patent Application Serial No. 60/314,259, filed August 20, 2001, and U.S. Patent Application Serial No. 09/948989 filed on September 7, 2001, both of which are incorporated herein by reference.

Prior art stents such as that shown in U.S. Patent. No. 6,241,762 expand into roughly diamond or hexagonal shaped cells. As described above, a measure of the distance from the stent elements or struts to the most distant tissue portions is the diameter of the inscribed circle which can be drawn between expanded stent elements. The size of the inscribed circles is similar for the stents having diamond or hexagonal shaped cells, given equal coverage ratios. The coverage ratio is defined as the ratio of the stent surface area to the area of the lumen in which the stent is deployed. Clinically preferred coverage ratios are in the about 12% to about range.

FIGS. 20-23 illustrate one example of an embodiment of the present invention that improves the spatial distribution of the beneficial agent. FIG. 23 shows an enlarged side view of this embodiment after device expansion. The shape of the cells bordered by the stent struts 18 and bridging elements 14 in this embodiment may be described as helically oriented parallelograms. The adjacent struts 18 form rows of alternately oriented "chevrons" or V-shapes when expanded.

It can be shown that the inscribed circle for this arrangement is approximately smaller than inscribed circles for the diamond or hexagonal cells of the stents mentioned above, for similar coverage ratios. Thus, the parallelogram shaped expanded cell structure provides a very substantial improvement in the spatial distribution of the beneficial agent delivered by the struts 18 and bridging elements 14.

Further, this improved spatial distribution can be accomplished without the longitudinal contraction of the beneficial agent bearing struts 18, and the corresponding longitudinal expansion of agent-poor bridging elements 14, that characterizes the stents of U.S. Patent No. 5,843,120. The improved spatial distribution of the struts achieves improved spatial distribution of beneficial agent whether the agent is provided in the opening, in a coating, in both openings and a coating, or otherwise loaded in or on the device.

As shown in FIG. 20, it can be seen that a single ductile hinge 20 is located at alternating ends of adjoining L-shaped struts 18. The center of rotation between any pair of adjoining struts 18 is thus displaced from the axis bisecting the strut pair, and strut motion during expansion is more complex than that of the double hinged struts described in U.S. Patent No. 6,241,762. Basically, the L-shape struts 18 on either side of a given ductile hinge 20 can be seen as rotating about an instant center that moves along a (circumferentially oriented) perpendicular bisector of the ductile hinge element. It should be noted that while a ductile hinge 20 is the preferred method for accomplishing this motion, any method which provided a pivoting action between adjoining L-shaped elements would be within the scope of this invention.

A simplified geometrical analysis of this motion of the struts upon stent expansion may be made with respect to FIGS. 25 and 26. Here 1 is the horizontal length of the L-shaped strut 18 or the length of the long leg 22 andfis the offset between the bottom of the strut and the instant center of rotation or roughly the length of the shorter leg 24 of the L-shaped strut 18. The initial position of the -31instant center is selected by specifying the initial position and curvature of the ductile hinge 20 and the circumferential width of the strut 18. As the device expands, the long leg rotates away from the horizontal axis as shown by the arrow A in FIG. 25, and the longitudinal component of long leg 22 of the strut 18 is decreased by the amount /(l-cos Simultaneously, however, this length contraction is offset by the rotation of the vertical elementf or the short leg 24. As shown in FIG. 26, the increase in the longitudinal component of the short leg 24 can be expressed as.lsin For smaller values of 0,sin 0) changes more rapidly than 1(1 cos with the result that the ratios of I tofor the ratios of the lengths of the long and short legs can be manipulated to give a net change of zero in the longitudinal extent of the strut pair over a range of angles, but generally less than about 400. This ratio can be expressed as: 1. (sin 0) f (l-cosO) For example, an expansion angle of 370 and an l/fratio of 2.99 would result in net longitudinal contraction of zero. A preferred ratio of the length of the long leg 22 to the length of the short leg is about 2:1 to about 6:1.

Further advantage can be made of this zero contraction geometry by inverting the orientation of ductile hinges in adjacent groups of struts, as shown in the expansion sequence of FIGS. 21-23. In this "counter rotating" configuration, unique pairs of points can be identified on adjacent strut groups (adjacent cylinders 12) for which the total distance between the point pairs remains essentially constant throughout the device expansion sequence. If the struts 18 are connected to the bridging elements 14 at these connecting points 40, the entire device deployment sequence can be thought of as the rotation of all the interconnected strut 18 and bridging elements 14 about these connecting points 40. Since only rotation, and not expansion is now required of the bridging elements 14, the bridging elements themselves may be modified to include inflexible elements (small struts) that may -32contain additional beneficial-agent bearing reservoirs or openings 32, thus further improving the uniformity of beneficial agent delivery.

As shown in the expansion sequence of FIGS. 21-23, a longitudinal distance X between the connecting points 40 on opposite ends of the bridging elements 14 or between the cylindrical tubes 12 remains substantially constant during expansion of the device 10. In addition, the longitudinal length Y of the cylindrical tubes 12 also remains substantially constant during radial expansion.

The design criteria of ductile hinges for the preferred embodiments described above is different for the ductile hinges in the stents described in U.S. Patent No.

6,241,762. Since the total number of ductile hinges 20 in the present embodiment is generally reduced by half over those in U.S. Patent No. 6,241,762, while the total deflection to be accommodated by the hinges remains the same, the length of individual hinges must generally be increased to keep material strains within acceptable limits. If the width of the hinge is kept constant along the axis of the hinge over this increased length, bending stresses and strains are not evenly distributed through the hinge and bending is not uniform.

FIG. 27 shows two struts 18 of the present invention joined by a ductile hinge 50, with a simple moment diagram showing the variation in bend moment along the horizontal axis of the strut 18 and the ductile hinge 50 as bending in the hinge commences by application of the forces F. It can be seen that the bend moment applied to the hinge 50 increases linearly from left to right. The hinge develops significant curvature as the device expands, with the result that the hinge is subjected to a complex array of stresses comprising significant axial, shear, and bending stress components. These stresses vary in both magnitude and direction as a function of hinge curvature. In general, bend moment will increase toward a hinge end 44 connected to the short leg 24 at all curvatures, while applied axial forces the component of applied forces aligned with the hinge axis) will increase toward the hinge end 46 connected to the long leg 22. The result for a long hinge 50 of constant cross section is illustrated in FIG. 28, wherein it can be seen that strain and peak stresses, and thus curvature, are concentrated in region close to the hinge end 44, rather than uniformly distributed along the entire length of the hinge.

One efficient hinge design for use in the present invention is one in which the hinge is uniformly strained along its entire axis. For the array of applied stresses outlined above, this can be achieved by varying the width of the hinge gradually along its axis to match the plastic moment of the hinge to the applied stresses at each hinge cross section. FIG. 29 shows a straight tapered ductile hinge 20 in which the hinge width is increased from left to right or from the end adjacent the long leg 22 to the end adjacent the short leg 24 of the strut 18, in a linear fashion. As shown in FIG. 29, the tapered hinge 20 is tapered such than an end of the ductile hinge closer to an apex of the V-shape formed by adjacent elongated struts has a width which is greater than a width of the ductile hinge at an opposite end. In a typical embodiment, a 0.010 inch long hinge might taper from about 0.0050 inch maximum width to about 0.0035 inch minimum width from one end to the other, resulting in a hinge taper of about 0.15 inches per inch. Preferred embodiments will generally have tapers ranging from about 0.1 to about 0.2 inches per inch.

Finite Element Analysis can be used to create optimized, non-linear tapers for specific strut/hinge geometries. For example, hinges may be created with an initial curvature, as described in U.S. Patent No. 6,241,762 for certain applications.

In this case, a hinge would be bounded by two curves, creating a non-linear taper, which would nevertheless fall within the same range of overall taper ratios described above.

U.S. Application Serial No. 09/688,092, filed October 16, 2000, and U.S.

Provisional Application Serial No. 60/314,259, filed August 20, 2001 are incorporated herein in their entirety.

While the invention has been described in detail with reference to the preferred embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made and equivalents employed, without departing from the present invention.

Claims (22)

1. An expandable medical device including: a plurality of substantially cylindrical tissue supporting bodies which are each expandable from a cylinder having a first diameter to a cylinder having a second diameter; a plurality of flexible bridging members connecting the substantially cylindrical tissue supporting bodies to form an expandable device; and a plurality of openings formed in the flexible bridging members, the openings containing a beneficial agent for delivery to tissue.

2. An expandable medical device according to Claim 1, wherein the substantially cylindrical tissue supporting bodies and the plurality of flexible bridging elements are formed from a tube.

3. An expandable medical device according to Claim 2, wherein the substantially cylindrical tissue supporting bodies are formed from a plurality of struts.

4. An expandable medical device according to Claim 1, further including a plurality of second openings formed in the substantially cylindrical tissue supporting bodies, the second openings containing the beneficial agent for delivery to tissue. An expandable medical device according to Claim 1, wherein the plurality of flexible bridging members are configured such that a total length of the flexible bridging members remains substantially constant during radial expansion.

6. An expandable medical device according to Claim 1, wherein portions of the plurality of flexible bridging members are configured to remain substantially parallel during expansion.

7. An expandable medical device according to Claim 1, wherein the expandable medical device is configured for radial expansion while an overall length of the device remains substantially constant.

8. An expandable medical device according to Claim 1, wherein the openings are formed as recesses in the plurality of flexible bridging members.

9. An expandable medical device according to Claim 1, wherein the openings are through openings extending through the plurality of flexible bridging members in a radial direction.

10. An expandable medical device according to Claim 9, wherein the openings are formed by laser drilling.

11. An expandable medical device according to Claim 1, wherein the plurality of flexible bridging members include at least one flexible portion and at least one opening containing portion, and wherein a width of the opening containing portion is greater than a width of the flexible portion.

12. An expandable medical device according to Claim 11, wherein the opening containing portions are substantially undeformed when the plurality of cylindrical tissue supporting bodies are expanded.

13. An expandable medical device according to Claim 11, wherein the openings have a largest dimension which is greater than the width of the at least one flexible portion.

14. An expandable medical device according to Claim 11, wherein the openings have an area of at least x 10 6 square inches. -36- An expandable medical device including: a plurality of elongated struts; a plurality of ductile hinges connecting the plurality of struts together in a substantially cylindrical medical device which is expandable from a cylinder having a first diameter to a cylinder having a second diameter, wherein the plurality of ductile hinges are tapered with the taper oriented to achieve uniform strain along the ductile hinge during expansion of the cylinder from the first diameter to the second diameter.

16. An expandable medical device according to Claim 15, wherein adjacent elongated struts form V-shapes when the cylinder is at the second diameter and wherein the plurality of ductile hinges are each tapered such that an end of the ductile hinge closer to the apex of the V-shape formed by the adjacent elongated struts have a width which is greater than a width of the ductile hinge at an opposite end.

17. An expandable medical device according to Claim 15, wherein the taper of the ductile hinges is about 0.1 to about 0.2 inches per inch.

18. An expandable medical device according to Claim 15, wherein the taper of the ductile hinges is about 0.2 inches per inch or less.

19. An expandable medical device according to Claim 15, wherein the taper is substantially constant along a length of the ductile hinges. An expandable medical device according to Claim 15, wherein the taper is a non-linear taper bounded by two curves.

21. An expandable medical device according to Claim 15, wherein the taper is a linear taper. I -37-

22. An expandable medical device according to Claim 15, wherein the ductile hinge has a largest cross sectional area at a point where stresses in the beam are greatest during expansion from the first diameter to the second diameter.

23. An expandable medical device according to Claim 15, wherein the taper extends along substantially an entire length of the ductile hinges.

24. An expandable medical device according to Claim 15, wherein the ductile hinges are configured such that as the device is expanded from the first diameter to the second diameter the ductile hinges experience plastic deformation while the struts are not plastically deformed.

25. An expandable medical device substantially as hereinbefore described with reference to the accompanying drawings. DATED: 12 August 2004 PHILLIPS ORMONDE FITZPATRICK Attorneys for: CONOR MEDSYSTES, INC.