Patent Document

FIELD OF THE INVENTION 
       [0001]    The present invention relates to implantable medical devices that release a therapeutic material and methods of forming such medical devices. 
       BACKGROUND OF THE INVENTION 
       [0002]    Drug-eluting implantable medical devices have become popular in recent times for their ability to perform their primary function (such as structural support) and their ability to medically treat the area in which they are implanted. 
         [0003]    For example, drug-eluting stents have been used to prevent restenosis in coronary arteries. Drug-eluting stents may administer therapeutic agents such as anti-inflammatory compounds that block local invasion/activation of monocytes, thus preventing the secretion of growth factors that may trigger VSMC proliferation and migration. Other potentially anti-restenotic compounds include antiproliferative agents, such as chemotherapeutics, which include rapamycin and paclitaxel. Other classes of drugs such as anti-thrombotics, anti-oxidants, platelet aggregation inhibitors and cytostatic agents have also been suggested for anti-restenotic use. 
         [0004]    Drug-eluting medical stents may be coated with a polymeric material which, in turn, is impregnated with a drug or a combination of drugs. Once the stent is implanted at a target location, the drug is released from the polymer for treatment of the local tissues. The drug is released by a process of diffusion through the polymer layer for biostable polymers, and/or as the polymer material degrades for biodegradable polymers. 
         [0005]    Controlling the rate of elution of a drug from the drug impregnated polymeric material is generally based on the properties of the polymer material. However, at the conclusion of the elution process, the remaining polymer material in some instances has been linked to an adverse reaction with the vessel, possibly causing a small but dangerous clot to form. Further, drug impregnated polymer coatings on exposed surfaces of medical devices may flake off or otherwise be damaged during delivery, thereby preventing the drug from reaching the target site. Still further, drug impregnated polymer coatings are limited in the quantity of the drug to be delivered by the amount of a drug that the polymer coating can carry and the size of the medical devices. Controlling the rate of elution using polymer coatings is also difficult. 
         [0006]    Bare metal, uncoated drug-eluting stents made from a hollow-tubular wire filled with a therapeutic material have been proposed. However, forming a hollow-wire stent by bending a hollow-wire into a stent form may cause kinking, cracking, or other undesirable properties in the finished stent. Accordingly, bare metal, uncoated drug-eluting stents are needed that utilize the advantages of a hollow-wire stent, such as the ability to delivery increased quantities of the therapeutic substance and improved control of the elution rate of the therapeutic substance, while reducing potential manufacturing difficulties of a hollow-wire stent. 
       BRIEF SUMMARY OF THE INVENTION 
       [0007]    Embodiments described herein are directed to methods of manufacturing an endovascular stent from a generally cylindrical thin-walled tubular component formed by a molding and sintering process. The thin-walled tubular metal component is molded to encapsulate a tubular core structure having a stent pattern. Portions of the thin-walled tubular component are removed, such as by laser cutting or etching, to form at least a portion of the endovascular stent in the stent pattern of the tubular core structure, wherein the tubular core structure or a corresponding channel left thereby are captured within a wall of the formed stent. If the tubular core structure is captured within the wall of the formed stent it is subsequently removed to leave a corresponding channel within the wall of the stent in its stead. A plurality of holes are formed in the wall of the stent to access the channel or channels therein, with the plurality of holes being configured for filling a channel of the stent with a therapeutic material and for eluting the therapeutic material therefrom when the stent is deployed within a vessel. 
     
    
     
       BRIEF DESCRIPTION OF DRAWINGS 
         [0008]    The foregoing and other features and advantages of the invention will be apparent from the following description of embodiments thereof as illustrated in the accompanying drawings. The accompanying drawings, which are incorporated herein and form a part of the specification, further serve to explain the principles of the invention and to enable a person skilled in the pertinent art to make and use the invention. The drawings are not to scale. 
           [0009]      FIG. 1  is a side view of an endovascular stent formed in accordance with an embodiment hereof 
           [0010]      FIG. 1A  is an end view of the stent of  FIG. 1  taken in the direction of line  1 A- 1 A thereof 
           [0011]      FIG. 1B  is a cross-sectional view of a strut of the stent of  FIG. 1  taken along line  1 B- 1 B thereof 
           [0012]      FIG. 1C  is a cross-sectional view of a crown of the stent of  FIG. 1  taken along line  1 C- 1 C thereof. 
           [0013]      FIG. 1D  is a cross-sectional view of a strut of the stent of  FIG. 1  in accordance with another embodiment. 
           [0014]      FIG. 2  is a side view of a tubular core structure in accordance with an embodiment hereof 
           [0015]      FIG. 3  is a perspective end view of the tubular core structure of  FIG. 2 . 
           [0016]      FIG. 4  is a perspective view of a molding apparatus in accordance with an embodiment hereof 
           [0017]      FIG. 4A  is a longitudinal sectional view of the molding apparatus of  FIG. 4  taken along line  4 A- 4 A thereof. 
           [0018]      FIG. 5  is a perspective side view of a metallic tubular component in accordance with an embodiment hereof. 
           [0019]      FIG. 5A  is a transverse perspective cross-sectional view of a portion of the metallic tubular component shown in  FIG. 5  taken along line  5 A- 5 A. 
           [0020]      FIG. 5B  is a partial longitudinal sectional view of a portion of the metallic tubular component shown in  FIG. 5  taken along line  5 B- 5 B thereof. 
           [0021]      FIG. 6  is a side view of a stent form in accordance with an embodiment hereof 
           [0022]      FIG. 6A  is a cross-sectional view of a strut of the stent form of  FIG. 6  taken along line  6 A- 6 A thereof. 
           [0023]    FIG.  6 AA is a cross-sectional view of a strut of the stent form of  FIG. 6  in accordance with another embodiment. 
           [0024]      FIG. 7  is an enlarged view of an end portion of a tubular core structure in accordance with another embodiment. 
           [0025]      FIGS. 8 and 9  are perspective views of portions of a tubular core structure in accordance with another embodiment hereof 
           [0026]      FIG. 10  is a perspective view of an end portion of a stent during formation in accordance with an embodiment hereof 
           [0027]      FIG. 11  is a perspective side view of an endovascular stent formed in accordance with another embodiment hereof 
           [0028]      FIG. 11A  is a cross-sectional view of a strut of the stent of  FIG. 11  taken along line  11 A- 11 A thereof. 
           [0029]      FIG. 11B  is a cross-sectional view of a crown of the stent of  FIG. 11  taken along line  11 B- 11 B thereof. 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0030]    Specific embodiments of the present invention are now described with reference to the figures, wherein like reference numbers indicate identical or functionally similar elements. The stent in accordance with the disclosure may be either of a balloon-expandable type or a self-expanding type. The term “self-expanding” is used in the following description with reference to the prostheses hereof and is intended to convey that the structures are shaped or formed from a material that can be provided with a mechanical memory to return the structure from a radially compressed or constricted delivery configuration to an expanded deployed configuration. Non-exhaustive exemplary materials that are suitable for forming a prosthesis in accordance with embodiments hereof include titanium,  316 L stainless steel, other low carbon chromium-nickel stainless steel, a pseudo-elastic metal such as a nickel titanium alloy (nitinol), or a so-called super alloy, which may have a base metal of nickel, cobalt, chromium, or other biocompatible metal. Mechanical memory may be imparted to a stent structure as described below by thermal treatment to achieve a spring temper in stainless steel, for example, or to set a shape memory in a susceptible metal alloy, such as nitinol. 
         [0031]    The following detailed description is merely exemplary in nature and is not intended to limit the invention or the application and uses of the invention. Although the description of embodiments hereof are in the context of treatment of blood vessels such as the coronary, carotid and renal arteries, the invention may also be used in any other body passageways where it is deemed useful. Furthermore, there is no intention to be bound by any expressed or implied theory presented in the preceding technical field, background, brief summary or the following detailed description. 
         [0032]    An endovascular stent  100  for delivering a therapeutic material within a vessel that may be formed by methods disclosed herein is shown in its deployed configuration in  FIG. 1 . More particularly, stent  100  may be a self-expanding endovascular prosthesis that is deformable or compressible into a reduced diameter delivery configuration (not shown) to be percutaneously deliverable to a treatment site within the vasculature via a delivery catheter (not shown), wherein stent  100  returns to an expanded or deployed configuration as shown in  FIG. 1  upon release from the delivery catheter during deployment. With reference to the end view of stent  100  shown in  FIG. 1A , stent  100  may be considered tubular or cylindrical with an inner or adluminal surface  101  that defines a blood flow lumen  102  therethrough and with an outer or abluminal surface  103  that sits in apposition with a vessel wall when stent  100  is deployed therein. Stent  100  has side openings  105  therethrough that are defined by generally straight segments or struts  104  and intersections or junctions  106 , as shown in  FIG. 1 , such that stent  100  has a lattice-like or diamond pattern. Crowns or bends  107  join pairs of struts  104  at the ends of stent  100 . In another embodiment (not shown), selected junctions  106  of stent  100  may be disconnected to form facing crowns so as to increase the flexibility of the stent. Stents formed in accordance with methods disclosed herein are not limited to the stent pattern shown in  FIG. 1 , and stent  100  may be formed into any stent pattern suitable for use as an endovascular stent. For example, and not by way of limitation, stent  100  can be formed into stent patterns disclosed in any of U.S. Pat. No. 4,733,665 to Palmaz, U.S. Pat. No. 5,292,331 to Boneau, U.S. Pat. No. 5,421,955 to Lau, U.S. Pat. No. 5,935,162 to Dang, and U.S. Pat. No. 6,730,116 to Wolinsky et al., each of which is incorporated by reference herein in its entirety. 
         [0033]      FIG. 1B  is an enlarged cross-sectional view of stent  100  taken along line B-B of  FIG. 1  at a strut  104  and  FIG. 1C  is an enlarged cross-sectional view taken along line C-C of  FIG. 1  at a crown  107 . Stent  100  is formed to have a channel  108  extending within struts  104  and junctions  106  thereof, such that the struts, crowns and junctions, as well as stent  100 , may be described as hollow or tubular, e.g. having a wall. In an embodiment, channel  108  extending within and between each of the struts  104  and junctions  106  of stent  100  may be described as a continuous channel. Channel  108  is shown in  FIGS. 1B and 1C  filled with a biologically or pharmacologically active therapeutic material  110 . 
         [0034]    Holes or apertures  112  are dispersed along the length of stent  100  to permit therapeutic material  110  to elute from channel  108 . In the embodiment shown in  FIG. 1 , holes  112  are disposed in the abluminal surface  103  directed outwardly or toward the vessel wall when stent  100  is deployed therein. In another embodiment, holes  112  may be provided as well or alternatively in the adluminal surface  101  of struts  104 . Holes  112  may be sized and shaped as desired to control the elution rate of therapeutic material  110  from stent  100  with larger sized openings generally permitting a faster elution rate and smaller sized openings generally providing a slower elution rate. Further, the size and/or quantity of holes  112  may be varied along the length of stent  100  in order to vary the quantity and/or rate of therapeutic material  110  being eluted from stent  100  at different portions of stent  100 . In accordance with embodiments hereof, holes  112  may be, for example and not by way of limitation, 5-30 μm in diameter. Holes  112  may have a constant diameter through a wall of strut  104 , as shown in  FIG. 1B , or may have a tapered or conical shape. 
         [0035]    A method of forming endovascular stent  100  for delivering therapeutic material  110  within a vessel is described with reference to  FIGS. 2-6 . A tubular core structure  214  for forming continuous channel  108  in stent  100  is shown in  FIGS. 2 and 3 . Tubular core structure  214  has a stent pattern with core side openings  205  therethrough that are defined by core struts  204  and core junctions  206  over which, or around which respective struts  104  and junctions  106  of stent  100  are to be formed respectively. In the embodiment of  FIG. 2 , tubular core structure  214  is a structure over which the entire stent  100  is formed such that the stent pattern of tubular core structure  214  serves as a template for the final stent pattern of stent  100 . Tubular core structure  214  also functions as a space-holding or channel-holding geometry that corresponds to the geometry of channel  108  within stent  100 . As such, core struts  204  and core junctions  206  of tubular core structure  214  may have any suitable cross-sectional shape, e.g. a substantially square cross-section for forming channel  108  as shown in  FIGS. 1B and 1C  or a circular cross-section for forming a channel  108 A as shown in  FIG. 1D . Tubular core structure  214  may be formed with a more complicated cross-sectional shape in accordance with other embodiments hereof for forming a channel within the struts, junctions and crowns of stent  100  with that corresponding cross-section. In embodiments hereof, tubular core structure  214  may be over-sized or made larger than a desired final dimension for channel  108  and stent  100  in order to account for shrinkage or compression of tubular core structure  214  that may occur during the molding and sintering process described below. 
         [0036]    In embodiments hereof, tubular core structure  214  is made in a rapid prototyping or a molding process, and consists of a sacrificial material that will burn away during the sintering process or is otherwise extracted or removed, such as by being evaporated, eroded or dissolved after formation of the stent to leave a corresponding channel or space within the stent. As would be understood by one of ordinary skill in the art, a rapid prototyping process is a process of making a three-dimensional solid object of virtually any shape from a digital model and utilizes 3D printing technology in which the three-dimensional object is “printed” using an additive layering process until the object is complete. In embodiments hereof, a digital model of tubular core structure  214  is created and  3 D printing technology is utilized in which successive layers of the sacrificial material are laid down until tubular core structure  214  is formed. Alternatively, the tubular core structure may be formed by molding processes such as compaction, compression or injection. 
         [0037]    Suitable sacrificial materials for making tubular core structure  214  are, by way of example but not limited to, urea or a similar material that is erodible by an acid-based solvent, sodium chloride or a similar material dissolvable by a water-based solvent, or magnesium or a similar material removable by evaporation at a temperature below the temperature used during the sintering process. In accordance with other embodiments hereof, certain polymeric materials such as polyurethane are suitable as sacrificial materials for making tubular core structures  214  as these polymeric materials may also be evaporated at a temperature below the temperature used during the sintering process. Extraction of the tubular core component can occur during the sintering step or it can happen after the sintering step. It can occur in a pressure and temperature controlled environment. 
         [0038]    With reference to  FIGS. 4 and 4A , tubular core structure  214  is positioned within an annular mold cavity  415  of a mold  416 , wherein the mold cavity  415  has a first or inner circumferential molding surface  418  for forming adluminal surface  101  of endovascular stent  100  and a second or outer circumferential molding surface  420  for forming abluminal surface  103  of stent  100 . When disposed within mold  416 , tubular core structure  214  is spaced apart from, and preferably centered between the first and second molding surfaces  418 ,  420  of mold cavity  415  so that tubular core structure  214  and channel  108  formed thereby will be substantially centered between the adluminal and abluminal surfaces  101 ,  103  of stent  100 . In one example illustrated in  FIG. 7 , knobs  728  help to center core structure  714  between the first and second molding surfaces of a mold cavity. Mold  416  includes a compression cap  422  having an annular protrusion  424  that is sized to be received within mold cavity  415 . Compression cap  422  is configured to receive a compressive force F C  that is transferred via annular protrusion  424  to the contents within mold cavity  415  as described in more detail below. It should be understood by one of ordinary skill in the art that mold  416  with compression cap  422  are by way of example only and are not meant to limit use of methods herein to such a molding tool as various other compression molding arrangements may be adapted for use herein. 
         [0039]    Metal particles  426  for forming stent  100  are placed, poured and/or packed within mold cavity  415  such that metal particles  426  fully surround and envelop core struts  204  and core junctions  206  of tubular core structure  214  and fill core side openings  205 . Magnetic, ultrasound or vibrational energy may be employed to ensure that the particles are settled around the tubular structure. Metal particles  426  may be sized as may be typical for metal injection molding (MIM), such as ultra-fine particles having an average size of around 5 μm, fine particles having an average size of around 10 μm, or larger particles up to around 200 μm is size. Suitable metal particles for forming stent  100  in accordance with methods herein include particles of the exemplary metals listed above. 
         [0040]    In another embodiment, tubular core structure  214  may be coated with metal particles  426  prior to positioning tubular core structure  214  within mold cavity  415 . Metal particles  426  may be applied to tubular core structure  214  by spraying, dipping, mixing, and/or brushing, and tubular core structure  214  so coated with metal particles  426  may then be disposed within mold  416  for further processing as described below. A binder material such as polyvinyl alcohol may be used to adhere the metal particles to the tubular core structure  214 . 
         [0041]    With reference to  FIG. 4A , compressive force F C  applied to cap  422  is converted to a mold pressure applied by annular protrusion  424  to the contents of mold cavity  415 , which includes tubular core structure  214  and metal particles  426 , to press together metal particles  426  to form a cold weld therebetween. More particularly, as will be understood by those familiar with powder metallurgy, compressive force F C  is of a sufficient magnitude to create a mold pressure such that a cold weld bonds metal particles  426  together.  FIG. 5  shows the resulting formed metallic tubular component  530 , removed from mold  416  and encapsulating tubular core structure  214  therewithin. In powder metallurgy embodiments hereof, cold-welding is utilized as a bonding process where metal particles  426  are combined to form metallic tubular component  530  through means of intense pressure that does not rely on heat to change the state of the metal particles being bonded, which means metal particles  426  remain in a solid state throughout the process. It is believed that during the cold-welding process, deformities occur across 60 to 80% of the bonding surface of metal particles  426 , and this allows permanent bonding to take place on the atomic level therebetween. A suitable pressure for forming a cold weld between the individual metal particles is material and particle size dependent, wherein metal particles  426  of a cobalt-chromium alloy or stainless steel  316 L may require a different compressive force F C  to achieve a cold weld between metal particles thereof, with smaller particle sizes of either material generally requiring less pressure for forming cold welds therebetween. A suitable pressure also depends on a volume of the mold cavity  415  and a volume of metal particles  426  therein. In an embodiment hereof, a suitable compressive force F C  or pressure to cold weld metal particles in the size range of 10-100 μm to form a stent having a 10 mm outer diameter and a 20 mm height may range from 1 to 50 tons. 
         [0042]    Metallic tubular component  530  created during the cold-welding process is then sintered to form a solid wall metal tube having smooth interior and exterior surfaces  501 ,  503  between which either tubular core structure  214  or a continuous channel  108  in the stent pattern of tubular core structure  214  is encased. Accordingly after the sintering step in an embodiment hereof, tubular core structure  214  may remain between interior and exterior surfaces  501 ,  503  of metallic tubular component  530 , as best shown in the cross-sectional and sectional views of a portion of metallic tubular component  530  that are shown in  FIGS. 5A and 5B , respectively. In another embodiment, tubular core structure  214  may burn away or evaporate during the sintering step such that continuous channel  108  in the stent pattern of tubular core structure  214  is encased or defined between interior and exterior surfaces  501 ,  503  of metallic tubular component  530 . As would be understood by one of ordinary skill in the art, sintering of metallic tubular component  530  is carried out in an appropriate furnace that provides an operator control over heating rate, time, temperature and an atmosphere/environment thereof. 
         [0043]    A suitable sintering temperature for use in embodiments hereof is in general the temperature at which a metal particle connects through its boundaries and merges with other metal particles so as to form a larger metal particle, with enough heat being applied for the metal particles to melt at the points where they have formed a cold weld. A sintering temperature is material and particle size dependent and is related to the material&#39;s melting point. In general a sintering temperature may be considered to be two-thirds of a melting point of that material, and in some instances is a temperature just below the melting point. In methods hereof once metallic tubular component  530  is brought to a suitable temperature for sintering the metal particles from which it is formed, the atoms in the metal particles cold welded together diffuse across the boundaries of the individual metal particles to thereby fuse them together such that metallic tubular component is further solidified and strengthened. In an embodiment in which metal particles  426  are of 316L stainless steel, which has a melting point of approximately 1400 degrees centigrade, a sintering temperature of approximately 1100 degrees centigrade would be appropriate for sintering the cold-welded particles thereof, with a sintering temperature in the range of 1000 to slightly under 1400 degrees centigrade also being suitable. Accordingly during formation of metallic tubular component  530 , metal particles  426  do not intermingle or mix with the material of tubular core structure  214  and do not form bonds or otherwise react with the material of tubular core structure  214 . Also post sintering, metallic tubular component  530  has a solid non-porous metallic wall within which one of tubular core structure  214  or continuous channel  108  are enclosed. By the use of “solid” to describe a wall of metallic tubular component  530  it is meant that the wall is substantially nonporous after the molding and sintering steps described above, such that a stent formed therefrom will have a nonporous wall surrounding channel  108  except where holes, such as drug loading and delivery holes  112 , are formed therein. 
         [0044]    Post sintering, metallic tubular component  530  is cut to remove portions of the solid wall thereof to create a stent form  600  in the stent pattern of tubular core structure  214 , as shown in  FIG. 6 . Care is taken during the cutting of metallic tubular component  530  to create side openings  105  without cutting the tubular core structure  214 , as shown in the cross-section of stent form strut  604  in  FIG. 6A . If the tubular core structure  214  is burned away during sintering, care is taken while forming side openings  105  to avoid cutting into the continuous channel  108  left thereby, as shown in the cross-section of an alternate stent form strut  604 A in FIG.  6 AA. Depending on the material selected for the tubular core structure, there may be some residual artifacts of the core structure left after the sintering step. In this case, a cleaning process can be employed afterward. Alternatively, the residual artifacts can be removed using pressure or a vacuum. In an embodiment, removing portions of the solid wall of metallic tubular component  530  includes laser cutting around the stent pattern of the tubular core structure  214 , such that tubular core structure  214  serves as a guide or template in creating stent form  600  in the same pattern as tubular core structure  214 . In another embodiment, in which the tubular core structure  214  is burned away during sintering, removing portions of the solid wall of metallic tubular component  530  includes laser cutting around continuous channel  108  that is in the stent pattern of tubular core structure  214 , such that continuous channel  108  serves as a guide or template in creating stent form  600  in the same pattern as tubular core structure  214 . In embodiments hereof in order to visualize tubular core structure  214  or continuous channel  108  such that one or the other may be used to guide the cutting and removing process, an x-ray may be used to distinguish between the less dense tubular core structure  214  or continuous channel  108  and the remaining material of metallic tubular component  530 . 
         [0045]    In an embodiment hereof with reference to  FIGS. 1 ,  1 B,  1 D, and  6  a plurality of holes  112  are formed through the abluminal surfaces  103  of stent form struts  604  to provide access to tubular core structure  214 . Tubular core structure  214  is then extracted from stent form  600  via the plurality of holes  112  to leave corresponding channel  108  in its stead or place, such that stent  100  is thereby formed. In various embodiments hereof, tubular core structure  214  is extracted from stent form  600  by eroding or dissolving the sacrificial material thereof using a suitable solvent as described above. This extraction step can occur in a controlled temperature and/or pressure environment, e.g. such as under vacuum or in a hydrogen atmosphere. However, it may not always be necessary to perform core extraction in a temperature and pressure controlled environment. Rather, this step may occur at room temperature and standard air conditions. In another embodiment hereof in which the tubular core structure  214  is burned away during sintering with reference to  FIGS. 1 ,  6 , and  6 AA, a plurality of holes  112  are formed through the abluminal surfaces  103  of stent form struts  604  to provide access to channel  108 , such that stent  100  is thereby formed. In embodiments hereof, holes  112  may be formed by any suitable process as would be apparent to one of ordinary skill in the art to include, by way of example and not limitation, laser drilling or etching the holes through the surface of stent form  600 . 
         [0046]      FIG. 7  is an enlarged perspective view of an end portion of a tubular core structure  714  having core struts  704  and core crowns  707  in accordance with another embodiment hereof. Core struts  704  of tubular core structure  714  include knobs  728  that extend radially outward therefrom. When tubular core structure  714  is disposed within mold cavity  415  of mold  416 , end surfaces  729  of knobs  728  will sit against outer circumferential molding surface  420 . Metal particles  426  will be disposed around knobs  728  as well as the remaining portions of tubular core structure  714  in accordance with the methods described above such that after molding and sintering steps are performed, knobs  728  will extend through a solid wall of metallic tubular component  530 . Subsequent removal of tubular core structure  714  by one of the methods described above will simultaneously leave a plurality of holes  112  formed by corresponding knobs  728 , as well as a corresponding channel formed by core structure  714 . Alternatively if tubular core structure  714  is burned away or evaporated during the sintering step, holes  112  will extend through the wall of metallic tubular component  530  at the former locations of knobs  728  without further processing. Accordingly, knobs  728  of tubular core structure  714  are configured to mold the plurality of holes  112  extending from the abluminal surface  103  through the strut wall of stent  100 , thereby eliminating the need for performing a separate process step for forming the plurality of holes. Although four knobs  728  are shown on each core strut  704  of tubular core structure  714  for forming a corresponding number of holes  112 , it should be understood that this is by way of example and not limitation and that any number of knobs  728  may be included for forming a corresponding number of holes  112 . In another embodiment (not shown), knobs  728  may be provided, as well or alternatively, extending inwardly from core struts  704  toward a lumen of tubular core structure  714  or toward an opposing core strut  704  without departing from the scope hereof for forming corresponding holes  112  through strut walls of the final stent. Knobs  728  may be sized and shaped such that corresponding holes  112  formed thereby provide a desired elution rate of therapeutic material  110 . Further, the size, quantity and/or shape of knobs  728  for forming holes  112  may be varied along the length of stent  100  in order to vary the quantity and/or rate of therapeutic material  110  being eluted from stent  100  at different portions of stent  100 . 
         [0047]    Channel  108  as formed by one of the methods described above is then filled with therapeutic material  110  via the plurality of holes  112 , such that stent  100  is ready for delivering therapeutic material  110  within a vessel wherein the therapeutic material will be released from channel  108  via the plurality of holes  112 . 
         [0048]    In another embodiment shown in  FIGS. 8 and 9 , a core structure  814  is disclosed that has a space holding geometry for forming a series of unconnected, separate channels  1108  within a stent  1100 , as shown in  FIGS. 11 ,  11 A and  11 B. Core structure  814  is a series of core struts  804  with an attachment member  825  extending parallel to each core strut and being spaced from and attached thereto by a plurality of knobs  828 . Each attachment member  825  is disposed along a radially outward-facing surface of a core strut  804 . An attachment member  825  of each core strut  804  is joined to the attachment member  825  of an adjacent core strut  804  by a band  827 , such that the series of core struts  804  are banded together to form a tubular shape of core structure  814  over which a ring or circular segment  1136  of struts  1104  of stent  1100  is to be formed. In the embodiment of  FIG. 8 , core struts  804  are disposed at an angle with respect to a longitudinal axis of core structure  814  such that a first end  807  of each core strut  804  is disposed toward a respective first end  807  of the core strut  804  on one side thereof and a second end  809  of each core strut  804  is disposed toward a respective second end  809  of the core strut  804  on the other side thereof 
         [0049]    A plurality of core structures  814  are loaded within a mold, such as mold  416 , and metal particles are added thereto. A pressure is applied to the contents of the mold to cold weld the metal particles together and thereby form a metallic tubular component that is then sintered, as described above. Portions of the metallic tubular component are then removed, by laser cutting for example, to form the stent pattern of stent  1100  shown in  FIG. 11 . With reference to  FIG. 10 , attachment members  825  and bands  827  are embedded within an external surface of the metallic tubular component after the molding and sintering process and are removed after formation of stent  1100  by either an erosion or dissolution process used to extract core structure  814  from stent  1100  or by an abrasion process performed prior to the extraction of core structure  814 . In an alternate embodiment, attachment members  825  and bands  827  are removed by an abrasion or erosion process applied to the metallic tubular component prior to cutting the pattern of stent  1100 . In another embodiment, core structures  814  may burn off or evaporate during the sintering process eliminating the need for further processing to remove the attachment member and band structures from the metallic tubular component or stent  1100 . Accordingly each core strut  804  of core structure  814  so described is configured to form a separate, individual channel  1108  and holes  1112  attendant thereto within a corresponding strut  1104  of stent  1100 , as shown in  FIG. 11A , with crowns  1106  that extend between adjacent struts  1104 , as well as connector segments  1111  of stent  1100 , having solid cross-sections as shown in  FIG. 11B . Channels  1108  of stent  1100  are then filled with a therapeutic material via the plurality of holes  1112  in the abluminal surface  1103  of stent  1100 , such that stent  1100  is ready for delivering the therapeutic material within a vessel wherein the therapeutic material will be released from channels  1108  via the plurality of holes  1112 . 
         [0050]    In accordance with embodiments hereof, channels  108 ,  1108  of stents  100 ,  1100  may be filled with a therapeutic material by methods described in U.S. Pat. Appl. Pub. No. 2011/0070357 to Mitchell et al, U.S. Pat. Appl. Pub. No. 2012/0070562 to Avelar et al, U.S. Pat. Appl. Pub. No. 2012/0067455 to Mitchell et al, U.S. Pat. Appl. Pub. No. 2012/0070563 to Mitchell et al, U.S. Pat. Appl. Pub. No. 2012/0067454 to Mitchell et al., and U.S. Pat. No. 8,381,774 to Mitchell et al, each of which is incorporated by reference herein in its entirety, or any other suitable method known to one of ordinary skill in the art. 
         [0051]    Further processing of the stents in the above-described embodiments, such as annealing, cleaning, and other processes known to one of ordinary skill in the art, can be performed at appropriate times in the methods described above. For example, and not by way of limitation, annealing the stent may take place before filling the stent with the therapeutic material if the annealing step may damage the therapeutic material. Similarly, a final cleaning step may occur after filling the stent with the therapeutic material. Further, holes used to allow an etchant or dissolvent access to the tubular core structure for removal and/or used to fill the channels with a therapeutic material may be closed to control the elution rate and elution time of the therapeutic material from the stent. 
         [0052]    The term “therapeutic material” refers to any biologically or pharmacologically active substance, whether synthetic or natural, that has a pharmacological, chemical, or biological effect on the body or a portion thereof. Suitable therapeutic materials that can be used in embodiments hereof include without limitation glucocorticoids (e.g. dexamethasone, betamethasone), antithrombotic agents such as heparin, cell growth inhibitors, hirudin, angiopeptin, aspirin, growth factors such as VEGF, antisense agents, anti-cancer agents, anti-proliferative agents, oligonucleotides, antibiotics, and, more generally, antiplatelet agents, anti-coagulant agents, antimitotic agents, antioxidants, antimetabolite agents, and anti-inflammatory agents may be used. Antiplatelet agents can include drugs such as aspirin and dipyridamole. Aspirin is classified as an analgesic, antipyretic, anti-inflammatory and antiplatelet drug. Dipyridamole is a drug similar to aspirin in that it has anti-platelet characteristics. Dipyridamole is also classified as a coronary vasodilator. Anticoagulant agents may include drugs such as heparin, protamine, hirudin and tick anticoagulant protein. Anti-cancer agents may include drugs such as taxol and its analogs or derivatives. Taxol is also classified as a cell-growth inhibitor. Antioxidant agents may include probucol. Anti-proliferative agents may include drugs such as amlodipine, doxazosin, and sirolimus (rapamycin) or other limus family compounds. Antimitotic agents and antimetabolite agents may include drugs such as methotrexate, azathioprine, vincristine, vinblastine, 5-fluorouracil, adriamycin and mutamycin. Antibiotic agents can include penicillin, cefoxitin, oxacillin, tobramycin, and gentamicin. Suitable antioxidants include probucol. Also, genes or nucleic acids, or portions thereof may be used. Such genes or nucleic acids can first be packaged in liposomes or nanoparticles. Furthermore, collagen-synthesis inhibitors, such as tranilast, may be used. 
         [0053]    The stents described herein may be used conventionally to support blood vessels of the body after an angioplasty procedure. It is known that certain therapeutic materials eluted from stents may prevent restenosis or other complications associated with angioplasty or stent implantation. The stents described herein may alternatively be used in other organs or tissues of the body for delivery of drugs to treat tumors, inflammation, nervous conditions, or other conditions that would be apparent to those skilled in the art. 
         [0054]    While various embodiments have been described above, it should be understood that they have been presented only as illustrations and examples of the present invention, and not by way of limitation. It will be apparent to persons skilled in the relevant art that various changes in form and detail can be made therein without departing from the spirit and scope of the invention. Thus, the breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the appended claims and their equivalents. It will also be understood that each feature of each embodiment discussed herein, and of each reference cited herein, can be used in combination with the features of any other embodiment. All patents and publications discussed herein are incorporated by reference herein in their entirety.

Technology Category: b