Medical devices and methods of making the same   

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of and claims priority under 35 U.S.C. §120 to U.S. application Ser. No. 11/855,019, filed on Sep. 13, 2007, which is a non-provisional of U.S. Provisional Application Ser. No. 60/845,046, filed on Sep. 15, 2006, the entire contents of which are hereby incorporated by reference.

TECHNICAL FIELD

The invention relates to medical devices, such as, for example, endoprostheses, and to related methods.

The body includes various passageways such as arteries, other blood vessels, and other body lumens. These passageways sometimes become occluded or weakened. For example, the passageways can be occluded by a tumor, restricted by plaque, or weakened by an aneurysm. When this occurs, a passageway can be reopened or reinforced, or even replaced, with a medical endoprosthesis. An endoprosthesis is typically a tubular member that is placed in a lumen in the body. Examples of endoprostheses include stents, stent-grafts, and covered stents.

An endoprosthesis can be delivered inside the body by a catheter that supports the endoprosthesis in a compacted or reduced-size form as the endoprosthesis is transported to a desired site. Upon reaching the site, the endoprosthesis is expanded, for example, so that it can contact the walls of the lumen.

The expansion mechanism may include forcing the endoprosthesis to expand radially. For example, the expansion mechanism can include the catheter carrying a balloon, which carries a balloon-expandable endoprosthesis. The balloon can be inflated to deform and to fix the expanded endoprosthesis at a predetermined position in contact with the lumen wall. The balloon can then be deflated, and the catheter withdrawn.

In another delivery technique, the endoprosthesis is formed of an elastic material that can be reversibly compacted and expanded (e.g., elastically or through a material phase transition). During introduction into the body, the endoprosthesis is restrained in a compacted condition. Upon reaching the desired implantation site, the restraint is removed, for example, by retracting a restraining device such as an outer sheath, enabling the endoprosthesis to self-expand by its own internal elastic restoring force.

To support a passageway and keep the passageway open, endoprostheses are sometimes made of relatively strong materials, such as stainless steel or Nitinol (a nickel-titanium alloy), formed into struts or wires.

SUMMARY

In one aspect, the invention features an endoprosthesis including a generally tubular member having a lumen and including at least one component selected from struts, bands, and combinations thereof. The component includes a bioerodible material selected from bioerodible metals, bioerodible metal alloys, and combinations thereof. The component has a first region including pores and a second region including pores, and the average maximum dimension (e.g., diameter) of the pores in the second region is greater than the average maximum dimension (e.g., diameter) of the pores in the first region.

In another aspect, the invention features an endoprosthesis including a generally tubular member having a lumen and including at least one component selected from struts, bands, and combinations thereof. The component includes a bioerodible material selected from bioerodible metals, bioerodible metal alloys, and combinations thereof. The component has a first region and a second region having a higher pore density than the first region.

In an additional aspect, the invention features an endoprosthesis including a generally tubular member having a lumen. The generally tubular member includes at least one component selected from struts, bands, and combinations thereof. The component includes a bioerodible material selected from bioerodible metals, bioerodible metal alloys, and combinations thereof. The component has at least one pore, and the endoprosthesis includes a polymer that is disposed within the pore.

In a further aspect, the invention features an endoprosthesis including a generally tubular member having a first region including pores and a second region including pores. The first region defines an interior surface of the generally tubular member, and the second region defines an exterior surface of the generally tubular member. The average maximum dimension of the pores in the second region is greater than the average maximum dimension of the pores in the first region. The generally tubular member includes a bioerodible material selected from bioerodible metals, bioerodible metal alloys, and combinations thereof.

In another aspect, the invention features an endoprosthesis including a generally tubular member. The generally tubular member has a first region defining an interior surface of the generally tubular member and a second region defining an exterior surface of the generally tubular member. The second region has a higher pore density than the first region. The generally tubular member includes a bioerodible material selected from bioerodible metals, bioerodible metal alloys, and combinations thereof.

In an additional aspect, the invention features an endoprosthesis including a generally tubular member and a polymer. The generally tubular member has at least one pore, and the polymer is disposed within the pore. The generally tubular member includes a bioerodible material selected from bioerodible metals, bioerodible metal alloys, and combinations thereof.

In a further aspect, the invention features a method including delivering an endoprosthesis into a lumen of a subject. The endoprosthesis includes a generally tubular member including a therapeutic agent and a bioerodible material selected from bioerodible metals, bioerodible metal alloys, and combinations thereof. The generally tubular member erodes at an erosion rate and the therapeutic agent elutes into the lumen of the subject at an elution rate. The elution rate is slower than the erosion rate.

In another aspect, the invention features an endoprosthesis including a generally tubular member having a lumen. The generally tubular member includes at least one component selected from struts, bands, and combinations thereof. The component includes a reservoir surrounded by a matrix including a bioerodible material and having at least one pore. The bioerodible material is selected from bioerodible metals, bioerodible metal alloys, and combinations thereof.

Embodiments can include one or more of the following features.

The first and/or second region of the component and/or the generally tubular member can include at least one pore (e.g., multiple pores). The average maximum dimension of the pores in the second region can be different from (e.g., greater than) the average maximum dimension of the pores in the first region. In some embodiments, the average maximum dimension of the pores in the second region can be at least about 1.5 times greater (e.g., at least about two times greater, at least about five times greater, at least about 10 times greater) than the average maximum dimension of the pores in the first region.

The endoprosthesis can include a therapeutic agent. The reservoir can contain a therapeutic agent. The endoprosthesis can include a polymer (e.g., a bioerodible polymer). The polymer can be supported by the component and/or the generally tubular member. The polymer can be disposed within pores of the component and/or the generally tubular member. In some embodiments, the polymer can be disposed within at least one pore (e.g., multiple pores) in the first region and/or the second region of the component and/or the generally tubular member. In certain embodiments, the endoprosthesis can include a composite including a therapeutic agent and a polymer.

The generally tubular member can have an exterior surface and an interior surface that defines the lumen of the generally tubular member. In some embodiments, the first region of the component can define at least a portion of the interior surface of the generally tubular member. In certain embodiments, the second region of the component can define at least a portion of the exterior surface of the generally tubular member.

The pore density of the second region of the component and/or the generally tubular member can be different from (e.g., higher than) the pore density of the first region of the component and/or the generally tubular member. In some embodiments, the pore density of the second region can be at least about 1.5 times higher (e.g., at least about two times higher, at least about five times higher, at least about 10 times higher) than the pore density of the first region.

In certain embodiments, the first and/or second regions of the component and/or the generally tubular member may not include any pores.

Embodiments can include one or more of the following advantages.

In some embodiments, a medical device (e.g., an endoprosthesis) including a bioerodible material can be used to temporarily treat a subject without permanently remaining in the body of the subject. For example, the medical device can be used for a certain period of time (e.g., to support a lumen of a subject), and then can erode after that period of time is over.

In certain embodiments, a medical device (e.g., an endoprosthesis) including a bioerodible metal and/or a bioerodible metal alloy can be relatively strong and/or can have relatively high structural integrity, while also having the ability to erode after being used at a target site.

In some embodiments, a medical device (e.g., an endoprosthesis) including a bioerodible material and having regions with different pore densities and/or with pores having different average maximum dimensions can erode at different rates in the different regions. In certain embodiments, a medical device can be designed to erode at a faster rate in some regions than in other regions. For example, an endoprosthesis can be designed so that its end regions erode at a faster rate than its center region. The result can be that the endoprosthesis erodes as one piece, starting at its end regions and progressing toward its center region.

In some embodiments, a medical device (e.g., an endoprosthesis) that includes a bioerodible material can also include at least one other material that is either bioerodible or non-bioerodible. The other material can, for example, enhance the strength and/or structural integrity of the medical device.

In certain embodiments, a medical device (e.g., an endoprosthesis) can provide a controlled release of one or more therapeutic agents into the body of a subject. For example, in some embodiments in which a medical device includes a bioerodible material and a therapeutic agent, the erosion of the bioerodible material can result in the release of the therapeutic agent over a period of time.

In some embodiments, a medical device (e.g., an endoprosthesis) having regions with different pore densities and/or with pores having different average maximum dimensions can deliver therapeutic agents at different rates and/or in different amounts from the different regions. For example, a region of an endoprosthesis having a relatively high pore density and/or having pores with a relatively high average maximum dimension may deliver therapeutic agent at a faster rate, and/or may deliver a greater total volume of therapeutic agent, than another region of the endoprosthesis having a relatively low pore density and/or having pores with a relatively low average maximum dimension. In certain embodiments, one region of a medical device can be designed to deliver more therapeutic agent, and/or to deliver therapeutic agent at a faster rate, than another region of the medical device. For example, a region of an endoprosthesis that is located along an outer diameter of the endoprosthesis can be designed to deliver a greater volume of therapeutic agent, and/or to deliver therapeutic agent at a faster rate, than a region of the endoprosthesis that is located along an inner diameter of the endoprosthesis.

In certain embodiments, a medical device (e.g., an endoprosthesis) having regions with different pore densities and/or with pores having different average maximum dimensions can deliver different therapeutic agents from the different regions. As an example, in some embodiments, a region of an endoprosthesis having a relatively high pore density and including pores having a relatively high average maximum dimension can deliver a therapeutic agent at a relatively fast rate, while another region of the endoprosthesis having a relatively low pore density and including pores having a relatively low average maximum dimension can be used to deliver a different therapeutic agent at a relatively slow rate.

In some embodiments in which a medical device (e.g., an endoprosthesis) includes both a bioerodible material (e.g., a bioerodible metal) and a therapeutic agent, the erosion rate of the bioerodible material can be independent of the elution rate of the therapeutic agent. As an example, in certain embodiments, a medical device can be formed of a porous bioerodible metal, and can include a composite including a bioerodible polymer combined with a therapeutic agent that is disposed within the pores of the bioerodible metal. As the polymer erodes, it can release the therapeutic agent at a rate that is different from the erosion rate of the bioerodible metal. In certain embodiments, the bioerodible metal can erode before all of the therapeutic agent has been released from the polymer. The remaining polymer can continue to elute the therapeutic agent. The therapeutic agent can be selected, for example, to help alleviate the effects, if any, of the erosion of the bioerodible metal on the body of the subject.

In some embodiments, a medical device (e.g., an endoprosthesis) including one or more metals (e.g., bioerodible metals) can be relatively radiopaque. This radiopacity can give the medical device enhanced visibility under X-ray fluoroscopy. Thus, the position of the medical device within the body of a subject may be able to be determined relatively easily.

An erodible or bioerodible endoprosthesis, e.g., a stent, refers to a device, or a portion thereof, that exhibits substantial mass or density reduction or chemical transformation, after it is introduced into a patient, e.g., a human patient. Mass reduction can occur by, e.g., dissolution of the material that forms the device and/or fragmenting of the device. Chemical transformation can include oxidation/reduction, hydrolysis, substitution, and/or addition reactions, or other chemical reactions of the material from which the device, or a portion thereof, is made. The erosion can be the result of a chemical and/or biological interaction of the device with the body environment, e.g., the body itself or body fluids, into which it is implanted and/or erosion can be triggered by applying a triggering influence, such as a chemical reactant or energy to the device, e.g., to increase a reaction rate. For example, a device, or a portion thereof, can be formed from an active metal, e.g., Mg or Ca or an alloy thereof, and which can erode by reaction with water, producing the corresponding metal oxide and hydrogen gas (a redox reaction). For example, a device, or a portion thereof, can be formed from an erodible or bioerodible polymer, or an alloy or blend erodible or bioerodible polymers which can erode by hydrolysis with water. The erosion occurs to a desirable extent in a time frame that can provide a therapeutic benefit. For example, in embodiments, the device exhibits substantial mass reduction after a period of time which a function of the device, such as support of the lumen wall or drug delivery is no longer needed or desirable. In particular embodiments, the device exhibits a mass reduction of about 10 percent or more, e.g. about 50 percent or more, after a period of implantation of one day or more, e.g. about 60 days or more, about 180 days or more, about 600 days or more, or 1000 days or less. In embodiments, the device exhibits fragmentation by erosion processes. The fragmentation occurs as, e.g., some regions of the device erode more rapidly than other regions. The faster eroding regions become weakened by more quickly eroding through the body of the endoprosthesis and fragment from the slower eroding regions. The faster eroding and slower eroding regions may be random or predefined. For example, faster eroding regions may be predefined by treating the regions to enhance chemical reactivity of the regions. Alternatively, regions may be treated to reduce erosion rates, e.g., by using coatings. In embodiments, only portions of the device exhibits erodibilty. For example, an exterior layer or coating may be erodible, while an interior layer or body is non-erodible. In embodiments, the endoprosthesis is formed from an erodible material dispersed within a non-erodible material such that after erosion, the device has increased porosity by erosion of the erodible material.

Erosion rates can be measured with a test device suspended in a stream of Ringer\'s solution flowing at a rate of 0.2 m/second. During testing, all surfaces of the test device can be exposed to the stream. For the purposes of this disclosure, Ringer\'s solution is a solution of recently boiled distilled water containing 8.6 gram sodium chloride, 0.3 gram potassium chloride, and 0.33 gram calcium chloride per liter.

Other aspects, features, and advantages are in the description, drawings, and claims.

FIG. 1A is a perspective view of an embodiment of a stent in a compressed condition.

FIG. 1B is a perspective view of the stent of FIG. 1A, in an expanded condition.

FIG. 1C is a cross-sectional view of the stent of FIG. 1A, taken along line 1C-1C.

FIG. 1D is an enlarged view of region 1D of the stent of FIG. 1C.

FIG. 2A is a cross-sectional view of an embodiment of a stent.

FIG. 2B is an enlarged view of region 2B of the stent of FIG. 2A.

FIG. 3 is a cross-sectional view of an embodiment of a stent.

FIG. 4A is a perspective view of an embodiment of a stent.

FIG. 4B is a cross-sectional view of the stent of FIG. 4A, taken along line 4B-4B.

FIG. 5 is a cross-sectional view of an embodiment of a stent.

FIG. 6A is a perspective view of an embodiment of a stent.

FIG. 6B is a cross-sectional view of the stent of FIG. 6A, taken along line 6B-6B.

FIG. 7 is a cross-sectional view of an embodiment of a stent.

FIG. 8A is a perspective view of an embodiment of a stent.

FIG. 8B is an enlarged view of region 8B of the stent of FIG. 8A.

FIG. 8C is a cross-sectional view of region 8B of FIG. 8B, taken along line 8C-8C.

FIG. 9 is a cross-sectional view of an embodiment of a component of a stent.

FIG. 10A is a perspective view of an embodiment of a stent.

FIG. 10B is a cross-sectional view of the stent of FIG. 10A, taken along line 10B-10B.

FIG. 11A is a perspective view of an embodiment of a stent.

FIG. 11B is a cross-sectional view of the stent of FIG. 11A, taken along line 11B-11B.

FIG. 12A is a perspective view of an embodiment of a stent.

FIG. 12B is a cross-sectional view of the stent of FIG. 12A, taken along line 12B-12B.

FIG. 13A is a perspective view of an embodiment of a stent.

FIG. 13B is an enlarged view of region 13B of the stent of FIG. 13A.

FIG. 13C is a cross-sectional view of region 13B of FIG. 13B, taken along line 13C-13C.

FIG. 14A is a perspective view of an embodiment of a stent.

FIG. 14B is a cross-sectional view of the stent of FIG. 14A, taken along line 14B-14B.

FIG. 15A is a perspective view of an embodiment of a stent.

FIG. 15B is a cross-sectional view of the stent of FIG. 15A, taken along line 15B-15B.

DETAILED DESCRIPTION

FIG. 1A shows a stent 10 including a generally tubular member 12 capable of supporting a body lumen and having a longitudinal axis A-A and a lumen 13. Generally tubular member 12 includes apertures 14 that are provided in a pattern to facilitate stent functions (e.g., radial expansion) and lateral flexibility. FIG. 1A shows stent 10 in a compressed condition, such that stent 10 has a relatively small diameter Dc suitable for delivery into a lumen of a subject. As shown in FIG. 1B, once stent 10 has been delivered into a lumen of a subject, stent 10 is expanded to a larger diameter, Dexp. This larger diameter can allow stent 10 to contact the walls of the lumen. In some embodiments, a stent such as stent 10 can be expanded by a mechanical expander (e.g., an inflatable balloon).

FIG. 1C shows a cross-sectional view of stent 10. As shown in FIG. 1C, generally tubular member 12 has in interior surface 15 and an exterior surface 17, and is formed of a metal matrix 16 including pores 18. Pores 18 can form an open pore system (in which different pores 18 are interconnected) or a closed pore system (in which different pores 18 are not interconnected). In certain embodiments, some pores 18 can be interconnected, and other pores 18 may not be interconnected. While pores 18 are shown as having an irregular cross-sectional shape, in some embodiments, the pores in a metal matrix can have one or more other cross-sectional shapes. For example, a pore in a metal matrix can be circular, oval (e.g., elliptical), and/or polygonal (e.g., triangular, square) in cross-section.

Metal matrix 16 includes (e.g., is formed of) one or more bioerodible metals and/or bioerodible metal alloys. In some embodiments (e.g., some embodiments in which metal matrix 16 is formed entirely of bioerodible metals and/or bioerodible metal alloys), generally tubular member 12 is bioerodible. In certain embodiments, generally tubular member 12 can erode after stent 10 has been used at a target site.

As shown in FIGS. 1C and 1D, different regions of generally tubular member 12 have different pore densities and/or include pores having different average maximum dimensions. As used herein, the pore density of a region is equal to the number of pores per square centimeter in that region. As an example, FIG. 1D shows a portion of generally tubular member 12 that has been divided by a line L1 into a region R1 and a region R2. Region R1 has a lower pore density than region R2, and also has pores with a lower average maximum dimension than the pores in region R2.

The variation in pore density and in the average maximum dimension of pores in different regions of generally tubular member 12 can be designed, for example, to result in a particular pattern and/or rate of erosion by generally tubular member 12. Typically, as the pore density and/or average maximum dimension of the pores in a region of generally tubular member 12 increases, the erosion rate of that region can also increase. Without wishing to be bound by theory, it is believed that as the pore density and/or average pore volume of a region of generally tubular member 12 increases, the surface area of bioerodible material in that region that is exposed to blood and/or other body fluids (e.g., at a target site) can also increase. As a result, region R2 of generally tubular member 12, with its relatively high pore density and with its pores having a relatively high average maximum dimension, may erode at a faster rate than region R1 of generally tubular member 12, with its relatively low pore density and with its pores having a relatively low average maximum dimension.

In some embodiments, a medical device (e.g., stent 10) or a component of a medical device (e.g., generally tubular member 12) that is formed of one or more bioerodible materials can substantially erode (can exhibit a mass reduction of about 95 percent or more) over a period of at least about five days (e.g., at least about seven days, at least about 14 days, at least about 21 days, at least about 28 days, at least about 30 days, at least about six weeks, at least about eight weeks, at least about 12 weeks, at least about 16 weeks, at least about 20 weeks, at least about six months, at least about 12 months). In some embodiments in which a medical device includes one or more radiopaque materials, the erosion of the medical device within the body of a subject can be monitored using X-ray fluoroscopy. In certain embodiments, the erosion of a medical device within the body of a subject can be monitored using intravascular ultrasound.

In some embodiments, region R1 can have a pore density of at least about 100 pores per square centimeter (e.g., at least about 500 pores per square centimeter, at least about 1000 pores per square centimeter, at least about 104 pores per square centimeter, at least about 105 pores per square centimeter, at least about 106 pores per square centimeter, at least about 107 pores per square centimeter, at least about 108 pores per square centimeter) and/or at most about 109 pores per square centimeter (e.g., at most about 108 pores per square centimeter, at most about 107 pores per square centimeter, at most about 106 pores per square centimeter, at most about 105 pores per square centimeter, at most about 104 pores per square centimeter, at most about 1000 pores per square centimeter, at most about 500 pores per square centimeter). In certain embodiments, region R2 can have a pore density of at least about 100 pores per square centimeter (e.g., at least about 500 pores per square centimeter, at least about 1000 pores per square centimeter, at least about 104 pores per square centimeter, at least about 105 pores per square centimeter, at least about 106 pores per square centimeter, at least about 107 pores per square centimeter, at least about 108 pores per square centimeter) and/or at most about 109 pores per square centimeter (e.g., at most about 108 pores per square centimeter, at most about 107 pores per square centimeter, at most about 106 pores per square centimeter, at most about 105 pores per square centimeter, at most about 104 pores per square centimeter, at most about 1000 pores per square centimeter, at most about 500 pores per square centimeter). In some embodiments, the pore density of region R2 can be at least about 1.5 times greater (e.g., at least about two times greater, at least about five times greater, at least about 10 times greater, at least about 25 times greater, at least about 50 times greater, at least about 75 times greater), and/or at most about 100 times greater (e.g., at most about 75 times greater, at most about 50 times greater, at most about 25 times greater, at most about 10 times greater, at most about five times greater, at most about two times greater), than the pore density of region R1. While FIG. 1D shows both region R1 and region R2 as including pores 18, in certain embodiments, a generally tubular member such as generally tubular member 12 can have one or more regions that do not include any pores.

In some embodiments, the average maximum dimension (e.g., diameter, length, width) of the pores in region R1 can be at least 0.01 micron (e.g., at least 0.05 micron, at least about 0.1 micron, at least about 0.5 micron, at least about one micron, at least about five microns) and/or at most about 10 microns (e.g., at most about five microns, at most about one micron, at most about 0.5 micron, at most about 0.1 micron, at most 0.05 micron). In certain embodiments, the average maximum dimension (e.g., diameter, length, width) of the pores in region R2 can be at least 0.01 micron (e.g., at least 0.05 micron, at least about 0.1 micron, at least about 0.5 micron, at least about one micron, at least about five microns) and/or at most about 10 microns (e.g., at most about five microns, at most about one micron, at most about 0.5 micron, at most about 0.1 micron, at most 0.05 micron). In some embodiments, the average maximum dimension of the pores in region R2 can be at least about 1.5 times greater (e.g., at least about five times greater, at least about 10 times greater, at least about 25 times greater, at least about 50 times greater, at least about 75 times greater), and/or at most about 100 times greater (e.g., at most about 75 times greater, at most about 50 times greater, at most about 25 times greater, at most about 10 times greater, at most about five times greater), than the average maximum dimension of the pores in region R1.

The bioerodible materials that are included in a medical device can include one or more metals and/or one or more metal alloys. Examples of bioerodible metals include alkali metals, alkaline earth metals (e.g., magnesium), iron, zinc, and aluminum. As used herein, a metal alloy refers to a substance that is composed of two or more metals or of a metal and a nonmetal intimately united, for example, by being fused together and dissolving in each other when molten. Examples of bioerodible metal alloys include alkali metal alloys, alkaline earth metal alloys (e.g., magnesium alloys), iron alloys (e.g., alloys including iron and up to seven percent carbon), zinc alloys, and aluminum alloys. Metal matrix 16 of generally tubular member 12 can include one metal or metal alloy, or can include more than one (e.g., two, three, four, five) metal or metal alloy. In some embodiments, metal matrix 16 can include one or more metals and one or more metal alloys. Bioerodible materials are described, for example, in Weber, U.S. Patent Application Publication No. US 2005/0261760 A1, published on Nov. 24, 2005, and entitled “Medical Devices and Methods of Making the Same”; Colen et al., U.S. Patent Application Publication No. US 2005/0192657 A1, published on Sep. 1, 2005, and entitled “Medical Devices”; Weber, U.S. patent application Ser. No. 11/327,149, filed on Jan. 5, 2006, and entitled “Bioerodible Endoprostheses and Methods of Making the Same”; Bolz, U.S. Pat. No. 6,287,332; Heublein, U.S. Patent Application Publication No. US 2002/0004060 A1, published on Jan. 10, 2002, and entitled “Metallic Implant Which is Degradable In Vivo”; and Park, Science and Technology of Advanced Materials, 2, 73-78 (2001).

In some embodiments, stent 10 can include one or more therapeutic agents. As an example, stent 10 can include one or more therapeutic agents that are disposed within pores 18 of generally tubular member 12. During delivery and/or use in a body of a subject, stent 10 can elute the therapeutic agents. For example, as generally tubular member 12 erodes, the therapeutic agents within pores 18 can be released into the body. The erosion of generally tubular member 12 can result in a relatively consistent release of therapeutic agent, as pores 18 continue to become exposed.

The variation in pore density and in the average maximum dimension of the pores in different regions of generally tubular member 12 can be designed, for example, to result in a particular pattern and/or rate of therapeutic agent elution from generally tubular member 12. Typically, a region of generally tubular member 12 having a relatively high pore density and/or including pores with a relatively high average maximum dimension can elute therapeutic agent at a faster rate than a region of generally tubular member 12 having a relatively low pore density and/or including pores with a relatively low average maximum dimension. For example, region R2 of generally tubular member 12 may elute therapeutic agent at a faster rate, and/or may elute a higher total volume of therapeutic agent, than region R1.

Examples of therapeutic agents include non-genetic therapeutic agents, genetic therapeutic agents, vectors for delivery of genetic therapeutic agents, cells, and therapeutic agents identified as candidates for vascular treatment regimens, for example, as agents targeting restenosis. In some embodiments, one or more therapeutic agents that are used in a medical device such as a stent can be dried (e.g., lyophilized) prior to use, and can become reconstituted once the medical device has been delivered into the body of a subject. A dry therapeutic agent may be relatively unlikely to come out of a medical device (e.g., a stent) prematurely, such as when the medical device is in storage.

Therapeutic agents are described, for example, in Weber, U.S. Patent Application Publication No. US 2005/0261760 A1, published on Nov. 24, 2005, and entitled “Medical Devices and Methods of Making the Same”, and in Colen et al., U.S. Patent Application Publication No. US 2005/0192657 A1, published on Sep. 1, 2005, and entitled “Medical Devices”.

Generally tubular member 12 of stent 10 can be formed by any of a number of different methods. In some embodiments, generally tubular member 12 can be formed by molding a mixture of a bioerodible metal and a second bioerodible material into a generally tubular shape, and exposing the generally tubular shape to a solvent that solvates the second bioerodible material (without also solvating the bioerodible metal), and/or to a temperature that causes the second bioerodible material to melt (without also causing the bioerodible metal to melt). When the second bioerodible material is solvated and/or when it melts, it can result in the formation of pores in the metal, thereby producing metal matrix 16.

While a stent including regions having different pore densities and having pores with different average maximum dimensions has been described, in some embodiments, a stent can alternatively or additionally include regions having the same pore density and/or having pores with the same average maximum dimension. For example, FIG. 2A shows a cross-sectional view of a stent 100 including a generally tubular member 112. Generally tubular member 112 has an interior surface 113, an exterior surface 114, and a lumen 115, and is formed out of a metal matrix 116 formed of one or more bioerodible metals and/or bioerodible metal alloys. Metal matrix 116 includes pores 118.

FIG. 2B shows a portion of generally tubular member 112 that has been divided by a line L2 into regions R3 and R4. As shown in FIG. 2B, regions R3 and R4 have the same pore density, and also include pores 118 having the same average maximum dimension.

While stents including generally tubular members formed out of a metal matrix and/or including a therapeutic agent have been described, in some embodiments, a stent can include one or more other materials. The other materials can be used, for example, to enhance the strength and/or structural support of the stent. Examples of other materials that can be used in conjunction with a metal matrix in a stent include metals (e.g., gold, platinum, niobium, tantalum), metal alloys, and/or polymers (e.g., styrene-isobutylene styrene (SIBS), poly(n-butyl methacrylate) (PBMA)). Examples of metal alloys include cobalt-chromium alloys (e.g., L605), Elgiloy® (a cobalt-chromium-nickel-molybdenum-iron alloy), and niobium-1 Zr alloy. In some embodiments, a stent can include a generally tubular member formed out of a porous magnesium matrix, and the pores in the magnesium matrix can be filled with iron compounded with a therapeutic agent.

In certain embodiments, a stent can include both a bioerodible metal matrix and one or more additional bioerodible materials that are different from the bioerodible materials in the bioerodible metal matrix. For example, in some embodiments, a stent can include both a bioerodible metal matrix and one or more non-metallic bioerodible materials (e.g., starches, sugars). In certain embodiments, a stent can include a bioerodible metal matrix and one or more additional bioerodible materials that erode at a different rate from the bioerodible metal matrix. The additional bioerodible materials can be added to the bioerodible metal matrix to, for example, tailor the erosion rate of the stent. For example, in some embodiments, a stent can include a generally tubular member that is formed of a porous bioerodible metal matrix, and a bioerodible polymer can be disposed within some or all of the pores of the bioerodible metal matrix. For example, FIG. 3 shows a cross-sectional view of a stent 200 including a generally tubular member 202. Generally tubular member 202 has an exterior surface 204, an interior surface 206, and a lumen 208, and is formed of a metal matrix 210 that is formed of one or more bioerodible metals and/or bioerodible metal alloys. Metal matrix 210 includes pores 212 that are filled with a bioerodible polymer 214. Examples of bioerodible polymers include polyiminocarbonates, polycarbonates, polyarylates, polylactides, and polyglycolic esters. A stent including a metal matrix and a bioerodible polymer disposed within the pores of the metal matrix can be made, for example, by forming a generally tubular member out of a metal matrix (e.g., as described above), immersing the generally tubular member in a solution of the polymer, and allowing the solution to dry, so that the solvent in the solution evaporates, and the polymer is left behind on the stent.

In some embodiments, a stent can include both a bioerodible metal matrix and one or more materials that carry a therapeutic agent. For example, a stent can include a generally tubular member that is formed of a porous bioerodible metal matrix, and a polymer containing a therapeutic agent can be disposed within the pores of the metal matrix. The polymer can be non-bioerodible, or can be bioerodible. In some embodiments in which the polymer is bioerodible, the polymer can erode at a different rate from the metal matrix. As an example, in some embodiments, the polymer can erode at a faster rate than the metal matrix, causing all of the therapeutic agent to be released into the body before the generally tubular member has completely eroded. As another example, in certain embodiments, the polymer can erode at a slower rate than the metal matrix. The result can be that after the matrix has completely eroded, at least some of the therapeutic-agent containing polymer can remain in the body (e.g., in the form of polymeric particles). In some embodiments in which the stent has been delivered into a lumen of a subject, the polymer can be at least partially embedded in a wall of the lumen. As the polymer continues to erode, it can release the therapeutic agent into the body. Thus, the body can continue to be treated with the therapeutic agent, even after the generally tubular member has eroded. The therapeutic agent can be selected, for example, to alleviate the effects, if any, of the erosion of the stent on the body. By including a material (such as a polymer) containing a therapeutic agent, the stent can have a therapeutic agent elution rate that is independent of the erosion rate of its generally tubular member.

In certain embodiments, a stent can include one or more coatings on one or more surfaces of the stent. For example, FIGS. 4A and 4B show a stent 300 including a generally tubular member 302 defining a lumen 304. Generally tubular member 302 is formed of a metal matrix 306 that is formed of one or more bioerodible metals and/or bioerodible metal alloys, and that includes pores 308. Stent 300 further includes a coating 310 disposed on the exterior surface 312 of generally tubular member 302. Coating 310 can be used, for example, to regulate therapeutic agent release from generally tubular member 302. For example, pores 308 can contain one or more therapeutic agents, and coating 310 (e.g., which can be bioerodible) can be used to control the release of the therapeutic agent(s) from pores 308 (e.g., by delaying the release of the therapeutic agent(s) until stent 300 has reached a target site).

In certain embodiments, a stent can include a coating that contains a therapeutic agent or that is formed of a therapeutic agent. For example, a stent can include a coating that is formed of a polymer and a therapeutic agent. The coating can be applied to a generally tubular member of the stent by, for example, dip-coating the generally tubular member in a solution including the polymer and the therapeutic agent. Methods that can be used to apply a coating to a generally tubular member of a stent are described, for example, in U.S. Provisional Patent Application Ser. No. 60/844,967, filed concurrently herewith and entitled “Medical Devices”.

While a stent with one coating has been shown, in some embodiments, a stent can include more than one (e.g., two, three, four, five) coating. For example, FIG. 5 shows a cross-sectional view of a stent 350 having a lumen 352. Stent 350 includes a generally tubular member 353 formed of metal matrix 354 that is formed of one or more bioerodible metals and/or bioerodible metal alloys, and that includes pores 355. Stent 350 also includes a coating 356 on the exterior surface 358 of generally tubular member 353, and a coating 360 on the interior surface 362 of generally tubular member 353. Coatings 356 and 360 can include one or more of the same materials, or can be formed of different materials.

Examples of coating materials that can be used on a stent include metals (e.g., tantalum, gold, platinum), metal oxides (e.g., iridium oxide, titanium oxide, tin oxide), and/or polymers (e.g., SIBS, PBMA). Coatings can be applied to a stent using, for example, dip-coating and/or spraying processes.

While stents including generally tubular members formed of a porous metal matrix have been described, in certain embodiments, a stent can alternatively or additionally include a coating that is formed of a porous metal matrix. For example, FIGS. 6A and 6B show a stent 400 having a lumen 402. Stent 400 includes a generally tubular member 404 that is not formed of a porous metal matrix. Generally tubular member 404 can be formed of, for example, one or more metals (e.g., gold, platinum, niobium, tantalum), metal alloys, and/or polymers (e.g., SIBS, PBMA). Examples of metal alloys include cobalt-chromium alloys (e.g., L605), Elgiloy® (a cobalt-chromium-nickel-molybdenum-iron alloy), and niobium-1 Zr alloy. Stent 400 further includes a coating 406 that is disposed on the exterior surface 408 of generally tubular member 404. Coating 406 is formed of a metal matrix 410 that is formed of one or more bioerodible metals and/or bioerodible metal alloys, and that includes pores 412. Metal matrix 410 can be used, for example, as a reservoir for one or more therapeutic agents. For example, one or more therapeutic agents can be disposed within pores 412 of metal matrix 410. During and/or after delivery of stent 400 to a target site in a body of a subject, metal matrix 410 can erode, thereby eluting therapeutic agent into the body of the subject.

A coating such as coating 406 can be formed using, for example, one or more sintering and/or vapor deposition processes.

While coating 406 is shown as having a relatively uniform pore density and as including pores having a relatively uniform average maximum dimension, in some embodiments, a porous coating on a stent can have a non-uniform pore density and/or can include pores having a non-uniform average maximum dimension. For example, FIG. 7 shows a cross-sectional view of a stent 450 including a generally tubular member 452 that is not formed of a porous metal matrix. Generally tubular member 452 can be formed of, for example, one or more metals (e.g., gold, platinum, niobium, tantalum), metal alloys, and/or polymers (e.g., SIBS, PBMA). Examples of metal alloys include cobalt-chromium alloys (e.g., L605), Elgiloy® (a cobalt-chromium-nickel-molybdenum-iron alloy), and niobium-1 Zr alloy. Stent 400 further includes a coating 456 that is disposed on the exterior surface 458 of generally tubular member 452. Coating 456 is formed of a metal matrix 460 that is formed of one or more bioerodible metals and/or bioerodible metal alloys, and that includes pores 462. Metal matrix 460 can be used, for example, as a reservoir for one or more therapeutic agents. As shown in FIG. 7, coating 456 has an interior surface 464 and an exterior surface 466. The pore density of metal matrix 460 is higher, and the average maximum dimension of pores 462 in metal matrix 460 is greater, in the regions of generally tubular member 452 that are closer to exterior surface 466 than in the regions of generally tubular member 42 that are closer to interior surface 464.

While stents having certain configurations have been described, in some embodiments, a stent including one or more bioerodible metals and/or bioerodible metal alloys can have a different configuration. For example, FIG. 8A shows a stent 520 that is in the form of a generally tubular member 521 formed of one or more bioerodible metals and/or bioerodible metal alloys. Generally tubular member 521 is defined by a plurality of bands 522 and a plurality of connectors 524 that extend between and connect adjacent bands. Generally tubular member 521 has a lumen 523.

FIG. 8B shows an enlarged view of a connector 524 of stent 520, and FIG. 8C shows a cross-sectional view of the connector of FIG. 8B. As shown in FIG. 8C, connector 524 is formed of a metal matrix 530 including pores 534. Metal matrix 530 is formed of one or more bioerodible metals and/or bioerodible metal alloys. A line L3 divides connector 524 into regions R5 and R6. As shown in FIG. 8C, region R5 has a higher pore density than region R6, and the pores in region R5 have a higher average maximum dimension than the pores in region R6.

During delivery and/or use of stent 520, bands 522 and/or connectors 524 can erode. The presence of pores 534 in connectors 524 can help to accelerate and/or control the erosion of connectors 524. In some embodiments, the presence of pores 534 in connectors 524 can result in connectors 524 eroding at a faster rate than bands 522. In certain embodiments, it may be desirable for connectors 524 to completely erode before bands 522, allowing stent 520 to move and flex within a target site (e.g., within a lumen in a body of a subject). By the time connectors 524 have completely eroded, tissue may have grown over the remaining parts of stent 520 (e.g., bands 522), thereby helping to hold bands 522 (and, therefore, stent 520) in place.

While a stent including connectors having regions with different pore densities and with pores having different average maximum dimensions has been described, in some embodiments, a stent can include one or more components having regions with relatively uniform pore densities and/or with pores having relatively uniform average maximum dimensions. For example, FIG. 9 shows a cross-sectional view of a connector 550 of a stent. As shown in FIG. 9, connector 550 is formed of a metal matrix 554 including pores 558. Metal matrix 554 is formed of one or more bioerodible metals and/or bioerodible metal alloys. A line L4 divides connector 550 into regions R7 and R8. As shown in FIG. 9, regions R7 and R8 have the same pore density and the pores in regions R7 and R8 have the same average maximum dimension.

While stents including connectors including pores have been described, in some embodiments, a stent can alternatively or additionally include one or more other components (e.g., bands) having pores.

While certain embodiments have been described, other embodiments are possible.

As an example, in some embodiments, a stent including a generally tubular member formed of a bioerodible metal can be manufactured using powder metallurgy methods. For example, a stent can be formed by sintering and compacting bioerodible metal particles and/or metal alloy particles into the shape of a generally tubular member. A metal particle or metal alloy particle can have a dimension (e.g., a width, a length, a diameter) of, for example, at least about 0.1 micron (e.g., at least about 0.5 micron, at least about one micron, at least about five microns) and/or at most about 10 microns (e.g., at most about five microns, at most about one micron, at most about 0.5 micron). Sintering the metal particles and/or the metal alloy particles can include exposing the metal particles and/or the metal alloy particles to heat and pressure to cause some coalescence of the particles. A generally tubular member that is formed by a sintering process can be porous or non-porous, or can include both porous regions and non-porous regions. In some embodiments in which the generally tubular member includes pores, the sizes of the pores can be controlled by the length of the sintering and compacting period, and/or by the temperature and/or pressure of the sintering process. Typically, as the temperature and/or pressure of a sintering process increases, the pore density of the resulting generally tubular member, and the average maximum dimension of the pores in the generally tubular member, can decrease. In certain embodiments, a generally tubular member can be formed by sintering metal particles and/or metal alloy particles having different sizes.

In certain embodiments in which a generally tubular member includes different regions having different pore densities and/or having pores with different average maximum dimensions, the generally tubular member can be formed using a sintering process employing thermal gradients. The sintering process can include exposing certain regions of the generally tubular member, as it is being formed, to higher temperatures than other regions of the generally tubular member. The regions that are exposed to higher temperatures ultimately can have relatively low pore densities and/or pores with relatively small average maximum dimensions, while the regions that are exposed to lower temperatures can have relatively high pore densities and/or pores with relatively large average maximum dimensions. Without wishing to be bound by theory, it is believed that this variation in pore density and in the average maximum dimension of the pores can occur because as the temperature of the sintering process decreases, the extent by which the metal particles and/or the metal alloy particles come together can decrease as well. In some embodiments, a sintering process that is used to form a stent can include forming a generally tubular member around a mandrel that is selectively heated so that certain regions of the mandrel are hotter than other regions of the mandrel. The result can be that the generally tubular member has different regions having different average pore volumes and/or having pores with different average maximum dimensions.

In some embodiments, a stent that is formed by sintering metal particles and/or metal alloy particles can erode after being used at a target site in a body of a subject, and the erosion of the stent can result in the formation of metal particles and/or metal alloy particles having the same size as the particles that were originally sintered together to form the stent. Thus, the size of the particles formed from the erosion of a stent can be selected, for example, by sintering metal particles and/or metal alloy particles of the desired size to form the stent.

As another example, while stents with certain porosity patterns have been described, in some embodiments, a stent can have a different porosity pattern. For example, FIGS. 10A and 10B show a stent 570 including a generally tubular member 574 having an interior surface 578, an exterior surface 582, and a lumen 586. Generally tubular member 574 is formed of a metal matrix 590 that is formed of one or more bioerodible metals and/or bioerodible metal alloys, and that includes pores 594. As shown in FIG. 10B, the pores in generally tubular member 574 that are relatively far from both interior surface 578 and exterior surface 582 are relatively large, while the pores that are relatively close to interior surface 578 or exterior surface 582 are relatively small. Stent 570 can be used, for example, to store a relatively large volume of therapeutic agent in the relatively large pores, and to provide a slow and/or controlled release of the therapeutic agent into the target site through the relatively small pores.

As an additional example, in some embodiments, a stent can include a porous generally tubular member that includes more than one therapeutic agent in its pores. For example, FIGS. 11A and 11B show a stent 600 including a generally tubular member 604 having an interior surface 605, an exterior surface 606, and a lumen 607. Generally tubular member 604 is formed of a metal matrix 608 that is formed of one or more bioerodible metals and/or bioerodible metal alloys. Metal matrix 608 includes pores 610. As shown in FIG. 11B, pores 610 are aligned in an inner circle 614 close to interior surface 605, and in an outer circle 618 close to exterior surface 606. In some embodiments, the pores that form inner circle 614 can be filled with one type of therapeutic agent (e.g., an anticoagulant, such as heparin), while the pores that form outer circle 618 can be filled with a different type of therapeutic agent (e.g., an anti-proliferative, such as paclitaxel).

As a further example, in some embodiments, a stent can include a porous bioerodible metal matrix surrounding a therapeutic agent-containing layer. For example, FIGS. 12A and 12B show a stent 650 including a generally tubular member 652 formed of three layers 654, 656, and 658. Layer 654 is formed of a metal matrix 660 that is formed of one or more bioerodible metals and/or bioerodible metal alloys, and that includes pores 662. Similarly, layer 658 is formed of a metal matrix 664 that is formed of one or more bioerodible metals and/or bioerodible metal alloys, and that includes pores 668. Layer 656, which is located between layer 654 and layer 658, includes one or more therapeutic agents. For example, layer 656 can be formed entirely of one or more therapeutic agents, or can be formed of one or more materials (e.g., a bioerodible polymer) that are combined with one or more therapeutic agents. Layers 654 and 658 can regulate the release of the therapeutic agent(s) from layer 656 into a target site.

As another example, in certain embodiments, a stent can include one or more components (e.g., bands and/or connectors) including a hollow reservoir that can be filled with, for example, one or more therapeutic agents. For example, FIG. 13A shows a stent 720 that is in the form of a generally tubular member 721 formed of one or more bioerodible metals and/or bioerodible metal alloys. Generally tubular member 721 is defined by a plurality of bands 722 and a plurality of connectors 724 that extend between and connect adjacent bands. Generally tubular member 721 has a lumen 723.

FIG. 13B shows an enlarged view of a connector 724 of stent 720, and FIG. 13C shows a cross-sectional view of the connector of FIG. 13B. As shown in FIG. 13C, connector 724 is formed of a metal matrix 730 surrounding a reservoir 732 and including pores 734. Metal matrix 730 is formed of one or more bioerodible metals and/or bioerodible metal alloys. Reservoir 732 is filled with a therapeutic agent 750 that can, for example, elute through pores 734 during and/or after delivery of stent 720 to a target site.

As an additional example, in some embodiments, a stent can include a generally tubular member having different regions along its length that have different pore densities and/or that include pores having different average maximum dimensions.

For example, FIGS. 14A and 14B show a stent 800 including a generally tubular member 802 having a lumen 804. Generally tubular member 802 is formed of a metal matrix 806 including pores 808. Metal matrix 806 is formed of one or more bioerodible metals and/or bioerodible metal alloys. As shown in FIG. 14B, different regions R9, R10, and R11 of generally tubular member 802 along the length L5 of generally tubular member 802 have different pore densities and include pores having different average maximum dimensions. More specifically, region R9 has a higher pore density than region R10, and includes pores with a higher average maximum dimension than the pores in region R10. Region R10, in turn, has a higher pore density than region R11, and includes pores with a higher average maximum dimension than the pores in region R11. These differences in the pore densities and average maximum dimensions of the pores in regions R9, R10, and R11 can, for example, result in region R9 eroding at a faster rate than both regions R10 and R11, and region R10 eroding at a faster rate than region R11.

FIGS. 15A and 15B show a stent including a generally tubular member having different regions along its length that include pores having different average maximum dimensions. As shown in FIGS. 15A and 15B, a stent 850 includes a generally tubular member 852 having a lumen 854. Generally tubular member 852 is formed of a metal matrix 856 including pores 858. Metal matrix 856 is formed of one or more bioerodible metals and/or bioerodible metal alloys. As shown in FIG. 15B, different regions R12, R13, and R14 of generally tubular member 852 along the length L6 of generally tubular member 852 include pores having different average maximum dimensions. More specifically, the pores in end regions R12 and R14 have higher average maximum dimensions than the pores in middle region R13. In some embodiments, one or more of the pores in generally tubular member 852 can contain one or more therapeutic agents that can treat thrombosis. The relatively large pores in end regions R12 and R14 can contain a higher volume of the therapeutic agent(s) than the relatively small pores in middle region R13.

As another example, in some embodiments, a stent including a metal matrix including pores can be a self-expanding stent. For example, in certain embodiments, a self-expanding stent can include a generally tubular member that is formed of Nitinol, and can further include a porous bioerodible metal supported by the generally tubular member (e.g., the porous bioerodible metal can be in the form of a coating on the generally tubular member).

As a further example, while stents have been described, in some embodiments, other medical devices can include pores, bioerodible metals, and/or bioerodible metal alloys. For example, other types of endoprostheses, such as grafts and/or stent-grafts, can include one or more of the features of the stents described above. Additional examples of medical devices that can have one or more of these features include bone screws.

As another example, in some embodiments, a medical device can include regions that are formed of a porous metal and/or a porous metal alloy (e.g., a bioerodible porous metal and/or a bioerodible porous metal alloy), and regions that are not formed of a porous metal or metal alloy. For example, a stent may include regions that are formed of a bioerodible porous metal, and regions that are formed of a metal that is neither bioerodible nor porous.

As an additional example, in certain embodiments, a medical device (e.g., a stent) including a coating formed of a porous metal and/or a porous metal alloy can be further coated with one or more other coatings. The other coatings can be formed of porous metals and/or porous metal alloys, or may not be formed of porous metals or porous metal alloys.

As a further example, in some embodiments, a coating can be applied to certain regions of a medical device, while not being applied to other regions of the medical device.

As another example, in certain embodiments, a medical device (e.g., a stent) can include one or more metal foams, such as one or more bioerodible metal foams. Medical devices including metal foams are described, for example, in U.S. Provisional Patent Application Ser. No. 60/844,967, which is incorporated by reference, filed Sep. 15, 2006 and entitled “Medical Devices”.

All publications, applications, references, and patents referred to in this application are herein incorporated by reference in their entirety.

Other embodiments are within the claims.