# Patent

## Title
Bioerodible composites for endoprostheses

## Abstract

A bioerodible endoprosthesis includes a composite including a matrix comprising a bioerodible magnesium alloy and a plurality of ceramic nanoparticles within the matrix. The bioerodible magnesium alloy has a microstructure including equiaxed Mg-rich solid solution-phase grains having an average grain diameter of less than or equal to 5 microns. The microstructure can be produced by one or more equal-channel high-strain processes.

## Background
TECHNICAL FIELD
This disclosure relates to bioerodible composites used in endoprostheses and methods of producing those composites.
BACKGROUND
Endoprostheses can be used to replace a missing biological structure, support a damaged biological structure, and/or enhance an existing biological structure. Frequently, only a temporary presence of the endoprosthesis in the body is necessary to fulfill the medical purpose. Surgical intervention to remove endoprostheses, however, can cause complications and may not even be possible. One approach for avoiding a permanent presence of all or part of an endoprosthesis is to form all or part of the endoprosthesis out of bioerodible material. The term “bioerodible” as used herein is understood as the sum of microbial procedures or processes solely caused by the presence of endoprosthesis within a body, which results in a gradual erosion of the structure formed of the bioerodible material.
At a specific time, the endoprosthesis, or at least the part of the endoprosthesis that includes the bioerodible material, loses its mechanical integrity. The erosion products are mainly absorbed by the body, although small residues can remain under certain conditions. A variety of different bioerodible polymers (both natural and synthetic) and bioerodible metals (particularly magnesium and iron) have been developed and are under consideration as candidate materials for particular types of endoprostheses. Many of these bioerodible materials, however, have significant drawbacks. These drawbacks include the erosion products, both in type and in rate of release, as well as the mechanical properties of the material.
SUMMARY
A bioerodible endoprosthesis provided herein includes a composite including a matrix comprising a bioerodible magnesium alloy and ceramic nanoparticles dispersed within the matrix. The bioerodible magnesium alloy can have a microstructure defined by equiaxed Mg-rich solid solution-phase grains (i.e., alpha-phase grains) having an average grain diameter of less than or equal to 5 microns. In some cases, the ceramic nanoparticles can be located in grain boundaries between the equiaxed Mg-rich solid solution-phase grains. In some cases, the ceramic nanoparticles can have an average longest dimension of 500 nanometers or less. Bioerodible magnesium alloys having the microstructures provided herein can have improved mechanical properties suitable for endoprostheses, such as stents.
A method of processing a bioerodible magnesium alloy for endoprostheses provided herein can include the steps of dispersing ceramic nanoparticles within a molten magnesium alloy, cooling the magnesium alloy and ceramic nanoparticle mixture to form an ingot or billet, and performing at least one high-strain process on the ingot or billet to form the composite microstructure provided herein. In some cases, the processing can include holding the ingot or billet at a temperature above the solvus temperature (e.g., between 400° C. and 450° C.) for at least 2 hours to homogenize the ingot or billet prior to performing the at least one high-strain process. The at least one high-strain process can be an equal-channel high-strain process and can be conducted at a temperature of less than the solvus temperature (e.g., a temperature below 400° C.). In some cases, multiple equal-channel high-strain processes are conducted using subsequently lower temperatures. Any suitable bioerodible magnesium alloy formulation capable of having magnesium-rich solid solution grains can be used in the bioerodible endoprostheses provided herein. In some cases, the bioerodible magnesium alloy can include aluminum, zinc, calcium, manganese, tin, neodymium, yttrium, cerium, lanthanum, gadolinium, or a combination thereof. For example, the bioerodible magnesium alloy can include greater than 85 weight percent magnesium, between 3 and 9 weight percent aluminum, between 0.1 and 3.0 weight percent zinc, less than or equal to 0.3 weight percent manganese, and between 0.6 and 1.5 weight percent neodymium.
Ceramic nanoparticles included in the endoprostheses and methods provided herein can include any suitable ceramic material. In some cases, the ceramic nanoparticles can be insoluble in the bioerodible magnesium alloy. In some cases, ceramic nanoparticles can include one or more of the following ceramic materials: TiC, TiO2 Si3N4, AlN, Al2O3, CeO2, Boron Nitride, B4C, and Y2O3.
Endorprostheses provided herein can have any suitable structure. In some cases, an endoprostheis provided herein is a stent. For example, a stent provided herein can include plurality of struts arranged to form a generally tubular structure that can be expanded or retracted between a plurality of different diameters. In some cases, an endoprosthesis provided herein can consist of a composite material provided herein. In some cases, an endorposthesis provided herein can include one or more additional materials. For example, in some cases an endoprosthesis provided herein can include a coating. In some cases, a coating provided on an endoprosthesis provided herein has a thickness of between 5 nm and 20 nm. In some cases, a coating provided on an endoprosthesis provided herein includes titanium oxide, aluminum oxide, or a combination thereof. In some cases, a coating provided on an endoprosthesis provided herein includes a therapeutic agent.
One advantage of an endoprosthesis including a composite provided herein is that the resulting endoprosthesis' mechanical properties and degradation rate can be tailored to maintain desired mechanical properties over a desired period of time and an optimal bioerosion rate. A bioerodible magnesium alloy having a microstructure provided herein can have improved ductility as compared to similar alloys having different microstructures. In some cases, ceramic nanoparticles provided in the composite provided herein can simplify a grain refinement procedure by pinching grain boundaries and inhibiting grain growth during one or more high-strain processes.
The details of one or more embodiments are set forth in the accompanying drawings and the description below. Other features, objects, and advantages will be apparent from the description and drawings, and from the claims.



DESCRIPTION OF DRAWINGS
FIG. 1 is a perspective view of a representative stent.
FIG. 2 depicts an exemplary arrangement for fabricating a magnesium-alloy ceramic-nanoparticle composite.
FIG. 3 depicts an exemplary Equal-Channel Angular Extrusion die.



DETAILED DESCRIPTION
A stent 20, shown in FIG. 1, is an example of an endoprosthesis. Stent 20 includes a pattern of interconnected struts forming a structure that contacts a body lumen wall to maintain the patency of the body lumen. For example, stent 20 can have the form of a tubular member defined by a plurality of bands 22 and a plurality of connectors 24 that extend between and connect adjacent bands. During use, bands 22 can be expanded from an initial, small diameter to a larger diameter to contact stent 20 against a wall of a vessel, thereby maintaining the patency of the vessel. Connectors 24 can provide stent 20 with flexibility and conformability that allow the stent to adapt to the contours of the vessel. Other examples of endoprostheses include covered stents and stent-grafts.
At least one strut of stent 20 can be adapted to erode under physiological conditions. In some cases, stent 20 is fully bioerodible. Stent 20 can include a composite of a matrix including a bioerodible magnesium alloy and ceramic nanoparticles within the matrix. A bioerodible magnesium alloy used in a composite provided herein can include additional elements, such as aluminum, zinc, and neodymium. A bioerodible magnesium alloy used in a composite provided herein can have a microstructure defined by relatively equiaxed magnesium-rich solid solution-phase grains having an average grain diameter of less than or equal to 5 microns (longest dimension in a metallography cross-section plane).
Ceramic nanoparticles used in a composite provided herein can have an average diameter of less than 500 nanometers. In some cases, ceramic nanoparticles used in a composite provided herein can have an average diameter of between 0.5 nanometers and 500 nanometers, between 1 nanometer and 200 nanometers, between 5 nanometers and 100 nanometers, or between 10 nanometers and 75 nanometers. In some cases, the ceramic nanoparticles in a composite provided herein can be predominantly located in grain boundaries rather than within grains (e.g., >50% of the combined area of ceramic nanoparticles are on grain boundaries in a given prepared metallography cross-section plane examined at 100-300× magnification). Composites having the microstructures provided herein can have improved mechanical properties suitable for endoprostheses, such as stents.
Although magnesium and magnesium alloys have been explored as candidate materials for bioerodible endoprostheses in the past, the mechanical properties of magnesium and magnesium alloys have presented certain difficulties that make the use of a bioerodible magnesium metal or alloy in certain endoprostheses, such as stents, impractical. In particular, magnesium alloys can have a limited ductility due to a lack of available slip planes in the Hexagonal Close Packed (HCP) crystal lattice. Slip planes can accommodate plastic deformation. Limited ductility can complicate certain uses that rely upon plastic deformation. For example, limited ductility can make stent crimping and stent expansion more complex due to an increased probability of stent fractures during these plastic deformations. Moreover, magnesium alloys typically have a lower tensile strength than iron alloys (such as stainless steel alloys). Composites provided herein, however, can have improved ductility and tensile strength.
Certain magnesium alloys were tested in order to identify magnesium alloys having suitable bioerosion rates and ductility. For example, L1c and WE43 (described in Table I below) were prototyped and tested as stents, but found to have a bioerosion rate that was too fast when subjected to in-vivo and in-vitro testing. It is possible, however, that a L1c and/or WE43 alloy having a microstructure provided herein would have a suitable bioerodison rate for an endoprosthesis.
















TABLE I





Alloy







Other



Ex.
Zn
Zr
Mn
Y
Ca
Ag
Fe
Elements
Mg
























L1c
2.87
≦0.02
0.15
—
0.22
0.10
0.0036
—
Balance


WE43
0.20
0.36
0.13
4.16
—
—
—
3.80
91.35









Certain modifications of the AZ80 alloy (see Table II below) have also been developed in an attempt to find a magnesium alloy having superior corrosion resistance to that of L1c, but also having sufficient ductility. Although initial mechanical testing of these AZ80 modified alloys showed an improvement in the mechanical and corrosion properties as compared to L1c, AZ80 modified alloy stents cracked and fractured at a nominal expanded diameter.
















TABLE II







Alloy










Example
Al
Zn
Mn
Y
Nd
La
Mg









AZ80
7.5
0.5
0.2
—
—
—
Balance



AZNd
7.3
0.6
0.1
—
0.7
—
Balance



AZY
7.4
0.6
0.1
0.5
—
—
Balance



AZNdY
7.0
0.6
0.2
0.5
0.6
—
Balance



AZM
7.3
0.6
0.4
—
—
—
Balance



AZL
7.0
0.5
0.2
—
—
1.2
Balance



AE82
8.0
0.5
0.2
0.5
1.0
—
Balance










An analysis of the stents identified the presence of large extrinsic intermetallic particles, e.g., oxide inclusions and coarse Mg solid solution grain sizes, which are deleterious to ductility. Low material ductility can result in stent cracking, especially in balloon-expandable stents that are crimped onto a balloon catheter, guided through a long tortuous path, and expanded to fill the diameter of the artery.
Composite microstructures and processes provided herein can eliminate this root cause of low material ductility and stent cracking by having lower extrinsic inclusion content (or at least much smaller inclusions) and stent material with refined Mg solid solution grain size to randomize grain texture, produce additional slip systems through grain size refinement, and raise the activation energy needed to initiate a crack due to the presence of a tortuous grain boundary network. Composite microstructures and processes provided herein can be tailored to manifest sufficient ductility in a balloon-expandable stent design such that the Mg alloy stent would allow the stent to be crimped onto a balloon catheter, wiggled through a long tortuous path, and expanded to fill the diameter of the artery without fracturing.
The microstructure of material can be at least partially dependent on the processing techniques and parameters. The grains (i.e., crystals) of a magnesium alloy can align themselves with their basal planes parallel to the direction of the processing material flow, which can result in different mechanical properties in the direction of flow as compared to the a direction perpendicular to the direction of flow. In the case of extruding stent tubing including the alloys of Table II, the resulting tube may have a strong preferred crystal orientation, aligning the basal planes in the extrusion direction, which produces increased ductility in the extrusion direction of the tubing, but less ductility in a direction perpendicular to the extrusion direction. The expansion of a stent, however, relies upon the material having suitable ductility in all directions. A strong grain texture with an unfavorable loading along the c-crystal axis components of the grains causes twinning and void nucleation under lower strains. The twinning with void nucleation can be the initiation of an eventual material failure. Stent tube extrusion may also produce a randomized crystal structure with no preferred orientation, which produces more isotropic mechanical properties, but still suffers from the ductility issues discussed above.
Composites provided herein can provide superior ductility and other mechanical properties in multiple directions. Ceramic nanoparticles can be dispersed within a matrix of a bioerodible magnesium alloy. Ceramic nanoparticles can pinch grain boundaries and/or impede grain growth during processing of the material, which can result in a fine grain microstructure of the magnesium alloy. The fine grain microstructure of the magnesium alloy can increase strength and ductility of the composite. In some cases, the grain boundaries can be decorated with ceramic nanoparticles. In some cases, the magnesium alloy can further include beta-phase precipitates, which can also decorate grain boundaries. The microstructures provided herein can be characterized in a number of ways. In some cases, the microstructures provided herein, when viewed at a 500× using x-ray diffraction, have no more than 5% by area filled with ceramic particles. In some case, the microstructures provided herein have no more than 3% by area filled with ceramic particles. In some case, the microstructures provided herein have no more than 2% by area filled with ceramic particles. In some case, the microstructures provided herein have at least 0.5% by area filled with ceramic particles. In some case, the microstructures provided herein have at least 1.0% by area filled with ceramic particles. In some case, the microstructures provided herein have between 0.5% and 5% by area filled with ceramic particles. In some case, the microstructures provided herein have between 1.0% and 3% by area filled with ceramic particles. In some case, the microstructures provided herein have about 1.5% by area filled with ceramic particles.
Ceramic nanoparticles provided in a composite provided herein can have any appropriate dimensions. In some cases, ceramic nanoparticles used in a composite provided herein have an average largest diameter of between 0.5 nanometers and 500 nanometers, between 1.0 nanometer and 200 nanometers, between 5 nanometers and 100 nanometers, between 10 nanometers and 100 nanometers, between 25 nanometers and 75 nanometers, or between 40 nanometers and 60 nanometers. In some cases, a maximum ceramic nanoparticle dimension will be 5 micron or less. In some cases, a maximum ceramic nanoparticle dimension will be 1 micron or less, 500 nanometers or less, 5 microns or less, or 200 nanometers or less.
Ceramic nanoparticles provided in a composite provided herein can include any suitable ceramic material. In some cases ceramic nanoparticles provided herein are insoluble in a magnesium alloy used in a composite provided herein. In some cases, ceramic nanoparticles can include one or more of the following ceramic materials: TiC, TiO2 Si3N4, AlN, Al2O3, CeO2, Boron Nitride, B4C, and Y2O3. In some cases, ceramic nanoparticles used in a composite provided herein include a radiopaque ceramic material. In some cases, ceramic nanoparticles used in a composite provided herein can have an electro-motive force within 50% of the electro-motive force of magnesium. In some cases, ceramic nanoparticles used in a composite provided herein can have an electro-motive force within 25% of the electro-motive force of magnesium. In some cases, ceramic nanoparticles used in a composite provided herein can have an electro-motive force within 10% of the electro-motive force of magnesium. In some cases, ceramic nanoparticles used in a composite provided herein can have an electro-motive force within 5% of the electro-motive force of magnesium. Suitable ceramic nanoparticles are available from SkySpring Nanomaterials, Houston Tex.
The microstructures provided herein can include equiaxed Mg-rich solid solution-phase grains with ceramic nanoparticles located within smooth and equiaxed alpha-phase-grain boundaries. In some cases, the equiaxed equiaxed Mg-rich solid solution-phase grains have an average grain size of 20 microns or less, 15 microns or less, 10 microns or less, 7.5 microns or less, 5 microns or less, 4 microns or less, 3 microns or less, 2 microns or less, or 1 microns or less. In some cases, the equiaxed Mg-rich solid solution-phase grains have an average grain size of between 0.1 microns and 10 microns, of between 0.5 microns and 5 microns, or between 1 micron and 4 microns. In some cases, at least 90% by volume of the ceramic nanoparticles can be found along alpha phase grain boundaries. In some cases, the average ceramic nanoparticle diameter or longest dimension is 1 microns or less, 500 nanometers or less, 300 nanometers or less, 200 nanometers or less, 100 nanometers or less, 75 nanometers or less, 50 nanometers or less, or 25 nanometers or less. In some cases, the average ceramic nanoparticle diameter or longest dimension is between 0.1 nanometers and 1 micron, between 0.5 nanometer and 500 nanometers, between 5 nanometers and 300 nanometers, between 10 nanometers and 200 nanometers, between 20 nanometers and 100 nanometers, between 25 nanometers and 75 nanometers, or between 40 nanometers and 60 nanometers. The microstructure provided herein can have a reduced number of twin bands. In some cases, less than 15% of the alpha grains will have twin bands. In some cases, the number of alpha grains having twin bands can be less than 10%, less than 5%, or less than 1% when the stent is cut and crimped.
Composites having microstructures provided herein can have enhanced ductility. The microstructures provided herein can overcome the basal plane alignment by randomizing grain orientations and result in isotropic mechanical properties. Finer grains also yield increased grain boundary areas, which can provide more grain boundary slip. Refinement of precipitate diameter may also allow additional grain boundary slip. Moreover, a homogenous dispersion of ceramic nanoparticles along the grain boundaries can improve strength and corrosion resistance. In some cases, the ceramic nanoparticles can be substantially centered on the grain boundary but be larger than the width of the grain boundary.
For example, a tubular body (e.g., stent tubing material) made from a composite of an AZNd alloy and 1.5 percent by volume of ceramic nanoparticles (e.g., SiC nanoparticles) can be made by a process as described below. The AZNd alloy can include between 3 weight percent and 9 weight percent aluminum, between 0.1 weight percent and 1.0 weight percent zinc, and between 0.1 weight percent and 1.5 weight percent neodymium. The composite can have an elastic modulus of between 39 and 200 GPa, a 0.2% Offset Yield Strength of between 150 and 600 MPa, an ultimate tensile strength of between 225 and 600 MPa, a tensile reduction in area (RIA) of between 30% and 80%. In some cases, stent tubing material provided herein can have a tensile RIA of between 45% and 80%. In some cases, stent tubing material provided herein can maintain its initial elastic modulus, Yield Strength, ultimate tensile strength, and a tensile RIA within +/−10% after storage of the tubing for 180 days at a temperature of between 20° C. and 25° C. and a relative humidity of less than 30%.
Composites having a microstructure provided herein can be polished to have a smooth surface finish. In some cases, an endoprosthesis provided herein can have a surface including a bioerodible magnesium alloy having a surface roughness Ra of less than 0.5 microns, less than 0.4 microns, less than 0.3 microns, less than 0.2 microns, less than 0.1 microns, or less than 0.05 microns. Composites provided herein can have improved corrosion resistance, which can provide a slower bioerosion rate. A stent body including a composite material provided herein can have an in-vitro corrosion penetration rate of less than 200 μm/year after a period of 28 days of continuous immersion in non-flowing, agitated Simulated Body Fluid (agitated at 60 rpm) at 37° C. where the Simulated Body Fluid (“SBF”) is present in an amount of at least 10 times the initial volume of the stent material. The ingredients of SBF, which are added to water, are shown in Table 3.







TABLE 3







SBF Ingredients










Chemical
Mass/Volume















NaCl
5.403
g



NaHCO3
0.504
g



Na2CO3
0.426
g



KCl
0.225
g



K2HPO4•3H2O
0.230
g



MgCl2•6H2O
0.311
g



0.2M NaOH
100
mL



HEPES
17.892
g



CaCl2
0.293
g



Na2SO4
0.072
g










In some cases, the magnesium alloy includes aluminum. Aluminum can form native oxide layers along grain boundaries, which can act as a protective layer for the grains and delay the onset of intergranular corrosion. Smaller grain sizes can also reduce the corrosion rate because corrosion must re-initiate past the protective oxide layer for each grain corroded.
Composites provided herein can be formed by using the following process steps: (a) disperse ceramic nanoparticles in a molten magnesium alloy; (b) cooling the molten magnesium alloy to form a ingot or billet; (c) solution treating a billet to solutionize any intermetallic precipitates formed during solidification of the alloy; (d) controlled cooling after solutionizing to form a distribution of precipitates (if any) along grain boundaries; and (e) thermomechanical deformation of the composite after or during cooling to refine the Mg-rich solid solution grain size and produce a substantially equiaxed grain morphology.
Ceramic nanoparticles can be dispersed within a molten magnesium alloy using any suitable method. FIG. 2 depicts an exemplary arrangement 200 for introducing ceramic nanoparticles 210 into a molten magnesium alloy 220. Magnesium metal and one or more alloying constituents (e.g., aluminum) can be introduced to a steel crucible 202 within a resistance furnace 204. In some case, magnesium is alloyed with alloying elements prior to introduction to steel crucible 202 or resistance furnace 204. In some cases, magnesium is alloyed with alloying elements in steel crucible 202 before, after, or concurrently with an addition of ceramic nanoparticles. A protection gas 206 can be used to prevent unwanted reactions or exposure to oxygen. In some cases, energy can be used to prevent ceramic nanoparticles from agglomerating during the mixing process. For example, an ultrasonic probe 230 can be placed within steel crucible 202 to impart ultrasonic energy to the mixture. The mixture can then be cooled to form a billet or ingot. For example, an ingot or billet can be formed or machined into a solid or hollow rod, homogenized, subjected to a high-strain process to refine the microstructure, and then shaped or machined into stent tubing from which the stent is manufactured into final dimensions (e.g., the dimensions of a stent body). In some cases, a billet or ingot provided herein can be formed into an endoprosthesis that does not normally undergo expansion, for example vascular closing plugs or embolical material (e.g., microbeads used to close off unwanted vascular structures or cancerous tissue).
Billets can be made using any suitable process. A billet can have a diameter of between 2 centimeters and 1 meter. In some cases, an ingot of a desired bioerodible magnesium alloy can be made by conventional melting and solidification in a mold (liquid casting), thixomolding (semi-solid processing) or powder metallurgy (solid-processing). The ingot can then be machined to the desired dimensions of the billet which will serve as the feedstock for subsequent processing and shaping. In some cases, a billet can be formed without additional machining process. To form an endoprosthesis (e.g., a stent body) including a composite provided herein out of a billet, the billet can be converted into a rod or hollow tube having a smaller diameter. In some cases, the ingot or billet is converted into a rod or hollow tube after the ingot or billet is homogenized. In some cases, the rod or hollow tube can have an outer diameter of between 1 centimeter and 6 centimeters. In the case of a stent, a hollow tube of a composite provided herein can then be further reduced in diameter and cut to form individual stent bodies, including fenestrations between stent struts. In some cases, the stent struts can have a width to thickness ratio of less than 1.2. In some cases, the thickness of the hollow tube and the stent struts can be between 80 microns and 160 microns.
An ingot or billet, in some cases, can be made by thixomolding the elements of the bioerodible magnesium alloy and ceramic nanoparticles. Thixomolding involves mixing solid constituents into a portion of the composition that is in a liquid phase and then cooling the mixture to reach a fully solid state. Thixomolding can reduce the number and size of brittle inter-metallic (IM) particles in the alloy. For example, thixomolding can use a machine similar to an injection mold. Room temperature magnesium alloy chips, chips of the other alloy constituents, and ceramic nanoparticles can be fed into a heated barrel through a volumetric feeder. The heated barrel can be filled with an inert gas (e.g., argon) to prevent oxidation of the magnesium chips. A screw feeder located inside the barrel can feed the magnesium chips and other alloy constituents forward as they are heated into a semi-solid temperature range. For example, the mixture can be heated to a temperature of about 442° C. The screw rotation can provide a shearing force that can further reduce the size of IM particles. Once enough slurry has accumulated, the screw can move forward to inject the slurry into a steel die having the shape of an ingot or billet.
An ingot or billet, in some cases, can be made by combining the elements of the bioerodible magnesium alloy using powder metallurgy. Powder metallurgy involves the solid-state sintering of elemental or pre-alloyed powder particles and ceramic nanoparticles. Using fine powders in a sintering process can avoid the formation of coarse IM particles. For example, fine powders of magnesium, other alloying constituents, and ceramic nanoparticles can be blended into a homogenous mixture, pressed into a desired shape (e.g., the shape of the ingot or billet), and heated while compressed to bond the powders together. Sintering can be conducted in an inert atmosphere (e.g., argon) to avoid oxidation of the magnesium.
An ingot or billet including all of the desired elements of a bioerodible magnesium alloy and the ceramic nanoparticles can be homogenized to reduce elemental concentration gradients. The ingot or billet can be homogenized by heating the ingot or billet to an elevated temperature below the liquidus temperature of the bioerodible magnesium alloy and holding the ingot or billet at that temperature for period of time sufficient to allow elemental diffusion within the ingot or billet to reduce elemental concentration gradients within the ingot or billet.
Homogenizing the ingot or billet can solutionize intermetallic (IM) second-phase precipitate particles, because the homogenization temperature is in excess of the phase boundary (solvus temperature) between the high-temperature single, solid phase (alpha) and two-phase field boundary on the Mg—Al phase diagram. A follow-on solutioning treatment at the same or similar position within the phase diagram can be used in some cases to refine the precipitate structure. For example, a follow-on solutioning treatment can be used if the homogenization treatment cooling was not controlled sufficiently to tailor the second-phase precipitate size and location. In some cases, the ingot or billet is cooled rapidly after holding the ingot or billet at the elevated temperature in order to form relatively fine IM ceramic nanoparticles. For example, the ingot or billet can be cooled from the elevated hold temperature via force gas cooling or liquid quenching. The ingot or billet can be homogenized in an inert atmosphere (e.g., in an argon atmosphere) or open atmosphere so long as surface oxides are removed. In some cases, the ingot or billet provided herein can be homogenized at a temperature of between 400° C. and 450° C. In some cases, the ingot or billet is held at a temperature of between 400° C. and 450° C. for at least 2 hours, at least 3 hours, or at least 4 hours. In some cases, the hold time at an elevated temperature is between 4 hours and 24 hours. For example, a bioerodible magnesium alloy ingot having a diameter of about 15 centimeters can be heated to a temperature of 440° C. for 6 hours to homogenize the ingot, followed by quenching the ingot in a cooled argon gas stream.
An ingot or billet can be subjected to one or more high-strain processes to refine the microstructure into a microstructure provided herein. In some cases, the high-strain process(es) can include one or more equal-channel high-strain processes. Equal-channel high-strain processes include Equal-Channel Angular Extrusion (“ECAE”) and Equal-Channel Angular Pressing (“ECAP”). ECAE is an extrusion process that produces significant deformation strain without reducing the cross sectional area of the piece. ECAE can be accomplished by extruding a composite including a magnesium alloy and ceramic nanoparticles (e.g., a billet of the material) around a corner. For example, a billet can be forced through a channel having a 90 degree angle. The cross section of the channel can be equal on entry and exit. The complex deformation of the composite as it flows around the corner can produce very high strains in the bioerodible magnesium alloy. In some cases, an ingot can be machined into a billet having the exact dimensions of the channel of an ECAE die prior to an ECAE process. Because the cross section can remain the same, the billet can be extruded multiple times with each pass introducing additional strain. With each ECAE process, the orientation of the billet can be changed to introduce strain along different planes. In some cases, an ECAE die can include multiple bends. For example, FIG. 3 depict an example of an ECAE die.
The ingot or billet provided herein can be extruded through one or more ECEA dies (e.g., as depicted in FIG. 3) at temperatures lower than a homogenization temperature. Multiple equal-channel high-strain extrusions can be performed at subsequently lower temperatures. The equal-channel high-strain processes can yield a fine grain size. Ceramic nanoparticles in the composite can become primarily located along the grain boundaries. In some cases, the dynamic recrystallization of the grain refinement caused by successive equal-channel high-strain extrusions at declining temperatures can introduce more strain into the material and result in finer grain sizes as compared to cold working and annealing steps. In some cases, an ingot or billet is subjected to at least two ECAE processes at two different sequentially-lower temperatures. In some cases, an ingot or billet is subjected to at least three ECAE processes at different sequentially-lower temperatures.
For example, a billet including a magnesium-aluminum alloy can be processed through two ECAE processes, with the first ECAE process occurring at a higher temperature than the second ECAE process. Each process can occur through a simple ECAE die have a single 90° corner, such as that depicted in FIG. 3. The first ECAE process can be conducted at a temperature of between 250° C. and 400° C. to allow good diffusion of aluminum to the grain boundaries. The first ECAE process can result in a microstructure having an average grain diameter of 15 microns or less. A second ECAE process can be done at a temperature of between 150° C. and 300° C. The second ECAE process can further refine the grain sizes and avoid coarsening.
In the ECAE process shown in FIG. 3, an ingot or prior-worked billet 30a is extruded through a channel 31a including two channel portions 32a, 33a of substantially identical cross-sectional areas having the respective centerlines thereof disposed at an angle 35a. As shown, angle 35a can be about 90°. In some cases, angle 35a can be between 45° and 170°, between 50° and 160°, between 60° and 135°, between 70° and 120°, between 80° and 100°, or between 85° and 95°. Billet 30a can have any appropriate cross section and machined to provide a snug fit into entry channel portion 32a. In some cases, billet 30a can have a circular cross sectional shape. A ram 38a can force billet 30a through channel 31a using an appropriate extrusion ram pressure. The strain imposed on billet 30a is a function of angle 35a. 
Composites provided can, in some cases, be made by sintering powders of metal alloy and ceramic nanoparticles together. In some cases, powder metallurgy techniques can be used to form a composite provided herein.
The billet can be formed into a rod or hollow tube having a reduced outer diameter after one or more high-strain processes. Tube or rod drawing from the billet can occur in multiple steps, with optional intermediate and final annealing steps, to reduce the diameter. The drawing and annealing processes can be controlled to preserve the microstructure formed in the one or more high-strain processes. In some cases, the material is annealed at a temperature of less than 300° C. In some cases, the material is annealed at a temperature of between 150° C. and 300° C., between 150° C. and 250° C., or between 150° C. and 200° C. Annealing steps can be used to allow recovery with limited recrystallization and avoid grain growth or changes in precipitate volume fraction and morphology Annealing steps can also maintain a homogenous dispersion of beta-phase precipitates at the grain boundaries.
Individual stent bodies can then be cut, including cutting fenestrations between stent struts, using any suitable technique. For example, the fenestrations can be cut using a laser.
Composites provided herein can include magnesium alloyed with any suitable combination of additional elements. In some cases, a bioerodible magnesium alloy provided herein can include aluminum. In some cases, a bioerodible magnesium alloy provided herein can include zinc. In some cases, a bioerodible magnesium alloy provided herein can include calcium. In some cases, a bioerodible magnesium alloy provided herein can include tin. In some cases, a bioerodible magnesium alloy provided herein can include manganese. In some cases, a bioerodible magnesium alloy provided herein can include neodymium. In some cases, a bioerodible magnesium alloy provided herein can include at least 85 weight percent magnesium, between 3 and 9 weight percent aluminum, between 0.1 and 3 weight percent zinc, and between 0.05 and 0.3 weight percent manganese, between 0.6 and 1.5 weight percent neodymium, up to 100 ppm copper, and up to 175 ppm iron. For example, a composite can include about 1.5 weigh percent ceramic nanoparticles and a bioerodible magnesium alloy including about 92-93 weight percent magnesium, between 6.0 and 6.5 weight percent aluminum, between 0.4 and 0.5 weight percent zinc, between 0.6 and 0.7 weight percent neodymium, up to 100 ppm copper, and up to 175 ppm iron. Other possible bioerodible magnesium alloys include those listed in Tables I and II above. Examples of other suitable bioerodible magnesium alloys can be found in U.S. Patent Application Publication No. 2012/0059455, which is hereby incorporated by reference in its entirety, particularly the sections describing particular bioerodible magnesium alloys.
A bioerodible magnesium alloy used in a composite provided herein can include a variety of different additional elements. In some cases, the bioerodible magnesium alloy includes less than 5 weight percent, in sum, of elements other than magnesium, aluminum, zinc, and manganese. In some cases, the bioerodible magnesium alloy includes less than 2 weight percent, in sum, of elements other than magnesium, aluminum, zinc, and manganese. The bioerodible magnesium alloy can consist essentially of magnesium, aluminum, zinc, manganese, and neodymium. As used herein, “consisting essentially of” means that the alloy can also include impurities normally associated with the commercially available forms of the constituent elements in amounts corresponding to the amounts found in the commercially available forms of the constituent elements. In some cases, the potential impurity elements of iron, copper, nickel, gold, cadmium, bismuth, sulfur, phosphorous, silicon, calcium, tin, lead and sodium are each maintained at levels of less than 1000 ppm. In still other embodiments, the potential impurity elements of iron, copper, nickel, cobalt, gold, cadmium, bismuth, sulfur, phosphorous, silicon, calcium, tin, lead and sodium are each maintained at levels of less than 200 ppm. Iron, nickel, copper, and cobalt have low solid-solubility limits in magnesium and can serve as active cathodic sites and accelerate the erosion rate of magnesium within a physiological environment. In still other embodiments, each of iron, nickel, copper, and cobalt is maintained at levels of less than 50 ppm. For example, each of the first five alloys listed in Table II has no more than 35 ppm of iron.
Bioerodible magnesium alloys used in a composite provided herein can optionally include one or more rare earth metals. In some cases, the bioerodible magnesium alloy includes between 0.1 and 1.5 weight percent of a first rare earth metal. In some cases, the first rare earth metal is yttrium, neodymium, lanthanum, or cerium. The bioerodible magnesium alloy can also include between 0.1 and 1.5 weight percent of a second rare earth metal. For example, a bioerodible magnesium alloy provided herein can include about 0.5 weight percent yttrium and 0.6 weight percent neodymium. In some cases, the bioerodible magnesium alloy includes three or more rare earth metals. In some cases, the total amount of rare earth metals within the bioerodible magnesium alloy is maintained at a level of less than 10.0 weight percent. In some cases, the total amount of rare earth metals within the bioerodible magnesium alloy is maintained at a level of less than 2.5 weight percent.
A coating can be applied over a composite of an endoprosthesis provided herein. For example, a stent provided herein can include a stent body formed of a composite provided herein and a coating overlying the surface of the stent body. A coating can slow or delay the initial degradation of the composite upon placement within a physiological environment by serving as a temporary barrier between the magnesium alloy and the environment. For example, delaying the bioerosion processes can allow the body passageway to heal and a stent to become endothelialized (surrounded by tissues cells of the lumen wall) before the strength of the stent is reduced to a point where the stent fails under the loads associated with residing within a body lumen (e.g., within a blood vessel). When an endothelialized stent fragments, the segments of the stent can be contained by the lumen wall tissue and are thus less likely to be released into the blood stream. Endothelialization can also block the oxygen-rich turbulent flow of the blood stream from contacting the endoprosthesis, thus further reducing the erosion rate of the endoprosthesis. In some case, a stent provided herein can include a coating that includes titanium oxide, aluminum oxide, or a combination thereof. Examples of suitable coatings can be found in U.S. Patent Application Publication No. 2012/0059455, which is hereby incorporate by reference in its entirety, particularly the sections describing coatings formed by atomic layer deposition.
In some cases, an endoprosthesis provided herein can include a sprayed layer of magnesium fluoride nanoparticles. Magnesium fluoride suspensions can be applied to an endoprosthesis provided herein using a suspension plasma spray (SPS) process, which can deliver nearly monodisperse nanoparticles in a gram scale yield to provide a protective magnesium fluoride layer. The SPS process can use a Sulzer Metco Triplex II torch attached on an ABB industrial robot.
The stent can optionally include a therapeutic agent. In some cases, the coating can include a therapeutic agent. In some cases, the coating can include a polymer (e.g., a bioerodible polymer). For example, a drug-eluting polymeric coating can be applied to the stent body provided herein. In some cases, a stent provided herein can be essentially polymer-free (allowing for the presence of any small amounts of polymeric materials that may have been introduced incidentally during the manufacturing process such that someone of ordinary skill in the art would nevertheless consider the coating to be free of any polymeric material). The therapeutic agent may be any pharmaceutically acceptable agent (such as a drug), a biomolecule, a small molecule, or cells. Exemplary drugs include anti-proliferative agents such as paclitaxel, sirolimus (rapamycin), tacrolimus, everolimus, biolimus, and zotarolimus. Exemplary biomolecules include peptides, polypeptides and proteins; antibodies; oligonucleotides; nucleic acids such as double or single stranded DNA (including naked and cDNA), RNA, antisense nucleic acids such as antisense DNA and RNA, small interfering RNA (siRNA), and ribozymes; genes; carbohydrates; angiogenic factors including growth factors; cell cycle inhibitors; and anti-restenosis agents. Exemplary small molecules include hormones, nucleotides, amino acids, sugars, lipids, and compounds have a molecular weight of less than 100 kD. Exemplary cells include stem cells, progenitor cells, endothelial cells, adult cardiomyocytes, and smooth muscle cells.
A stent provided herein can include one or more imaging markers. Imaging markers can assist a physician with the placement of the stent. Imaging markers can be radiopaque marks to permit X-ray visualization of the stent.
Stent 20 can be configured for vascular, e.g., coronary and peripheral vasculature or non-vascular lumens. For example, it can be configured for use in the esophagus or the prostate. Other lumens include biliary lumens, hepatic lumens, pancreatic lumens, and urethral lumens.
Stent 20 can be of a desired shape and size (e.g., coronary stents, aortic stents, peripheral vascular stents, gastrointestinal stents, urology stents, tracheal/bronchial stents, and neurology stents). Depending on the application, the stent can have a diameter of between, e.g., about 1 mm to about 46 mm. In certain embodiments, a coronary stent can have an expanded diameter of from about 2 mm to about 6 mm. In some cases, a peripheral stent can have an expanded diameter of from about 4 mm to about 24 mm. In certain embodiments, a gastrointestinal and/or urology stent can have an expanded diameter of from about 6 mm to about 30 mm. In some cases, a neurology stent can have an expanded diameter of from about 1 mm to about 12 mm. An abdominal aortic aneurysm (AAA) stent and a thoracic aortic aneurysm (TAA) stent can have a diameter from about 20 mm to about 46 mm. The stent can be balloon-expandable, self-expandable, or a combination of both (e.g., see U.S. Pat. No. 6,290,721).
Non-limiting examples of additional endoprostheses that can include a bioerodible magnesium alloy including a microstructure provided herein include stent grafts, heart valves, and artificial hearts. Such endoprostheses are implanted or otherwise used in body structures, cavities, or lumens such as the vasculature, gastrointestinal tract, lymphatic system, abdomen, peritoneum, airways, esophagus, trachea, colon, rectum, biliary tract, urinary tract, prostate, brain, spine, lung, liver, heart, skeletal muscle, kidney, bladder, intestines, stomach, pancreas, ovary, uterus, cartilage, eye, bone, joints, and the like. In some cases, an endoprosthesis can include a biodegradable scaffold for the lymphatic system.
All publications, patent applications, patents, and other references mentioned herein are incorporated by reference herein in their entirety.
Still further embodiments are within the scope of the following claims.

## Claims

1. A bioerodible endoprosthesis comprising:
a composite comprising a matrix comprising a bioerodible magnesium alloy and a plurality of ceramic nanoparticles within the matrix, the bioerodible magnesium alloy comprising magnesium and one or more additional alloying elements, the bioerodible magnesium alloy comprising equiaxed Mg-rich solid solution phase grains;
wherein the equiaxed Mg-rich solid solution phase grains have an average grain diameter of less than or equal to 20 microns and the ceramic nanoparticles have an average longest dimension of between 0.1 nanometers and 1 micron.

2. The endoprosthesis of claim 1, wherein the ceramic nanoparticles are primarily centered upon the grain boundaries and do not extend into a Mg-rich solid solution phase grain interior by more than 1 micron from the grain boundary when viewed at 200-500X magnification on a metallography plane.

3. The endoprosthesis of claim 1, wherein the equiaxed Mg-rich solid solution phase grains have an average grain diameter of less than or equal to 1 micron and the ceramic nanoparticles have an average longest dimension of between 0.5 nanometer and 200 nanometers.

4. The endoprosthesis of claim 1, wherein less than 50% of the equiaxed Mg-rich solid solution-phase grains have twin bands.

5. The endoprosthesis of claim 4, wherein less than 15% of the equiaxed Mg-rich solid solution-phase grains have twin bands.

6. The endoprosthesis of claim 1, wherein the bioerodible magnesium alloy includes beta-phase precipitates.

7. The endoprosthesis of claim 1, wherein the ceramic nanoparticles are insoluble in the bioerodible magnesium alloy.

8. The endoprosthesis of claim 1, wherein the ceramic nanoparticles comprise a ceramic material selected from the group consisting of TiC, Si3N4, AlN, Al2O3, CeO2, Boron Nitride, B4C, Y2O3, and combinations thereof.

9. The endoprosthesis of claim 1, wherein the alloy has an elastic modulus of between 39 GPa and 200 GPa, a 0.2% offset yield strength of between 150 MPa and 600 MPa, an ultimate tensile strength of between 250 MPa and 600 MPa, and a tensile reduction in area of at least 30%.

10. The endoprosthesis of claim 1, wherein the bioerodible magnesium alloy comprises aluminum.

11. The endoprosthesis of claim 1, wherein the bioerodible magnesium alloy comprises zinc, calcium, manganese, neodymium, tin, yttrium, cerium, lanthanum, gadolinium, or a combination thereof.

12. The endoprosthesis of claim 1, wherein the bioerodible magnesium alloy comprises between 3 and 9 weight percent aluminum, between 0.1 and 3.0 weight percent zinc, up to 0.3 weight percent manganese, and between 0.6 and 1.5 weight percent neodymium, and balance magnesium.

13. The endoprosthesis of claim 1, wherein the endoprosthesis is a stent comprising a plurality of struts, wherein the struts have a width to thickness ratio of less than 1.2.

14. The endoprosthesis of claim 1, wherein the endoprosthesis has a surface finish having an Ra surface roughness of less than 0.2 microns.

15. The endoprosthesis of claim 1, wherein the fully manufactured non-sterile or sterile finished product bare bioerodible magnesium alloy-ceramic composite endoprothesis has a mass loss of less than 10% after 28 days of continuous immersion in non-flowing, agitated Simulated Body Fluid at 37° C., where the Simulated Body Fluid has a volume of at least 10 times an initial volume of the stent.

16. A bioerodible endoprosthesis comprising:
a composite comprising a matrix comprising a bioerodible magnesium alloy and a plurality of ceramic nanoparticles within the matrix, the bioerodible magnesium alloy comprising magnesium and one or more additional alloying elements, the bioerodible magnesium alloy comprising equiaxed Mg-rich solid solution phase grains:
wherein less than 50% of the equiaxed Mg-rich solid solution-phase grains have twin bands.

17. A bioerodible endoprosthesis comprising:
a composite comprising a matrix comprising a bioerodible magnesium alloy and a plurality of ceramic nanoparticles within the matrix, the bioerodible magnesium alloy comprising magnesium and one or more additional alloying elements, the bioerodible magnesium alloy comprising equiaxed Mg-rich solid solution phase grains;
wherein the bioerodible magnesium alloy includes beta-phase precipitates.