Self-buffering medical implants

[0001] This application claims priority under 35 USC §119(e) to U.S. Patent Application Ser. No. 61/156,636, filed on Mar. 2, 2009, the entire contents of which are hereby incorporated by reference.

[0002] This invention relates to self-buffering medical implants.

[0003] A medical implant can replace, support, or act as a missing biological structure. Some examples of medical implants can include orthopedic implants; bioscaffolding; endoprostheses such as stents, covered stents, and stent-grafts; bone screws; and aneurism coils. A medical implant can also add a new function to the body. For example, medical implants can include identification tags, communication devices, and/or pacemaking electrodes. Some medical implants are designed to erode under physiological conditions.

[0004] Medical endoprostheses can, for example, be used in various passageways in a body, such as arteries, other blood vessels, and other body lumens (e.g., neural pathways). 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, the 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, covered stents, and stent-grafts.

[0005] Endoprostheses 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.

[0006] The expansion mechanism can 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 The balloon can then be deflated, and the catheter withdrawn.

[0007] 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.

[0008] A medical implant is described that includes a bioerodible portion adapted to degrade under physiological conditions to form degradation products that buffer the medical implant. The bioerodible polymer matrix degrades under physiological conditions to form acidic degradation products. The bioerodible metal degrades under physiological conditions to form basic degradation products. In one aspect, the bioerodible portion includes a bioerodible polymer matrix and a bioerodible metal within the bioerodible polymer matrix.

[0009] The bioerodible portion can include a plurality of particles of the bioerodible metal within the bioerodible polymer matrix. The plurality of particles can include nanoparticles. In other embodiments, the bioerodible polymer can include a plurality of fibers including the bioerodible polymer metallized with the bioerodible metal. In some embodiments, the medical implant can consist essentially of the bioerodible portion.

[0010] The bioerodible metal can be selected from the group consisting of magnesium, iron, calcium, and alloys thereof. The medical implant can also include a therapeutic agent. The therapeutic agent can be incorporated in the bioerodible polymer matrix and can elute as the bioerodible polymer degrades under physiological conditions.

[0011] The medical implant can be bioscaffolding, an aneurysm coil, an orthopedic implant, a bone screw, an identification tag, a pacemaking electrode, or an endoprosthesis. For example, the medical implant can be a stent.

[0012] In another aspect, the medical implant can include a body, a plurality of discrete deposits of the bioerodible polymer on the body, and a plurality of discrete deposits of the bioerodible metal on the body. In some embodiments, the discrete deposits of the bioerodible polymer and the discrete deposits of the bioerodible metal can each have an average diameter of no greater than 50 microns. In some embodiments, the body can include stainless-steel, platinum-enhanced stainless steel, a cobalt-chromium alloy, a nickel-titanium alloy, or a combination thereof.

[0013] In another aspect, a stent is described that includes a bioerodible portion. The bioerodible body includes a bioerodible polymer matrix and micro or nano particles within the bioerodible polymer matrix. The bioerodible polymer matrix degrades under physiological conditions to form acidic degradation products. The micro or nano particles degrade under physiological conditions to form basic degradation products. The acidic degradation products and the basic degradation products buffer at least a portion of the endoprosthesis.

[0014] The details of one or more embodiments are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.

[0018] Like reference symbols in the various drawings indicate like elements.

[0019] The medical implant can include one or more bioerodible metal portions adapted to degrade under physiological conditions to form degradation products that buffer the medical implant. A stent 20, shown in FIG. 1, is discussed below as an example of one medical implant according to the instant disclosure. Other examples of medical implants can include orthopedic implants; bioscaffolding; bone screws; aneurism coils, an identification tag, a pacemaking electrode, and other endoprostheses such as covered stents and stent-grafts.

[0020] As shown in FIG. 1, 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 the stent 20 against a wall of a vessel, thereby maintaining the patency of the vessel. Connectors 24 can provide the stent 20 with flexibility and conformability that allow the stent to adapt to the contours of the vessel.

[0021] The stent 20 includes a bioerodible portion adapted to degrade under physiological conditions to form degradation products that buffer the stent 20 as the bioerodible portion erodes within a body. In some embodiments, the bioerodible portion is a composite bioerodible polymer-bioerodible metal material where the bioerodible polymer degrades under physiological conditions to form acidic degradation products and the bioerodible metal degrades under physiological conditions to form basic degradation products. In some embodiments, the bioerodible portion is a composite of bioerodible polymer and micro or nano particles where the bioerodible polymer degrades under physiological conditions to form acidic degradation products and the micro or nano particles degrade under physiological conditions to form basic degradation products. Micro or nano particles can include bioerodible metals, calcium compounds, titanium oxide (TiO₂), bioglass, citric acid, salts of citric acid, and combinations thereof. In some embodiments, the stent 20 can be entirely or almost entirely composed of the bioerodible portion. In some embodiments, a bioerodible portion can include therapeutic agents that can be released as the bioerodible portion degrades.

[0022] When the stent 20 is, for example, implanted into a vessel of a mammal, the acidic and basic degradation products can buffer each other to keep the pH in the vicinity of the vessel wall tissue within a pH range of 5-8. In some embodiments, the stent 20 can be configured to keep the pH in the vicinity of the vessel wall tissue within the physiological range of 6-7. The buffering can prevent an inflammatory response in the vessel wall tissue. The buffering can also alter the degradation kinetics of the bioerodible polymer, the bioerodible metal, or both. For example, this buffering can prevent the bulk erosion of a bioerodible polymer by reducing the degradation rate of the polymer at the interface between the bioerodible polymer and the bioerodible metal relative to the degradation rate of the polymer at an outer surface of the stent 20. Furthermore, for example, the prevention of the buildup of acidic degradation products can prevent the “acid-burst” phenomena, as discussed below.

[0023] The bioerodible metal can be selected to produce basic degradation products when degrading in a physiological environment. For example, the bioerodible metal can be magnesium, iron, calcium, or alloys thereof. In some embodiments, the bioerodible metal can be at least 50% by weight magnesium. For example, the bioerodible metal can include a bioerodible iron alloy that includes up to twenty percent manganese, up to 10 percent silver, and up to five percent carbon. A bioerodible magnesium alloy that can contain up to 10% of a mix of the rare metal species from the following: lanthanum, neodymium, holmium, erbium, gadolinium, cerium, dysprosium, praseodymium, promethium, samarium, europium, terbium, thulium, ytterbium, lutetium, actinium, thorium, einsteinium, americium, protactinium, californium, uranium, neptunium, plutonium, curium, berkelium, fermium, mendelevium, nobelium and lawrencium. In some embodiments, a bioerodible magnesium alloy can includes up to nine percent aluminum, up to five percent rare earth metals, up to five percent zirconium, up to five percent lithium, up to five percent manganese, up to ten percent silver, up to five percent chromium, up to five percent silicon, up to five percent tin, up to six percent yttrium, and up to ten percent zinc. Suitable magnesium bioerodible alloys include ZK31, which includes three percent zinc and one percent zirconium; ZK61, which includes six percent zinc and one percent zirconium; AZ31, which includes three percent aluminum and one percent zinc; AZ91, which includes nine percent aluminum and one percent zinc; WE43, which includes four percent yttrium and three percent rare earth metals, and WE54, which includes five percent yttrium and four percent rare earth metals.

[0024] The bioerodible polymer can be selected to produce acidic degradation products when degrading in a physiological environment. Examples of such bioerodible polymers can include polyesters (e.g., polyhydroxyalkanoates), polyamides, and polysulfones. For example, the bioerodible polymer can be polylactic acid (“PLA”), poly(lactic-co-glycolic acid) (“PLGA”), Poly(propylene-ram-ε-caprolactone carbonate) (“PPCL”), polycaprolactone (“PCL”), poly-L-lactic-acid (“PLLA”), poly(3-hydroxybutyrate) (“PHB”), and combinations thereof. For example, PLA can degrade by hydrolysis to produce lactic acid and PLGA can degrade by hydrolysis to produce lactic acid and glycolic acid. When PLA and PLGA are exposed to an electrolyte (e.g., when exposed to a physiological environment), the polymer can absorb the electrolyte and swell. The absorbed electrolyte can then hydrolyze the entire matrix of PLA and/or PLGA polymer. The hydrolysis reaction, however, can be accelerated by an acidic environment. These two factors can result in “acid-burst phenomena,” in which an internal portion of a PLA and/or PLGA portion can become more acidic as the internal portion of the PLA and/or PLGA portion hydrolyzes while the physiological environment prevents a buildup of acidic degradation products at an exterior portion of the PLA and/or PLGA portion (e.g., natural buffering agents that cannot penetrate the interior portion of the PLA and/or PLGA portion or the natural flow of the circulatory system). Accordingly, an exterior portion of the PLA and/or PLGA portion can degrade at a slower rate than an internal portion and result in a shell of PLA and/or PLGA around a concentrated solution of water and lactic acid (and possibly glycolic acid). The presence of a bioerodible metal within a bioerodible polymer matrix can prevent this buildup of acid within a bioerodible portion of the stent 20, and thus prevent the “acid-burst phenomena.”

[0025] The bioerodible portion, in some embodiments, can include a matrix of the bioerodible polymer and a plurality of particles within the polymer. In some embodiments, the plurality of particles include a bioerodible metal. In some embodiments, the particles include micro and/or nano particles. In some embodiments, the particles are nanoparticles. In some embodiments, the nanoparticles can be up to 10 micrometers in diameter. In some embodiments, the nanoparticles can be as small as 5 nanometers in diameter. For example, the average diameter of the nanoparticles can be between 5 nanometers and 10 micrometers (e.g., between 50 nanometers and 1 micrometer). The nanoparticles can be evenly distributed throughout the matrix, or can be distributed to affect different erosion rates in different portions of the bioerodible portion. The presence of nanoparticles of bioerodible metal within a matrix of bioerodible polymer can produce a bioerodible polymer that is dynamically self buffered. For example, the bioerodible portion can include a matrix of PLA having magnesium nanoparticles evenly distributed throughout the matrix. Suitable nanoparticles can be provided by Mantis Ltd., located in England.

[0026] Micro and/or nano particles within a matrix of bioerodible polymer can include bioerodible metals, calcium compounds, titanium oxide (TiO₂), bioglass, citric acid, salts of citric acid, and combinations thereof. Calcium compounds can include calcium dihydrogenphosphate (“CDHP”), calcium hydrogenpohosphate, calcium phosphate, calcium carbonate, hydroxyapatite, and wollastonite. Bioglass can also sometimes include calcium. For example, the micro and/or nano particles can include bioglass 45S5. In some embodiments, micro and/or nano particles include a combination of citric acid and a citric acid salt (e.g., sodium citrate). The bioerodible portion, in some embodiments, can include bioerodible polymer fibers metalized with a bioerodible metal. Metallizing a bioerodible polymer fiber with a bioerodible metal can provide a bioerodible polymer fiber that is both self buffered and reinforced. A composite fiber of bioerodible polymer metalized with a bioerodible metal can be produced, for example, by electrospinning and/or metal vapor synthesis techniques. For example, the bioerodible portion can include PLA fibers metalized with magnesium. An example of a metal vapor synthesis technique for producing a PLA/magnesium material can include producing magnesium vapor by the resistive heating a crucible containing magnesium powder, condensing that magnesium vapor with a solvent (e.g., 1-hexene and mesitylene) at liquid nitrogen temperatures, and heating the condensed mixture to the melting point of the mixture to produce a solution of magnesium. For example, the metal content of the solution can be between 2 and 8 mg/ml. The solution can then be added to a solution of the PLA polymer, stirred, and the solvents removed to produce a composite PLA/magnesium material. The electro-spinning process can be performed using dichloromethane (DCM), which is an apolar solvent that is unlikely to contain water. Further information about the preparation of electrospin solutions is given in WO 2007/062393, “METHOD OF SOLUTION PREPARATION OF POLYOLEFIN CLASS POLYMERS FOR ELECTROSPINNING PROCESSING INCLUDED,” which is hereby incorporated by reference.

[0027] The bioerodible portion can, in some embodiments, be deposited onto a body of the medical implant. For example, the body of a stent can define a flow passage there through. The body can include stainless-steel, platinum-enhanced stainless steel, a cobalt-chromium alloy, a nickel-titanium alloy, or a combination thereof. In other embodiments, the body can comprise a bioerodible metal such as iron, magnesium, zinc, or alloys thereof.

[0028] The body of the medical device can include multiple bioerodible portions with different buffering properties. For example, FIGS. 2A and 2B depict stent arrangements having a first quick release layer 26, which has a weak buffer, and a second slow release layer 28, which has a strong buffer. The stronger buffer reduces the erosion time for layer 28 as compared to layer 26. The strength of the buffer can be controlled by the selection and amount of bioerodible metal or other material that degrades to form basic byproducts. In some embodiments, one or more of layers 26 and 28 include therapeutic agents. As shown in FIGS. 2A and 2B, the layers 26 and 28 can be adjacent and/or overlap.

[0029] The bioerodible portion can include a plurality of discrete deposits of a bioerodible polymer on the body and a plurality of discrete deposits of a bioerodible metal on the body. Each deposit of the plurality of deposits of the bioerodible metal can be adjacent to at least one deposit of the bioerodible polymer. For example, the deposits of the bioerodible polymer and the bioerodible metal can be in a checkerboard pattern or in the form of an array of dots. For example, as shown in FIG. 3, deposits 32 of bioerodible polymer and of bioerodible metal can be deposited onto an abluminal surface of bands 22 and/or connectors 24 of a stent 20 with the use of an engraved donor 36. The stent 20 can be placed on a mandrel 34. A doctors blade 38 can be used to limit the placement of the material to be within the engravings in the engraved donor 36. In some embodiments, deposits of bioerodible polymer and bioerodible metal can each be deposited in separate steps. In addition, maskless mesoscale materials deposition (“M3D”) technology, available from Optomec, can also be used to make deposits of bioerodible metal and bioerodible polymer. The discrete deposits of the bioerodible polymer and the discrete deposits of the bioerodible metal can each have an average diameter of no greater than 50 microns (e.g., between 5 and 15 microns). The size of the deposits can ensure that the degradation process does not produce a physiologically significant emboli.

[0030] In some embodiments, the stent 20 can also include a therapeutic agent. In some embodiments, the therapeutic agent can be incorporated into the bioerodible portion. For example, the therapeutic agent can be incorporated in the bioerodible polymer and elude as the bioerodible polymer degrades under physiological conditions.

[0031] The terms “therapeutic agent”, “pharmaceutically active agent”, “pharmaceutically active material”, “pharmaceutically active ingredient”, “drug” and other related terms may be used interchangeably herein and include, but are not limited to, small organic molecules, peptides, oligopeptides, proteins, nucleic acids, oligonucleotides, genetic therapeutic agents, non-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 that reduce or inhibit restenosis. By small organic molecule it is meant an organic molecule having 50 or fewer carbon atoms, and fewer than 100 non-hydrogen atoms in total.

[0032] Exemplary non-genetic therapeutic agents for use in conjunction with the presently disclosed endoprostheses can include: (a) anti-thrombotic agents such as heparin, heparin derivatives, urokinase, and PPack (dextrophenylalanine proline arginine chloromethylketone); (b) anti-inflammatory agents such as dexamethasone, prednisolone, corticosterone, budesonide, estrogen, sulfasalazine and mesalamine; (c) antineoplastic/antiproliferative/anti-miotic agents such as paclitaxel, 5-fluorouracil, cisplatin, vinblastine, vincristine, epothilones, endostatin, angiostatin, angiopeptin, monoclonal antibodies capable of blocking smooth muscle cell proliferation, and thymidine kinase inhibitors; (d) anesthetic agents such as lidocaine, bupivacaine and ropivacaine; (e) anti-coagulants such as D-Phe-Pro-Arg chloromethyl ketone, an RGD peptide-containing compound, heparin, hirudin, antithrombin compounds, platelet receptor antagonists, anti-thrombin antibodies, anti-platelet receptor antibodies, aspirin, prostaglandin inhibitors, platelet inhibitors and tick antiplatelet peptides; (f) vascular cell growth promoters such as growth factors, transcriptional activators, and translational promotors; (g) vascular cell growth inhibitors such as growth factor inhibitors, growth factor receptor antagonists, transcriptional repressors, translational repressors, replication inhibitors, inhibitory antibodies, antibodies directed against growth factors, bifunctional molecules consisting of a growth factor and a cytotoxin, bifunctional molecules consisting of an antibody and a cytotoxin; (h) protein kinase and tyrosine kinase inhibitors (e.g., tyrphostins, genistein, quinoxalines); (i) prostacyclin analogs; (j) cholesterol-lowering agents; (k) angiopoietins; (l) antimicrobial agents such as triclosan, cephalosporins, aminoglycosides and nitrofurantoin; (m) cytotoxic agents, cytostatic agents and cell proliferation affectors; (n) vasodilating agents; (o) agents that interfere with endogenous vasoactive mechanisms; (p) inhibitors of leukocyte recruitment, such as monoclonal antibodies; (q) cytokines; (r) hormones; (s) inhibitors of HSP 90 protein (i.e., Heat Shock Protein, which is a molecular chaperone or housekeeping protein and is needed for the stability and function of other client proteins/signal transduction proteins responsible for growth and survival of cells) including geldanamycin; (t) alpha receptor antagonist (such as doxazosin, Tamsulosin) and beta receptor agonists (such as dobutamine, salmeterol), beta receptor antagonist (such as atenolol, metaprolol, butoxamine), angiotensin-II receptor antagonists (such as losartan, valsartan, irbesartan, candesartan and telmisartan), and antispasmodic drugs (such as oxybutynin chloride, flavoxate, tolterodine, hyoscyamine sulfate, diclomine); (u) bARKct inhibitors, (v) phospholamban inhibitors; (w) Serca 2 gene/protein; (x) immune response modifiers including aminoquizolines, for instance, imidazoquinolines such as resiquimod and imiquimod, and (y) human apolioproteins (e.g., AI, AII, AIII, AIV, AV, etc.).

[0033] Specific examples of non-genetic therapeutic agents include paclitaxel, (including particulate forms thereof, for instance, protein-bound paclitaxel particles such as albumin-bound paclitaxel nanoparticles, e.g., ABRAXANE), sirolimus, everolimus, tacrolimus, zotarolimus (e.g., sold as ABT-578 by Abbott Laboratories), picrolimus, Epo D, dexamethasone, estradiol, halofuginone, cilostazole, geldanamycin, trapidil, liprostin, Actinomcin D, Resten-NG, Ap-17, abciximab, clopidogrel, Ridogrel, beta-blockers, bARKct inhibitors, phospholamban inhibitors, Serca 2 gene/protein, imiquimod, human apolioproteins (e.g., AI-AV), growth factors (e.g., VEGF-2), as well a derivatives of the forgoing, among others.

[0034] Exemplary genetic therapeutic agents for use in conjunction with the presently disclosed endoprostheses include anti-sense DNA and RNA as well as DNA coding for the various proteins (as well as the proteins themselves): (a) anti-sense RNA, (b) tRNA or rRNA to replace defective or deficient endogenous molecules, (c) angiogenic and other factors including growth factors such as acidic and basic fibroblast growth factors, vascular endothelial growth factor, endothelial mitogenic growth factors, epidermal growth factor, transforming growth factor α and β, platelet-derived endothelial growth factor, platelet-derived growth factor, tumor necrosis factor α, hepatocyte growth factor and insulin-like growth factor, (d) cell cycle inhibitors including CD inhibitors, and (e) thymidine kinase (“TK”) and other agents useful for interfering with cell proliferation. Also of interest is DNA encoding for the family of bone morphogenic proteins (“BMP's”), including BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 (Vgr-1), BMP-7 (OP-1), BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15, and BMP-16. Currently preferred BMP's are any of BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 and BMP-7. These dimeric proteins can be provided as homodimers, heterodimers, or combinations thereof, alone or together with other molecules. Alternatively, or in addition, molecules capable of inducing an upstream or downstream effect of a BMP can be provided. Such molecules include any of the “hedgehog” proteins, or the DNA's encoding them.

[0035] Vectors for delivery of genetic therapeutic agents include viral vectors such as adenoviruses, gutted adenoviruses, adeno-associated virus, retroviruses, alpha virus (Semliki Forest, Sindbis, etc.), lentiviruses, herpes simplex virus, replication competent viruses (e.g., ONYX-015) and hybrid vectors; and non-viral vectors such as artificial chromosomes and mini-chromosomes, plasmid DNA vectors (e.g., pCOR), cationic polymers (e.g., polyethyleneimine, polyethyleneimine (PEI)), graft copolymers (e.g., polyether-PEI and polyethylene oxide-PEI), neutral polymers PVP, SP1017 (SUPRATEK), lipids such as cationic lipids, liposomes, lipoplexes, nanoparticles, or microparticles, with and without targeting sequences such as the protein transduction domain (PTD).

[0036] Cells for use in conjunction with the presently disclosed endoprostheses include cells of human origin (autologous or allogeneic), including whole bone marrow, bone marrow derived mono-nuclear cells, progenitor cells (e.g., endothelial progenitor cells), stem cells (e.g., mesenchymal, hematopoietic, neuronal), pluripotent stem cells, fibroblasts, myoblasts, satellite cells, pericytes, cardiomyocytes, skeletal myocytes or macrophage, or from an animal, bacterial or fungal source (xenogeneic), which can be genetically engineered, if desired, to deliver proteins of interest.

[0037] Numerous therapeutic agents, not necessarily exclusive of those listed above, have been identified as candidates for vascular treatment regimens, for example, as agents targeting restenosis. Such agents are useful for the presently disclosed endoprostheses and include one or more of the following: (a) Ca-channel blockers including benzothiazapines such as diltiazem and clentiazem, dihydropyridines such as nifedipine, amlodipine and nicardapine, and phenylalkylamines such as verapamil; (b) serotonin pathway modulators including: 5-HT antagonists such as ketanserin and naftidrofuryl, as well as 5-HT uptake inhibitors such as fluoxetine; (c) cyclic nucleotide pathway agents including phosphodiesterase inhibitors such as cilostazole and dipyridamole, adenylate/Guanylate cyclase stimulants such as forskolin, as well as adenosine analogs; (d) catecholamine modulators including α-antagonists such as prazosin and bunazosine, β-antagonists such as propranolol and α/β-antagonists such as labetalol and carvedilol; (e) endothelin receptor antagonists; (f) nitric oxide donors/releasing molecules including organic nitrates/nitrites such as nitroglycerin, isosorbide dinitrate and amyl nitrite, inorganic nitroso compounds such as sodium nitroprusside, sydnonimines such as molsidomine and linsidomine, nonoates such as diazenium diolates and NO adducts of alkanediamines, S-nitroso compounds including low molecular weight compounds (e.g., S-nitroso derivatives of captopril, glutathione and N-acetyl penicillamine) and high molecular weight compounds (e.g., 5-nitroso derivatives of proteins, peptides, oligosaccharides, polysaccharides, synthetic polymers/oligomers and natural polymers/oligomers), as well as C-nitroso-compounds, O-nitroso-compounds, N-nitroso-compounds and L-arginine; (g) ACE inhibitors such as cilazapril, fosinopril and enalapril; (h) ATII-receptor antagonists such as saralasin and losartin; (i) platelet adhesion inhibitors such as albumin and polyethylene oxide; (j) platelet aggregation inhibitors including cilostazole, aspirin and thienopyridine (ticlopidine, clopidogrel) and GP IIb/IIIa inhibitors such as abciximab, epitifibatide and tirofiban; (k) coagulation pathway modulators including heparinoids such as heparin, low molecular weight heparin, dextran sulfate and β-cyclodextrin tetradecasulfate, thrombin inhibitors such as hirudin, hirulog, PPACK (D-phe-L-propyl-L-arg-chloromethylketone) and argatroban, FXa inhibitors such as antistatin and TAP (tick anticoagulant peptide), Vitamin K inhibitors such as warfarin, as well as activated protein C; (l) cyclooxygenase pathway inhibitors such as aspirin, ibuprofen, flurbiprofen, indomethacin and sulfinpyrazone; (m) natural and synthetic corticosteroids such as dexamethasone, prednisolone, methprednisolone and hydrocortisone; (n) lipoxygenase pathway inhibitors such as nordihydroguairetic acid and caffeic acid; (o) leukotriene receptor antagonists; (p) antagonists of E- and P-selectins; (q) inhibitors of VCAM-1 and ICAM-1 interactions; (r) prostaglandins and analogs thereof including prostaglandins such as PGE1 and PGI2 and prostacyclin analogs such as ciprostene, epoprostenol, carbacyclin, iloprost and beraprost; (s) macrophage activation preventers including bisphosphonates; (t) HMG-CoA reductase inhibitors such as lovastatin, pravastatin, fluvastatin, simvastatin and cerivastatin; (u) fish oils and omega-3-fatty acids; (v) free-radical scavengers/antioxidants such as probucol, vitamins C and E, ebselen, trans-retinoic acid and SOD mimics; (w) agents affecting various growth factors including FGF pathway agents such as bFGF antibodies and chimeric fusion proteins, PDGF receptor antagonists such as trapidil, IGF pathway agents including somatostatin analogs such as angiopeptin and ocreotide, TGF-β pathway agents such as polyanionic agents (heparin, fucoidin), decorin, and TGF-β antibodies, EGF pathway agents such as EGF antibodies, receptor antagonists and chimeric fusion proteins, TNF-α pathway agents such as thalidomide and analogs thereof, Thromboxane A2 (TXA2) pathway modulators such as sulotroban, vapiprost, dazoxiben and ridogrel, as well as protein tyrosine kinase inhibitors such as tyrphostin, genistein and quinoxaline derivatives; (x) MMP pathway inhibitors such as marimastat, ilomastat and metastat; (y) cell motility inhibitors such as cytochalasin B; (z) antiproliferative/antineoplastic agents including antimetabolites such as purine analogs (e.g., 6-mercaptopurine or cladribine, which is a chlorinated purine nucleoside analog), pyrimidine analogs (e.g., cytarabine and 5-fluorouracil) and methotrexate, nitrogen mustards, alkyl sulfonates, ethylenimines, antibiotics (e.g., daunorubicin, doxorubicin, macrolide antibiotics such as erythromycin), nitrosoureas, cisplatin, agents affecting microtubule dynamics (e.g., vinblastine, vincristine, colchicine, Epo D, paclitaxel and epothilone), caspase activators, proteasome inhibitors, angiogenesis inhibitors (e.g., endostatin, angiostatin and squalamine), rapamycin, cerivastatin, flavopiridol and suramin; (aa) matrix deposition/organization pathway inhibitors such as halofuginone or other quinazolinone derivatives and tranilast; (bb) endothelialization facilitators such as VEGF and RGD peptide; and (cc) blood rheology modulators such as pentoxifylline. Further additional therapeutic agents for the presently disclosed endoprostheses are also disclosed in U.S. Pat. No. 5,733,925.

[0038] Where a therapeutic agent is included, a wide range of therapeutic agent loadings can be used in conjunction with the presently disclosed endoprostheses, with the therapeutically effective amount being readily determined by those of ordinary skill in the art and ultimately depending, for example, upon the condition to be treated, the age, sex and condition of the patient, the nature of the therapeutic agent, the nature of the ceramic region(s), and/or the nature of the endoprosthesis, among other factors. The delivery mediated is formulated as needed to maintain cell function and viability.

[0039] Stent 20 can be of any desired shape and size (e.g., coronary stents, aortic stents, peripheral vascular stents, gastrointestinal stents, urology stents, and neurology stents). Depending on the application, the stent can have a diameter of between, for example, 1 mm to 46 mm. In certain embodiments, a coronary stent can have an expanded diameter of from 2 mm to 6 mm. In some embodiments, a peripheral stent can have an expanded diameter of from 5 mm to 24 mm. In certain embodiments, a gastrointestinal and/or urology stent can have an expanded diameter of from 6 mm to about 30 mm. In some embodiments, 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.

[0040] In use, a stent can be used, e.g., delivered and expanded, using a catheter delivery system. Catheter systems are described in, for example, Wang U.S. Pat. No. 5,195,969, Hamlin U.S. Pat. No. 5,270,086, and Raeder-Devens, U.S. Pat. No. 6,726,712. Stents and stent delivery are also exemplified by the Sentinol® system, available from Boston Scientific Scimed, Maple Grove, Minn.

[0041] All publications, references, applications, and patents referred to herein are incorporated by reference in their entirety.

[0042] A number of embodiments have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of this disclosure. Accordingly, other embodiments are within the scope of the following claims.