Abstract:
The present invention provides methods, systems, and devices that deliver therapeutic to the inner lumens, chambers, cavities, and vessels of the body. In one embodiment, a therapeutic delivery device for delivery of therapeutic to a target site within the body of a patient is provided. This device may include a catheter, an expandable multi-port housing fluidly coupled to the catheter and a sheath. The multi-port housing in this device may be sized to travel within a lumen of a patient and may be adapted to expand from a first configuration to a second configuration. The multi-port housing may also contain at least two ejection ports coupled to an internal lumen of the multi-port housing. In some embodiments the multi-port housing is a bladder, while in others it is a frame or a group of outwardly extending arms. In each case, the device is configured to deliver therapeutic to a remote site in the body of a patient.

Description:
FIELD OF THE INVENTION  
       [0001]     The present invention regards the delivery of therapeutic to a target site in the body of a patient. More specifically, the present invention regards systems, devices, and methods that employ an expandable multi-port therapeutic delivery device to deliver therapeutic to a target vessel or other target site in the body of a patient.  
       BACKGROUND  
       [0002]     The delivery of therapeutic to a target site in the body of a patient is an often repeated procedure of contemporary medicine. Delivery procedures can range from minimally invasive techniques such as hypodermic needle delivery and intra-luminal catheter delivery of therapeutics, to more invasive delivery techniques such as the direct manual injection of therapeutic into the mycardium of the heart during open heart surgery.  
         [0003]     Intra-luminal therapeutic delivery procedures include guiding an injection catheter within a lumen of the body to a target site, delivering therapeutic from the catheter to the target site, and withdrawing the catheter from the target site. When the target area is large, such as an entire chamber of the heart, a medical practitioner may need to repeat the delivery portion of the procedure many times in order to adequately dispense the therapeutic over the entire target area. As the number of injection points increases, the time necessary to complete the procedure increases and the uniformity of the spacing and depth of each injection may vary, this despite the best efforts of the medical practitioner.  
       SUMMARY OF THE INVENTION  
       [0004]     The present invention provides methods, systems, and devices that deliver therapeutic to the inner lumens and vessels of the body. In one embodiment, a therapeutic delivery device for delivery of therapeutic to a target site within the body of a patient is provided. This device may include a catheter, an expandable multi-port housing fluidly coupled to the catheter and a sheath. The multi-port housing in this device may be sized to travel within a lumen of a patient and may be adapted to expand from a first configuration to a second configuration. The multi-port housing may also contain at least two ejection ports coupled to an internal lumen of the multi-port housing. In some embodiments the multi-port housing is a bladder, while in others it is a frame or a group of outwardly extending arms. In each case, the device is configured to deliver therapeutic to a remote site in the body of a patient. 
     
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0005]      FIG. 1  is a side view of an embodiment of the present invention.  
         [0006]      FIG. 2  is a side view of the device of  FIG. 1  as it may be employed in the left ventricle of the heart of a patient.  
         [0007]      FIG. 3  is a side view of the device in  FIG. 1  as it may be employed in the left ventricle of the heart of a patient.  
         [0008]      FIG. 4  is a side view of another embodiment of the present invention.  
         [0009]      FIG. 5  is a side view of another embodiment of the present invention.  
         [0010]      FIG. 6  is a side view of the device of  FIG. 5  in an expanded and extended position.  
         [0011]      FIG. 7  is a side view of the device of  FIG. 5  in a retracted position.  
         [0012]      FIG. 8  is a side view of another embodiment of the present invention.  
         [0013]      FIG. 9  is a side view of the device of  FIG. 8  with a housing wrap.  
         [0014]      FIG. 10  is an end-view of the device in  FIG. 11  taken along line  11 - 11 .  
         [0015]      FIG. 11  is a side view of the device of  FIG. 8  in a retracted position.  
         [0016]      FIG. 12  is a side view of another embodiment of the present invention when the left ventricle is relaxed.  
         [0017]      FIG. 13  is a side view of the embodiment from  FIG. 12  when the left ventricle is contracted. 
     
    
     DETAILED DESCRIPTION  
       [0018]      FIG. 1  is a side view of an expandable multi-port therapeutic delivery device  100  in accord with the present invention. The expandable multi-port delivery device  100  in  FIG. 1  contains ports  102 , multi-port housing  101 , catheter  106 , lumen  103 , inflation port  104 , and therapeutic supply port  105 . In this embodiment, as well as in others, the catheter  106  may be constructed of the same material as that comprising the multi-port housing  101 . Alternatively, the catheter may be constructed of one material, e.g., nylon, while the multi-port housing  101  may be constructed of or reinforced with another, e.g., nitinol. Likewise, the ports may be constructed of or reinforced with one material, e.g., nitinol, while the housing may be constructed of another, e.g., rubber. As can be seen, the catheter  106  may contain an inflation port  104  and be coupled to a therapeutic supply at port  105 . During a medical procedure, the catheter  106  may be used to control the positioning of the multiple-port housing  101 , to inflate and contract the multi-port housing  101 , and to deliver therapeutic to and out of the injection ports  102  of the multi-port housing  101 . While the multi-port housing  101  is depicted as a balloon in this example, it may take on numerous other configurations. For example, it may be the frame shown in later embodiments.  
         [0019]     As can be seen, the ports  102  of the multi-port housing may be raised above the surface of the multi-port housing and may contain internal lumens that allow for the passage of therapeutic therethrough. When the ports  102  are raised or otherwise extend from the housing they will be better able to pierce into tissue when the housing  101  is expanded. For instance, when the housing  101  is expanded, the ports  102  may become seated in the tissue due to their position.  
         [0020]     While a single lumen  103  is shown in the device  100 , multiple lumens may be present in the device  100  as well. Separate lumens may be used to control the inflation of the housing  101  and the delivery of therapeutic. They may be used for other functions as well. The ports  102  may be positioned on the multi-port housing  101  in aligned rows and columns as well as other patterns. The ports  102  may also be randomly positioned on the multi-port housing  101 . The ports  102  may even be placed in a single area or region of the housing  101  such that only a portion of the myocardium or other target area may receive therapeutic. The ports  102  may also be aligned along a surface arc of the housing  101 .  
         [0021]     The flow of fluid or therapeutic through the ports  102  may be regulated by some sort of valve or other mechanism. In each case, it is preferred that the therapeutic be delivered to each of the ports  102  in uniform quantities, although other configurations, where only certain ports receive therapeutic, where the ports  102  have different shapes and sizes, and where the rate of flow through the ports  102  varies, are all also within the spirit and scope of the present invention.  
         [0022]      FIG. 2  shows the delivery device  100  of  FIG. 1  as it may be used to delivery therapeutic to the left ventricle  201  of a beating heart  250 . As can be seen, the multi-port housing  101  is sized and dimensioned such that it may be snaked to and positioned within the left ventricle. While the multi-port housing  101  is shown being snaked through the aortic valve it may also be snaked through other valves of the heart to reach this and other target areas. As can also be seen, when the multi-port housing  101  is inserted into the left ventricle it may be sized such that it does not touch any of the internal walls of the chamber when the housing  101  is deflated. By comparison, when it is inflated, the multi-port housing  101  may be shaped to closely conform to the internal dimensions of the left ventricle or other target area. By having the multi-port housing  101  closely mimic the dimensions of the target vessel, therapeutic delivered via the ports  102  is more apt to be evenly delivered throughout the target area.  
         [0023]     Therapeutic may be delivered before, during, and after the multi-port housing  101  is expanded. In other words, therapeutic may be dispensed to the surrounding fluid upon reaching the target area, to the tissue after the housing  101  is expanded, and then to the surrounding fluid again after the housing  101  is deflated and prior to its removal from the target area. Therapeutic may also be delivered during only portions of this cycle, as may be required by the medical procedure being performed.  
         [0024]     In this embodiment, the multi-port housing  101  may be an expandable bladder coupled to a catheter  106  with an internal lumen. The housing may comprise a highly compliant material so that it will readily conform to the shape of the vessel it may reside within. The housing  101  may be made with resilient and/or flexible material including, but not limited to latex, silicone, polyurethane, rubber, nylon, and/or shape memory polymers. The ports  102  may take on various shapes and configurations. In  FIG. 1  the ports  102  have a frustom like configuration while they may also be funnel shaped and obconic, as well as many other shapes. In a preferred embodiment, the ports  102  are in fluid communication with the lumen  103  within the catheter  106  and have piercing edges capable of piercing the target tissue.  
         [0025]     In use, once the housing  101  is positioned at a target site, compressed gas or a liquid such as saline may be piped into the device through the inflation port to inflate the housing  101 . Then, after the inflation port is closed, therapeutic may be forced from the therapeutic supply port  105 , through the lumen  103 , and out the ports  102 . The therapeutic may be forced, manually or automatically, from a storage vessel. In so doing, therapeutic may be delivered to numerous points without the need to reposition the delivery device  100  within the target vessel. When the desired amount of therapeutic has been delivered to the target site, the delivery end may be deflated so that the ports will no longer be penetrating into the myocardium. The housing  101  may be then repositioned and the inflation and therapeutic cycle repeated.  
         [0026]      FIG. 3 , shows the multiple-port housing  101  of the previous two illustrations in an expanded state. In  FIG. 3 , the ports  102  are positioned against and have penetrated into the walls of the heart chamber. There is no space  302  around most of the chamber and only a small space  301  near the bottom. In other configurations, the multi-port housing  101  may be sized to leave no space whatsoever or to cover only a portion of the ventricle or other vessel wall.  
         [0027]     As can also be seen in  FIG. 3 , the catheter  106  is sized to fill the opening in the aortic valve  303 . Comparatively, in other embodiments, the catheter  106  may have a smaller diameter such that the mitral valve or other entry point to the heart may more readily allow fluid to pass when the procedure is being performed.  
         [0028]     Therapeutic delivery may also be accomplished in this and the other embodiments by coating the surface of the multi-port housing  101  with therapeutic to be delivered. Additionally, the housing  101  may also be porous so as to allow the therapeutic to diffuse through the pores of the housing into the target site. The ports and micropores, which provide for this diffusion, may be sized in this and the other embodiments such that the therapeutic is able to pass through them only when positive pressure is exerted to urge the therapeutic through the ports or micro-pores.  
         [0029]      FIG. 4  shows an embodiment of the present invention similar to the device of  FIGS. 1-3  except that the multi-port housing  401  is bifurcated into two chambers via a partition  408 . The multi-port therapeutic delivery device  400  includes a first chamber  421 , a second chamber  421 , valves  407 , a multi-port housing  401 , ports  402 , a catheter  406 , a catheter lumen  409 , and a partition  408 . In this embodiment, the lumen  409  extends into the first chamber  421  past the partition  408 . In so doing, the device of  FIG. 4  allows blood or other fluids to flow between valves  407  when the Figure is inflated. Thus, therapeutic may be delivered through the lumen  409 , housing  401 , and the ports  402  of the first chamber while blood or some other fluid may continue to flow through the second chamber. While the shunt area or second chamber  420  is in the proximal section of this embodiment, which is preferred if the device is used in the left ventricle, the shunt area may also run along a longitudinal axis of the device, thereby allowing blood or some other fluid to pass through a lumen that is otherwise occluded by the expanded device. The shunt area may be in other positions as well.  
         [0030]     In the embodiment of  FIG. 5 , the multi-port housing  501  comprises a frame having two or more flexible struts  510 . These struts  510  may have lumens within and may have one or more ports  502  fluidly coupled to those lumens. Alternatively, only some of the struts may contain ports and lumens. Moreover, the ports may be identically positioned on each strut in the delivery end as well as be uniquely positioned on each of the struts. This frame can take on many figurations and contain many or only a few struts  510 . As can be seen, the struts  501  of the frame in the embodiment are aligned in an arcuate configuration where, when expanded, would define an obround structure. Comparatively, when the frame is unexpanded, as shown, the frame takes on a more elongate configuration.  
         [0031]     As can be seen, the housing  501  is coupled to a catheter  506 , which is coupled to a therapeutic supply line  505 . In  FIG. 6 , the catheter  506  is shown surrounded by a sheath or cover  512 . When the housing is extended from the sheath  512 , it may expand and when it is pulled back into the sheath it may contract. Alternatively, the frame or housing  501  may remain in a contracted orientation even after it is extended from the sheath  512  and may, instead, expand when therapeutic is dispensed into the lumens and out the ports  502 .  FIG. 7 , shows the frame  501  retracted into the cover  512 . This may be both before or after the device  500  has been used for a medical procedure.  
         [0032]     The biasing of the frame into an open or closed configuration can be performed by pre-shaping the struts during fabrication. The struts  510  may be formed from nitinol or some other material having a shape retaining characteristic. Likewise, the tip  511  of the frame  501  may also be formed of a different material in order to force the frame open or closed, this may be in addition to a natural biasing of the struts or it may be the sole mechanism generating an opening force on the frame.  
         [0033]     As described above, once in the expanded state, the ports  502  on the frame  501  may penetrate tissue at the target site and therapeutic may be delivered through the ports  502  to the target tissue. Once the appropriate amount of therapeutic is delivered, the frame  501  may be retracted from the target site, preferably within the target site, but it may be outside of it as well.  
         [0034]     In  FIG. 8 , the injection device  800  the multi-port housing comprises a bundle of hollow flexible tubes or arms  810  that are fluidly connected to the catheter  806  through the junction  813 . While six flexible tubes or arms  810  are shown, any number may be employed to accommodate the varying sizes of each target site. In use, the multi-port housing  801  would be urged from the sheath  812  and towards a target area. The orifices may be placed adjacent to or into target tissue and therapeutic may be dispensed therefrom. The tubes or struts  810  may be made from various materials. In a preferred embodiment, the struts  810  are rigid enough to penetrate the target tissue and embed the ports  802  therein.  
         [0035]      FIG. 9  is another embodiment that operates similar to the embodiment in  FIG. 8 . As seen in  FIG. 9 , the housing wrap  914  partially covers at least a portion of the distal ends of tubes  810 . The housing wrap  914  does not penetrate into the target site, and hence limits the distance the ports  802  of the tubes  810  may travel into the target site. The housing wrap may be attached to any of the tubes  810  or the catheter  806 . The housing wrap  914 , the struts  810 , or both, may have a memory-shape or elastic characteristic tending to bias the tubes in one desired direction or configuration.  
         [0036]      FIG. 10  shows the injection device  800  with the tubes  810  withdrawn inside the first sheath  812  prior to the device  800  arriving at the target site. When the device  800  is placed at the target site, the housing  801  is urged out of the sheath  812  and towards the target site. The tubes  810  then penetrate the target site, wherein the agent may then be supplied through the catheter  806 . Once the agent has been delivered, the device  800  is urged proximally, so that the tubes  810  are at least partially withdrawn into the sheath  812 . A dye may be introduced into the lumen of the sheath  812  and forced out the distal end of the sheath  812 . This may assist in observing the procedure being performed.  
         [0037]      FIG. 10  shows the end view of the device in  FIG. 11  along line  11 - 11 . As can be seen, the sheath  812  is circular and the struts  810  are uniformly spaced within it. In other embodiment, the struts may not be evenly spaced, but may, rather, be randomly positioned as well as grouped in other patterned configurations.  
         [0038]      FIGS. 12 and 13  show a therapeutic delivery device in the left ventricle while the ventricle is relaxed (diastole) and pumping (systole). As can be seen the therapeutic delivery device  1200  in both figures has been sized to contact the ventricle wall  1204  when the ventricle is contracted. When the ventricle wall  1204  contacts the device  1200 , the ports  1202  of the multi-port housing  1201  may penetrate into the wall. The housing, in this instance has been sized to urge the ports into the ventricle wall when the ventricle wall is pumping but not to contact the ventricle wall  1204  when the ventricle is in a relaxed state. As the contraction and relaxation cycle is repeated therapeutic may be cyclically pumped into the multi-port housing such that it may be injected into the ventricle wall  1204  when the ports  1202  are in contact with or penetrating into the wall  1204 . The ports  1202  may contain ball valves that themselves further retard the expulsion of therapeutic until the ports are in contact with the myocardium.  
         [0039]     In addition to being sized to simply fit within the ventricle or other vessel when the vessel is in a reduced or constricted position, the housing may also be sized to fit within or be larger than a vessel when it is in a relaxed or expanded state. For instance, the housing may be slightly larger than an artery when the housing is used in angioplasty procedures.  
         [0040]     The term “therapeutic” as used herein includes pharmaceutically active compounds, nucleic acids with and without carrier vectors such as lipids, compacting agents (such as histones), virus (such as adenovirus, adenoassociated virus, retrovirus, lentivirus and a-virus), polymers, hyaluronic acid, proteins, cells and the like, with or without targeting sequences. The therapeutics administered in accordance with the invention include the therapeutic agent(s) and solutions thereof.  
         [0041]     Specific examples of therapeutics used in conjunction with the present invention include, for example non-genetic therapeutic agents, a biomolecule, a small molecule, or cells.  
         [0042]     Exemplary non-genetic therapeutic agents include anti-thrombogenic agents such heparin, heparin derivatives, prostaglandin (including micellar prostaglandin E1), urokinase, and PPack (dextrophenylalanine proline arginine chloromethylketone); anti-proliferative agents such as enoxaprin, angiopeptin, sirolimus (rapamycin), tacrolimus, everolimus, monoclonal antibodies capable of blocking smooth muscle cell proliferation, hirudin, and acetylsalicylic acid; anti-inflammatory agents such as dexamethasone, rosiglitazone, prednisolone, corticosterone, budesonide, estrogen, estrodiol, sulfasalazine, acetylsalicylic acid, mycophenolic acid, and mesalamine; anti-neoplastic/anti-proliferative/anti-mitotic agents such as paclitaxel, epothilone, cladribine, 5-fluorouracil, methotrexate, doxorubicin, daunorubicin, cyclosporine, cisplatin, vinblastine, vincristine, epothilones, endostatin, trapidil, halofuginone, and angiostatin; anti-cancer agents such as antisense inhibitors of c-myc oncogene; anti-microbial agents such as triclosan, cephalosporins, aminoglycosides, nitrofurantoin, silver ions, compounds, or salts; biofilm synthesis inhibitors such as non-steroidal anti-inflammatory agents and chelating agents such as ethylenediaminetetraacetic acid, O,O′-bis(2-aminoethyl)ethyleneglycol-N,N,N′,N′-tetraacetic acid and mixtures thereof; antibiotics such as gentamycin, rifampin, minocyclin, and ciprofolxacin; antibodies including chimeric antibodies and antibody fragments; anesthetic agents such as lidocaine, bupivacaine, and ropivacaine; nitric oxide; nitric oxide (NO) donors such as lisidomine, molsidomine, L-arginine, NO-carbohydrate adducts, polymeric or oligomeric NO adducts; anti-coagulants such as D-Phe-Pro-Arg chloromethyl ketone, an RGD peptide-containing compound, heparin, antithrombin compounds, platelet receptor antagonists, anti-thrombin antibodies, anti-platelet receptor antibodies, enoxaparin, hirudin, warfarin sodium, Dicumarol, aspirin, prostaglandin inhibitors, platelet aggregation inhibitors such as cilostazol and tick antiplatelet factors; vascular cell growth promotors such as growth factors, transcriptional activators, and translational promotors; 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; cholesterol-lowering agents; vasodilating agents; agents which interfere with endogeneus vascoactive mechanisms; inhibitors of heat shock proteins such as geldanamycin; and any combinations and prodrugs of the above.  
         [0043]     Exemplary biomolecules include peptides, polypeptides and proteins; 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. Nucleic acids may be incorporated into delivery systems such as, for example, vectors (including viral vectors), plasmids or liposomes.  
         [0044]     Non-limiting examples of proteins include monocyte chemoattractant proteins (“MCP-1) and bone morphogenic proteins (“BMP&#39;s”), such as, for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 0(Vgr-1), BMP-7 (OP-1), BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15. Preferred BMPS are any of BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, and BMP-7. These BMPs can be provided as homdimers, 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 “hedghog” proteins, or the DNA&#39;s encoding them. Non-limiting examples of genes include survival genes that protect against cell death, such as anti-apoptotic Bcl-2 family factors and Akt kinase and combinations thereof. Non-limiting examples of angiogenic factors include acidic and basic fibroblast growth factors, vascular endothelial growth factor, 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. A non-limiting example of a cell cycle inhibitor is a cathespin D (CD) inhibitor. Non-limiting examples of anti-restenosis agents include p15, p16, p18, p19, p21, p27, p53, p57, Rb, nFkB and E2F decoys, thymidine kinase (“TK”) and combinations thereof and other agents useful for interfering with cell proliferation.  
         [0045]     Exemplary small molecules include hormones, nucleotides, amino acids, sugars, and lipids and compounds have a molecular weight of less than 100 kD.  
         [0046]     Exemplary cells include stem cells, progenitor cells, endothelial cells, adult cardiomyocytes, and smooth muscle cells. Cells can be of human origin (autologous or allogenic) or from an animal source (xenogenic), or genetically engineered. Non-limiting examples of cells include side population (SP) cells, lineage negative (Lin − ) cells including Lin − CD34 − , Lin − CD34 + , Lin − cKit + , mesenchymal stem cells including mesenchymal stem cells with 5-aza, cord blood cells, cardiac or other tissue derived stem cells, whole bone marrow, bone marrow mononuclear cells, endothelial progenitor cells, skeletal myoblasts or satellite cells, muscle derived cells, go cells, endothelial cells, adult cardiomyocytes, fibroblasts, smooth muscle cells, adult cardiac fibroblasts+5-aza, genetically modified cells, tissue engineered grafts, MyoD scar fibroblasts, pacing cells, embryonic stem cell clones, embryonic stem cells, fetal or neonatal cells, immunologically masked cells, and teratoma derived cells.  
         [0047]     Any of the therapeutic agents may be combined to the extent such combination is biologically compatible.  
         [0048]     Any of the above mentioned therapeutic agents may be incorporated into a polymeric coating on or in the medical device. The polymers of the polymeric coatings may be biodegradable or non-biodegradable. Non-limiting examples of suitable non-biodegradable polymers include polystrene; polyisobutylene copolymers and styrene-isobutylene-styrene block copolymers such as styrene-isobutylene-styrene tert-block copolymers (SIBS); polyvinylpyrrolidone including cross-linked polyvinylpyrrolidone; polyvinyl alcohols, copolymers of vinyl monomers such as EVA; polyvinyl ethers; polyvinyl aromatics; polyethylene oxides; polyesters including polyethylene terephthalate; polyamides; polyacrylamides; polyethers including polyether sulfone; polyalkylenes including polypropylene, polyethylene and high molecular weight polyethylene; polyurethanes; polycarbonates, silicones; siloxane polymers; cellulosic polymers such as cellulose acetate; polymer dispersions such as polyurethane dispersions (BAYHDROL®); squalene emulsions; and mixtures and copolymers of any of the foregoing.  
         [0049]     Non-limiting examples of suitable biodegradable polymers include polycarboxylic acid, polyanhydrides including maleic anhydride polymers; polyorthoesters; poly-amino acids; polyethylene oxide; polyphosphazenes; polylactic acid, polyglycolic acid and copolymers and mixtures thereof such as poly(L-lactic acid) (PLLA), poly(D,L,-lactide), poly(lactic acid-co-glycolic acid), 50/50 (DL-lactide-co-glycolide); polydioxanone; polypropylene fumarate; polydepsipeptides; polycaprolactone and co-polymers and mixtures thereof such as poly(D,L-lactide-co-caprolactone) and polycaprolactone co-butylacrylate; polyhydroxybutyrate valerate and blends; polycarbonates such as tyrosine-derived polycarbonates and arylates, polyiminocarbonates, and polydimethyltrimethylcarbonates; cyanoacrylate; calcium phosphates; polyglycosaminoglycans; macromolecules such as polysaccharides (including hyaluronic acid; cellulose, and hydroxypropylmethyl cellulose; gelatin; starches; dextrans; alginates and derivatives thereof), proteins and polypeptides; and mixtures and copolymers of any of the foregoing. The biodegradable polymer may also be a surface erodable polymer such as polyhydroxybutyrate and its copolymers, polycaprolactone, polyanhydrides (both crystalline and amorphous), maleic anhydride copolymers, and zinc-calcium phosphate.  
         [0050]     Such materials used with the present invention may be formed by any method known to one in the art. For example, an initial polymer/solvent mixture can be formed and then the therapeutic agent added to the polymer/solvent mixture. Alternatively, the polymer, solvent, and therapeutic agent can be added simultaneously to form the mixture. The polymer/solvent mixture may be a dispersion, suspension or a solution. The therapeutic agent may also be mixed with the polymer in the absence of a solvent. The therapeutic agent may be dissolved in the polymer/solvent mixture or in the polymer to be in a true solution with the mixture or polymer, dispersed into fine or micronized particles in the mixture or polymer, suspended in the mixture or polymer based on its solubility profile, or combined with micelle-forming compounds such as surfactants or adsorbed onto small carrier particles to create a suspension in the mixture or polymer. The material may comprise multiple polymers and/or multiple therapeutic agents.  
         [0051]     A coating can be applied to the medical device by any known method in the art including dipping, spraying, rolling, brushing, electrostatic plating or spinning, vapor deposition, air spraying including atomized spray coating, and spray coating using an ultrasonic nozzle.  
         [0052]     The coating is typically from about 1 to about 50 microns thick Very thin polymer coatings, such as about 0.2-0.3 microns and much thicker coatings, such as more than 10 microns, are also possible. It is also within the scope of the present invention to apply multiple layers of polymer coatings onto the medical device. Such multiple layers may contain the same or different therapeutic agents and/or the same or different polymers. Methods of choosing the type, thickness and other properties of the polymer and/or therapeutic agent to create different release kinetics are well known to one in the art.  
         [0053]     The medical device may also contain a radio-opacifying agent within its structure to facilitate viewing the medical device during insertion and at any point while the device is implanted. Non-limiting examples of radio-opacifying agents are bismuth subcarbonate, bismuth oxychloride, bismuth trioxide, barium sulfate, tungsten, and mixtures thereof.  
         [0054]     It is contemplated that a device of the present invention may also embody any combination of the previously mentioned features and embodiments. Accordingly, the scope of the invention is not limited to the exact embodiments described herein.