Abstract:
A coating for implantable devices, such as stents, and a method of making the same is disclosed. Moreover, an apparatus for depositing the coating is disclosed.

Description:
BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     This invention relates generally to implantable devices, such as stents. More particularly, the present invention relates to an apparatus and method for coating stents. 
     2. Description of the Background 
     Implanting a stent, after a percutaneous transluminal coronary angioplasty (PTCA) procedure, is often used to avoid or mitigate the effects of restenosis at a surgical site. In general, stents are small, cylindrical devices whose structure serves to create or maintain an unobstructed opening within a lumen. Stents are typically made of, for example, stainless steel, Nitinol or other materials and are delivered to the target site via a balloon catheter. Although the stents are effective in opening the stenotic lumen, the foreign material and structure of the stents themselves may exacerbate the occurrence of restenosis or thrombosis. 
     In addition to using a stent, drugs or therapeutic agents that limit migration and/or proliferation of vascular smooth muscle cells are used to significantly reduce the incidence of restenosis and thrombosis. Examples of therapeutic agents commonly used include heparin, aspirin, IIb/IIIa inhibitors, antithrombogenic agents, dexamethasone, steroids, antiinflammatory agents, cytostatic agents, cytotoxic agents, antimicrobials, thrombolytics, monoclonal antibodies, tranilast, and antifibrosis agents. Since the therapeutic agents are applied systemically to the patient, they are absorbed not only by the tissues at the target site, but by other areas of the body. As such, one drawback associated with the systemic application of drugs is that areas of the body not needing treatment are also affected. To provide more site-specific treatment, stents are frequently used as a means of delivering drugs exclusively to the target site. Drugs are suspended in tissue-compatible polymers such as silicones, polyurethanes, polyvinyl alcohol, poly(ethylene-co-vinyl alcohol), polyethylene, hydrogels, substituted methacrylates, poly(ethylene-co-vinyl acetate), and hyaluronic acid and blended mixtures thereof. By positioning the stent at the target site, the drugs can be applied directly to the area of the lumen requiring therapy. 
     Although stents with a drug coating have been an advance for the treatment of restenosis and other similar vascular ailments, the stents, and the methods and apparatus for their production have not yet been perfected. For instance, conventional techniques often apply a single coating of a homogenous composition that contains a mixture of a polymer and a therapeutic substance. The use of a homogenous composition may have several flaws. The polymeric portion of the coating may not be stable in the vascular environment (i.e., the polymer may leach into the blood), and may not be capable of holding a sufficient amount of the drug. In addition, conventional coatings may not have a blood compatible surface to the vascular environment. Moreover, the drug release rate of a coating made from a homogenous composition cannot be tailored to provide for different release profiles. 
     As an alternative to using a homogenous composition to coat a stent, some conventional techniques apply a coating to a stent that has more than one layer, with each layer having a different composition. These techniques also suffer from some flaws. For example, the different layers may not strongly adhere to each, thereby allowing one or more layer to leach into the blood or become detached creating an embolization hazard. Also, the coating process of these techniques may not be very efficient because each layer must be applied, and then dried before the next layer is applied. Finally, the application of the composition for each additional layer subsequent to the drying of the previously applied layer can cause the extraction of the drug out of the previous layer. Accordingly, the concentration of the drug will reside in the upper most layers, causing a rapid release of the drug subsequent to the implantation procedure. This “burst-effect” leads to a reduced residence time of the drug at the implantation site, which may be undesirable depending on the type of condition being treated. 
     Accordingly, what is needed is an apparatus and process for coating stents that does not suffer from the aforementioned drawbacks. More particularly, there is a need for a method and apparatus for coating a stent that is able to modify the coating formulation as the formulation is being applied to the stent. 
     SUMMARY OF THE INVENTION 
     The present invention is directed to a method of forming a coating on an implantable device such as a stent including applying a coating formulation to a stent, the coating formulation including a first ingredient and a second ingredient, and modifying the ratio of the first ingredient with respect to the second ingredient in the coating formulation as the coating formulation is being applied to the stent. In one embodiment, the act of applying includes spraying the coating formulation on the stent. 
     The present invention is further directed to a system for applying a coating on a stent, including a nozzle for spraying a composition onto a stent, a first reservoir in fluid communication with the nozzle for supplying a first ingredient of the composition to the nozzle, a second reservoir in fluid communication with the nozzle for supplying a second ingredient of the composition to the nozzle, and a control assembly for adjusting the amount of the first or second ingredient that is fed into the nozzle wherein the amount of the first or second ingredient that is sprayed by the nozzle can be modified by the control assembly without interrupting the application of the composition onto the stent. The system may further have a mixer for mixing the first ingredient with the second ingredient. In one embodiment, the control assembly includes a valve for adjusting the input rate of the first or second ingredient to the nozzle. 
     The present invention is also directed to an implantable medical device having a coating having a first ingredient and a second ingredient, wherein from a deep region of the coating to a more shallow region of the coating, the ratio of the concentration of the first ingredient to the concentration of the second ingredient gradually increases or decreases. 
     In the embodiments of the present invention, the ingredients can be a polymeric material and a therapeutic substance. Some examples of polymeric materials can include ethylene vinyl alcohol copolymer, polybutylmethacrylate, polyethylene glycol, amorphous Teflon, and poly(ethylene-co-vinyl acetate). Some examples of therapeutic substances can include actinomycin D, paclitaxel, docetaxel, rapamycin, β-estradiol and BAK Heparin. 
    
    
     
       BRIEF DESCRIPTION OF THE FIGURES 
         FIG. 1  illustrates a coating system for forming a coating on a stent; 
         FIG. 2  illustrates a coating system for forming a coating on a stent; 
         FIG. 3  is a graph showing the relative concentration of two ingredients as a function of application time; 
         FIGS. 4 and 5  are graphs, in accordance with two embodiments, showing the concentration of two ingredients as a function of application time and thickness of the coating; 
         FIGS. 6 and 7  are graphs, in accordance with other embodiments, showing the concentration of three ingredients as a function of application time and thickness of the coating; 
         FIG. 8  is a diagram of an embodiment of an implantable medical device inserted into a body vessel; and 
         FIG. 9  illustrates a partial cross-section of a strut, in accordance with one exemplary embodiment, along the line  9 — 9  of  FIG. 8 . 
     
    
    
     DETAILED DESCRIPTION OF THE EMBODIMENTS 
     System for Coating 
     An embodiment of the present invention involving a system for spray coating an implatable device such as a stent is depicted in  FIG. 1 . Although a spray system is depicted in the spirit of convenience and brevity, it should be noted that other systems and methods are also within the scope of the claimed invention. 
     Referring to  FIG. 1 , a gas source such as an air compressor  10  may provide air pressure to a first reservoir  16  and a second reservoir  20  through a first air hose  12  and a second air hose  14 , respectively. First reservoir  16  can hold a first solution  18  which includes a first ingredient (e.g., a polymeric material) and a solvent. Second reservoir  20  can hold a second solution  22  which includes a second ingredient (e.g., a therapeutic substance) and a solvent. It is understood that any number of reservoirs can be used to contain any number of ingredients. The air pressure delivered from air compressor  10  can be sufficiently high enough to promote uptake of the solutions in first reservoir  16  and second reservoir  20  into a first fluid hose  24  and a second fluid hose  26 . First solution  18  and second solution  22 , in turn, can be fed into a control assembly  34 , which controls the rate that compositions from first reservoir  16  and second reservoir  20  are delivered to a mixer  32 . 
     First solution  18  and second solution  22  are mixed in mixer  32 , and then moved as a mixed solution to a nozzle  42 . As the mixed solution enters the chamber of nozzle  42 , the mixed solution is exposed to pressurized air from two sources: an actuating gas source  38  and an atomizing gas source  40 . Atomizing gas source  40 , which can deliver air or another gas, provides sufficient pressure and velocity to atomize the solution into small droplets. Actuating gas source  38 , on the other hand, can provide a sufficient amount of pressure so that the droplets are forced out of nozzle  42  and directed to a target (e.g., a stent). 
     As noted above, control assembly  34  can monitor and control the rate of fluid delivered to mixer  32  and nozzle  42 . Control assembly  34  can have a controller  36  (e.g., a CPU) that is in communication with a first valve  28  and a second valve  30 . First valve  28  and second valve  30  may be, for example, high precision proportioning valves as is well known and commonly available to those of ordinary skill in the art. Alternatively, first valve  28  and second valve  30  could be very low volume, high speed valves (Lee Electro-Fluidic Systems, Westbrook, Conn.). 
     In another embodiment, referring to  FIG. 2 , a first reservoir  54  and a second reservoir  56  are in fluid communication with nozzle  42  for delivering two different ingredients to nozzle  42 . Instead of a gas source such as air compressor  10 , a first syringe pump  50  and a second syringe pump  52  may provide pressure to first reservoir  54  and second reservoir  56 , respectively. Syringe pumps  50  and  52 , in turn, are in communication with controller  36 . Controller  36  may provide signals to syringe pumps  50  and  52  and control the amount of motive force that syringe pumps  50  and  52  provide to reservoirs  54  and  56 , thereby controlling the amount of ingredients that are ultimately delivered to nozzle  42 . 
     Various approaches may be used to mix the ingredients delivered by the reservoirs. In one embodiment, referring to  FIG. 1 , the ingredients are mixed in mixer  32  before they are delivered to nozzle  42 . Representative examples of types of mixers that can be employed include an ultrasonic mixer having a piezoelectric transducer, a static mixer and a mechanical mixer. Alternatively, the ingredients can be mixed as the ingredients are introduced into and/or ejected out from nozzle  42 . 
     Various structures can be used to support the stents while they are being sprayed by nozzle  42 . By way of example, and not limitation, a stent  44  ( FIG. 1 ) can be attached to a mandrel  46  that rotates and/or moves in a linear direction during the application process. Alternatively, nozzle  42  can pivotly rotate around and move linearly along a stationary stent. 
     Method of Applying Coating 
     In one embodiment of the present invention, a method is used to apply a coating formulation to a stent, whereby the coating formulation has at least two ingredients and the relative concentrations of the ingredients are modified as the coating formulation is applied to the stent. In one embodiment, the coating formulation is applied to the stent by spraying. Referring to  FIG. 1 , first solution  18  can contain a first ingredient (e.g., a polymeric material), and second solution  22  can contain a second ingredient (e.g., a therapeutic substance). A gas source such as air compressor  10  can provide the motive force to deliver first solution  18  and second solution  22  to first valve  28  and second valve  30 , respectively. Control assembly  34  can be used to control the amount of first solution  18  and second solution  22  that is delivered to mixer  32 , and ultimately the amount delivered to nozzle  42 . For example, while nozzle  42  is spraying a stent, controller  36  can modify the ratio of first solution  18  with respect to second solution  22  by controlling the operation of first and second valve  28  and  30 . 
     In one embodiment, for example, first solution  18  contains ingredient A (a therapeutic substance), and second solution  22  contains ingredient B (a polymeric material). While nozzle  42  is spraying stent  44 , controller  36  can send signals to first valve  28  to reduce the flow rate of first solution  18 . As a result, the amount of first solution  18 , and therefore ingredient A, that is delivered to mixer  32  is reduced, thereby modifying the contents of the composition of the coating formation that is sprayed onto stent  44 . In addition, while nozzle  42  is spraying stent  44 , controller  36  can send signals to second valve  30  to increase the flow rate of second solution  22 . For example, as shown in  FIG. 3 , at the early segments of the application process, the concentration of ingredient A relative to the concentration of ingredient B is significantly higher. However, as the application process proceeds, the concentration of ingredient B can be incrementally increased while the concentration of ingredient A is concurrently decreased relative to the concentration of ingredient B. 
     In another embodiment, the coating formulation contains ingredient C and ingredient D. Referring to  FIG. 4 , the concentration of ingredient C can remain constant as the coating is applied, while the concentration of ingredient D remains constant for an initial period, then increases, and then becomes constant at a later stage of the application. 
     In yet another embodiment, the coating formulation can contain ingredient E and ingredient F. Referring to  FIG. 5 , ingredient E can first be applied as a primer, and then ingredient F can be gradually mixed with ingredient E at an increasing concentration. 
     In one exemplary implementation of the ingredients of  FIG. 5 , ingredient E can be ethylene vinyl alcohol copolymer (EVAL), and ingredient F can be polyethylene glycol (PEG). EVAL is considered to have relatively good adhesion potential, whereas PEG is considered to have relatively high blood compatibility. A single coating with a large fraction of PEG relative to EVAL would likely give high blood compatibility but would swell significantly, perhaps dissolving off of the stent, releasing PEG into the blood, and generally not adhering well to the stent. A formulation with a high percentage of EVAL, in turn, would likely adhere to the stent surface, but would not be as blood compatible as PEG. In order to realize the benefits of combining EVAL and PEG, one could apply a coating formulation as shown in  FIG. 5 . 
     In another embodiment, the coating formulation contains ingredient G, ingredient H and ingredient I. By way of example and not limitation, ingredient G can be a therapeutic substance, ingredient H can be EVAL, and ingredient I can be poly(ethylene-co-vinyl acetate). Referring to  FIG. 6 , ingredient H can be first applied to the stent at constant concentration as a primer. Then, ingredient G can be added with an increasing concentration to provide a drug layer. About one-half the way through the application process, ingredient I is added to the coating formulation. The concentration of ingredient I increases through the rest of the coating process, while the concentration of ingredient H decreases. At the end of the coating process, with respect to ingredient G, ingredient H and ingredient I, the coating formulation only contains ingredient I, thereby providing a topcoat layer. 
     In another embodiment, the coating formulation contains ingredient J, ingredient K and ingredient L. Referring to  FIG. 7 , ingredient J is initially applied to a stent as a primer. However, as the application process continues, the concentration of ingredient J in the coating formulation decreases. While ingredient J is being applied, ingredients K and L are added to the coating formulation, and the concentrations of ingredient K and L increase throughout the remainder of the coating application. For example, ingredient J is polybutylmethylmethacrylate (PBMA), ingredient K is EVAL and ingredient L is Actinomycin D, with the common solvent dimethylacetamide. 
     Implantable Device 
     A stent is broadly intended to include self-expandable stents, balloon-expandable stents, and stent-grafts. One of ordinary skill in the art, however, understands that other medical devices on which a polymeric material can be coated can be used with the practice of the present invention, such as grafts (e.g., aortic grafts), artificial heart valves, cerebrospinal fluid shunts, axius coronary shunts, pacemaker electrodes, and endocardial leads (e.g., FINELINE and ENDOTAK, available from Guidant Corporation). The underlying structure of the device can be of virtually any design. The device can be made of a metallic material or an alloy such as, but not limited to, cobalt chromium alloy (e.g., ELGILOY), stainless steel (316L), “MP35N,” “MP20N,” ELASTINITE (Nitinol), tantalum, nickel-titanium alloy, platinum-iridium alloy, gold, magnesium, or combinations thereof. “MP35N” and “MP20N” are trade names for alloys of cobalt, nickel, chromium and molybdenum available from standard Press Steel Co., Jenkintown, Pa. “MP35N” consists of 35% cobalt, 35% nickel, 20% chromium, and 10% molybdenum. “MP20N” consists of 50% cobalt, 20% nickel, 20% chromium, and 10% molybdenum. Devices made from bioabsorbable or biostable polymers could also be used with the embodiments of the present invention. 
       FIG. 8  illustrates an implantable prosthetic medical device. In the spirit of convenience and brevity, the medical device referenced in the text and figures of the present disclosure is a stent  60 . Stent  60  can be cylindrical or tubular in shape, and can be inserted into a body lumen  62 . The structure of stent  60  should allow stent  60  to be inserted into and physically uphold an anatomical passageway such as body lumen  62 , by exerting a radially outward-extending force against the walls or inner lumen surface of the passageway. If desired, stent  60  can also expand the opening of lumen  62  to a diameter greater than its original diameter and, thereby, increase fluid flow through lumen  62 . 
     Stent  60  can include struts  70  that form a network structure. Struts  70  have an outer (or lumen contacting) surface  64  and an inner surface  66 , as shown in  FIG. 8 . In addition, a hollow bore  68  extends longitudinally through the body structure of stent  60 . 
     In one embodiment of the present invention, a coating formulation with a first ingredient and a second ingredient is used to coat outer surface  64  of struts  70 , and the resultant coating has a first region and a second region, where the quantity of the first ingredient with respect to the second ingredient is different in the first region as compared to the second region. In another embodiment, the coating formulation has three or more different ingredients. In a further embodiment, the coating has three or more different regions. Referring to  FIG. 9 , by way of illustration, the coating of strut  70  has a first region  72 , a second region  74 , a third region  76 , a fourth region  78 , a fifth region  80  and a sixth region  82 . In the interests of brevity and simplification, the different regions are illustrated only on outer surface  64  of strut  70 . However, one of ordinary skill in the art will understand that the coating can also be on inner surface  66  of strut  70 , as well as all other surfaces of stent  60 . 
     Referring to  FIG. 9 , first region  72  may be used as a primer, and fifth region  80  may used as a rate reduction membrane to reduce the release rate of a therapeutic substance contained in second region  74 , third region  76 , and fourth region  78 . Sixth region  82  may be used as a blood compatible layer. Furthermore, by gradually changing the concentration of the ingredients contained in the regions, there may be increased interlayer adhesion. For instance, second region  74 , third region  76 , fourth region  78 , and fifth region  80  can be used for increased interlayer adhesion between first region  72  and sixth region  82 . One of ordinary skill in the art will understand that fewer than six regions or more than six regions may be applied as part of the present invention. 
     By way of example, the coating formulation may include ingredient M, ingredient N, ingredient O and ingredient P. Referring to Table I, for instance, the concentrations of the various ingredients relative to each other may be changed in the different regions. 
     
       
         
               
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
                 TABLE I 
               
             
             
               
                   
                   
               
               
                   
                 Concentration Relative to Other Ingredients (%) 
               
             
          
           
               
                 Region 
                 Ingredient M 
                 Ingredient N 
                 Ingredient O 
                 Ingredient P 
               
               
                   
               
             
          
           
               
                 First Region 72 
                 100 
                 0 
                 0 
                 0 
               
               
                 Second Region 
                 60 
                 20 
                 20 
                 0 
               
               
                 74 
               
               
                 Third Region 
                 30 
                 30 
                 30 
                 10 
               
               
                 76 
               
               
                 Fourth Region 
                 10 
                 40 
                 30 
                 20 
               
               
                 78 
               
               
                 Fifth Region 80 
                 0 
                 50 
                 25 
                 25 
               
               
                 Sixth Region 
                 0 
                 40 
                 20 
                 40 
               
               
                 82 
               
               
                   
               
             
          
         
       
     
     In yet another embodiment of the present invention, the coating formulation includes ingredient Q, ingredient R, ingredient S and ingredient T. Referring to Table II, for example, the concentrations of the various ingredients may be changed in the different regions. In one exemplary implementation of the ingredients of Table II, ingredient Q is PBMA, ingredient R is EVAL, ingredient S is Actinomycin D, and ingredient T is PEG (molecular weight 15,000 amu). 
     
       
         
               
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
                 TABLE II 
               
             
             
               
                   
                   
               
               
                   
                 Concentration (mg/ml) 
               
             
          
           
               
                 Region 
                 Ingredient Q 
                 Ingredient R 
                 Ingredient S 
                 Ingredient T 
               
               
                   
               
             
          
           
               
                 First Region 72 
                 1100 
                 0 
                 0 
                 0 
               
               
                 Second Region 
                 733 
                 380 
                 0 
                 0 
               
               
                 74 
               
               
                 Third Region 
                 367 
                 760 
                 0 
                 0 
               
               
                 76 
               
               
                 Fourth Region 
                 0 
                 1026 
                 114 
                 0 
               
               
                 78 
               
               
                 Fifth Region 80 
                 0 
                 1140 
                 0 
                 0 
               
               
                 Sixth Region 
                 0 
                 977 
                 0 
                 163 
               
               
                 82 
               
               
                   
               
             
          
         
       
     
     The pure PBMA in first region  72  can act as a primer and afford good adhesion with the stent surface. Also, one disadvantage of the current coating processes is that there is poor interlayer compatibility among some components, such as polymeric materials. Certain polymeric materials, for instance, do not properly adhere to each other when they are applied in layers in their pure form. The graduated interface between the PBMA and EVAL in regions  72 ,  74  and  76 , as depicted numerically in Table II, may provide better interlayer adhesion. 
     In a further embodiment of the present invention, the coating formulation includes ingredient U, ingredient V, ingredient W and ingredient X. In one exemplary implementation of the ingredients of Table III, ingredient U is PBMA, ingredient V is EVAL, ingredient W is β-Estradiol, and ingredient X is the benzylalkonium salt of heparin (BAK Heparin). 
     
       
         
               
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
                 TABLE III 
               
             
             
               
                   
                   
               
               
                   
                 Concentration (mg/ml) 
               
             
          
           
               
                 Region 
                 Ingredient U 
                 Ingredient V 
                 Ingredient W 
                 Ingredient X 
               
               
                   
               
             
          
           
               
                 First Region 72 
                 0 
                 1140 
                 0 
                 0 
               
               
                 Second Region 
                 0 
                 760 
                 380 
                 0 
               
               
                 74 
               
               
                 Third Region 
                 550 
                 570 
                 0 
                 0 
               
               
                 76 
               
               
                 Fourth Region 
                 1100 
                 0 
                 0 
                 0 
               
               
                 78 
               
               
                 Fifth Region 80 
                 550 
                 570 
                 0 
                 0 
               
               
                 Sixth Region 
                 0 
                 1026 
                 0 
                 114 
               
               
                 82 
               
               
                   
               
             
          
         
       
     
     Composition of Coating Formulation 
     The ingredients contained in the coating formulation can be prepared by conventional methods. More particularly, in accordance to one embodiment, a predetermined amount of a polymeric material or combination of polymeric materials can be added to a predetermined amount of a solvent or a combination of solvents. If necessary, heating, stirring and/or mixing can be employed to effect dissolution of the polymeric material(s) into the solvent(s) —for example in an 80° C. water bath for two hours. 
     A therapeutic substance can be also be an ingredient contained in the coating formulation. In accordance to one embodiment, a predetermined amount of a therapeutic substance or combination of therapeutic substances can be added to a predetermined amount of a solvent, a combination of solvents, with or without a polymeric material. The therapeutic substance should be in true solution or saturated in the composition of the coating formulation. If the therapeutic substance is not completely soluble in the composition, operations including mixing, stirring, and/or agitation can be employed to effect homogeneity of the residues. The therapeutic substance may be added so that dispersion is in fine particles. The mixing of the therapeutic substance can be conducted at ambient pressure and at room temperature. 
     Representative examples of polymeric material that can be used to coat a medical device in accordance with the present invention include ethylene vinyl alcohol copolymer (commonly known by the generic name EVOH or by the trade name EVAL); polybutylmethacrylate; poly(hydroxyvalerate); poly(L-lactic acid); polycaprolactone; poly(lactide-co-glycolide); poly(hydroxybutyrate); poly(hydroxybutyrate-co-valerate); polydioxanone; polyorthoester; polyanhydride; poly(glycolic acid); poly(D,L-lactic acid); poly(glycolic acid-co-trimethylene carbonate); polyphosphoester; polyphosphoester urethane; poly(amino acids); cyanoacrylates; poly(trimethylene carbonate); poly(iminocarbonate); copoly(ether-esters) (e.g., PEO/PLA); polyalkylene oxalates; polyphosphazenes; biomolecules, such as fibrin, fibrinogen, cellulose, starch, collagen and hyaluronic acid; polyurethanes; silicones; polyesters; polyolefins; polyisobutylene and ethylene-alphaolefin copolymers; acrylic polymers and copolymers; vinyl halide polymers and copolymers, such as polyvinyl chloride; polyvinyl ethers, such as polyvinyl methyl ether; polyvinylidene halides, such as polyvinylidene fluoride and polyvinylidene chloride; polyacrylonitrile; polyvinyl ketones; polyvinyl aromatics, such as polystyrene; polyvinyl esters, such as polyvinyl acetate; copolymers of vinyl monomers with each other and olefins, such as ethylene-methyl methacrylate copolymers, acrylonitrile-styrene copolymers, ABS resins, and ethylene-vinyl acetate copolymers; polyamides, such as Nylon 66 and polycaprolactam; alkyd resins; polycarbonates; polyoxymethylenes; polyimides; polyethers; epoxy resins; polyurethanes; rayon; rayon-triacetate; cellulose; cellulose acetate; cellulose butyrate; cellulose acetate butyrate; cellophane; cellulose nitrate; cellulose propionate; cellulose ethers; amorphous Teflon; and carboxymethyl cellulose. EVAL is functionally a very suitable choice of polymeric material. The copolymer possesses good adhesive qualities to the surface of a stent, particularly stainless steel surfaces, and has illustrated the ability to expand with a stent without any significant detachment of the copolymer from the surface of the stent. The copolymer, moreover, allows for good control capabilities over the release rate of the therapeutic substance. 
     Representative examples of solvents include chloroform, acetone, water (buffered saline), dimethylsulfoxide (DMSO), propylene glycol methyl ether (PM), iso-propylalcohol (IPA), n-propylalcohol, methanol, ethanol, tetrahydrofuran (THF), dimethylformamide (DMF), dimethyl acetamide (DMAC), benzene, toluene, xylene, hexane, cyclohexane, heptane, octane, nonane, decane, decalin, ethyl acetate, butyl acetate, isobutyl acetate, isopropyl acetate, butanol, diacetone alcohol, benzyl alcohol, 2-butanone, cyclohexanone, dioxane, methylene chloride, carbon tetrachloride, tetrachlroro ethylene, tetrachloro ethane, chlorobenzene, 1,1,1-trichloroethane, formamide, pentane, trifluoroethanol, hexafluoroisopropanol, freon, hexamethylphosphorus triamide, and combinations thereof. 
     The therapeutic substance can be for inhibiting the activity of vascular smooth muscle cells. More specifically, the therapeutic substance can be aimed at inhibiting abnormal or inappropriate migration and/or proliferation of smooth muscle cells for the inhibition of restenosis. The therapeutic substance can also include any substance capable of exerting a therapeutic or prophylactic effect in the practice of the present invention. For example, the therapeutic substance can be for enhancing wound healing in a vascular site or improving the structural and elastic properties of the vascular site. Examples of therapeutic substances include antiproliferative substances such as actinomycin D, or derivatives and analogs thereof (manufactured by Sigma-Aldrich 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233; or COSMEGEN available from Merck). Synonyms of actinomycin D include dactinomycin, actinomycin IV, actinomycin I 1 , actinomycin X 1 , and actinomycin C 1 . The active agent can also fall under the genus of antineoplastic, anti-inflammatory, antiplatelet, anticoagulant, antifibrin, antithrombin, antimitotic, antibiotic, antiallergic and antioxidant substances. Examples of such antineoplastics and/or antimitotics include paclitaxel (TAXOL® by Bristol-Myers Squibb Co., Stamford, Conn.), docetaxel (Taxotere®, from Aventis S. A., Frankfurt, Germany), methotrexate, azathioprine, vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride (Adriamycin® from Pharmacia &amp; Upjohn, Peapack N.J.), and mitomycin (e.g., Mutamycin® from Bristol-Myers Squibb Co., Stamford, Conn.). Examples of such antiplatelets, anticoagulants, antifibrin, and antithrombins include sodium heparin, low molecular weight heparins, heparinoids, hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclin analogues, dextran, D-phe-pro-arg-chloromethylketone (synthetic antithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membrane receptor antagonist antibody, recombinant hirudin, and thrombin inhibitors such as Angiomax ä (Biogen, Inc., Cambridge, Mass.). Examples of such cytostatic or antiproliferative agents include angiopeptin, angiotensin converting enzyme inhibitors such as captopril (Capoten® and Capozide® from Bristol-Myers Squibb Co., Stamford, Conn.), cilazapril or lisinopril (Prinivil® and Prinzide® from Merck &amp; Co., Inc., Whitehouse Station, N.J.), calcium channel blockers (such as nifedipine), colchicine, fibroblast growth factor (FGF) antagonists, fish oil (omega 3-fatty acid), histamine antagonists, lovastatin (an inhibitor of HMG-CoA reductase, a cholesterol lowering drug, brand name Mevacor® from Merck &amp; Co., Inc., Whitehouse Station, N.J.), monoclonal antibodies (such as those specific for Platelet-Derived Growth Factor (PDGF) receptors), nitroprusside, phosphodiesterase inhibitors, prostaglandin inhibitors, suramin, serotonin blockers, steroids, thioprotease inhibitors, triazolopyrimidine (a PDGF antagonist), and nitric oxide. An example of an antiallergic agent is permirolast potassium. Other therapeutic substances or agents which may be appropriate include alpha-interferon, genetically engineered epithelial cells, rapamycin and dexamethasone. The foregoing substances are listed by way of example and are not meant to be limiting. Other therapeutic substances which are currently available or that may be developed in the future are equally applicable. 
     The dosage or concentration of the therapeutic substance required to produce a favorable therapeutic effect should be less than the level at which the therapeutic substance produces toxic effects and greater than the level at which non-therapeutic results are obtained. The dosage or concentration of the therapeutic substance required to inhibit the desired cellular activity of the vascular region can depend upon factors such as the particular circumstances of the patient; the nature of the trauma; the nature of the therapy desired; the time over which the ingredient administered resides at the vascular site; and if other therapeutic agents are employed, the nature and type of the substance or combination of substances. Therapeutic effective dosages can be determined empirically, for example by infusing vessels from suitable animal model systems and using immunohistochemical, fluorescent or electron microscopy methods to detect the agent and its effects, or by conducting suitable in vitro studies. Standard pharmacological test procedures to determine dosages are understood by one of ordinary skill in the art. 
     While particular embodiments of the present invention have been shown and described, it will be obvious to those skilled in the art that changes and modifications can be made without departing from the embodiments this invention in its broader aspects and, therefore, the appended claims are to encompass within their scope all such changes and modifications as fall within the true spirit and scope of the embodiments this invention.