Abstract:
This present disclosure relates to a medical device and method capable of locally administering therapeutic agents efficiently. The medical device preferably includes one balloon catheter with conduits external to the balloon and with ports in the conduits where the conduits provide adequate sealing and sufficient penetration of the body vessel wall. Moreover, the placement of the conduits and location of the ports help ensure the optimal and sufficient administration of the therapeutic agent evenly to the entire treatment site. Other embodiments of the present disclosure relate to providing means to isolate the inflation medium and the therapeutic agent during administration to the treatment site and to introduce more than one therapeutic agent simultaneously to the treatment site.

Description:
RELATED APPLICATIONS 
       [0001]    This application claims priority to U.S. Provisional Patent Application No. 60/905,273, entitled “THERAPEUTIC AGENT DELIVERY SYSTEM,” filed on Mar. 6, 2007, which is incorporated herein by reference in its entirety. 
     
    
     TECHNICAL FIELD 
       [0002]    The present invention relates to medical devices configured to release a therapeutic agent. More particularly, the present invention relates to medical devices and systems commonly used with balloon catheters that locally administer therapeutic agents to a treatment site in a body vessel, as well as methods for the local administration of the therapeutic agents to a treatment site in a body vessel. 
       BACKGROUND 
       [0003]    The localized delivery of therapeutic agents within body vessels may be advantageous for treatment of a variety of medical conditions. Localized delivery may be particularly desirable for treatment of conditions that respond to administration of the therapeutic agent to a portion of a body vessel. Percutaneous delivery systems permitting administration of the therapeutic agent from a catheter placed within the body vessel permit the therapeutic agent to contact the body vessel proximate the desired treatment site. For example, vascular diseases such as atherosclerosis or peripheral vascular disease may involve stenosis of a blood vessel that may be desirably treated by administration of a therapeutic agent from a medical device within the blood vessel at or near the disease site. In general, vascular diseases may include a stenosis, i.e., the narrowing of a body vessel at stenotic lesions. Stenosis may be caused by the calcification and/or plaque (“plaque”) build-up within the body vessel. Plaque can form, for example, when cholesterol, fat and other substances form in the inner liner of the body vessel. 
         [0004]    Angioplasty is one common treatment for stenosis. In angioplasty, balloon catheters and/or stents are used to expand the narrowed body vessel and/or treatment site. For example, Percutaneous Transluminal Coronary Angioplasty (PTCA) can widen the narrowing of a body vessel by dilation with a balloon. However, at times after PTCA an abrupt closure or more gradual closure of the body vessel occasionally follows such procedure. This phenomenon is called restenosis, which is the reoccurrence of stenosis at the treated site within the blood vessel. It is thought that restenosis may be a response to angioplasty. For instance, restenosis may result from an elastic rebound of the body vessel wall and/or by the deposition of blood platelets and fibrin along a damaged length of the newly opened body vessel near the site of an angioplasty procedure. Additionally, restenosis may result from the natural healing reaction to the injury of the body vessel wall. For example, intimal hyperplasia occurs when smooth muscle cells continuously migrate and proliferate the treatment site until the body vessel is again narrowed. 
         [0005]    Angioplasty may include the implantation of one or more stents within a blood vessel to prevent further narrowing of the body vessel after angioplasty. Generally, the balloon catheter is positioned to predilate the stenosis in preparation of stent placement. After predilation, the stent is deployed across the treatment site once the balloon catheter is removed. One example of a device used with angioplasty to limit the slippage of the inflated device with respect to the vessel wall is U.S. Patent Application Pub. No. 2006/0085025 to Farnan et al. Here, the angioplasty balloon includes a non-deployable stent that is adapted to be secured to the balloon and to seemingly engage the vessel wall when the balloon is in the expanded state. However, restenosis may still occur over the length of the stent and/or past the ends of the stent where the inward forces of the stenosis are unopposed. Besides restenosis, tumor formation and thrombosis, the formation of a fibrinous clot in a blood vessel, are other common drawbacks associated with stent placement during angioplasty. 
         [0006]    As a result, procedures have been developed using catheters to deliver therapeutic agents to the treatment site within a body vessel to mitigate or eliminate conditions such as restenosis, tumor formation and/or thrombosis. Some catheters, such as U.S. Pat. No. 4,423,725 to Baran, comprise of a plurality of balloons where two expanded balloons each located on the outermost extremes of the treatment site isolate the treatment site in preparation for the administration of the therapeutic agents from the catheter in the region between the balloons. After inflation of the two balloons, the therapeutic agent may be locally introduced from apertures in the catheter. However, the inflation of the multiple catheter balloons may require undesirably extended inflation time and/or dwell time of the catheter. 
         [0007]    Some medical devices comprise catheters with a single balloon and a plurality of perforations or ports. For example, U.S. Pat. No. 5,112,305 to Barath, describes such a device, and related method of use, relating to a double lumen catheter having tubular extensions in communication with a drug-delivery and inflation lumen. The tubular extensions protrude at various angles from the outermost surface of the balloon. Upon inflation of the balloon in a body vessel, the tubular extensions penetrate the body vessel wall, and a therapeutic agent then is propelled through the tubular extensions into the wall of the body vessel. Although the tubular extensions may provide adequate sealing to localize the administration of the therapeutic agent within the body vessel wall, the projections may not ensure even administration of the therapeutic agent along the entire treatment site, and excessive amounts of the therapeutic agent may be needed to ensure adequate treatment. Furthermore, the inflation medium and the therapeutic agent are mixed together before being administered to the treatment site, preventing the simultaneous administration of different therapeutic agents from different tubular extensions. 
         [0008]    Another example of a catheter adapted for the localized administration of a therapeutic agent is U.S. Pat. No. 5,232,444 to Just et al., which describes a balloon catheter with a plurality of pore-like apertures in the balloon. The therapeutic agent is disposed inside the balloon with the dilating medium containing the therapeutic agent. One embodiment has a plurality of compartments within the balloon, which are sealed from one another with neighboring compartments accommodating different therapeutic agents. Although the porous balloon catheter can accommodate the simultaneous introduction of more than one therapeutic agent, the therapeutic agent(s) are administered through the pores of the balloon surface that are not embedded within the walls of the body vessel, permitting the therapeutic agent to be carried through the body vessel during the delivery process. This may require excessive amounts of therapeutic agent to ensure administration of adequate amount of the therapeutic agent to the wall of the body vessel. 
         [0009]    Angioplasty may also include an atherotomy procedure, or cutting balloon angioplasty. Cutting balloons conventionally consist of a plurality of cutting edges, or atherotomes, mounted longitudinally along the surface of an inflatable balloon. With dilation of the balloon at a treatment site within a body vessel, the cutting edges can score the plaque and can press fatty matter into the vessel wall. The dilation pressure of the cutting balloons is generally less than the dilation pressure of balloons used in PCTA. Also, less force may be applied to the vessel wall with less abruptness. Therapeutic agents can also be delivered to the treatment site after cutting balloon angioplasty. Once introduced, therapeutic agents can be locally introduced from the apertures of the infusion catheter. The therapeutic agents treat restenosis after the cutting balloon is removed. Nevertheless, the use of cutting balloons can damage and traumatize the body vessel wall to a degree of leading to restenosis. 
         [0010]    One example of a cutting balloon which incorporates the delivery of a therapeutic agent is U.S. Patent Application Pub. No. 2006/0259005 to Konstantino et al. Here, the methods and systems for providing a drug to a luminal site includes angioplasty balloon with scoring elements adapted to deliver a drug. The scoring elements can include a well or a horizontal through hole where the drug is applied to the elements before being introduced to the body lumen. After positioning the scoring elements at the luminal site, the scoring elements can engage the wall of the body lumen, which typically involves the radial expansion of an expandable shaft or balloon. Once the scoring elements are engaged into the wall of the body lumen, the drug can then be released. However, these systems and methods require a scoring of the body vessel wall prior to releasing the drug to locations in or beneath the intimal layer of the body vessel wall. The scoring members penetrate the wall of the body vessel to contain the released drug within the incision formed by the scoring process. While the scoring of the vessel wall permits delivery of the drug to intimal or subintimal layers surrounding the blood vessel, the scoring process also damages the vessel wall. This damage to the vessel wall may, in turn, lead to additional complications, such as thrombus formation or inflammation of the scoring site. What is needed are improved systems and methods for delivering a therapeutic agent to a body vessel using a catheter-based delivery system without the need to score the body vessel. 
         [0011]    There is a need for a medical device, and method of related use, capable of locally administering a therapeutic agent efficiently to a treatment site within a body vessel, for example to mitigate the occurrence of restenosis, tumor formation and thrombosis during or after angioplasty procedures. In particular, there is a need for a medical device adapted to disperse a therapeutically effective dose of a therapeutic agent to a localized area of a body vessel wall without substantial loss of the therapeutic agent from the treatment area. For example, medical devices adapted to release a therapeutic agent into a sealed area of the body vessel wall may be desirable for such an application. In addition, there is also a need for medical devices adapted to simultaneously administer desired amounts of multiple therapeutic agents to two separate treatment site areas within a single body vessel. When administering therapeutic agents into a vessel, it is more efficient to deliver the drug directly to the body vessel wall as opposed to infusing the lumen with a larger amount of the drug with the hope that enough of the therapeutic agent interacts with the body vessel wall before being transported further down the vessel by blood flow. Finally, there is also a need to provide catheter-based means for delivering one or more therapeutic agents a body vessel wall and maintaining the delivered therapeutic agent in intimate contact with the body vessel wall without cutting the body vessel wall. 
       BRIEF SUMMARY 
       [0012]    This present disclosure relates to medical devices and methods for locally administering therapeutic agents within a body vessel. The medical devices preferably include one balloon catheter with one or more conduits external to the balloon. The conduits preferably include drug delivery ports and may be configured to provide adequate sealing between the port and the body vessel wall, as well as sufficient penetration of the port within the body vessel wall. Moreover, the position and configuration of the conduits and location of the ports may be selected to provide local administration of the therapeutic agent evenly to an entire treatment site within the body vessel. The conduits may be formed from a material having a rigidity sufficient to permit the body vessel to enclose the conduit upon expansion of the balloon in a manner to force the conduit into the wall of the body vessel without cutting the wall of the body vessel. Other embodiments relate to providing more than one therapeutic agent simultaneously to the treatment site. 
         [0013]    According to a first embodiment, a therapeutic agent delivery system comprises a catheter shaft and a therapeutic agent delivery conduit. The catheter shaft has an expandable portion that is inflatable from a deflated configuration to an inflated configuration. The catheter shaft may extend along a longitudinal axis from a proximal end to a distal end and may include an inflation lumen in communication with the expandable portion. The therapeutic agent delivery conduit may include a therapeutic agent delivery lumen and also include a therapeutic agent delivery port in communication with the therapeutic agent delivery lumen. The therapeutic agent delivery conduit is preferably positioned external to the expandable portion of the catheter shaft and may contact at least a portion of an external surface of the expandable portion while the expandable portion is in the inflated configuration. The therapeutic agent delivery conduit desirably moves independently of the expandable portion while the expandable portion is in the deflated configuration. 
         [0014]    In a first aspect of the first embodiment, the therapeutic agent delivery system can comprise a plurality of therapeutic agent delivery ports. The plurality of ports are preferably located along one or more therapeutic agent conduits and can face radially away from the portion of the external surface of the expandable portion that contacts the therapeutic agent delivery conduit. Preferably, the plurality of therapeutic agent delivery ports are disposed longitudinally along the therapeutic agent delivery conduit(s) in a substantially straight line. Furthermore, the plurality of therapeutic agent delivery ports can include a first therapeutic agent delivery port located distally to a second therapeutic agent delivery port, where the first therapeutic agent delivery port has a larger cross-sectional area than the second therapeutic agent delivery port. 
         [0015]    In a second aspect of the first embodiment, the therapeutic agent delivery system can further comprise a second therapeutic agent delivery conduit. The second therapeutic agent delivery conduit includes a second therapeutic agent delivery lumen and also includes a second therapeutic agent delivery port in communication with the therapeutic agent delivery lumen. The second therapeutic agent delivery conduit is positioned external to the expandable portion of the catheter shaft and contacts at least a portion of an external surface of the expandable portion while the expandable portion is in the inflated configuration. The second therapeutic agent delivery conduit also moves independently of the expandable portion while the expandable portion is in the deflated configuration. 
         [0016]    In a third aspect of the first embodiment, the therapeutic agent delivery system can further comprise a distal tip. A distal end of the first therapeutic agent delivery conduit and a distal end of the second therapeutic agent delivery conduit are joined to form the distal tip. The distal tip is positioned distal to the expandable portion of the catheter shaft. Furthermore, the distal tip includes an annular opening adapted for receiving a guide wire and moves independently of the expandable portion in the deflated configuration. Additionally, the first portion of the external surface of the expandable portion and the second portion of the external surface of the expandable portion can be spaced such that a circumferential distance between each portion, measured perpendicular to the longitudinal axis, is substantially equal. 
         [0017]    In a fourth aspect of the first embodiment, a therapeutic agent delivery device comprises a first therapeutic agent delivery conduit, a second therapeutic agent delivery conduit, a distal tip, and a proximal base. The distal tip preferably joins the first and second therapeutic agent delivery conduits. The distal tip may also include an annular opening aligned along a longitudinal axis. The proximal base is separated proximally from the distal tip by a longitudinal distance. The proximal base joins the first and second therapeutic agent delivery conduits and is preferably adapted to receiving a catheter shaft. The first therapeutic agent delivery conduit and the second therapeutic agent delivery conduit are desirably separated from each other and are preferably adapted to move independently from each other between the distal tip and the proximal base. The first therapeutic agent delivery conduit may include a first therapeutic agent delivery lumen and also a therapeutic agent delivery port in communication with the first therapeutic agent delivery lumen. The second therapeutic agent delivery conduit may also include a second therapeutic agent delivery lumen and a second therapeutic agent delivery port in communication with the second therapeutic agent delivery conduit. Each therapeutic agent delivery conduit is preferably positioned at a radial distance from the longitudinal axis in a low-profile configuration. In the low-profile configuration, the longitudinal distance between the distal tip and the proximal base is at or near a maximum longitudinal separation distance. Each therapeutic agent delivery conduit is preferably configured to bend resiliently from a low-profile configuration to an expanded configuration upon longitudinal translation of the distal tip toward the proximal base along the longitudinal axis. Preferably, the radial distance of at least a portion of each therapeutic agent delivery conduit from the longitudinal axis increases when each therapeutic agent delivery conduit is moved from the low-profile configuration to the expanded configuration. 
         [0018]    In a second embodiment, methods of treatment are provided that relate to delivering a therapeutic agent(s) to an interior wall of a body vessel at or near a treatment site using a medical device described according to the first embodiment. In one aspect, methods of delivering a therapeutic agent delivery system are provided that include administration of a therapeutic agent from one or more therapeutic agent delivery ports in a therapeutic agent delivery conduit. The conduit may be attached to a catheter shaft having an expandable portion that is inflatable from a deflated configuration to an inflated configuration. The therapeutic agent delivery system may be inserted into a body vessel. A portion of the therapeutic agent delivery system may be translated within the body vessel until a therapeutic agent delivery conduit with the therapeutic agent delivery port is positioned proximate the treatment site within the body vessel. The expandable portion of the catheter shaft may be inflated within the body vessel until at least the portion of the external surface of the expandable portion contacts the therapeutic agent delivery conduit. The pressure of the expandable portion of the catheter shaft may be increased until the therapeutic agent delivery conduit is pressed into the wall of the body vessel. A therapeutic agent may be injected from the therapeutic agent delivery lumen through the therapeutic agent delivery port to the wall of the body vessel proximate the treatment site. A portion of the body vessel may enclose one or more ports in the conduit, permitting the injected therapeutic agent to remain in an interstitial space between the body vessel wall and the conduit port while the therapeutic agent diffuses into the body vessel wall tissue. In this manner, the therapeutic agent may be absorbed by the body vessel without scoring or cutting the wall of the body vessel. After treatment, the expandable portion of the catheter shaft may be deflated and the therapeutic agent delivery system removed from the body vessel. The therapeutic agent absorbed by the wall of the body vessel may diffuse slowly through multiple layers of the body vessel tissue after treatment, permitting the gradual administration of the therapeutic agent throughout the body vessel after removal of the conduit from the body vessel. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0019]    The following detailed description of certain exemplary embodiments can be understood when with reference to the following drawings, where like structure is indicated with like reference numerals and in which: 
           [0020]      FIG. 1  is a perspective view of a first therapeutic agent delivery system in the deflated configuration. 
           [0021]      FIG. 2  is a cross sectional view taken along line  2 - 2  of the first therapeutic agent delivery system in  FIG. 1 . 
           [0022]      FIG. 3  is a cross sectional view taken along line  3 - 3  of the first therapeutic agent delivery system in  FIG. 1 . 
           [0023]      FIG. 4   a  is a cross sectional view taken along line  4 - 4  of the first therapeutic agent delivery system in  FIG. 1  showing the inflation lumen coaxial with the guide wire and the therapeutic agent delivery lumen. 
           [0024]      FIG. 4   b  is a cross sectional view taken along line  4 - 4  of the first therapeutic agent delivery system in  FIG. 1  showing the inflation lumen and the therapeutic agent delivery lumen contained within the catheter shaft. 
           [0025]      FIG. 5  is a perspective view of a first therapeutic agent delivery system in the inflated configuration. 
           [0026]      FIG. 6  is a cross sectional view taken along line  6 - 6  of the first therapeutic agent delivery system in  FIG. 5 . 
           [0027]      FIG. 7  is a cross sectional view taken along line  7 - 7  of the first therapeutic agent delivery system in  FIG. 5 . 
           [0028]      FIG. 8  is an enlarged proximal portion of the first therapeutic agent delivery system of  FIG. 1  and  FIG. 5 . 
           [0029]      FIG. 9  is an enlarged proximal portion of the first therapeutic agent delivery system of  FIG. 1  and  FIG. 5 . 
           [0030]      FIG. 10  is an enlarged cut-away view of the distal portion of the first therapeutic agent delivery system of  FIG. 1  and  FIG. 5 . 
           [0031]      FIG. 11  is a perspective view of a second therapeutic agent delivery device in the low-profile configuration. 
           [0032]      FIG. 12  is a perspective view of the second therapeutic agent delivery device in the expanded configuration. 
           [0033]      FIG. 13  is a cross sectional view taken along line  13 - 13  of the second therapeutic agent delivery device in  FIG. 11 . 
           [0034]      FIG. 14  is a cross sectional view taken along line  14 - 14  of the second therapeutic agent delivery device in  FIG. 12 . 
           [0035]      FIG. 15  is a side elevation view, partially in section, of the second therapeutic agent delivery system in the inflated configuration being applied within the body vessel. 
           [0036]      FIG. 16  is a cross sectional view taken along line  16 - 16  of the second therapeutic agent delivery device in  FIG. 15 . 
       
    
    
     DETAILED DESCRIPTION 
       [0037]    As used herein, the term “implantable” refers to an ability of a medical device to be positioned at a location within a body, such as within a body vessel. Furthermore, the terms “implantation” and “implanted” refer to the positioning of a medical device at a location within a body, such as within a body vessel. 
         [0038]    The term “biocompatible” refers to a material that is substantially non-toxic in the in vivo environment of its intended use, and that is not substantially rejected by the patient&#39;s physiological system (i.e., is non-antigenic). This can be gauged by the ability of a material to pass the biocompatibility tests set forth in International Standards Organization (ISO) Standard No. 10993 and/or the U.S. Pharmacopeia (USP) 23 and/or the U.S. Food and Drug Administration (FDA) blue book memorandum No. G95-1, entitled “Use of International Standard ISO-10993, Biological Evaluation of Medical Devices Part-1: Evaluation and Testing.” Typically, these tests measure a material&#39;s toxicity, infectivity, pyrogenicity, irritation potential, reactivity, hemolytic activity, carcinogenicity and/or immunogenicity. A biocompatible structure or material, when introduced into a majority of patients, will not cause an undesirably adverse, long-lived or escalating biological reaction or response, and is distinguished from a mild, transient inflammation which typically accompanies surgery or implantation of foreign objects into a living organism. 
         [0039]    As used herein, the term “body vessel” means any body passage lumen that conducts fluid, including but not limited to blood vessels, esophageal, intestinal, billiary, urethral and ureteral passages. 
         [0040]    The medical devices of the embodiments described herein may be oriented in any suitable absolute orientation with respect to a body vessel. The recitation of a “first” direction is provided as an example. Any suitable orientation or direction may correspond to a “first” direction. For example, the first direction can be a radial direction in some embodiments. 
         [0041]      FIG. 1  and  FIG. 5  show an exemplary embodiment of a first therapeutic agent delivery system  10  comprising a catheter shaft  12  extending along a longitudinal axis  16  and a therapeutic agent delivery conduit  20 . The catheter shaft  12  has an expandable portion  14  which is inflatable from a deflated configuration (as shown in  FIG. 1 ) to an inflated configuration (as shown in  FIG. 5 ). The expandable portion  14  is preferably a balloon or other similar type structure used in the art for angioplasty treatment of a stenosis. The catheter shaft  12  includes an inflation lumen  15  in communication with the expandable portion  14 . The inflation of the expandable portion  14  is accomplished by any suitable means known in the art, e.g., by introducing an inflation fluid (e.g., air, saline, etc.) through the inflation lumen  15  into the expandable portion  14 . The catheter shaft  12  extends along the longitudinal axis  16  from a proximal end  17  to a distal end  18 . 
         [0042]    The expandable portion  14  comprises any suitably non-elastic material such as linear low density polyethylene, polyethyleneterephthalate (PET), polyurethanes, irradiated polyethylene, ionomers, copolyesters, rubbers, polyamides including nylons, polyester, or any medical grade polymers suitable for use in forming catheter balloons. Preferably, the geometry, material and configuration of the expandable portion  14  is selected to withstand an internal inflation fluid pressure of about 5 atmospheres and, preferably, about 10 atmospheres without any leakage or rupture. The thickness of the expandable portion  14  and the catheter shaft  12  should be selected to provide an expandable portion  14  that will exert sufficient force against the luminal wall without rupturing, while providing sufficient radial force to direct the conduit  20  into the body vessel wall. The expandable portion  14  and the catheter shaft  12  may have any suitable dimension, but is preferably shaped and configured for the intended use in a body vessel. The catheter shaft  12  preferably includes a lumen configured to house a guide wire  50 . For example, the guide wire  50  lumen of the catheter shaft  12  may have an inside diameter of about approximately 0.5 mm. The catheter shaft  12  may have any suitable length for an intended use, such as approximately 110-180 cm. The catheter shaft  12  may optionally be configured as a rapid exchange catheter, such as the catheter devices described in U.S. Pat. Nos. 5,690,642 and 5,814,061. In a rapid exchange configuration, the proximal terminus of the guide wire  50  lumen may be positioned distal to the proximal end  17  of the catheter shaft  12 . For example, the guide wire  50  lumen may extend from the distal end  18  of the catheter shaft  12  to a rapid exchange access port positioned at least 5, 10 or 15 cm distal to the distal end  17  of the catheter shaft  12 . The outside diameter of the catheter shaft  12  is typically approximately 1-1.5 mm. When configured for use in a peripheral blood vessel, the inflated diameter of the expandable portion  14  may be selected based on the diameter of a body vessel. Typically, the inflated diameter of the expandable portion  14  is at least about 1-5% greater than the diameter of the body vessel at a treatment site. For example, the expandable portion  14  may be placed at a treatment site that is a stenosis in a body vessel, and expanded to an outer diameter of about 1.5 mm to about 8 mm. For a treatment site intended for coronary vascular applications, the outer diameter of the expandable portion  14  preferably expands to an inflated diameter in the range of about 1.5 mm to about 4 mm. When configured for use in bile ducts, the expanded diameter of the expandable portion  14  may be about 5-15 mm with a length of approximately 15-60 mm, the outer diameter of the catheter shaft  12  may be up to about 3.5 mm. 
         [0043]    Referring again to  FIG. 1  and  FIG. 5 , the first therapeutic agent delivery system  10  further comprises a therapeutic agent delivery conduit  20 , which includes a therapeutic agent delivery lumen  22  in communication with a therapeutic agent delivery port  24 .  FIG. 7  is a cross sectional view taken along line  7 - 7  of the therapeutic agent delivery system as shown in  FIG. 5 . With reference to  FIG. 7 , the expandable portion  14  is inflated and the therapeutic agent delivery conduit  20  is positioned external to the expandable portion  14  and is in contact with at least a portion  23  of an external surface  13  of the expandable portion  14  while the expandable portion  14  is in the inflated configuration. Portions of the inflated expandable portion  14  may radially expand between the conduits  20 ,  30  and may urge the conduits  20 ,  30  radially outward from the longitudinal axis  16 . The therapeutic agent delivery conduit  20  can be disposed substantially parallel to the longitudinal axis  16  while the expandable portion  14  is in the deflated configuration, as shown in  FIG. 1 . Referring to  FIG. 1 , the therapeutic agent delivery conduit  20  is moveable independent of the expandable portion  14  while the expandable portion  14  is in the deflated configuration.  FIG. 3  is a cross sectional view taken along line  3 - 3  of the therapeutic agent delivery system in  FIG. 1 , with the expandable portion  14  deflated.  FIG. 3  shows the conduit  20  being spaced apart from the expandable portion  14  to permit independent movement of the therapeutic agent delivery conduit  20  from the expandable portion  14 . Optionally, as shown in  FIG. 3 , the therapeutic agent delivery conduit  20  may be radially spaced apart from the expandable portion  14  of the catheter shaft  12 . 
         [0044]    In one aspect of the first embodiment, the therapeutic agent delivery system  10  preferably includes multiple therapeutic agent delivery conduits  20 ,  30 . For example in the first therapeutic agent delivery system  10  shown in  FIG. 1  and  FIG. 5 , the system  10  contains a second therapeutic agent delivery conduit  30  along with two other conduits (one shown and one conduit being positioned behind the expandable portion  14  and not shown in  FIG. 1  or  FIG. 5 ). The second therapeutic agent delivery conduit  30  is preferably substantially similar or identical to the first therapeutic agent delivery conduit  20  except with respect to its position and orientation relative to the expandable portion  14  of the catheter shaft  12 . Similar to the first therapeutic agent delivery conduit  20 , the second therapeutic agent delivery conduit  30  preferably includes a second therapeutic agent delivery lumen  32  and a second therapeutic agent delivery port  34 . The second therapeutic agent delivery port  34  is in communication with the second therapeutic agent delivery lumen  32 . The second therapeutic agent delivery conduit  30  may be disposed substantially parallel to the longitudinal axis  16  while the expandable portion  14  is in the deflated configuration. As shown in  FIG. 7 , the second therapeutic agent delivery conduit  30  is positioned external to the expandable portion  14  and is in contact with at least a second portion  33  of an external surface  13  of the expandable portion  14  while the expandable portion  14  is in the inflated configuration. The second therapeutic agent delivery conduit  30  may be spaced apart from and moveable independent of the expandable portion  14  while the expandable portion  14  is in the deflated configuration.  FIG. 3  also shows the second conduit  30  being detached from, and spaced apart from, the expandable portion  14  to permit independent movement of the therapeutic agent delivery conduit  20  from the expandable portion  14 . 
         [0045]    The therapeutic agent delivery conduits may be oriented in any suitable direction with respect to the longitudinal axis  16 . In the first therapeutic agent delivery system  10 , the therapeutic agent delivery conduits  20 ,  30  are oriented substantially parallel to the longitudinal axis  16 . Alternatively, the therapeutic agent delivery conduits  20 ,  30  can also be arranged in a spiral pattern around the expandable portion  14  of the catheter shaft  12 . The conduit is preferably a separate tube from the expandable portion  14 . 
         [0046]    The therapeutic agent delivery conduits  20 ,  30  may be made of any material. Preferably, the material is selected to be more rigid than the material of the expandable portion  14 . Preferred materials are sufficiently rigid to maintain the patency of the lumens  22 ,  32  within the conduits  20 ,  30 , as well as the drug delivery ports  24 ,  34 , upon compression of the conduits  20 ,  30  between the expanded expandable portion  14  and the wall of a body vessel. The materials may be selected to have a rigidity that permits the conduits  20 ,  30  to maintain a substantially constant cross sectional shape and volume within the drug delivery lumen while passing a fluid comprising a therapeutic agent therethrough at a desired rate and pressure. Preferred materials are thermoformable medical-grade polymers such as polyethylene or polyurethane polymers or co-polymers. Optionally, the therapeutic agent delivery conduits may include a radiopaque material permitting identification of the location and orientation of the conduit(s) within a body vessel by a suitable medical imaging technique such as fluoroscopy. 
         [0047]    In the therapeutic agent delivery system  10  of  FIG. 1  and  FIG. 5 , the conduit  20  may have a plurality of therapeutic agent delivery ports  24 , as well as the conduit  30  may have a plurality of therapeutic agent delivery ports  34 . Other embodiments can have one therapeutic agent delivery port  24 . Ports  24 ,  34  are desirably arranged and oriented away from the expandable portion  14 . In use, inflation of the expanded portion  14  of the catheter shaft  12  presses the conduit  20  into the body vessel wall. A therapeutic agent may be injected into the therapeutic agent delivery lumen  22  of the conduit  20 ,  30  and released at the treatment site within the portion of the body vessel radially distended away from the longitudinal axis  16  by the conduits  20 ,  30 . Upon inflation of the expandable portion  14 , the ports  24 ,  34  can face away from the portion  23  of the external surface  13  of the expandable portion  14  that is in contact with the therapeutic agent delivery conduit  20 ,  30  as shown in  FIG. 7 . Furthermore, the ports  24 ,  34  can be disposed longitudinally along the conduit  20 ,  30 , for example in a substantially straight line as shown in  FIG. 1  and  FIG. 5 . The ports  24  can be located along on only a portion  29  of the therapeutic agent delivery conduit  20 . A portion  29  comprising the ports  24  may be positioned external to the expandable portion  14  of the catheter shaft  12  and can be disposed substantially parallel to the longitudinal axis  16  while the expandable portion  14  is in the deflated configuration ( FIG. 1 ). 
         [0048]    In another aspect of the first embodiment of the therapeutic agent delivery system  10  may include ports  24  having different cross-sectional areas. Preferably, the cross-sectional area of the ports  24  increase moving in the distal direction along the longitudinal axis  16  to compensate for the fluid pressure losses associated with the walls of the conduit  20  and the ports  24  and to provide a more evenly distribution of the release of the therapeutic agent at the treatment site. As shown in  FIG. 1 , a first therapeutic agent delivery port  24   a  located distally to a second therapeutic agent delivery port  24   b . The first therapeutic agent delivery port  24   a  may have a larger cross-sectional area than the second therapeutic agent delivery port  24   b . Similarly, the plurality of ports  34  may include a distal therapeutic agent delivery port  34   a  located distally to proximal therapeutic agent delivery port  34   b . The distal therapeutic agent delivery port  34   a  may have a larger cross-sectional area than the proximal therapeutic agent deliver port  34   b . The plurality of ports  34  may be similarly sized and situated as the plurality of ports  24 , or may be differently sized or situated. The therapeutic agent delivery ports  24 ,  34  can be made in any traditional manner, preferably with either sideport machine or drill. Further with respect to accommodating fluid pressure losses and providing even distribution, the lumens  22 ,  32  may also have portions of different cross-sectional areas. For example, the cross-sectional area of the lumens  22 ,  32  may decrease or taper distally along the lumen. 
         [0049]    The expandable portion  14  may have a longitudinally curved external surface  27  while in the inflated configuration, as shown in  FIG. 5 . Inflation of the expandable portion  14  from the deflated configuration to the inflated configuration may bend the therapeutic agent delivery conduit  20  from a substantially straight configuration  26   a  (as shown in  FIG. 1 ) to a substantially arcuate configuration  26   b  (as shown in  FIG. 5 ) along the longitudinally curved external surface  27  of the expandable portion  14  in the inflated configuration. 
         [0050]    Preferably, the catheter shaft  12  houses one or more therapeutic agent delivery lumens  22  in communication one or more therapeutic agent delivery conduits  20  and a separate inflation lumen  15  in communication with the expandable portion  14 . At least a portion of the catheter shaft  12  may contain a third lumen adapted to receive a guide wire  50  or stiffening member. The catheter shaft  12  may alternatively be configured as a rapid exchange catheter (not shown).  FIG. 4   a  and  FIG. 4   b  are cross sectional views taken along line  4 - 4  of the therapeutic agent delivery system in  FIG. 1  showing two different examples of suitable catheter shaft  12  configurations. The proximal portion  62  of the catheter shaft  12  shown in  FIG. 1  and  FIG. 5  extends from a proximal end  19  of the expandable portion  14  to the proximal end  17  of the catheter shaft  12 . Therein, the therapeutic agent delivery lumen  22  and the inflation lumen  15  may be coaxially oriented along the longitudinal axis  16  from the proximal end  17  of the catheter shaft  12  to the proximal end  19  of the expandable portion  14  as shown in  FIG. 4   a . Alternatively,  FIG. 4   b  is a cross sectional view taken along line  4 - 4  of the therapeutic agent delivery system in  FIG. 1  showing the inflation lumen  15  and the therapeutic agent delivery lumen  22  arranged side-by-side with the lumen housing the guide wire  50  within the catheter shaft  12 . 
         [0051]      FIG. 8  and  FIG. 9  are detailed cut-away views of two different proximal end  19  configurations of the expandable portion  14  shown in  FIG. 1  and  FIG. 5 . In  FIG. 8 , a first configuration of the proximal portion  62  of the catheter shaft  12  can include a portion of a single therapeutic agent delivery lumen  22  proximal to, and in communication with, the therapeutic agent delivery conduit  20 . Alternatively, in  FIG. 9 , a second configuration of the proximal portion  62  of the catheter shaft  12  can include more than one therapeutic agent delivery lumen  22 ,  32  proximal to, and in communication with, each respective therapeutic agent delivery conduit  20 ,  30 . The second configuration ( FIG. 9 ) permits therapeutic agents to be delivered to different conduits from separate therapeutic agent delivery lumens  22 ,  32  simultaneously, whereas a single first configuration ( FIG. 8 ) delivers a single stream of the therapeutic agent from one therapeutic agent delivery lumen  22  to multiple conduits  20 . In both of the configurations shown in  FIG. 8  and  FIG. 9 , the inflation medium and the therapeutic agent are isolated from each other because of the separate walls of the lumen  15  of the catheter shaft and the lumen  22  of the therapeutic agent delivery conduit  20 . Also, because more than one therapeutic agent delivery conduit  20 ,  30  are present in  FIG. 9 , more than one therapeutic agent can be administered simultaneously to the treatment site. As a result, multiple therapeutic agents can be delivered to the treatment site. 
         [0052]      FIG. 10  is a cut-away view of a distal tip  40  positioned at the distal end of the medical device shown in  FIGS. 1-9 .  FIG. 2  is a cross sectional view of a distal tip  40  taken along line  2 - 2  of the therapeutic agent delivery system in  FIG. 1  and  FIG. 6  is a cross sectional view of a distal tip  40  taken along line  6 - 6  of the therapeutic agent delivery system in  FIG. 5 .  FIG. 2 ,  FIG. 6  and  FIG. 10  further illustrate the distal tip  40  formed where a distal end  43  of the first therapeutic agent delivery conduit  20  and a distal end  44  of the second therapeutic agent delivery conduit  30  are joined. The distal tip  40  is positioned distal to the expandable portion  14  of the catheter shaft  12 . The distal tip  40  includes an annular opening  42  adapted for receiving a guide wire  50 . 
         [0053]    The distal tip  40  is preferably unattached to the expandable portion  14 . The distal tip  40  is also preferably moveable independent of the expandable portion  14  in the deflated configuration. For example, the distal tip  40  may be longitudinally moveable with respect to the expandable portion  14  and the catheter shaft  12 . The distal tip  40  is preferably joined to one or more of the conduits  20 ,  30 . Most preferably, all of the conduits  20 ,  30  are joined together at the distal tip  40 , without being attached to the expandable portion  14 . Upon inflation of the expanded portion  14  of the catheter shaft  12  and subsequent radial expansion of the conduits  20 ,  30  away from the longitudinal axis  16 , the distal tip  40  may translate longitudinally toward the proximal end  19 , as represented by arrows  36 . As shown in  FIG. 10 , the distal tip  40  is preferably adapted to translate longitudinally along the guide wire  50 , substantially parallel to the longitudinal axis  16  of the catheter shaft  12 . Alternatively, in alternative embodiments, the distal tip  40  may be attached to the distal end of the expandable portion  14 , and the conduits  20 ,  30  may have sufficient elasticity to allow for expansion of the conduits  20 ,  30  with respect to each other without cracking or breaking the distal tip  40 . 
         [0054]    The first therapeutic agent delivery system  10  may include any suitable number of conduits, including one, two, three, four, five, six, seven, eight or more conduits. Preferably, the conduits are substantially equally spaced with respect to one another around the circumference of the inflated expandable portion  14 . In other words, the radial angle from the longitudinal axis  16  between the centers of adjacent conduits is preferably 2 π/n radians, where n is an integer equal to the total number of conduits (e.g., n=1, 2, 3, 4, 5, 6, 7, 8 or more). As shown in  FIG. 7 , a first portion  23  and a second portion  33  of the external surface  13  of the expandable portion  14  can be spaced such that a circumferential distance  38  between each portion, measured perpendicular to the longitudinal axis, is substantially equal. Equal spacing will likely produce better local distribution of the therapeutic agent along the entire treatment site. However, the circumstantial distance  38  need not be substantially equal. Alternatively, one or more of the conduits may also be oriented helically around the expandable portion, instead of parallel to the longitudinal axis. 
         [0055]      FIGS. 11-15  show a second therapeutic agent delivery device  110 , without a balloon catheter. Optionally, the second therapeutic agent delivery device  110  may be configured for use with a balloon catheter having one or more different sizes as part of a kit.  FIG. 11  is a perspective view of the second therapeutic agent delivery device  110  in the low-profile configuration and  FIG. 12  is a perspective view of the second therapeutic agent delivery device  110  in the expanded configuration, when expanded by an expandable portion  114  (optionally supplied) of a catheter (not shown) along a guidewire  150  (optionally supplied). Alternatively, the second therapeutic agent delivery device  110  may be moved from the low-profile configuration in  FIG. 11  to the expanded configuration in  FIG. 12  by translating the distal tip  40  in the proximal direction along the guide wire  250 . For example, a restraining means such as a tether or wire may be attached to the distal tip  40  and extend through the catheter shaft. By pulling on the restraining means, a user may longitudinally translate the distal tip  40  toward the proximal base  146 , bowing the conduits  20  radially outward from the longitudinal axis to assume the expanded configuration shown in  FIG. 12 . 
         [0056]    Referring to  FIG. 11  and  FIG. 12 , a preferred embodiment of a therapeutic agent delivery device  110  comprises a first therapeutic agent delivery conduit  120 , a second therapeutic agent delivery conduit  130 , or more therapeutic agent delivery conduits, a distal tip  140 , and a proximal base  146 , which are substantially similar to the corresponding portions of the first therapeutic agent delivery device  10  described above. The distal tip  140  joins the first and second therapeutic agent delivery conduits  120 ,  130  and includes an annular opening  142  aligned along a longitudinal axis  116 . The proximal base  146  is separated proximally from the distal tip  140  by a longitudinal distance  170  and joins the first and second therapeutic agent delivery conduits  120 ,  130 . The proximal base  146  is also adaptable for receiving a catheter shaft (not shown) with the expandable portion  114  (optionally supplied) along a guide wire  150  (optionally supplied). The first and second therapeutic agent delivery conduits  120 ,  130  are separated from each other and moveable independent of each other between the distal tip  140  and the proximal base  146 . 
         [0057]      FIG. 13  is a cross sectional view taken along line  13 - 13  of the therapeutic agent delivery device in  FIG. 11 . As shown in  FIG. 13 , each therapeutic agent delivery conduit  120 ,  130  is positioned at a radial distance  180  from the longitudinal axis  116  when each therapeutic agent delivery conduit  120 ,  130  is in a low-profile configuration and the longitudinal distance  170  of the distal tip  140  and the proximal base  146  is at a maximum distance ( FIG. 11 ).  FIG. 14  is a cross sectional view taken along line  14 - 14  of the therapeutic agent delivery device in  FIG. 12 . As shown in  FIG. 14 , each therapeutic agent delivery conduit  120 ,  130  resiliently bends from the low-profile configuration ( FIG. 11 ) to an expanded configuration ( FIG. 12 ) upon longitudinal translation of the distal tip  140  toward the proximal base  146  along the longitudinal axis  116 . A portion  126  of the therapeutic agent delivery conduit is shown to bend resiliently in  FIG. 12 . When the distal tip  140  translates toward the proximal base  146  from a maximal longitudinal distance  170  to a smaller distance by proximal translation along a longitudinal distance  171 , the radial distance  180  from the longitudinal axis  116  of each therapeutic agent delivery conduit increases to larger radial distance by an increased radial distance  181 . When this occurs, each therapeutic agent delivery conduit  120 ,  130  bends from the low-profile configuration ( FIG. 11 ) to the expanded configuration ( FIG. 12 ). 
         [0058]      FIG. 11  and  FIG. 12  further depict the first therapeutic agent delivery conduit  120  having a first therapeutic agent delivery lumen  122  and a first therapeutic agent delivery port  124 . The first therapeutic agent delivery port  124  is in communication with the first therapeutic agent delivery lumen  122 . The first therapeutic agent delivery port  124  faces away from the second therapeutic agent delivery conduit  130 . The second therapeutic agent delivery conduit  130  includes a second therapeutic agent delivery lumen  132  and a second therapeutic agent delivery port  134 . The second therapeutic agent delivery port  134  is in communication with the second therapeutic agent delivery lumen  132 . The second therapeutic agent delivery port  134  faces away from the first therapeutic agent delivery conduit  120 . 
         [0059]    Preferably, one or more of the therapeutic agent delivery conduits  120 ,  130  can include a plurality of therapeutic agent delivery ports  124 ,  134 . The ports  124 ,  134  may be disposed or sized similarly to ports  24 ,  34  as discussed previously. The ports  124 ,  134  can have different cross sectional areas. For example, the plurality of ports  124  may include a distal therapeutic agent delivery port  124   a  located distally to a proximal therapeutic agent delivery port  124   b . The distal therapeutic agent delivery port  124   a  may have a larger cross-sectional area than the proximal therapeutic agent delivery port  124   b . Similarly, the plurality of ports  134  may include a distal therapeutic agent delivery port  134   a  located distally to proximal therapeutic agent delivery port  134   b . The distal therapeutic agent delivery port  134   a  may have a larger cross-sectional area than the proximal therapeutic agent deliver port  134   b . The plurality of ports  134  may be similarly sized and situated as the plurality of ports  124 , or may be differently sized or situated. Further with respect to accommodating fluid pressure losses and providing even distribution, the lumens  122 ,  132  may also have portions of different cross-sectional areas. For example, the cross-sectional area of the lumens  122 ,  132  may decrease or taper distally along the lumen from the proximal base  146  or proximal end  117 . Alternatively, the cross-sectional area of the lumens  122 ,  132  may increase or enlarge distally along the lumen from the proximal base  146  or proximal end  117 . 
         [0060]    The second therapeutic agent delivery device  110  may further comprise a drug delivery conduit  190  extending in the proximal direction from the proximal end  117 . The drug delivery conduit  190  defines a third therapeutic agent delivery lumen  192  that is in communication with the first therapeutic agent delivery lumen  122 . The third therapeutic agent delivery lumen  192  also can be in further communication with the second therapeutic agent delivery lumen  132 . 
         [0061]    As shown in  FIG. 11  and  FIG. 12 , the second therapeutic agent delivery device  110  is adapted to receive one or more differently-sized catheter shafts. The catheter shaft may be placed between the conduits  120 ,  130  with an expandable catheter portion placed between the therapeutic agent delivery conduits  120 ,  130  and the distal tip  140  securable within the distal tip  140 . In one aspect, kits comprising one or more catheters comprising an expandable portion may be combined with a therapeutic agent delivery device  110 . The kit can also comprise a catheter shaft comprising an expandable portion similar to the therapeutic agent delivery system  10  discussed previously. The expandable portion of a catheter may be positioned between two or more of the conduits  120 ,  130  and between the proximal base  146  and the distal tip  140 , where the expandable portion may be inflated from a deflated configuration to an inflated configuration within a body vessel. The catheter shaft may extend from a proximal end  117  of the drug delivery conduit  190  along the longitudinal axis  116  to a distal end  118  positioned between the distal tip  140  and the expandable portion. The catheter shaft also may contact the proximal base  146  between the expandable portion and the proximal end  117 . The catheter shaft also includes an inflation lumen in communication with the expandable portion and extends from the proximal end  117  to the expandable portion. 
         [0062]    In a second embodiment, methods of delivering a therapeutic agent to a body vessel are provided. The methods include the step of inserting a therapeutic delivery system, such as the systems described with respect to the first embodiment above, within a body vessel in a low-profile (radially compressed) configuration. The therapeutic agent delivery system preferably includes at least one conduit moveable from the low-profile configuration to an expanded configuration within a body vessel. The conduit contains one or more ports configured and adapted to release a therapeutic agent. In the expanded configuration, the conduit is adapted to release the therapeutic agent through one or more ports into direct contact with the wall of a body vessel, preferably without cutting or scoring the wall of the body vessel. The conduit may be pressed into the body vessel in the expanded configuration so as to shape the body vessel around the conduit, causing the body vessel to continuously wrap around a portion of the conduit having a port. The therapeutic agent may be expelled through the port at a pressure sufficient to further distend the wall of the body vessel, creating a sinus region containing the therapeutic agent. During and after ejecting the therapeutic agent through the port, the conduit may be maintained in the expanded configuration for a period of time effective to permit absorption of the therapeutic agent into portions of the body vessel contacting the conduit or forming the sinus region surrounding the ejected therapeutic agent. The therapeutic agent may be ejected from the port with a pressure adequate to distend a portion of the body vessel wall contacting or wrapping around the conduit, forming a sinus containing the therapeutic agent trapped between the body vessel wall and the conduit, without scoring or cutting the wall of the body vessel. The conduit(s) of the medical device may be moved from the low-profile configuration to the expanded configuration my any suitable means, such as expansion of an expandable member (e.g., a catheter balloon) enclosed by one or more conduit(s), or a means for longitudinally translating a distal tip toward the proximal end, therby bowing the conduit arm(s) radially outward into the expanded configuration. 
         [0063]    In one aspect of the second embodiment, the therapeutic agent is delivered to an interior wall  201  of a body vessel  230  at or near a treatment site  200  are provided, as shown in  FIG. 15  and  FIG. 16 .  FIG. 16  is a cross sectional view taken along line  16 - 16  of the second therapeutic agent delivery device  210  in  FIG. 15 . The therapeutic agent delivery system  210  may be configured as described with respect to the first embodiment ( 10 ,  110 ), preferably comprising a catheter shaft and at least one therapeutic agent delivery conduit  220 . Optionally, the catheter shaft may include an expandable portion  214  that is inflatable from a deflated configuration to an inflated configuration. Furthermore, the catheter shaft extends along a longitudinal axis  216  from a proximal end to a distal end and includes an inflation lumen in communication with the expandable portion  214 . The therapeutic agent delivery conduit  220  includes a therapeutic agent delivery lumen  222  and also includes a therapeutic agent delivery port  224  in communication with the therapeutic agent delivery lumen  222 . The therapeutic agent delivery conduit  220  is positioned external to the expandable portion  214  of the catheter shaft  212  and contacts at least a portion of an external surface of the expandable portion  214  while the expandable portion  214  is in the inflated configuration. The therapeutic agent delivery conduit  220  preferably moves independently of the expandable portion  214  while the expandable portion  214  is in the deflated configuration. 
         [0064]    The therapeutic agent delivery system  210  may be inserted into a body vessel by any suitable technique. Typically, the therapeutic agent delivery system  210  is inserted by being pushed along a guide wire  250  already inserted into the body vessel. A portion of the at least one therapeutic agent delivery conduit  220 , which contacts the external surface of the expandable portion  214  in the inflated configuration and has the therapeutic agent delivery port  224 , is positioned proximate the treatment site  200 . The treatment site  200  is typically within an artery or vein, preferably a peripheral vascular site in the arms or legs. Examples of suitable peripheral arterial vascular sites include: iliac arteries, femoropopliteal arteries, infrapopliteal arteries, femoral arteries, superficial femoral arteries, popliteal arteries, and the like. Alternatively, the treatment site  200  is present in a heart associated vessel, e.g. the aorta, a coronary artery or branch vessel thereof, or a carotid artery or a branch vessel thereof. In one example, the present invention can be used in contralateral superficial femoral artery (SFA) vessel advancement for critical limb salvage cases, which may be particularly useful in treating diabetic patients. Similarly, the present invention can be used to affect various procedures in the abdominal or femoral arteries, and can be used to treat occlusive peripheral vascular disease, critical limb ischemia, and other related conditions. The medical devices described with respect to the first embodiment may be placed in a body vessel to treat peripheral vascular disease, for example by releasing a therapeutic agent within a peripheral blood vessel. Peripheral vascular disease (PVD) is a common condition with variable morbidity affecting mostly men and women older than 50 years. Peripheral vascular disease of the lower extremities comprise a clinical spectrum that goes from asymptomatic patients, to patients with chronic critical limb ischemia (CLI) that might result in amputation and limb loss. Methods of treating peripheral vascular disease, including critical limb ischemia, preferably comprise the endovascular implantation of one or more coated medical devices provided herein. Atherosclerosis underlies many cases of peripheral vascular disease, as narrowed vessels that cannot supply sufficient blood flow to exercising leg muscles may cause claudication, which is brought on by exercise and relieved by rest. As vessel narrowing increases, critical limb ischemia (CLI) can develop when the blood flow does not meet the metabolic demands of tissue at rest. While critical limb ischemia may be due to an acute condition such as an embolus or thrombosis, most cases are the progressive result of a chronic condition, most commonly atherosclerosis. The development of chronic critical limb ischemia usually requires multiple sites of arterial obstruction that severely reduce blood flow to the tissues. Critical tissue ischemia can be manifested clinically as rest pain, nonhealing wounds (because of the increased metabolic requirements of wound healing) or tissue necrosis (gangrene). 
         [0065]    Once placed at the treatment site  200 , the expandable portion  214  of the catheter shaft is inflated. The inflation may be performed in a therapeutically effective manner. For example, the inflation may be performed gradually for about 1 minute to 10 minutes to about 30 minutes in stepped increments until at least the portion of the external surface of the expandable portion  214  contacts the at least one therapeutic agent delivery conduit  220 , as shown in  FIG. 16 . Then the pressure of the expandable portion  214  of the catheter shaft may be increased until the at least one therapeutic agent delivery conduit  220  is pressed into a portion  240  of the wall  201  of the body vessel as shown in  FIG. 15  and  FIG. 16 . By pressing the at least one conduit  220  into the body vessel wall  201 , not only does the expandable portion  214  of the catheter shaft seal and prevent blood flow, but also a seal is created in between the at least one conduit  220  and the body vessel wall  201 . A therapeutic agent can then be injected into the therapeutic agent delivery lumen  222  to release the therapeutic agent through the therapeutic agent delivery port  224  to the wall  201  of the body vessel proximate the treatment site  200 . The seal between the at least one conduit  220  and the body vessel wall  201  directs the therapeutic agent into the body vessel wall  201 . In addition, with the pressing of the at least one conduit  220  into the body vessel wall  201 , sufficient penetration of the body vessel wall  201  is achieved, thereby allowing the effective administration of the therapeutic agent into the body vessel. The at least one therapeutic agent delivery conduit  220  also provides areas of increased pressure to the treatment site  200 . Inducing higher stress upon the treatment site  200  would help disrupt plaque buildup. Preferably, these areas of increased pressure would not be “sharp” enough to perforate the body vessel wall  201  or cause undesired harm. After treatment, the expandable portion  214  of the catheter shaft is deflated and the therapeutic agent delivery system  210  is removed from the body vessel. 
         [0066]    Alternatively, the method of delivering one or more therapeutic agents can be delivered with a therapeutic agent delivery system  210  with at least two therapeutic agent delivery conduits  220 . Referring to  FIGS. 15 and 16 , the therapeutic agent delivery system  210  can include at least one at least one first therapeutic agent delivery conduit  220  including a first therapeutic agent delivery lumen  222  and a port  224  in communication with the first therapeutic agent delivery lumen  222 . The at least one first therapeutic agent delivery conduit  220  can be positioned external to the expandable portion  214  of the catheter shaft and moveable independent of the expandable portion  214  in the deflated configuration. The port  224  of the at least one first therapeutic agent delivery conduit  220  can face away from a first portion of an external surface of the expandable portion  214  of the catheter shaft for contacting the at least one first therapeutic agent delivery conduit  220  when the expandable portion  214  is in the inflated configuration. Moreover, the therapeutic agent delivery system  210  can also include at least one second therapeutic agent delivery conduit  220  including a second therapeutic agent delivery lumen  232  and a port  234  in communication with the second therapeutic agent delivery lumen  232 . The at least one second therapeutic agent delivery conduit  220  can be positioned external to the expandable portion  214  of the catheter shaft and moveable independent of the expandable portion  214  in the deflated configuration. The port of the at least one second therapeutic agent delivery conduit  220  can face away from a second portion of the external surface of the expandable portion of the catheter shaft for contacting the at least one second therapeutic agent delivery conduit when the expandable portion is in the inflated configuration. 
         [0067]    Once placed at the treatment site  200 , the expandable portion  214  of the catheter shaft may be inflated for about 1 minute to about 30 minutes in stepped increments until at least the portion of the external surface of the expandable portion  214  contacts the at least one of the first and second therapeutic agent delivery conduits  220 , as shown in  FIG. 16 . Other suitable inflation times include 5, 10, 15, and 25 minutes. Then the pressure of the expandable portion  214  of the catheter shaft may be increased until the at least one first and second therapeutic agent delivery conduits  220  are pressed into a portion  240  of the wall  201  of the body vessel as shown in  FIG. 15  and  FIG. 16 . By pressing the at least one first and second conduits  220  into the body vessel wall  201 , not only does the expandable portion  214  of the catheter shaft seal and prevent blood flow, but a seal may also be created between the at least one first and second conduits  220  and the body vessel wall  201 . A therapeutic agent can then be injected into the at least one therapeutic agent delivery lumens  222 ,  232  to release the therapeutic agent through the therapeutic agent delivery port  224 , port  234 , or both to the wall  201  of the body vessel proximate the treatment site  200 . The seal between the at least one first and second conduits  220  and the body vessel wall  201  directs the therapeutic agent into the body vessel wall  201 . A therapeutically effective rate of ejection of the therapeutic agent through the ports  224 ,  234  may be selected. For instance, ejection of the therapeutic agent may distend the wall of the body vessel radially outward away from the ports  224 ,  234 , forming a sinus region that retains the therapeutic agent between the conduit  220  and the portion of the body vessel wall  201  wrapped around the conduit  220 . By pressing the at least one first and second conduits  220  into the body vessel wall  201 , sufficient penetration of the body vessel wall  201  is achieved to allow the effective administration of the therapeutic agent into the body vessel without scoring or cutting the body vessel wall  201 . The at least one first and second therapeutic agent delivery conduits  220  also provide areas of increased pressure to the treatment site  200 . Inducing higher stress upon the treatment site  200  would help disrupt plaque buildup. Preferably, these areas of increased pressure would not be “sharp” enough to perforate the body vessel wall  201  or cause undesired harm. After treatment, the expandable portion  214  of the catheter shaft is deflated and the therapeutic agent delivery system is removed from the body vessel. 
         [0068]    A second therapeutic agent, or more, can also be injected into the second therapeutic delivery lumen  232  of the at least one second therapeutic agent delivery conduit  220 . The second therapeutic agent can be released through the port  234  to the body vessel wall  201  proximate the treatment site. Preferably, the first and second therapeutic agent delivery lumens  222 ,  232  are isolated from one another where it is desirable to introduce at least two therapeutic agents to the treatment site simultaneously, or shortly thereafter. In one embodiment, the at least one first and second therapeutic agent delivery conduits  220  circumferentially alternate about the expandable portion when inflated. This embodiment will allow a more effective and equal distribution of the first and second therapeutic agents throughout the body vessel wall  201 . Alternatively, the at least one first and second therapeutic agent delivery conduits  220  may not circumferentially alternate about the expandable portion  214  when inflated, but instead may be grouped. In this embodiment, it may be more desirable to deliver two therapeutic agents in isolation to two different regions of the body vessel wall  201 . The at least one first and second therapeutic agent delivery conduits  220  may also be circumferentially spaced apart from one another by a circumferential distance  238  measured perpendicular to the longitudinal axis  216  when the expandable portion  214  is in the inflated configuration. Preferably, the circumferential distances  238  are substantially equal. 
         [0069]    These methods of locally administering therapeutic agents with the therapeutic agent delivery system  210  described herein could eliminate the need of cutting balloons with cutting balloon angioplasty, and eliminate the additional steps of providing an infusion catheter delivering therapeutic agents. The methods of treatment may be performed without one or more of the following steps: (i) inserting the cutting balloon and manipulating the cutting balloon to score the body vessel wall to accommodate the release of the therapeutic agent beneath the surface of the body vessel wall or (ii) inserting the infusion catheter to deliver a therapeutic agent to the body vessel wall, and preferably, to scored regions underneath the body vessel wall. In contrast, the preferred methods of treatment can be performed without requiring these steps. Instead of scoring, the method of increasing pressure to the at least one of the first and second therapeutic agent delivery conduits  220  can provide areas of increased pressure to the treatment site  200 . Inducing higher stress upon the treatment site  200  would help disrupt plaque buildup. Preferably, these areas of increased pressure would not be “sharp” enough to perforate the body vessel wall  201  or cause undesired harm or trauma, unlike scoring with cutting balloons. Furthermore, during the inflation of the expandable portion  214 , therapeutic agents can be introduced to perform multiple functions including modulating angiogenesis, restenosis, cell proliferation, thrombosis, platelet aggregation, clotting, and vasodilation to prepare the region for the penetration of conduits. Additionally, after suitable inflation, subsequent therapeutic agents can be delivered to perform multiple functions including modulating angiogenesis, restenosis, cell proliferation, thrombosis, platelet aggregation, clotting, and vasodilation during the engagement of the therapeutic agent delivery system  210  or to perform such functions after the removal of the therapeutic agent delivery system  210 . 
         [0070]    The following are particularly preferred methods. In one example, a method of delivering a therapeutic agent to an interior wall of a body vessel at or near a treatment site, the method comprising the steps of: 
         [0071]    (a) inserting a therapeutic agent delivery system into a body vessel, the therapeutic agent delivery system comprising:
       (i) a catheter shaft having an expandable portion being inflatable between a deflated configuration and an inflated configuration, the catheter shaft extending along a longitudinal axis from a proximal end to a distal end and including an inflation lumen in communication with the expandable portion, and   (ii) a therapeutic agent delivery conduit including a therapeutic agent delivery lumen and a port in communication with the therapeutic agent delivery lumen; the therapeutic agent delivery conduit positioned external to the expandable portion of the catheter shaft and moveable independent of the expandable portion in the deflated configuration;       
 
         [0074]    (b) positioning a portion of the therapeutic agent delivery conduit having the port proximate the treatment site; 
         [0075]    (c) inflating the expandable portion of the catheter shaft until at least a portion of the external surface of the expandable portion contacts the therapeutic agent delivery conduit; and 
         [0076]    (d) injecting a therapeutic agent into the therapeutic agent delivery lumen of the therapeutic agent delivery conduit to release the therapeutic agent through the port to a wall of the body vessel proximate the treatment site. 
         [0077]    This method may further comprise one or more of the following steps: (1) the step of increasing the pressure of the expandable portion of the catheter shaft until the therapeutic agent delivery conduit is pressed into the body vessel wall and the port is sealably engaged with the body vessel wall; and/or (2) deflating the expandable portion of the catheter shaft, and removing the therapeutic agent delivery system from the body vessel. 
         [0078]    Optionally, the therapeutic agent delivery system further comprises a plurality of therapeutic agent delivery conduits each including a therapeutic agent delivery lumen and a port in communication with said therapeutic agent delivery lumen; each therapeutic agent delivery conduit positioned external to the expandable portion of the catheter shaft and moveable independent of the expandable portion in the deflated configuration. A portion of each therapeutic agent delivery lumen of the plurality of therapeutic agent delivery conduits may be in fluid communication. The therapeutic agent delivery conduit may further comprise a plurality of ports in communication with the therapeutic agent delivery lumen and facing away from the portion of the external surface of the expandable portion for contacting the therapeutic agent delivery conduit. The plurality of ports may be disposed longitudinally along the therapeutic agent delivery conduit in a substantially straight line. The plurality of ports may include a first port located distally to a second port, the first port having a larger cross-sectional area than the second port. The catheter shaft may have a proximal portion extending from a distal end of the expandable portion to the proximal end of the catheter shaft, and where the therapeutic agent delivery conduit and the catheter shaft may be coaxially oriented about the longitudinal axis at said proximal portion. In addition, the catheter shaft may have a proximal portion extending from a distal end of the expandable portion to the proximal end of the catheter shaft, said proximal portion including a portion of the therapeutic agent delivery lumen proximal to, and in communication with, the therapeutic agent delivery conduit. 
         [0079]    In another example, a method of delivering a therapeutic agent to an interior wall of a body vessel at or near a treatment site, the method comprising the steps of: 
         [0080]    (a) inserting a therapeutic agent delivery system into a body vessel, the therapeutic agent delivery system comprising:
       (i) a catheter shaft having an expandable portion being inflatable between a deflated configuration and an inflated configuration, the catheter shaft extending along a longitudinal axis from a proximal end to a distal end and including an inflation lumen in communication with the expandable portion,   (ii) at least one first therapeutic agent delivery conduit including a first therapeutic agent delivery lumen and a port in communication with the first therapeutic agent delivery lumen; the at least one first therapeutic agent delivery conduit positioned external to the expandable portion of the catheter shaft and moveable independent of the expandable portion in the deflated configuration, the port of the at least one first therapeutic agent delivery conduit facing away from a first portion of an external surface of the expandable portion of the catheter shaft for contacting the at least one first therapeutic agent delivery conduit when the expandable portion is in the inflated configuration, and   (iii) at least one second therapeutic agent delivery conduit including a second therapeutic agent delivery lumen and a port in communication with the second therapeutic agent delivery lumen; the at least one second therapeutic agent delivery conduit positioned external to the expandable portion of the catheter shaft and moveable independent of the expandable portion in the deflated configuration, the port of the at least one second therapeutic agent delivery conduit facing away from a second portion of the external surface of the expandable portion of the catheter shaft for contacting the at least one second therapeutic agent delivery conduit when the expandable portion is in the inflated configuration;       
 
         [0084]    (b) positioning a portion of the at least one first and second therapeutic agent delivery conduits having the port proximate the treatment site; 
         [0085]    (c) inflating the expandable portion of the catheter shaft until the first and second portions of the external surface of the expandable portion contact at least one first therapeutic agent delivery conduit and at least one second therapeutic agent delivery conduit, respectively; and 
         [0086]    (d) injecting a first therapeutic agent into at least one of the first and second therapeutic agent delivery lumens to release the first therapeutic agent through at least one of the ports of the at least one first and second therapeutic agent delivery conduits to a wall of the body vessel proximate the treatment site. 
         [0087]    The method may further comprise the step of injecting a second therapeutic agent into the second therapeutic agent delivery lumen of the at least one second therapeutic agent delivery conduit to release the second therapeutic agent through the port of the at least one second therapeutic agent delivery conduit to the body vessel wall proximate the treatment site. The method may also further comprise the step of increasing the pressure of the expandable portion of the catheter shaft until the at least one first and second therapeutic agent delivery conduits are pressed into the body vessel wall and each port is sealably engaged with the body vessel wall. In addition, or in the alternative, the method may further comprise the steps of deflating the expandable portion of the catheter shaft, and removing the therapeutic agent delivery system from the body vessel. 
         [0088]    Optionally, a distal end of the at least one first and second therapeutic agent delivery conduits may be joined to one another to form a distal tip positioned distally to the expandable portion of the catheter shaft and moveable independent of the expandable portion in the deflated configuration, the distal tip including an annular opening adapted for receiving a guide wire. The at least one first therapeutic agent delivery conduit may further comprise a plurality of ports in communication with the first therapeutic agent delivery lumen and facing away from the first portion of the external surface of the expandable portion, and the at least one second therapeutic agent delivery conduit may further comprise a plurality of ports in communication with the second therapeutic agent delivery lumen and facing away from the second portion of the external surface of the expandable portion. The plurality of ports may be disposed longitudinally along each of the at least one first and second therapeutic agent delivery conduits in a substantially straight line, the plurality of ports of each of the at least one first and second therapeutic agent delivery conduits including a first port located distally to a second port, the first port having a larger cross-sectional area than the second port. In addition or in the alternative. The at least one first therapeutic agent delivery conduit and the at least one second therapeutic agent delivery conduit may be disposed circumferentially and/or may be spaced apart from one another by a circumferential distance measured perpendicular to the longitudinal axis, the circumferential distance between each of the at least one first and second therapeutic agent delivery conduits being substantially equal. The catheter shaft may have a proximal portion extending from a distal end of the expandable portion to the proximal end of the catheter shaft, said proximal portion including a portion of the first therapeutic agent delivery lumen proximal to, and in communication with, the at least one first therapeutic agent delivery conduit, and a portion of the second therapeutic agent delivery lumen proximal to, and in communication with, the at least one second therapeutic agent delivery conduit. 
         [0089]    This method of locally administering therapeutic agents could also eliminate the need for a stent or at least the need for a stent to deliver the therapeutic agent. In a first aspect, the therapeutic agents may alter the composition of the stenosis such that the stenosis breaks down. The method of the invention can be used to treat disorders by delivery of any composition, e.g., drug or gene with a catheter, as described herein. For example, patients with peripheral arterial disease, e.g., critical limb ischemia (Isner, J. M. et al, Restenosis Summit VIII, Cleveland, Ohio, 1996, pp 208-289) can be treated as described herein. Any composition that inhibits smooth muscle cell (SMC) proliferation and migration, platelet aggregation and extracellular modeling is also desirable. 
         [0090]    In a first aspect, the therapeutic agent may be, for example, any bioactive material selected for a desired therapeutic effect. In particular, therapeutic agents preferably inhibit or mitigate one or more events implicated in the restenosis process, such as: (a) destruction of endothelial and subendothelial structures, (b) traumatization of medial regions with rupture of the internal elastic lamina, (c) release of thrombogenic factors such as collagen or tissue factor, (d) stretching of smooth muscle cells with subsequent expression of proto-oncogenes (c-fos, c-myc, c-myb), (e) release of growth factors from cells of the bloodstream, endothelial cells and SMCs, and (f) thrombin production with autocatalytic activation of the SMC thrombin receptor. Overlapping the inflammation period, granulation begins 3 days after angioplasty. Proteinases such as plasmin as well as collagenases induce the disintegration of extracellular matrix structures, thereby modulating plaque formation, and lead to an organelle-rich SMC phenotype within the intima and media. Overlapping with the granulation period, induction of different components of the extracellular matrix occurs 12 weeks after angioplasty, possibly mediated by TGF-beta (phase of matrix formation). Smooth muscle cells produce and secrete matrix proteins such as tenascin, fibronectin, collagens and proteoglycans, and thereby induce a marked increase of the neointimal plaque volume. 
         [0091]    For example, the therapeutic agent may be an antisense compound is selected to interact within a cell to inhibit or mitigate restenosis by inhibiting the activity of mRNA produced from proto-oncogenes such as c-myc. C-myc is a proto-oncogene which regulates cell growth and differentiation, is involved in the process of vascular remodeling, regulating smooth muscle cell proliferation and extracellular matrix synthesis, in addition to playing a role in apoptosis. As used herein, the term “antisense” refers to a molecule that binds to a messenger RNA (mRNA) or a nucleic acid molecule that hybridizes to such a molecule. For example, the antisense compound may be an oligomer having a particular sequence of nucleotide bases and a subunit-to-subunit backbone that allows the antisense oligomer to form an RNA:oligomer heteroduplex within the target sequence, typically with an mRNA. The oligomer may have exact sequence complementarity to the target sequence or near complementarity. These antisense oligomers may block or inhibit translation of the mRNA, and/or modify the processing of an mRNA to produce a splice variant of the mRNA. Preferred antisense compounds are those that interact with the c-myc gene, for example by binding to mRNA produced by the gene. The therapeutic agent may be a c-myc antisense compound, preferably a nuclease-resistant antisense morpholino compound having high affinity (i.e., “specifically hybridizes”) to a complementary or near-complementary c-myc nucleic acid sequence, e.g., the sequence including and spanning the normal AUG start site. Preferred c-myc antisense compounds are described in U.S. Pat. No. 7,094,765 to Iversen et al., filed Jan. 29, 2000, the portion of which pertaining to the synthesis, sequences and administration of c-myc antisense compounds is incorporated herein by reference. Preferably, the antisense compounds include a morpholino backbone structure. In particular, the therapeutic agent may be a morpholino antisense compound having (i) a polynucleotide (preferably containing from 8 to 40 nucleotides) including a targeting base sequence that is complementary to a region that spans the translational start codon of a c-myc mRNA and (ii) uncharged, phosphorous-containing intersubunit linkages. The synthesis, structures, and binding characteristics of such morpholino oligomers are detailed in above-cited U.S. Pat. Nos. 5,698,685, 5,217,866, 5,142,047, 5,034,506, 5,166,315, 5,521,063, and 5,506,337, all of which are incorporated herein by reference. The antisense oligomers therapeutic agents are preferably composed of morpholino subunits of the form shown in the above cited patents, where (i) the morpholino groups are linked together by uncharged phosphorus-containing linkages, one to three atoms long, joining the morpholino nitrogen of one subunit to the 5′ exocyclic carbon of an adjacent subunit, and (ii) the base attached to the morpholino group is a purine or pyrimidine base-pairing moiety effective to bind, by base-specific hydrogen bonding, to a base in a polynucleotide. The purine or pyrimidine base-pairing moiety is typically adenine, cytosine, guanine, uracil or thymine. Preparation of such oligomers is described in detail in U.S. Pat. No. 5,185,444 (Summerton and Weller, 1993), which is hereby incorporated by reference in its entirety. As shown in the reference, several types of nonionic linkages may be used to construct a morpholino backbone. 
         [0092]    Other examples of suitable therapeutic agents include antiproliferative agents, an antineoplastic agent, an antibiotic agent, an anti-inflammatory agent and/or a free radical scavenger. Therapeutic agents may perform multiple functions including modulating angiogenesis, restenosis, cell proliferation, thrombosis, platelet aggregation, clotting, and vasodilation. More specifically, the therapeutic agent may be paclitaxel, dexamethasone, rapamycin (sirolimus), a rapamycin analog (including tacrolimus or everolimus), a nonsteroidal anti-inflammatory drug and/or a steroidal anti-inflammatory drug. The therapeutic agent may also include a pH-altering substance, such as an acid or base, selected to dissolve a vascular blockage. For treatment of vascular calcified occlusions with the therapeutic agent delivery systems, an acidic dissolution fluid may be delivered for a period of time sufficient for fluid flow to be to be enhanced through the vascular site, for example as described by Delaney in U.S. Pat. No. 6,290,689, filed Oct. 22, 1999. 
         [0093]    In another aspect, the therapeutic agent delivery system could be used to treat post-deep vein thrombosis (DVT) patients. The therapeutic agent delivery system could be used to deliver thrombolytics agents to the body vessel wall  201 , which creates a chain reaction of thrombis breakdown. After breakdown, further dilation of the therapeutic agent delivery system would restore the vessel to its native diameter. Examples of suitable thrombolytic therapeutic agents include anticoagulant agents, antiplatelet agents, antithrombogenic agents and fibrinolytic agents. Anticoagulants are bioactive materials which act on any of the factors, cofactors, activated factors, or activated cofactors in the biochemical cascade and inhibit the synthesis of fibrin. Antiplatelet bioactive materials inhibit the adhesion, activation, and aggregation of platelets, which are key components of thrombi and play an important role in thrombosis. Fibrinolytic bioactive materials enhance the fibrinolytic cascade or otherwise aid is dissolution of a thrombus. Examples of antithrombotics include but are not limited to anticoagulants such as thrombin, Factor Xa, Factor VIIa and tissue factor inhibitors; antiplatelets such as glycoprotein IIb/IIIa, thromboxane A2, ADP-induced glycoprotein IIb/IIIa, and phosphodiesterase inhibitors; and fibrinolytics such as plasminogen activators, thrombin activatable fibrinolysis inhibitor (TAFI) inhibitors, and other enzymes which cleave fibrin. Further examples of antithrombotic bioactive materials include anticoagulants such as heparin, low molecular weight heparin, covalent heparin, synthetic heparin salts, coumadin, bivalirudin (hirulog), hirudin, argatroban, ximelagatran, dabigatran, dabigatran etexilate, D-phenalanyl-L-poly-L-arginyl, chloromethy ketone, dalteparin, enoxaparin, nadroparin, danaparoid, vapiprost, dextran, dipyridamole, omega-3 fatty acids, vitronectin receptor antagonists, DX-9065a, CI-1083, JTV-803, razaxaban, BAY 59-7939, and LY-51,7717; antiplatelets such as eftibatide, tirofiban, orbofiban, lotrafiban, abciximab, aspirin, ticlopidine, clopidogrel, cilostazol, dipyradimole, nitric oxide sources such as sodium nitroprussiate, nitroglycerin, S-nitroso and N-nitroso compounds; fibrinolytics such as alfimeprase, alteplase, anistreplase, reteplase, lanoteplase, monteplase, tenecteplase, urokinase, streptokinase, or phospholipid encapsulated microbubbles; and other bioactive materials such as endothelial progenitor cells or endothelial cells. 
         [0094]    The dosage ranges for the administration of the therapeutic agent in the methods of treatment are those large enough to produce the desired effect in which the symptoms of the disease/injury are ameliorated. The dosage should not be so large as to cause adverse side effects. Generally, the dosage will vary with the age, condition, sex and extent of the disease in the patient and can be determined by one of skill in the art. The dosage can be adjusted by the individual physician in the event of any complication. When used for the treatment of inflammation, post-reperfusion injury, microbial/viral infection, or vasculitis, or inhibition of the metastatic spread of tumor cells, for example, the therapeutic composition may be administered at a dosage which can vary from about 1 mg/kg to about 1000 mg/kg, preferably about 1 mg/kg to about 50 mg/kg, in one or more dose administrations. 
         [0095]    Instead of administering a therapeutic agent that is effective immediately, it is also possible to embed the therapeutic agent in a bioabsorbable material that allows a controlled release once the material is transferred into the lesion. Optionally, the therapeutic agent may be incorporated into particles of a polymeric substance such as polyesters, polyamino acids, hydrogels, polylactide/glycolide copolymers, or ethylenevinylacetate copolymers. The therapeutic agent may be contained in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, by the use of hydroxymethylcellulose or gelatin-microcapsules or poly(methylmethacrolate) microcapsules, respectively, or in a colloid drug delivery system. Colloidal dispersion systems include macromolecule complexes, nanocapsules, microspheres, beads, and lipid-based systems including oil-in-water emulsions, micelles, mixed micelles, and liposomes. 
         [0096]    Having described certain preferred embodiments in detail, it will be apparent that modifications and variations are possible without departing from the scope of the invention defined in the appended claims. More specifically, although some aspects of the present invention are identified herein as preferred or particularly advantageous, it is contemplated that the present invention is not necessarily limited to these preferred aspects of the invention.