Abstract:
Systems and methods for delivering drugs or other substances to target locations outside of blood vessel lumens or other body lumens. In some embodiments, a catheter having a penetrator is advanced into the body lumen and the penetrator is then advanced from the catheter toward a target location outside of that body lumen. The substance is then delivered through a the penetrator itself or through a delivery catheter that has been advanced through the penetrator to the target location. In other embodiments, the blood vessel or other body lumen is blocked at spaced-apart first and second locations and a quantity of the substance is introduced into the closed-off body lumen between the blocked first and second locations. The substance then diffuses into or through the wall of the vessel or body conduit to reach the target location.

Description:
RELATED APPLICATIONS 
       [0001]    This application is a continuation of copending U.S. patent application Ser. No. 12/715,252 filed Mar. 1, 2010 and issued on Dec. 27, 2011 as U.S. Pat. No. 8,083,708, which is a continuation of U.S. patent application Ser. No. 11/646,644 filed on Aug. 15, 2006 and issued on Mar. 2, 2010, as U.S. Pat. No. 7,670,868, which is a continuation of U.S. patent application Ser. No. 10/738,226 filed Dec. 16, 2003 and issued on Aug. 22, 2006, as U.S. Pat. No. 7,094,230, which is a continuation of U.S. patent application Ser. No. 09/826,049 filed Apr. 3, 2001 and issued as U.S. Pat. No. 6,685,648, which is a Division of U.S. patent application Ser. No. 09/048,147 filed on Mar. 25, 1998 and issued as U.S. Pat. No. 6,283,951. This application does not claim priority prior to Mar. 25, 1998. 
     
    
     FIELD OF THE INVENTION 
       [0002]    The present invention relates generally to systems and methods for delivering substances into a body, more particularly to systems and methods that use the cardiovascular system as a conduit to deliver drugs, such as therapeutic drugs, genes, growth factors and the like, directly to selected tissue regions within the body, and most particularly to systems and methods that deliver drugs from the venous system transvascularly to selected remote tissue regions. 
       BACKGROUND 
       [0003]    It is often desirable to deliver drugs into a patient&#39;s body to treat medical conditions. In particular, a variety of drug therapies are available for treating the coronary system, either alone or in combination with more invasive procedures. Such therapies may include delivering substances, such as nitroglycerin, epinepharin, or lydocaine, endocardially or into the pericardial space to treat the coronary system. In addition, heparin, hirudin, ReoPro™ or other anti-thrombotic compounds may be infused into blood vessels associated with the coronary system, such as occluded coronary arteries, or elsewhere in the cardiovascular system. More recently, gene therapy, e.g. introducing genetic material, and growth factor therapy, e.g. introducing proteins, cells or vectors including angiogenic growth factors, have been demonstrated to provide potential benefits in treating ischemic heart tissue and other regions of the coronary system, for example, by stimulating growth of neovascular conduits, which may evolve into new blood vessels. 
         [0004]    In current medical therapy, one method of delivering such drugs involves percutaneously introducing an infusion catheter into the patient&#39;s cardiovascular system. A distal portion of the catheter is directed to a desired endovascular location, for example into a coronary artery, and a drug is infused into the artery at a location reachable intraluminally. The catheter may include a lumen extending between its proximal and distal ends, the distal end having one or more outlet ports. A source of the drug, such as a syringe, may be connected to the proximal end and the drug delivered through the lumen and outlet port(s) into the desired location. 
         [0005]    For example, a “bolus,” i.e. a relatively large single dose of a drug, may be delivered using an infusion catheter into an artery, which may be absorbed by the arterial wall, the surrounding tissue, and/or may be carried by blood flow to regions further downstream from the delivery location. Alternatively, the drug may be infused continuously or intermittently into the artery for an extended period of time. 
         [0006]    The infusion catheter often includes a porous perfusion balloon on its distal end, the interior of which communicates with the outlet port(s) and lumen in the catheter. Pores or holes in the balloon may be arranged to direct the drug from the balloon towards the arterial wall to improve penetration into the arterial wall and attempt to localize delivery. In addition, the infusion catheter may be provided with an electrode and/or a heating element on or in the balloon to cause electroporation or to heat the surrounding tissue to further improve localized delivery. 
         [0007]    Some devices try to enhance localized delivery of drugs using ionophoresis. A first electrode may be provided within a perfusion balloon, and a second electrode provided on an external region of the patient&#39;s body near the artery. When direct current is applied between the electrodes, a drug carried by an electrically charged compound may be directed along the path of current flow from the internal electrode towards the external electrode in an attempt to improve penetration of the drug into the arterial wall and surrounding tissue. 
         [0008]    As an alternative to perfusion balloons and/or infusion catheters, a drug may be embedded in or deposited on a catheter, e.g. in the catheter wall, the wall of a non-porous balloon on the catheter, and/or a coating on the catheter. After the distal end is directed to a desired location, the drug may be delivered into an artery, for example, by ionophoresis similar to that described above or by simply allowing the drug to dissolve within the artery. 
         [0009]    In an alternative to delivering a bolus of drugs, it is often desirable to provide sustained delivery of a drug within the cardiovascular system. For example, a pair of occlusion balloons disposed along the length of a catheter may be provided on an infusion catheter that may be directed endovascularly to a desired location within an artery. The balloons may be inflated to isolate a section of the artery between them, and a drug may be delivered into the isolated section in an attempt to provide sustained delivery to the isolated section. The balloons are then deflated, and the catheter removed from the body. 
         [0010]    Drug delivery devices may also be implanted within an artery to provide sustained delivery. For example, U.S. Pat. No. 5,628,784 issued to Strecker discloses an expandable annular sleeve that may be deployed within an artery. A small quantity of drugs may be introduced between the sleeve wall and the surrounding arterial wall to directly contact the arterial wall, where they may be absorbed over an extended period of time. PCT Publication No. WO 95/01138 discloses a porous ceramic sleeve that may be implanted directly in tissue, such as in bone marrow or a surgically created pouch. The sleeve includes drugs within a cell culture or matrix in the sleeve, which may, for example, be dispersed in the pores of the sleeve or be provided in a cylindrical insert. 
         [0011]    In addition, a number of extravascular methods have also been suggested. For example, drugs may be injected directly into a desired tissue region, typically by accessing the region through a chest incision. Alternatively, a polymer gel or drug-soaked sponge may be attached to the outside of a vessel or to a portion of the endocardium to be absorbed by the contacted region. In addition, the pericardial space may have substances injected directly into it, for example by accessing the pericardial sac through a chest incision. Such methods may provide either single dose or sustained delivery of drugs to the heart. 
         [0012]    One of the problems often associated with existing methods is dilution or “wash-out” of the drug during delivery. Dilution may substantially reduce the effectiveness of a therapy by preventing sufficient quantities of the drug from reaching a desired region. For example, during endovascular delivery using an infusion catheter, the drug may be diluted as it travels through the arterial wall or may be carried downstream through the artery to other regions within the coronary system and/or elsewhere in the body. 
         [0013]    The volume of drug may be increased to offset dilution concerns, but this may exacerbate concerns about undesired dissemination of the drug. For example, certain therapeutic drugs, genetic material and growth factors may have undesired global side effects. Releasing a drug into the blood stream may allow it to be carried throughout the coronary system or elsewhere in the body where it may have significant adverse effects. Similar adverse effects may result from pericardial delivery, in which a drug may be absorbed throughout the coronary system, rather than only in a desired local region. 
         [0014]    Further, many conventional methods are unable to provide effective sustained delivery, which may be important to the success of certain treatments, such as gene or growth factor therapy, where it may be desirable to maintain a drug in a desired region for hours, days or even longer. Occlusion systems, such as the dual occlusion balloon catheter, or the implantable sleeves described above, may be able to isolate a region of an artery for some sustained treatments. 
         [0015]    Such occlusion devices, however, may introduce additional risks associated with obstructing flow within the coronary system for extended periods of time. In particular, if the arterial system is occluded for more than short periods of time during treatment, substantial damage may occur, for example, ischemia and possibly infarction of tissue downstream from the occluded region. 
         [0016]    Conventional endovascular systems may also be inadequate to access certain tissues in need of treatment. For example, infusion catheters may be unable to pass through an occluded region of an artery to treat ischemic tissue downstream of the region. Further, it may be hazardous to direct an endovascular device through a stenotic region because of the risk of releasing embolic material from the arterial wall, which may travel downstream and become embedded in other vessels or even travel to vital organs, such as the brain, where they may cause substantial damage or even death. 
         [0017]    More invasive methods, such as direct injection of drugs, may provide access to otherwise unattainable regions. Such methods, however, typically involve open-chest or other invasive surgical procedures, and the costs and risks associated with them. 
         [0018]    Accordingly, there is a need for improved systems and methods of delivering drugs to desired locations within the body with greater precision, reduce global side-effects, and/or that substantially reduce the problems of the previous systems and methods. 
       SUMMARY OF THE INVENTION 
       [0019]    The present invention is directed to systems and methods for delivering a drug to a tissue region within a patient&#39;s body, and in particular to systems and methods that use the venous system as a conduit to deliver a drug directly to a remote tissue region, or to facilitate a catheter-based intervention. “Drug” as defined herein includes any therapeutic drugs, genetic materials, growth factors, cells, e.g. myocites, vectors carrying growth factors, and similar therapeutic agents or substances that may be delivered within a patient&#39;s body for any therapeutic, diagnostic or other procedure. In one aspect of the present invention, a transvascular catheter system is provided that generally includes a catheter, a drug delivery element, an orientation element, and possibly a puncturing element and/or an imaging element. The catheter has a proximal portion and a distal portion adapted for insertion into a blood vessel, and defines a periphery and a longitudinal axis. The puncturing element is deployable from the distal portion in a predetermined relationship with the circumference or periphery of the catheter, and includes a distal tip adapted to penetrate a wall of a blood vessel to access a tissue region beyond the wall of the blood vessel. The drug delivery element is provided on the distal portion for delivering a drug to the tissue region, and an orientation element is also provided on the distal portion in a predetermined relationship with the periphery of the catheter and the puncturing element. 
         [0020]    Preferably, the catheter has a peripheral opening at a predetermined location on the periphery of the distal portion through which the puncturing element may be deployed, and a needle lumen communicating with the peripheral opening for receiving the puncturing element therethrough. The needle lumen includes a deflecting element adapted to direct the distal tip substantially transversely with respect to the longitudinal axis when the puncturing element is deployed. 
         [0021]    The system may include an imaging element adjacent the orientation element for detecting the location of the orientation element with respect to the tissue region. For example, the imaging element may be an ultrasound transducer which may be received in a lumen extending between the proximal and distal portions of the catheter. 
         [0022]    In a first preferred embodiment, the puncturing element is a needle and the drug delivery element is a lumen in the needle. The needle may include an array of outlet ports for providing a predetermined flow pattern of fluid into the tissue region accessed by the needle. In addition, at least a portion of the needle may be a conductive material electrically coupled to a proximal end of the puncturing element for coupling the needle to a source of electric current. Alternatively, the puncturing element may be a plurality of needles deployable from predetermined locations on the distal portion to provide a selected trajectory pattern into the tissue region. 
         [0023]    In a second preferred embodiment, the puncturing element includes a guide wire, and the drug delivery element is deployable over the guide wire. For example, the drug delivery element may be an infusion catheter, possibly including a perfusion balloon. Alternatively, the drug delivery element may include an indwelling catheter which is delivered over the guide wire, either before or after removal of the transvascular catheter. The drug delivery element may include a first electrode thereon adapted to be electrically coupled to a second electrode. When direct current is directed between the first and second electrodes, fluid from the drug delivery element may be ionophoretically directed from the drug delivery element towards the second electrode. Alternatively, the drug delivery element may be an osmotic surface on the transvascular catheter, the infusion catheter or the indwelling catheter. 
         [0024]    To assist in orienting the system during use, the orientation element preferably has an asymmetric configuration aligned with the puncturing element, for example with the peripheral opening through which the puncturing element may be deployed. In a first preferred embodiment, the orientation element is a “cage” structure that includes a plurality of struts extending axially along the distal portion. Preferably, a first strut is provided at a location in direct axial alignment with the peripheral opening, and a pair of struts are provided opposite the first strut to “point” towards the peripheral opening. Alternatively, the orientation element may include a marker that may be imaged using an external imaging system, and preferably a pair of markers disposed opposite one another on the periphery, either instead of or preferably in addition to the “cage” structure. 
         [0025]    A transvascular catheter system in accordance with the present invention may be used to deliver a drug to a tissue region within a patient&#39;s body, such as into the myocardium or a coronary artery from the coronary venous system, in a method which may proceed as follows. The distal portion of the catheter may be percutaneously introducing into a blood vessel, and directed endovascularly to a vessel location adjacent to the tissue region selected for treatment. The puncturing element may be oriented towards the selected tissue region, and deployed to access the tissue region. A drug may then be delivered with the drug delivery element to the tissue region. 
         [0026]    Preferably, when the puncturing element is being oriented, the orientation element is imaged, for example with an imaging element adjacent the orientation element. The imaging element is preferably operated to obtain an image of the orientation element in relation to the surrounding tissue, thereby identifying the orientation of the puncturing element because of the predetermined relationship between the orientation element and the puncturing element. Preferably, the imaging element is an ultrasound transducer within the catheter that may be used to obtain image slices along a plane substantially normal to the longitudinal axis of the catheter, the images preferably including the orientation element, the selected tissue region and/or other landmarks within the vessel or the surrounding tissue. 
         [0027]    Where the puncturing element is a drug delivery needle, the needle may be deployed, penetrating a wall of the blood vessel and entering the tissue region, and the drug may be delivered through a lumen in the needle. Alternatively, a drug delivery element may be deployed in combination with the puncturing element. For example, an infusion catheter may be advanced over the puncturing element to the tissue region, and the drug infused therethrough, or through a porous balloon on the infusion catheter which may be inflated within the tissue region. 
         [0028]    Prior to delivering the drug, a “mapping” procedure may be used to ensure that the drug will be delivered as desired into the specific tissue region selected for treatment. For example, a radiographic agent may be delivered using the drug delivery element to observe the flow thereof with respect to the selected tissue region. Once it has been confirmed that the radiographic agent flows as desired into the selected tissue region, the drug may then be introduced, thereby possibly avoiding misdelivery of what are often quite expensive drugs. Alternatively, a radiographic agent and the like may be mixed with the drug to track the flow of the drug within the body, particularly with respect to the selected tissue region. 
         [0029]    In another preferred method, the transvascular catheter system may be used to create a drug reservoir directly in a selected tissue region. For example, a tissue ablation device may be provided that is deployable in combination with the puncturing element for creating a cavity in an extravascular tissue region. The ablation device may be advanced over the puncturing element into the tissue region, and an ablation element thereon activated to create a cavity or drug reservoir within the tissue region. A drug may then be introduced into the drug reservoir, which may be sealed from the vessel, for example by introducing a sealant or matrix into the drug reservoir. Alternatively, the drug reservoir may be formed by removing a portion of the tissue region, for example with a cutting instrument or similar mechanical device. 
         [0030]    In a further alternative, the transvascular system may be used to facilitate an indwelling catheter-based intervention. The catheter may be introduced into a vessel, and then the puncturing element may be oriented and deployed into a tissue region, such as interstitial tissue or another blood vessel. A guide wire may be advanced into the tissue region, and the transvascular catheter may then be removed, leaving the guide wire in place, possibly anchored to the tissue region. A thin, floppy catheter may be tracked over the guide wire into the tissue region, and left in place within the tissue region, and the wire may be removed. The indwelling catheter may be taped, ported or otherwise secured to the patient depending upon the length of time therapy is desired. The tissue region may then be accessed via the indwelling catheter to deliver a drug to the tissue region as often as desired. 
         [0031]    In another aspect of the present invention, an implantable drug reservoir system may be used to provide sustained delivery of a drug within the cardiovascular system of a patient. Generally, the system includes a reservoir device having an expandable frame and a flexible membrane thereon. The frame is adapted to expand between a collapsed condition for insertion into a blood vessel and an enlarged condition for engaging a wall of the blood vessel. The frame is preferably biased towards the enlarged condition, and also preferably defines a longitudinal axis and a periphery. 
         [0032]    The flexible membrane is attached to the frame to define a reservoir therein, and includes a porous region, such as a semi-permeable material, that is preferably disposed along the periphery of the frame. A drug, possibly together with an anti-coagulant, is provided within the reservoir that is adapted to pass through the porous region of the membrane. An end region of the membrane may be penetrable, for example by a needle, to facilitate in situ filling of the reservoir. 
         [0033]    In an alternative embodiment of the implantable drug reservoir system, a reservoir device similar to that described above may be provided with a septum dividing the reservoir within the membrane into first and second reservoir regions. The membrane preferably includes an osmotic region communicating with the first reservoir region, and the porous region of the membrane preferably communicates with the second reservoir region. 
         [0034]    During use, the reservoir device may be introduced along a blood vessel to a location adjacent a selected tissue region, for example within a coronary vein adjacent to an occluded artery or ischemic myocardial tissue. The reservoir device may be deployed and expanded, preferably automatically, to its enlarged condition to anchor the reservoir device within the blood vessel. A drug may be prefilled within the reservoir or an injection device may be advanced to penetrate the membrane of the reservoir device and fill the reservoir in situ with the drug. 
         [0035]    The drug may then permeate, seep, or otherwise pass through the porous region, preferably directly into the wall of the vessel and the surrounding tissue region. If desired, the reservoir may be refilled in situ using an injection device as the drug is dispersed or otherwise absorbed by the tissue. Similarly, a reservoir device having a septum panel may deliver the drug in the second reservoir region to the tissue region as the first reservoir region osmotically fills, thereby slowly forcing or “pumping” the drug through the porous region. 
         [0036]    In another preferred embodiment of an implantable drug reservoir system, a pair of expandable devices, similar to the reservoir devices may be used. The expandable devices, or endovascular “blockers,” include an expandable frame, and a non-porous membrane covering at least one end of the frame, and preferably extending along at least a portion of the periphery. 
         [0037]    The first blocker is advanced in a collapsed condition along the blood vessel to a location adjacent the selected tissue region. The first blocker is then expanded to its enlarged condition, thereby sealing the blood vessel at the location from fluid flow along the blood vessel. The second blocker is then advanced in a collapsed condition along the blood vessel to the location, preferably adjacent the first blocker. The second blocker is then expanded to its enlarged condition, thereby further sealing the blood vessel at the location from fluid flow along the blood vessel. The second blocker is preferably deployed a predetermined distance from the first blocker, thereby defining a substantially sealed drug reservoir within the blood vessel itself between the blockers. 
         [0038]    A drug may be introduced into the blood vessel adjacent the first blocker, either before or after the second blocker is deployed. For example, the second blocker may include an end panel only on the end away from the drug reservoir between the blockers, and an injection device may be advanced to penetrate the end panel. The drug may then be introduced into the second blocker and consequently into the drug reservoir between the blockers. Thus, a section of a blood vessel may be isolated and a drug delivered therein to provide sustained and localized delivery of the drug into the selected tissue region surrounding the vessel. 
         [0039]    Accordingly, a principal object of the present invention is to provide a system and method for precisely delivering a drug to a selected tissue location within the body. 
         [0040]    It is also an object to provide a system and method for providing sustained delivery of a drug to a desired location within the body over an extended period of time. 
         [0041]    It is also an object to provide a system and method for creating a reservoir within the body for receiving a drug to provide sustained delivery to a desired tissue region within the body. 
         [0042]    It is also an object to provide a system and method that use the cardiovascular system as a conduit to deliver a drug to a selected remote tissue region within the body with substantial precision. 
         [0043]    It is also an object to provide a system and method for delivering a drug transvascularly using the venous system as a conduit to access a selected remote tissue region. 
         [0044]    More particularly, it is specifically an object of the present invention to use the coronary venous system to provide access to a highly remote tissue region of the body, e.g. heart tissue. 
         [0045]    Other objects and features of the present invention will become apparent from consideration of the following description taken in conjunction with the accompanying drawings. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0046]      FIG. 1A  is a cross-sectional view of a transvascular catheter system in accordance with one aspect of the present invention. 
           [0047]      FIGS. 1B and 1C  are side views of a handle on the catheter for the transvascular catheter system of  FIG. 1A . 
           [0048]      FIG. 1D  is a cross-sectional view of the distal portion of a catheter for the transvascular catheter system of  FIG. 1A . 
           [0049]      FIG. 1E  is a side view of a needle assembly for the transvascular catheter system of  FIG. 1A . 
           [0050]      FIG. 2  is a cross-sectional view of the distal portion of the transvascular catheter system of  FIG. 1 , showing the needle assembly deployed into a remote blood vessel. 
           [0051]      FIG. 3A  is a cross-sectional view of the transvascular catheter system and surrounding heart tissue of  FIG. 2 , taken along line  3 - 3  using an internal imaging element, showing artifacts directing the catheter towards another blood vessel. 
           [0052]      FIG. 3B  is a cross-sectional view of the transvascular catheter system and surrounding heart tissue, similar to  FIG. 3A , but showing artifacts directing the catheter towards the myocardium of the heart. 
           [0053]      FIG. 4  is a side view detail of a catheter, showing a preferred embodiment of an externally detectable orientation element in accordance with the present invention. 
           [0054]      FIG. 5A  is a side view of an alternative embodiment of the distal portion, including a plurality of needle assemblies. 
           [0055]      FIG. 5B  is a side view of another alternative embodiment of the distal portion, including a dual lumen needle assembly. 
           [0056]      FIG. 5C  is another alternative embodiment of the distal portion, including a plurality of outlet ports for providing a predetermined flow pattern. 
           [0057]      FIG. 5D  is another alternative embodiment of the distal portion, including a feedback sensor on the needle assembly. 
           [0058]      FIG. 6  is a cross-sectional view of another preferred embodiment of a transvascular catheter system in accordance with the present invention, including a guide wire assembly and a drug delivery catheter deployed into a remote tissue region. 
           [0059]      FIG. 7  is a perspective view of an implantable port assembly for use with a transvascular catheter system in accordance with the present invention. 
           [0060]      FIG. 8  is a cross-sectional view of another preferred embodiment of a transvascular catheter system, including a guide wire assembly and an ablation device. 
           [0061]      FIG. 9A  is a side view of an implantable endovascular drug reservoir device in accordance with the present invention. 
           [0062]      FIG. 9B  is a side view of another embodiment of an implantable endovascular drug reservoir device, including a recrossable end panel. 
           [0063]      FIGS. 9C and 9D  are side views of the implantable endovascular drug reservoir device of  FIG. 9B , showing an injection device for filling the reservoir. 
           [0064]      FIG. 10  is a cross-sectional side view of the drug reservoir device of  FIG. 9A , deployed within a vein adjacent to a stenotic region of an artery. 
           [0065]      FIG. 11  is a side view of an alternative embodiment of an implantable endovascular drug reservoir device in accordance with the present invention. 
           [0066]      FIG. 12  is a side view of another implantable system in accordance with the present invention for creating a drug delivery reservoir, shown within a vein adjacent to a stenotic region of an artery. 
           [0067]      FIG. 13  is a cross-sectional view of a transvascular catheter system in accordance with the present invention delivered downstream of a stenotic region in a blood vessel. 
       
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
       [0068]    Turning now to the drawings,  FIGS. 1A-1E  and  2  show a preferred embodiment of a transvascular catheter system  10  in accordance with the present invention for delivering a drug to a selected remote tissue region within a body from a blood vessel near the tissue region. The system  10  generally includes a catheter  12 , a puncturing element  14 , an orientation element (e.g. a “cage” structure  16  described below), and an imaging element  18 . 
         [0069]    The catheter  12  may be an elongate member having substantially flexible and/or semi-rigid sections, and defining a circumference or periphery  20  and a longitudinal axis  22  between proximal and distal ends  24 ,  26 . The catheter  12  includes a proximal portion  28  having a handle  50  and a distal portion  30  having a size and shape to facilitate insertion into a blood vessel. 
         [0070]    An IVUS lumen  32  extends through the catheter  12  from an IVUS entry port  52  in the handle  50  to a tip member  44  on the distal portion  30  for receiving the imaging element  18 . A needle lumen  36  also extends from a needle entry port  54  in the handle  50  to a peripheral opening  34  in the distal portion  30  for receiving the puncturing element  14 . The needle lumen  36  includes a deflecting element or ramp  48  adjacent the peripheral opening  34 . 
         [0071]    The catheter  12  may include an extruded dual lumen catheter encapsulated within an outer jacket (not shown), and/or may have a proximal portion that is substantially more rigid than a distal portion. For example, in the preferred embodiment shown in  FIG. 1A , the catheter  12  includes a proximal portion  12   a , an intermediate portion  12   b , and a distal portion  12   c , each having a dual lumen catheter segment and an outer jacket segment. The rigidity or Durometer of the dual lumen catheter and outer jacket segments of the proximal portion  12   a  is preferably 63 and 70, while the remaining segments preferably have a Durometer of 40. Additional information on the construction of the catheter  12 , e.g. its material composition, its size and shape, may be found in co-pending application Ser. Nos. 08/730,327 and 08/730,496, both filed on Oct. 11, 1996, and in PCT Application No. PCT/US97/01459, filed on Jan. 31, 1997, the disclosures of which are expressly incorporated herein by reference. 
         [0072]    The orientation element is preferably a marker “cage” structure  16  including a plurality of elongate members or struts  38 ,  40  on the distal portion  30  located distally of the peripheral opening  34 . The struts  38 ,  40  preferably extend distally from the distal end  26  substantially parallel to the longitudinal axis  22  to the proximal edge  42  of the tip member  44 , thereby further defining the IVUS lumen  36 . The struts  38 ,  40  preferably define a peripheral window  46 , which may be covered by a material substantially transparent to the imaging element  18  or may remain open to blood flow. The struts  38 ,  40  are preferably substantially rigid tubular members, such as hypotubes, which are reflective to the imaging element  18 , i.e. will produce a reflection or artifact when the imaging element  18  is operated, and/or may be substantially opaque to an external imaging apparatus (not shown). 
         [0073]    Preferably, the struts  38 ,  40  have an asymmetrical configuration about the periphery  20  that has a predetermined relationship with the location of the peripheral opening  34 . More preferably, a first strut  38  is located on the periphery  20  directly distally from the location of the peripheral opening  34 . A pair of struts  40  are then positioned opposite the first strut  38 , thereby defining an isosceles triangle or TRI-POINT™ cross-sectional configuration, with the first bar  38  at the top of the triangle. Thus, the orientation element  16  may “point” circumferentially towards the location of the peripheral opening  34  on the periphery  20 , i.e. towards the location from which the puncturing element  14  may be deployed, as described further below. 
         [0074]    In an alternative embodiment shown in  FIGS. 4A and 4B , the orientation element may include one or more externally visible markers  116  placed at one or more predetermined locations on the periphery  20  of the catheter  12 . The markers  116  define a pattern to facilitate detection of the orientation of the distal portion  30  about the longitudinal axis  22  with the aid of an external imaging apparatus. For example, the markers  116  may be formed from a radiopaque material visible using a fluoroscopic imaging system. Preferably, a pair of fluoroscopic markers  116   a ,  116   b  are provided on the periphery  20  that uniquely indicate the rotational orientation of the peripheral opening  34 , such as the “bulls-eye” arrangement shown. Further discussion of such markers may be found in U.S. Ser. No. 08/730,327 filed Oct. 11, 1996, the disclosure of which is expressly incorporated herein by reference. Although the transvascular catheter system  10  may include both internal and external markers  16 ,  116  on the catheter  12 , preferably only one marker or orientation element is necessary to effectively orient the puncturing element  14 . 
         [0075]    Returning to  FIGS. 1A-1E  and  2 , the tip member  44  attached to the struts  38 ,  40  has an annular shape formed from a substantially flexible material to further define the IVUS lumen  32 . The tip member  44  is preferably tapered to facilitate insertion into and direction along the lumen of a blood vessel, and is substantially coaxial with the IVUS lumen  32  in the catheter  12  to facilitate the introduction of a guide wire or other instrument axially therethrough. 
         [0076]    With particular reference to  FIGS. 1A-1C , the handle  50  is preferably a substantially rigid member including the IVUS entry port  52 , the needle entry port  54 , and a needle lumen flush port  58  in communication with the needle lumen  36 . The ports  52 ,  54  and  58  may include one or more seals to prevent backflow, as will be appreciated by those skilled in the art. A control and/or locking mechanism  58  is located on the handle  50  that includes a needle thumb slide  68  and an adjustable needle stop  70  that cooperatively slide along a graduated region  60  of the handle  50 . 
         [0077]    The needle thumb slide  68  may be directed axially along the graduated region  60  to deploy the puncturing element  14 , as described more particularly below. The adjustable needle stop  70  is slidable on the handle  50  and is securable at a plurality of positions on the graduated region  60  of the handle  50 . Thus, the adjustable needle stop  70  may be locked at a first position on the graduated region  60 , loosened, directed axially to a second position on the graduated region  60 , and locked at the second position to limit the movement of the needle thumb slide  68 , and consequently the depth of penetration of the puncturing element  14 . 
         [0078]    Turning to  FIGS. 1A-1E , the puncturing element  14  is preferably a needle assembly  62  including an elongate tubular body  63  having a puncturing distal tip  64  and a proximal safety clip  66 . The needle assembly  62  and/or the distal tip  64  are preferably formed from a shape memory alloy, such as Nitinol, that is precurved to enhance transverse deployment of the distal tip  64 . The distal tip  64  may be inserted into the needle entry port  54  and directed distally through the needle lumen  36  until the safety clip  66  abuts the needle thumb slide  68  on the handle  50 . The needle thumb slide  68  then may be secured to the needle assembly  62 , for example with ball detents that extend radially into the needle lumen  36  from the needle thumb slide  68  (not shown), for controlling axial movement of the needle assembly  62 . 
         [0079]    Preferably, the needle assembly  62  includes a drug delivery lumen  72  extending from the safety clip  66  to an outlet  74  in the distal tip  64 . The outlet  74  may be a single opening for directing fluid distally beyond the distal tip  64 , or may include a plurality of openings having a predetermined outlet pattern. For example, as shown in  FIG. 5C , the distal tip  64  may include a closed tip  73  and one or more side openings  75  for directing the drug substantially laterally from the distal tip  64  into the tissue region. Preferably, the distal tip  64  also has a sufficiently small gauge diameter such that the passage  123  between the vessel  102  and the tissue region  100  is substantially self-sealing to prevent escape of the drug from the tissue region back into the vessel  102  upon removal of the distal tip  64 . 
         [0080]    Alternatively, as shown in  FIG. 5B , the needle assembly  62  may include dual lumens  78   a ,  78   b  that extend between a multiple line manifold on the proximal end (not shown) to two adjacent outlet ports  74   a ,  74   b . A dual lumen needle assembly may be useful for delivering a radiographic agent or other compound through one lumen in combination with a drug in the other. More preferably, the dual lumens may allow two drugs to be independently injected, which may then react with one another once within the selected tissue region, as will be appreciated by those skilled in the art. 
         [0081]    The distal tip  64  may also be at least partially conductive, for example, by providing an electrode thereon (not shown) or by forming the distal tip  64  from a conductive material such as platinum, gold, or possibly stainless steel. A conductor, such as an electrically conductive wire (not shown), may extend proximally from the distal tip  64  through the tubular member  63  to the safety clip  66  of the needle assembly  62 . A source of electric current may then be coupled to the conductor to enhance absorption of the drug by the tissue region. For example, the distal tip  64  may facilitate electroporation, i.e. energizing the distal tip  64  may create microscopic pores in the surrounding tissue to enhance penetration of the drug therein. 
         [0082]    With respect to the imaging element  18 , in a first preferred embodiment best seen in  FIG. 2 , an intravascular ultrasound (“IVUS”) device  80  is provided. A conventional ultrasound transducer  82  is provided on the distal end  84  of the IVUS device  80  that is oriented towards an imaging plane substantially normal to the longitudinal axis  22 . The ultrasound transducer  82  or a reflector on the IVUS device  80  (not shown) may be rotatable about the longitudinal axis  22  to provide ultrasonic image slices along the imaging plane in a conventional manner, or alternatively, a phased array of ultrasound transducers may be provided to allow imaging along a plane substantially normal to the longitudinal axis  22 , as will be appreciated by those skilled in the art. Further information on the use of an IVUS device for imaging tissue and other surrounding landmarks from within a blood vessel may be found in “Transvenous Coronary Ultrasound Imaging—A Novel Approach to Visualization of the Coronary Arteries” by Sudhir et al., the disclosure of which is expressly incorporated herein by reference. 
         [0083]    During use, the transvascular catheter system  10  may be used to deliver a drug to a selected remote tissue region within a patient&#39;s body in the following manner. The catheter  12  may be introduced percutaneously into a blood vessel in a conventional manner, while the needle assembly  62  remains retracted within the needle lumen  36 , i.e. while the distal tip  64  is positioned within the needle lumen  36  proximal to the deflecting element  48 . The distal portion  30  of the catheter  12  may be directed endovascularly to a vessel location adjacent to a remote tissue region for which treatment is selected. 
         [0084]    For example, in one preferred method shown in  FIGS. 2 and 3A , the catheter  12  may be directed through the patient&#39;s venous system to a coronary vein  102  adjacent to a coronary artery  100  selected for treatment. In another preferred method shown in  FIGS. 6 and 3B  the catheter  12  may be directed to a location within a coronary vein  102  adjacent to a selected ischemic region  220  of the myocardium  112  for delivering a drug therein. Once the desired endovascular location is reached, the catheter  12  may be oriented towards the selected tissue region using ultrasound imaging with the IVUS device  80 , external imaging, such as fluoroscopy, or both. 
         [0085]    Turning to  FIGS. 2 and 3A , the IVUS device  80  is shown being used to orient the system  10  for delivering a drug into a coronary artery  100  from a nearby coronary vein  102 . The distal portion  30  of the catheter  12  is directed endovascularly through the venous system, for example over a guidewire  86 , until it is within the coronary vein  102  and adjacent the selected coronary artery  100 . The ultrasound transducer  82  may then be operated to provide a cross-sectional image of the region, shown illustratively in  FIG. 3A . The resulting image aids the user in orienting the catheter  12  with respect to the tissue surrounding the vein  102 , for example to identify landmarks such as the pericardium  109 , the endocardium  111 , the epicardium  113 , and/or the heart chamber  110 . Further, because the struts  38 ,  40  are opaque to the ultrasound transducer  82  (not shown in  FIG. 3A ), they produce artifacts  104 ,  106  on the image, thereby providing the orientation of the distal portion  30  of the catheter  12  with respect to the surrounding myocardium  112  and the selected coronary artery  100 . 
         [0086]    More particularly, because of the triangular arrangement of the struts  38 ,  40 , their artifacts  104 ,  106  “point” circumferentially in the direction of the periphery  20  corresponding to the location of the peripheral opening  34 , and consequently in the direction towards which the distal tip  64  of the needle assembly  62  will be deployed from the catheter  12 . The catheter  12  may be torqued about its longitudinal axis  22  to rotate the distal portion  30 , as observed by the artifacts  104 ,  106 , until it can be seen that the distal tip  64  of the needle assembly  62 , i.e. the artifact  104 , is directed towards the selected the coronary artery  100 . 
         [0087]    The resulting ultrasound image may also be scalable, allowing the user to measure the distance to the selected target region from the catheter  12 , and thereby determine the precise distance that the distal tip  64  of the needle assembly  62  will need to be directed to reach the selected tissue region. The needle stop  70  on the handle  50  may then be loosened, adjusted along the graduated region  60 , and then locked at a predetermined position corresponding to the precise distance. 
         [0088]    Once the catheter  12  is properly oriented and the needle stop  70  is locked at the predetermined position, the distal tip  64  of the needle assembly  62  may be deployed from the catheter  12  to penetrate the wall  103  of the vessel location  102  and enter the selected tissue region  100 . Preferably, the needle thumb slide  68  is directed distally by the user, thereby directing the distal tip  64  against the deflecting element  48  and causing the distal tip  64  to deflect radially outward as it exits the peripheral opening  34 . 
         [0089]    Because of the secured position of the needle stop  70  on the handle  50 , the needle thumb slide  68  may be quickly advanced distally until it abuts the needle stop  70 , thereby puncturing the wall  103  of the vein  102  and delivering the distal tip  64  the precise distance, i.e. precisely within the selected target region of the artery  100 . Alternatively, it may be desirable to overshoot, i.e. pass a predetermined distance through and beyond the selected target region, and then slowly withdraw the distal tip  64  until it reaches the selected tissue region. 
         [0090]    A drug may then be introduced into the selected tissue region, for example by connecting a source of the drug such as a syringe (not shown), to the proximal end (not shown) of the needle assembly  62 , and injecting the drug through the lumen  72  and the outlet  74  in the distal tip  64 . The distal tip  64  may then be withdrawn back into the needle lumen  36  and the catheter  12  withdrawn from the patient in a conventional manner. 
         [0091]    Prior to delivering the drug, a “mapping” procedure may be used to ensure that the drug will be delivered as desired into the specific tissue region selected for treatment. For example, a radiographic agent may be delivered through the outlet  74  in the distal tip  64 . The flow of the radiographic agent may be observed with respect to the selected tissue region, for example using fluoroscopy. Once it has been confirmed that the radiographic agent flows as desired into the selected tissue region, the drug may then be introduced, thereby possibly avoiding misdelivery of what are often quite expensive drugs. Alternatively, a radiographic agent and the like may be mixed with the drug to track the flow of the drug within the body, particularly with respect to the selected tissue region. 
         [0092]    Turning now to  FIG. 6 , another preferred embodiment of a transvascular catheter system  10  for delivering a drug to a remote tissue region  220  within the myocardium  112  is shown. Several of the elements are similar to those previously described and consequently have the same reference numbers and will not be described further. The system  10  of this embodiment includes a drug delivery element, namely a drug delivery catheter  214 , that may be deployed from the distal portion  30  of the catheter  12 , preferably in combination with the puncturing element  14 . 
         [0093]    The puncturing element  14  preferably includes a solid needle or guide wire assembly  162 , without a lumen but otherwise similar to the needle assembly  62  previously described, over which the drug delivery catheter  214  may be deployed. The guide wire assembly  162  may include an anchoring tip (not shown) for fixing the distal tip  164  of the guide wire assembly  162  in the tissue region  220  and/or to facilitate introduction of instruments, such as the drug delivery catheter  214 , to the tissue region  220 . 
         [0094]    The drug delivery catheter  214  may include a porous balloon  218  for infusing the drug in a predetermined pattern within the tissue region  220 , and generally includes a plurality of lumens extending between its proximal portion (not shown), and a distal portion  222 . The drug delivery catheter  214  preferably has a guide wire lumen  224  such that the drug delivery catheter  214  may be delivered to the tissue region  220  over the guide wire assembly  162 , and also has a drug delivery lumen (not shown) communicating with a portion, e.g. the interior, of the porous balloon  218 . The porous balloon  218  includes a porous region, such as a plurality of holes  226 , a permeable membrane and the like, preferably arranged to provide a predetermined flow pattern through the balloon  218  into the tissue region  220 . 
         [0095]    During use, the catheter  12  may be introduced percutaneously into a blood vessel  102 , and oriented with respect to the selected tissue region  220  (see  FIG. 3B ). The guide wire assembly  162  may then be deployed transvascularly to access the selected tissue region  220 , similar to the process previously described. The drug delivery catheter  214  may then be advanced over the guide wire assembly  162  until it enters the tissue region  220 . The balloon  218  may then be inflated, expanding it from a collapsed condition around the drug delivery catheter  214  to an enlarged condition contacting the surrounding tissue  220 . The balloon  218  may be inflated simply by introducing a drug through the drug delivery lumen, which may then seep through the porous region  226  and pass into the tissue region  220 . Alternatively, the catheter  214  may include a separate inflation lumen (not shown) through which an inflation media such as saline may be introduced into a non-porous region within the balloon isolated from the porous region, as will be appreciated by those skilled in the art. In a further alternative, the drug delivery element may be a flexible, thin, floppy catheter which may be left behind to serve as an “indwelling” transcutaneous access catheter, as described more particularly below. 
         [0096]    In further alternatives, the drug delivery catheter  214  and/or the guide wire assembly  162  may include an electrode or other element (not shown) to enhance penetration of the delivered drug into the tissue region. For example, an internal heating element (not shown) may be provided within the balloon  218  to heat the fluid therein and/or the surrounding tissue  220 , which may enhance absorption of the drug delivered into the tissue. Alternatively, an electrode (not shown) may be provided on or within the balloon  218  which may be coupled to an external electrode (not shown). Direct current may then be applied between the electrodes to ionophoretically direct drugs from the drug delivery catheter  214  deep into the surrounding tissue  220 . In a further alternative, the distal tip  164  of the guide wire assembly  162  may be formed from an electrically conductive material such as gold or platinum, or may include an electrode on a portion thereof (not shown), which may be coupled to an external source of electric current via a conductor (not shown) extending proximally through the guide wire assembly  162 . 
         [0097]    Thus, a transvascular catheter system  10  in accordance with the present invention may be used to deliver a single dose or bolus of a drug directly and precisely into a selected remote tissue region. Alternatively, the system may be used for sustained delivery by keeping the distal portion  30  of the catheter  12  and/or the distal tip  64  of the needle assembly  62  within the blood vessel and/or selected tissue region for an extended period of time. 
         [0098]    For example, the needle assembly  62  or infusion catheter  214  may be used to inject a matrix material into a tissue region which may slowly diffuse a drug into the tissue region. Alternatively, a stent or similar structure may be delivered into the tissue region, the structure including a drug therein that may be released over time. 
         [0099]    In addition, to provide sustained delivery and/or a series of treatments of a drug, an indwelling catheter (not shown) may be left behind within the selected tissue region. For example, the transvascular catheter system  10  may be introduced into a blood vessel, and the puncturing element  14 , e.g. the needle assembly  62  or the guide wire assembly  162 , may be oriented and deployed within a selected tissue region, such as an interstitial tissue region or another blood vessel. 
         [0100]    A guide wire (not shown) may be advanced into the tissue region, and possibly anchored in place. The transvascular catheter  12  may be withdrawn from the blood vessel, leaving the guide wire, and a thin, floppy catheter (not shown), which may be an infusion catheter similar to that previously described or simply a single delivery port device, may be tracked over the guide wire into the tissue region and left there. The guide wire may then be removed, and the proximal end (not shown) of the thin, floppy catheter may be secured to the patient, for example taped or ported (such as using a port assembly such as that described below) depending upon the length of time therapy is desired. The distal end of the indwelling catheter may then remain in place within the tissue region, possibly for extended periods of time, to provide access whenever needed. 
         [0101]    Alternatively, turning to  FIG. 7 , the transvascular catheter system  10  may include an implantable port assembly  350 . The port assembly  350  includes a body  352  which may be implantable on or beneath the skin of the patient, and one or more seals  354 . The body includes a hollow hub  356  the interior of which communicates with the seal  354  which may be attached to the transvascular catheter system  10 , such as the proximal end  24  of the catheter  12  or preferably to an indwelling catheter (not shown). 
         [0102]    For example, the catheter  12  shown in  FIG. 1  may be percutaneously introduced into a patient&#39;s cardiovascular system, and the distal portion  30  may be advanced into a selected vessel, whereupon the distal tip  64  of the needle assembly  62  (not shown in  FIG. 7 ) may be advanced into a selected remote tissue region, similar to the methods previously described. The handle  50  (not shown in  FIG. 7 ) may then be removed from the proximal end  24  and replaced with the port assembly  350  such that the hub  356  may communicate with the needle lumen  36 , the IVUS lumen  32 , and/or a drug delivery lumen in the indwelling catheter. The port assembly  350  may then be stitched or otherwise implanted onto an accessible region of the patient&#39;s body (not shown). 
         [0103]    Whenever it is desired to access the tissue region, an instrument such as a needle, an infusion device, a sensor and the like (not shown) may be directed through the seal  354  to communicate with the drug delivery element extending to the selected tissue region. For example, during gene or growth factor therapy, it is often desired to subject the selected tissue region to compounds, such as angiogenic growth factors, for extensive periods of time. The implantable system of the present invention facilitates such sustained treatment by allowing the tissue region to be accessed as often as necessary to maintain a desired level of growth factor at the selected tissue region. 
         [0104]    Turning now to  FIG. 8 , another preferred embodiment of a transvascular catheter system  10  in accordance with the present invention is shown, which may be used to create a drug reservoir  224  within a selected tissue region  220  itself to provide sustained delivery. A catheter  12 , similar to that previously described, may be introduced endovascularly into a blood vessel  102  until the distal portion  30  is adjacent the tissue region  220 . The distal tip  64  of the needle assembly  62  may be oriented and deployed to puncture the wall  103  of the vessel  102  and enter the tissue region  220 , using methods similar to those described above. 
         [0105]    An ablation device  230 , such as a radio frequency (RF) device, a laser device, and the like, may be advanced over the needle assembly  62  into the tissue region  220 . One or more electrodes  232  or similar elements on the ablation device  230  may be activated to create a cavity  224  within the tissue region  220  in a manner known to those skilled in the art. The ablation device  230  may then be removed, and a drug may be introduced into the cavity  224  to create a drug reservoir in continuous contact with the surrounding tissue  220 , thereby providing sustained delivery as the drug is slowly absorbed by the surrounding tissue  220 . 
         [0106]    As an alternative to ablation of tissue, a non-porous balloon catheter (not shown) may be advanced over the needle assembly  62  into the tissue region  220 . The balloon may be inflated to its enlarged condition to contact and push aside the surrounding tissue  220 , and create a cavity  224 . No additional treatment of the tissue  220  may be needed to create the cavity  224 , particularly in ischemic tissue which is substantially non-resilient as compared to healthy tissue and unlikely to expand back to fill the cavity  224 . It is also within the spirit of the present invention that other devices, such as cutting, coring or other mechanical instruments, may also be used to remove tissue to create the cavity  224  by being advanced over the needle assembly  62  into the tissue region  220 , as will be appreciated by those skilled in the art. 
         [0107]    In addition, it may be desirable to inject a sealant or matrix material, such as collagen or a filament structure (e.g. drug-impregnated suture material), into the cavity  224  or into the passage  223  extending between the blood vessel  102  and the cavity  224 . Although the distal tip  64  may be sufficiently small so as to create a self-sealing passage  223 , advancement of instruments, such as the drug delivery catheter  214  of  FIG. 6 , may dilate the passage  223 , which may result in the drug leaking through the passage  23  back into the blood vessel  102  from the cavity  224 . To substantially reduce the risk of this occurring, a sealant, matrix material, or filament (not shown) may be injected into the cavity  224  itself, or into the passage  223 , for example through a lumen in the drug delivery element  214  or the needle assembly  62  before or while it is being withdrawn from the cavity  224 . 
         [0108]    In a further alternative shown in  FIG. 5A , the transvascular catheter system  10  may include a plurality of needle assemblies  62 , similar to the individual needle assembly described above, to be deployed in a predetermined arrangement along the periphery  20  of the catheter  12 . Preferably, the needle assemblies  62  are arranged axially in a row, aligned with the strut of the “cage” structure orientation element (not shown in  FIG. 5A ). In particular, it may desirable to access an extended remote tissue region, for example extending substantially parallel to a vessel, especially within the myocardium. With a multiple needle transvascular catheter system, a single device may be delivered into a vessel and oriented. The array of needles may be sequentially or simultaneously deployed to inject one or more drugs into the extended tissue region, thereby providing a selected trajectory pattern. 
         [0109]    Other directional drug delivery elements may also be provided within the present invention. For example, a catheter having a drug delivery element, an orientation element and possibly an imaging element may be provided similar to those described above. Instead of a needle or guide wire assembly, the distal portion of the catheter may include an osmotic surface on a portion of the circumference or periphery and extending axially along the distal portion (not shown). 
         [0110]    The osmotic surface preferably has a predetermined relationship to the orientation element, such that the osmotic surface may be directed circumferentially towards a selected tissue region, e.g. a specific portion of a vessel wall and/or a tissue region beyond the vessel wall. The catheter may include a balloon or other expandable structure which may push the osmotic surface into direct contact with the vessel wall to further facilitate delivery. A drug, possibly embedded within the osmotic surface itself or in a chamber beneath the osmotic surface, may then be delivered with or without ionophoresis or other assisted delivery mechanism. 
         [0111]    Turning to  FIG. 13 , the systems and methods of the present invention may also be used to provide access downstream of an occluded or stenotic region of a blood vessel, for example to treat a coronary artery or ischemic tissue region of the myocardium downstream of an occluded coronary artery. First, a location downstream of an occluded section  404  of a coronary artery  400  may be selected for treatment, and a transvascular catheter device (not shown) percutaneously introduced into the venous system and advanced until it reaches a coronary vein  402  adjacent the selected artery  400 . An interstitial passage  406  may be created between the coronary vein  402  and the coronary artery  400 , and a guide wire  410  may be advanced through the interstitial passage  406  into the coronary artery  400 . The guide wire  410  may be substantially anchored within the coronary artery  400 , for example by embedding the distal end of the guide wire  410  into the wall of the coronary artery  400  (not shown). Further details on the systems and methods for performing interstitial or transvascular procedures between the venous and arterial systems may be found in co-pending application Ser. Nos. 08/730,327 and 08/730,496, both filed Oct. 11, 996, the disclosures of which are expressly incorporated herein by reference. 
         [0112]    A transvascular catheter system  10 , similar to those previously described, may then be advanced over the guide wire  410  along the venous system, through the interstitial passage  406  and into the coronary artery  400  downstream of the occluded region  404 , thus without disturbing plaque or otherwise affecting flow through the arterial system. It will be appreciated by those skilled in the art that the transvascular catheter system  10  used to deliver the drug may also be used to create the interstitial passage  406 . 
         [0113]    The artery  400  itself may then be treated, for example, using the needle assembly  62  of  FIG. 1  or the drug delivery catheter  214  of  FIG. 6 . A drug may be delivered into the lumen  408  of the artery  400 , into the vessel wall  412  and/or the surrounding tissue  414 . In addition, one or more drug reservoirs (not shown) may be created within the surrounding tissue  414 , most preferably within myocardial tissue adjacent to a coronary artery, for receiving a drug that may be absorbed by the surrounding tissue  414  over an extended period of time. 
         [0114]    Other useful features may also be included in any of the embodiments of the transvascular catheter system  10  in accordance with the present invention. For example, the catheter  12  may include one or more stabilizing balloons (not shown) on the distal portion  30 , for example proximal to the peripheral opening  34 . An inflation lumen may be provided in the catheter  12  to allow an inflation medium, e.g. saline, to be introduced into the stabilizing balloon to substantially anchor the catheter  12  at a desired location within the blood vessel, i.e. to prevent the catheter  12  from moving axially within the vessel once the distal portion  30  is adjacent to a remote tissue region selected for treatment. 
         [0115]    In addition, one or more of the elements of the system may include a sensor for measuring information relevant to the treatment of the selected tissue region. For example, a pressure sensor may be provided on the catheter  12 , the needle assembly  62  and/or the drug delivery element. A lumen may extend proximally through the respective element, thereby allowing the user to continuously monitor pressure at or near the delivery site. The drug delivery element may also include a flow measurement sensor, allowing the amount of drug being delivered to the selected tissue region to be precisely measured. 
         [0116]    Other feedback elements may also be provided, for example, a thermocouple or other temperature sensor may be provided on systems including ionophoresis electrodes or ablation devices to monitor the amount of heating being experienced by tissue during a procedure. Alternatively as shown in  FIG. 5D , the needle assembly  62  or other component may include a feedback element  79  for measuring a physiological condition. For example, an EKG lead may be included on the distal tip or otherwise delivered within the selected tissue region, thereby allowing electrical events within the heart to be monitored during drug delivery. During treatment, for example, a drug may be delivered into a tissue region until a desired condition is met, such as until the tissue becomes non-tachycardic, or until tachycardia is induced. 
         [0117]    An important aspect of the transvascular catheter system of the present invention is the ability to precisely deliver a drug to a selected remote location within a reference frame, preferably including a circumferential or peripheral component and a radial component. The orientation element provides the peripheral component because of its predetermined relationship with the periphery of the catheter and the drug delivery element. The imaging element preferably provides the radial component by detecting the relationship of the orientation element to the selected remote location (e.g. the distance between them), or landmarks in a known relationship with the selected remote location. Once the location of the selected remote location is known within the reference frame, the drug delivery element may be directed towards the selected remote location for precise delivery of a drug. 
         [0118]    In another aspect of the present invention,  FIGS. 9A-9D  and  10  show a preferred embodiment of an implantable reservoir device  400  that may be used to provide sustained delivery of a drug to tissue surrounding a blood vessel, preferably within a coronary vein  102  adjacent to ischemic myocardial tissue  112 . The reservoir device  400  includes a substantially cylindrical frame  402  adapted to expand between a collapsed condition for insertion into a blood vessel and an enlarged condition for engaging a wall  103  of the blood vessel  102 , and defining a longitudinal axis  404 . 
         [0119]    The frame  402  is sufficiently flexible to expand between the collapsed and enlarged conditions during use without substantial risk of failing or fatiguing, yet sufficiently rigid to anchor the reservoir device  400  within the blood vessel  102 . Preferably, the frame  402  is resiliently biased towards the enlarged condition to prevent substantial movement of the frame  402  axially within the blood vessel  102 . The frame  402  may be formed from a woven mesh of wire of, for example, a shape memory alloy such as Nitinol, stainless steel, platinum, polymers or other plastics and the like. The frame  402  may be woven into a criss-cross structure, a sinusoidal structure, or may include a pair of expandable rings connected by spacers to retain the rings apart axially. 
         [0120]    A flexible membrane  408  is attached to the frame  402 , preferably to the exterior of frame  402  such that the membrane  408  may enhance a fluid-tight seal when pressed against the wall  103  of the vessel  102  by the frame  402  after deployment. The membrane  408  includes a periphery  412  and end panels  414 ,  416 , which together define a sealed reservoir  410  within the membrane  408  and the frame  402 . The membrane  408  should be substantially flexible, and may be elastic if tension over the frame is preferred, or plastic if a small initial diameter is preferred. Preferred materials include dacron and PTFE, which may also be silicone dipped. 
         [0121]    The membrane  408  includes a porous region  418 , which is preferably disposed along at least a portion of the periphery  412  of the membrane  408 . The porous region  418  may be a permeable or semi-permeable material bonded or otherwise attached to non-permeable segment(s) of the membrane  408 . Alternatively, the entire membrane  408  may be formed from a non-permeable material with holes formed through discrete areas to define the porous region  418 . 
         [0122]    In addition, as shown in  FIGS. 9B and 9C , at least one of the end panels  416  may be recrossable, i.e., may be penetrable by a needle  432 , but automatically resealable, to facilitate in situ filling or refilling of the reservoir  410 , preferably having a concave shape to facilitate penetration by the needle  432 . Alternatively, the reservoir  410  may be prefilled with a drug, possibly together with an anti-coagulant or other compound, prior to delivery into the blood vessel  422 . In addition, the drug and the pore size of the porous region  418  may have a predetermined relationship such that the drug permeates or flows through the porous region  418  into the surrounding tissue at a predetermined flow rate. 
         [0123]    During use, the reservoir device  400  is percutaneously delivered into a blood vessel in its collapsed condition using a delivery device, for example within a lumen of a delivery catheter or sheath adapted to receive the reservoir device  400 . Alternatively, the frame  402  may include a control hub on one end (not shown), which may be gripped and compressed radially inward to collapse the frame  402 . 
         [0124]    Once the reservoir device  400  is in a blood vessel adjacent the target region, such as the coronary vein  102  adjacent to the selected tissue region  112 , the reservoir device  400  is deployed from the delivery device, for example using a plunger within the delivery catheter lumen (not shown). Preferably, the frame  402  automatically expands to its enlarged condition, thereby substantially anchoring the device  400  in position within the vessel  102 . The frame  402  may also create a substantially fluid-tight seal with the wall  103  of the vessel  102 , to prevent substantial leakage of fluid delivered through the periphery  412  downstream within the vessel  102 . 
         [0125]    If the reservoir  410  is empty during deployment, for example, to prevent rupture of the membrane  408  when the frame  402  is collapsed, a drug delivery element may be introduced into the vessel  102  to fill the reservoir  410 . For example, as shown in  FIGS. 9C and 9D , an injection device  430  including a sheath  434  covering a hollow needle  432  may be delivered endovascularly, or the delivery catheter used to deliver the reservoir device  400  may include an additional drug delivery needle lumen. The needle  432  may be deployed to penetrate the recrossable end region  416 , whereupon the reservoir  410  may be filled by introducing the drug through the needle  432 . 
         [0126]    The reservoir device  400  may remain in the vessel  102  for a substantial period of time, possibly hours or days, allowing the drug to slowly absorb into the wall of the vessel and preferably the surrounding tissue. In addition, the drug delivery element, e.g. the sheath-covered hollow needle, may be reintroduced into the vessel  423  to refill the reservoir  410 , for example using an implantable port assembly similar to that shown in  FIG. 7 . Alternatively, the reservoir device  400  may include an electrode (not shown) to enable ionophoresis or other enhanced delivery. A catheter including a conductor (not shown) may be introduced into the vessel  102 , coupled to the electrode, and then energized by an external source of electric current (not shown) for this purpose. 
         [0127]    In an alternative embodiment, shown in  FIG. 11 , the reservoir device  400  may provide an endovascular “pump” for time-release delivery of a drug. In this embodiment, the reservoir device  400  includes a septum panel  420  dividing the reservoir  410  into first and second regions  410   a ,  410   b . The first end panel  414  of the membrane  408  is an osmotic membrane and the first reservoir  410   a  is filled with a fluid absorbing compound. The porous region  418  of the membrane  408  communicates only with the second reservoir  410   b , which is filled with a drug in situ or before deployment. 
         [0128]    When the reservoir device  400  is deployed within a vessel (not shown), using a procedure similar to that just described, the compound in the first reservoir  410   a  begins to slowly draw fluid osmotically from within the lumen of the vessel. As this occurs, the septum panel  420  is forced to expand towards the second end panel  416 , thereby applying a force within the second reservoir  410   b , which “pumps” or otherwise encourages the drug to flow out the porous region  418 , and preferably into the wall of the vessel. 
         [0129]    In other arrangements, instead of the septum panel  420 , a cylindrical septum may be provided, creating an internal first reservoir and an annular second reservoir surrounding the first reservoir (not shown). The area of one or both end panels in contact with the internal first reservoir may be provided from an osmotic material, thereby creating a similar flow out of a porous region on the periphery of the membrane in communication with the annular second reservoir. 
         [0130]    Other shapes and configurations of the reservoir device  400  may also be provided that may be deployed and substantially anchored adjacent a selected tissue region. In addition, a drug reservoir device similar to those described may be delivered directly into tissue, for example, using one of the transvascular catheter systems previously described, as will be appreciated by those skilled in the art. 
         [0131]    In another preferred embodiment shown in  FIG. 12 , an implantable system including a pair of endovascular blocker devices  500  may be used to create a drug reservoir  508   a  within a blood vessel  102  itself, i.e. between the blockers  500  and the wall  103   a  of the vessel  102  between them. The blockers  500  preferably include an expandable frame  502  and a flexible membrane  504  attached to the frame  502 , similar to that described above. The membrane  504 , however, is preferably non-permeable, although alternatively a permeable periphery (not shown) may be provided to increase the surface area through which the drug may be directed towards the vessel wall  103 . 
         [0132]    To create the reservoir  508   a , the first blocker  500   a  is deployed within a vessel  102  adjacent a selected tissue region, such as a stenotic region  105  within an artery  102 , using a method similar to that described above for the reservoir device  400 . A drug is introduced into the vessel lumen  108   a , and a second blocker  500   b  is deployed within the vessel  102 , thereby encapsulating the drug in the lumen  108   a  between the blockers  500   a ,  500   b.    
         [0133]    Alternatively, the drug may be delivered into the reservoir  508   a  after both blockers  500  are deployed and in secured within the vessel  102 . For example, the second blocker  500   b  may include a recrossable end panel  514  on one end, and an open interior that may communicate directly with the reservoir  108   a . Thus, an injection needle device (not shown) may be used to inject the drug through the recrossable end panel  514  and into the reservoir  508   a  in situ. 
         [0134]    It has been determined clinically that one or more segments of the venous system, even within the coronary system, may be occluded for extensive periods of time without adversely affecting the performance of the coronary system. Accordingly, an implantable reservoir system in accordance with the present invention may be used to create a reservoir within a coronary vein without interfering substantially with the flow of return blood from the myocardium. A drug within the reservoir may then be absorbed by the vessel wall and surrounding tissue to treat selected tissue regions adjacent the reservoir site. 
         [0135]    Of further note, it has been clinically determined that complete occlusion and shutdown of the coronary venous system may not impair normal operation of the heart. The endocardial veins may take over at least a portion of the additional venous return. Furthermore, within thirty minutes of complete occlusion, the Thebesian system, which includes capillaries, venals and porous tissue that makes up the myocardium itself, may replace the venous system and return one hundred percent of the return blood from the myocardium. Thus, the reservoir devices in accordance with the present invention may be deployed in one or more regions within the coronary venous system without substantial risk of adversely affecting coronary blood flow or damaging the tissues of the coronary system. 
         [0136]    While the invention is susceptible to various modifications, and alternative forms, specific examples thereof have been shown in the drawings and are herein described in detail. It should be understood, however, that the invention is not to be limited to the particular forms or methods disclosed, but to the contrary, the invention is to cover all modifications, equivalents and alternatives falling within the spirit and scope of the appended claims.