MXPA00009335A

MXPA00009335A - Systems and methods for delivering drugs to selected locations within the body

Info

Publication number: MXPA00009335A
Application number: MXPA/A/2000/009335A
Authority: MX
Inventors: christopher flaherty J; Makower Joshua; Philip C Evard; E Macaulay Patrick; Jason B Whitt; Robert C Colloton; K Angela Macfarlane
Original assignee: Transvascular Inc
Priority date: 1998-03-25
Filing date: 2000-09-22
Publication date: 2002-06-05

Abstract

A trans-vascular system (10) for delivering a drug to a tissue region from a blood vessel, such as a coronary vein, includes a catheter (12) having a distal portion (26) with puncturing (14), orientation (16), drug delivery (62), and imaging elements (18). The puncturing element (14) is deployed for penetrating the vessel wall to access the tissue region. The orientation element (16), e.g., a"cage"including a plurality of struts (38, 40), and/or a radiopaque marker has a predetermined relationship with the location of the orientation element (16) with respect to the tissue region to orient the puncturing element (14). The catheter (12) is percutaneously introducing into the vessel, the puncturing element (14) is oriented towards the tissue region, the puncturing element (14) is deployed to access the tissue region, and the drug is delivered to the tissue region. An ablation device (230) may also be deployed to create a cavity in the tissue region for receiving the drug therein, or an indwelling catheter (214) may be advanced into, and left in the tissue region. An implanted reservoir device (350) is also disclosed, including an enclosed membrane (354) on an expandable frame (352) that defines a reservoir, and includes a porous region. The reservoir device may be deployed, expanded within a blood vessel, and may be filled in situ or pre-filled with a drug that passes through the porous region. Alternatively, a pair of expandable endovascular blockers may be used to isolate a section of a blood vessel which may be filled with a drug that may be absorbed by the surrounding tissue.

Description

SYSTEMS AND METHODS FOR SUPPLYING DRUGS TO SELECTED LOCATIONS WITHIN THE BODY This application is a continuation in part of the applications serial numbers 08 / 730,327 and 08 / 730,496, both published on October 11, 1996, the descriptions of which are expressly incorporated herein by reference.

FIELD OF THE INVENTION The present invention relates generally to systems and methods for delivering substances to a body, particularly to systems and methods that use the cardiovascular system as a conduit for delivering drugs, such as therapeutic drugs, genes, growth factors and the like, directly to regions of selected tissue within the body, and more particularly to systems and methods that deliver drugs from the venous system transvascularly to selected remote tissue regions.

BACKGROUND OF THE INVENTION It is often convenient to deliver drugs to a patient's body to treat medical conditions. In particular, a wide variety of drug therapies are available to treat the coronary system, either alone or in combination with more invasive procedures. Such therapies may include the delivery of substances, such as nitroglycerin, epinefarin, or lidocaine, endocardially or in the pericardial space to treat the coronary system. In addition, heparin, hirudin, ReoPro ™ or other anti-thrombotic compounds can be infused into blood vessels associated with the coronary system, such as occluded coronary arteries, or elsewhere in the cardiovascular system. Recently, gene therapy, for example, introduction of genetic material, and growth factor therapy, for example introduction of proteins, cells or vectors including angiogenic growth factors, have been shown to provide potential benefits in the treatment of ischemic heart tissue. and other regions of the coronary system, for example, stimulating the growth of neovascular canals, which can evolve into new blood vessels. In current medical therapy, a method for delivering such drugs involves percutaneously introducing an infusion catheter into the patient's cardiovascular system. A distal portion of the catheter is directed to a desired endovascular location, for example to a coronary artery, and a drug is introduced into the artery at an intraluminally attainable location. The catheter may include a lumen extending between its proximal and distal ends, the distal end having one or more exit ports. A source of the drug, such as a syringe, can be connected to the proximal end and the drug delivered through the lumen and the exit port (s) to the desired location. For example, a "bolus", that is a relatively large single dose of a drug, can be delivered using an infusion catheter into an artery, which can be absorbed by the arterial wall, the surrounding tissue, and / or can be transported by the blood flow to the regions downstream of the supply location. Alternatively, the drug can be introduced continuously or intermittently into the artery for a prolonged period of time. The infusion catheter often includes a porous perfusion balloon at its distal end, the interior of which communicates with the exit port (s) and the lumen in the catheter. The pores or holes in the balloon can be placed to direct the drug from the balloon to the arterial wall to improve penetration into the arterial wall and to try to locate the supply. In addition, the infusion catheter can be provided with an electrode and / or a heating element on or in the balloon to cause electroporation or heat the surrounding tissue to further improve localized delivery. Some devices try to increase localized drug delivery using iontophoresis. A first electrode can be provided inside an infusion balloon, and a second electrode is provided on an external region of the patient's body near the artery. When direct current is applied between the electrodes, a drug carried by an electrically charged compound can be directed along the current flow path from the inner electrode to the outer electrode in an attempt to improve the penetration of the drug into the arterial wall and the surrounding tissue. As an alternative for infusion balloons and / or infusion catheters, a drug can be embedded or deposited in a catheter, for example, in the wall of the catheter, the wall of a non-porous balloon on the catheter, and / or a coating on the catheter After the distal end is led to a desired location, the drug can be delivered to an artery, for example, by iontophoresis similar to that described above or simply by allowing the drug to dissolve within the artery. In an alternative to provide a bolus of drugs, it is convenient to provide sustained supply of a drug within the cardiovascular system. For example, a pair of occlusion balloons disposed along the length of a catheter can be provided over an infusion catheter that can be endovascularly directed to a desired location within an artery. The balloons can be inflated to isolate a section of the artery between them, and a drug can be delivered in the isolated section in an attempt to provide sustained supply to the isolated section. Then the balloons are deflated, and the catheter removed from the body. Drug delivery devices can also be implanted within an artery to provide sustained delivery. For example, the patent of E.U.A. No. 5,628,784 issued to Strecker describes an expandable annular sleeve that can be deployed within an artery. A small amount of drugs can be introduced between the wall of the cuff and the surrounding arterial wall to directly contact the arterial wall, where they can be absorbed for a prolonged period of time. PCT Publication No. WO 95/01138 discloses a porous ceramic sleeve that can be implanted directly into tissue, such as in the bone marrow or a surgically created pouch. The cuff includes drugs within a cell culture or matrix in the cuff, which may, for example, disperse in the pores of the cuff or be provided in a cylindrical graft. In addition, numerous extravascular methods have been suggested. For example, the drugs can be injected directly into a desired region of tissue, typically entering the region through an incision in the chest. Alternatively, a polymeric gel or sponge soaked with drug can be fixed 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, for example entering the pericardial sac through an incision in the chest. These methods can provide sustained delivery or in individual doses of drugs to the heart. One of the problems frequently associated with existing methods is the dilution or "washing" of the drug during delivery.

Dilution can substantially reduce the effectiveness of a therapy by preventing sufficient amounts of the drug from reaching a desired region. For example, during endovascular delivery using an infusion catheter, the drug can be diluted as it travels through the arterial wall or can be transported downstream through the artery to other regions within the coronary system and / or other part of the body. The volume of drug may be increased to counteract the dilution, but this may exacerbate the undesired spread of the drug. For example, certain therapeutic drugs, genetic material and growth factors may have undesired overall side effects. The release of a drug into the bloodstream allows it to be transported through the coronary system or another part of the body where it can have significant adverse effects. Similar adverse effects can result from pericardial delivery, where a drug can be absorbed through the coronary system, instead of only in a desired local region. In addition, many conventional methods are unable to provide effective sustained delivery, which is important for the success of certain treatments, such as growth factor or gene therapy, where it is convenient to keep a drug in a desired region for hours, days or even more time Occlusion systems, such as the dual occlusion balloon catheter, or the implantable cuffs described above, have the ability to isolate a region of an artery for certain sustained treatments.

Such occlusion devices, however, may introduce additional risks associated with flow obstruction 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 tissue infarction downstream of the occluded region. Conventional endovascular systems may also be inadequate to access certain tissues that need 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. Furthermore, it can be dangerous to direct an endovascular device through a stenotic region due to the risk of releasing embolic material from the arterial wall, which can travel downstream and become embedded in other vessels or even travel to vital organs, such as the brain, in where it can cause substantial damage or even death. More invasive methods, such as direct drug injection, can provide access to other hard-to-reach regions. Such methods, however, typically involve opening the chest or other invasive surgical procedures, as well as the costs and risks associated with them. There is also a need to find improved systems and methods for delivering drugs to desired locations within the body with greater precision, reduced overall side effects, and / or substantially reducing the problems of previous systems and methods.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to systems and methods for delivering a drug to a region of tissue within a patient's body, and in particular to systems and methods that utilize the venous system as a conduit for delivering a drug directly to a tissue region. remote, or to facilitate a catheter-based intervention. "Drug" as defined herein includes any therapeutic drug, genetic materials, growth factors, cells, eg, myocytes, vectors that carry growth factors, and similar therapeutic agents or substances that can be delivered within a patient's body to any therapeutic procedure, diagnosis 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 pricking 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 can be deployed 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 region of tissue beyond the wall of the vessel. 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 puncture element. Preferably, the catheter has a peripheral opening at a predetermined location on the periphery of the distal portion through which the puncture element can be deployed, and a needle lumen communicating with the peripheral opening for receiving the puncture element at through it. The needle lumen includes a baffle element adapted to direct the distal tip substantially transverse to the longitudinal axis when the puncture element is deployed. The system may include an image element adjacent to the orientation element to detect the location of the orientation element with respect to the tissue region. For example, the imaging element may be an ultrasound transducer that can be received in a lumen extending between the proximal and distal portions of the catheter. 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 exit port arrangement to provide a predetermined fluid flow pattern in the region of tissue reached by the needle. In addition, at least a portion of the needle may be an electrically conductive material coupled to a proximal end of the prong for coupling the needle to an electrical current source. Alternatively, the prong may be a plurality of deployable needles from predetermined locations on the distal portion to provide a selected trajectory pattern in the tissue region. In a second preferred embodiment, the prong includes a guidewire, and the drug delivery element can be deployed on the guidewire. For example, the drug delivery element may be an infusion catheter, possibly including an infusion balloon. Alternatively, the drug delivery element may include a permanent catheter that is delivered over the guidewire, either before or after removal of the transvascular catheter. The drug delivery element may include a first electrode adapted to be electrically coupled to a second electrode. When direct current is conducted between the first and second electrodes, the fluid of the drug delivery element can be directed iontophoretically from the drug delivery element to the second electrode. Successively, the drug delivery element can be an osmotic surface on the transvascular catheter, the infusion catheter or the permanent catheter. To help orient the system during use, the targeting element preferably has an asymmetric configuration aligned with the piercing element, for example with the peripheral opening through which the piercing element can be deployed. In a first preferred embodiment, the orientation element is a "cage" shaped structure that includes a plurality of rods extending axially along the distal portion. Preferably, a first rod is provided at a location in direct axial alignment with the peripheral opening, and a pair of rods is provided opposite the first rod to "point" toward the peripheral opening. Alternatively, the orientation element may include a marker that can be seen using an external image system, and preferably a pair of markers arranged opposite each other on the periphery, either instead or preferably in addition to the "cage" structure " A transvascular catheter system according to the present invention can be used to deliver a drug to a tissue region within the body of a patient, such as in the myocardium or coronary artery of the coronary venous system, in a method that functions as follow. The distal portion of the catheter can be introduced percutaneously into a blood vessel, and directed endovascularly to a vessel location adjacent to the region of tissue selected for treatment. The pricking element can be oriented towards the selected tissue region, and deployed to enter the tissue region. A drug with the drug delivery element can then be delivered to the tissue region. Preferably, when the puncture element is being oriented, the orientation element is seen, for example with an image element adjacent to the orientation element. The image element preferably functions to obtain an image of the orientation element in relation to the surrounding tissue, thereby identifying the orientation of the pricking element due to the predetermined relationship between the orientation element and the pricking element. Preferably, the imaging element is an ultrasound transducer within the catheter that can be used to obtain image portions along a plane substantially normal to the longitudinal axis of the catheter, the images preferably include the orientation element, the region of selected tissue and / or other marks within the vessel or the surrounding tissue. When the puncture element is a drug delivery needle, the needle can be deployed, penetrating a wall of the blood vessel and entering the tissue region, and the drug can be delivered through a lumen in the needle. Alternatively, a drug delivery element can be deployed in combination with the puncture element. For example, an infusion catheter can be advanced over the puncture element into the tissue region, and the drug introduced therein, or through a porous balloon over the infusion catheter that can be inflated within the tissue region. Before delivering the drug, a "mapping" procedure can be used to ensure that the drug will be delivered as desired in the specific tissue region selected for treatment. For example, a radiographic agent can be delivered using the drug delivery element to observe the flow thereof with respect to the selected tissue region. Once confirmed that the radiographic agent flows as desired in the selected tissue region, the drug can be introduced, thus possibly avoiding the poor supply of what are expensive drugs. Optionally, a radiographic agent and the like can be mixed with the drug to track the flow of the drug within the body, particularly with respect to the selected tissue region. In another preferred method, the transvascular catheter system can be used to create a drug reservoir directly in a selected tissue region. For example, a tissue ablation device that is deployed in combination with the puncture element may be provided to create a cavity in an extravascular tissue region. The ablation device can advance over the puncture element towards the tissue region, and an ablation element therein activated to create a cavity or drug reservoir within the tissue region. Then a drug can be introduced into the drug reservoir, which can be sealed from the vessel, for example by introducing a sealant or matrix into the drug reservoir. Alternatively, the drug reservoir can be formed by removing a portion of the tissue region, for example with a cutting instrument or similar mechanical device. In another alternative, the transvascular system can be used to facilitate a permanent catheter-based intervention. The catheter can be inserted into a vessel, and then the puncture element oriented or deployed in a region of tissue, such as interstitial tissue or another blood vessel. A guide wire can advance into the tissue region and the transvascular catheter can be removed, leaving the guidewire in place, possibly fixed to the tissue region. A flexible, thin catheter can be traced over the guide wire to the tissue region, and placed inside the tissue region, and then the wire removed. The permanent catheter can be secured with tape, with port or otherwise to the patient depending on the length of time desired in the therapy. The tissue region can be reached through the permanent catheter to deliver a drug to the tissue region as frequently as desired. In another aspect of the present invention, an implantable drug reservoir system can be used to provide sustained delivery of a drug within the cardiovascular system of a patient. In general, the system includes a reservoir device having an expandable frame and a flexible membrane therein. The frame is adapted to expand between a collapsed condition for insertion into a blood vessel and an enlarged condition for coupling a wall of the blood vessel. The frame is preferably polarized towards the enlarged condition, and also preferably defines a longitudinal axis and a periphery. The flexible membrane is fixed to the frame to define a deposit therein, and includes a porous region, such as a semi-permeable material, which is preferably disposed along the periphery of the frame. A drug, possibly in conjunction with an anticoagulant, 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 on-site filling of the reservoir. In an alternative embodiment of the implantable drug reservoir system, a reservoir device similar to that described above can be provided with a septum by dividing the reservoir within the membrane in first and second reservoir regions. The membrane preferably includes an osmotic region that communicates with the first reservoir region, and the porous region of the membrane preferably communicates with the second reservoir region. During use, the reservoir device can be introduced along a blood vessel to a location adjacent to a selected tissue region, for example within a coronary vein adjacent to an occluded artery or ischemic myocardial tissue. The reservoir device can be deployed and expanded, preferably automatically, to its enlarged condition to fix the reservoir device within the blood vessel. A drug can be prefilled within the reservoir or an injection device can be introduced to penetrate the membrane of the reservoir device and fill the device in situ with the drug. The drug can pass, penetrate or diffuse through the porous region, preferably directly into the vessel wall and surrounding tissue region. If desired, the reservoir can be filled in place using an injection device as the drug is dispersed or absorbed by the tissue. Similarly, a reservoir device having a septum panel can deliver the drug in the second reservoir region to the tissue region while the first reservoir region is osmotically filled, thus slowly forcing or "pumping" the drug through the porous region. In another preferred embodiment of an implantable drug reservoir system, a pair of expandable devices, similar to reservoir devices, may be used. The endovascular expandable devices, or "blockers", include an expandable frame, and a non-porous membrane that covers at least one end of the frame, and that preferably extends along at least a portion of the periphery. The first blocker advances in a collapsed condition along the blood vessel to a location adjacent to the selected tissue region. The first blocker expands to its enlarged condition, thus sealing the blood vessel at the location from the fluid flow along the blood vessel. The second blocker progresses in a collapsed condition along the blood vessel to the location, preferably adjacent to the first blocker. The second blocker expands to its enlarged condition, thus additionally sealing the blood vessel at the location from the fluid flow along the blood vessel. The second blocker is preferably deployed at a predetermined distance from the first blocker, thereby defining a drug reservoir substantially sealed within the blood vessel itself between blockers. A drug can be introduced into the blood vessel adjacent to the first blocker, either before or after the second blocker is deployed. For example, the second blocker may include an end board only on the far end of the drug reservoir between the blockers, and an injection device may advance to penetrate the end board. The drug can be introduced into the second blocker and consequently into the drug reservoir between the blockers. Therefore, a section of a blood vessel can be isolated and a drug delivered there to provide sustained and localized delivery of the drug into the selected tissue region surrounding the vessel. Also, a main object of the present invention is to provide a system and method for accurately delivering a drug to a selected tissue location within the body. Another object is to provide a system and method for providing sustained delivery of a drug to a desired location within the body for a prolonged period of time. Another object is to provide a system and method for creating a reservoir within the body to receive a drug and provide sustained delivery to a desired region of tissue within the body.

Another object is to provide a system and method that uses the cardiovascular system as a conduit for delivering a drug to a selected remote tissue region within the body with substantial precision. A further object is 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. Particularly, a specific object of the present invention is to use the coronary venous system to provide access to an extremely remote tissue region of the body, for example cardiac tissue. Other objects and advantages of the present invention will be apparent from the following description taken in conjunction with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1A is a cross-sectional view of a transvascular catheter system in accordance with an aspect of the present invention. Figures 1 B and 1C are side views of a handle on the catheter for the transvascular catheter system of Figure 1 A. Figure 1 D is a cross-sectional view of the distal portion of a catheter for the transvascular catheter system of Figure 1 A. Figure 1 E is a side view of a needle assembly for the transvascular catheter system of Figure 1 A.

Figure 2 is a cross-sectional view of the distal portion of the transvascular catheter system of Figure 1, showing the needle assembly deployed in a remote blood vessel. Figure 3A is a cross-sectional view of the transvascular catheter and surrounding cardiac tissue system of Figure 2, taken along line 3-3 using an internal imaging element, showing artifacts that direct the catheter to another vessel blood Figure 3B is a cross-sectional view of the transvascular catheter system and the surrounding cardiac tissue, similar to Figure 3A, but showing artifacts that direct the catheter to the myocardium of the heart. Figure 4 is a detailed side view of a catheter, showing a preferred embodiment of an externally detectable orientation element according to the present invention. Figure 5A is a side view of an alternative embodiment of the distal portion, including a plurality of needle assemblies. Figure 5B is a side view of another alternative embodiment of the distal portion, including a dual lumen needle assembly. Figure 5C is another alternative embodiment of the distal portion, including a plurality of exit ports to provide a predetermined flow pattern. Figure 5D is another alternative embodiment of the distal portion, including a feedback sensor on the needle assembly.

Figure 6 is a cross-sectional view of another preferred embodiment of a transvascular catheter system according to the present invention, including a guidewire assembly and a drug delivery catheter deployed in a remote tissue region. Figure 7 is a perspective view of a port assembly Implantable for use with a transvascular catheter system in accordance with the present invention. Figure 8 is a cross-sectional view of another preferred embodiment of a transvascular catheter system, including a guide wire assembly and an ablation device. Figure 9A is a side view of an implantable endovascular drug reservoir device according to the present invention. Figure 9B is a side view of another embodiment of an implantable endovascular drug reservoir device, including a traversable end panel. Figures 9C and 9D are side views of the implantable endovascular drug reservoir device of Figure 9B, showing an injection device for filling the reservoir. Figure 10 is a cross-sectional side view of the drug reservoir device of Figure 9A, deployed within a vein adjacent to a stenotic region of an artery.

Figure 11 is a side view of an alternative embodiment of an implantable endovascular drug reservoir device in accordance with the present invention. Figure 12 is a side view of another implantable system according to the present invention for creating a drug delivery reservoir, shown within a vein adjacent to a stenotic region of an artery. Figure 13 is a cross-sectional view of a transvascular catheter system according to the present invention delivered downstream of a stenotic region in a blood vessel.

DETAILED DESCRIPTION OF THE PREFERRED MODALITIES With reference to the drawings, Figures 1A-1 E and 2 show a preferred embodiment of a transvascular catheter system 10 according to 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 puncture element 14, an orientation element (eg, a "cage" structure 16 described below), and an image element 18. The catheter 12 may be an elongate element having substantially flexible and / or semi-rigid sections, and defining a circumference or periphery 20 and a longitudinal axis 22 between the proximal and distal ends 24, 26. The catheter 12 includes a proximal portion 28 having a handle 50 and a distal portion. 30 which has a size and shape to facilitate insertion into a blood vessel. An IVUS 32 lumen extends through the catheter 12 from the IVUS inlet port 52 in the handle 50 to a tip member 44 on the distal portion 30 to receive the image 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 piercing element 14. The needle lumen 36 includes a baffle member or ramp 48 adjacent to the peripheral opening 34. The catheter 12 it may include an extruded dual lumen catheter encapsulated within an outer sleeve (not shown), and / or have a proximal portion that is substantially stiffer than a distal portion. For example, in the preferred embodiment shown in Figure 1A, catheter 12 includes a proximal portion 12a, an intermediate portion 12b and a distal portion, 12c, each having a dual lumen catheter segment and an outer jacket segment. The stiffness or durometer of the dual lumen and outer sleeve catheter segments of the proximal portion 12a is preferably 63 and 70, although the remaining segments preferably have a durometer of 40. Further information on the construction of the catheter 12, for example its composition of materials, their size and shape, can be found in co-pending applications serial numbers 08 / 730,327 and 08 / 730,496, both published on October 11, 1996, and in PCT application No. PCT / US97 / 01459, published on January 31, 1997, whose descriptions are expressly incorporated herein by reference. The targeting element is preferably a marker "cage" structure 16 including a plurality of elongate elements or rods 38, 40 on the distal portion 30 located distally of the peripheral aperture 34. The rods 38, 40 preferably extend distally from the distal end 26 substantially parallel to the longitudinal axis 22 to the proximal end 42 of the tip element 44, thus further defining the IVUS lumen 36. The rods 38, 40, preferably define a peripheral window 46, which may be covered by a material substantially transparent to the 18 image element or can remain open for blood flow. The rods 38, 40 are preferably substantially rigid tubular elements, such as hypotube, which are reflectors to the image element 18, ie they will produce a reflection or artifact when the image element 18 is operated, and / or may be substantially opaque to an external image apparatus (not shown). Preferably, the rods 38, 40 have an asymmetric configuration around the periphery 20 having a predetermined relationship with the location of the peripheral opening 34. Most preferably, a first rod 38 is located at the periphery 20 directly distally from the location of the peripheral opening 34. A pair of rods 40 are positioned opposite the first rod 38, thereby defining an isosceles triangle or cross-sectional configuration TRI-POINT ™, with the first rod 38 at the top of the triangle. Therefore, the orientation element 16 can "point" circumferentially towards the location of the peripheral opening 34 on the periphery 20, ie to the location from which the pricking element 14 can be deployed, as is further described herein. In an alternative embodiment shown in Figures 4A and 4B, the targeting element may include one or more externally visible markers 116 placed in 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, markers 116 may be formed of a visible radiopaque material using a fluoroscopic imaging system. Preferably, a pair of fluoroscopic markers 116a, 116b are provided at the periphery 20 which only indicate the rotational orientation of the peripheral aperture 34, such as the "ocular" arrangement shown. Further discussion of such markers can be found in U.S.A. Serial No. 08 / 730,327, published October 11, 1996, the disclosure of which is hereby expressly incorporated by reference. Although the transvascular catheter system 10 may include both internal and external markers 16, 116 on the catheter 12, preferably a single marker or orientation element is necessary to effectively orient the puncture element 14.

Again with reference to Figures 1A-1 E and 2, the tip member 44 attached to the rods 38, 40 has an annular shape formed of a substantially flexible material to further define the IVUS lumen 32. The tip element 44 is preferably fixed with tape to facilitate insertion into and direction along the lumen of a blood vessel, and is substantially coaxial with the IVUS lumen 32 in catheter 12 to facilitate the introduction of a guide wire or other instrument axially through the same. In particular reference to Figures 1A-1C, the handle 50 is preferably a substantially rigid element including the IVUS inlet port 52, the needle entry port 54, and a needle lumen rinsing port 58 in communication with the lumen. Needle 36. Ports 52, 54 and 58 include one or more seals to prevent return flow, as will be apparent to those skilled in the art. A control and / or lock mechanism 58 is located on the handle 50 that includes a needle slider 68 and an adjustable needle retainer 70 that slides along a graduated region 60 of the handle 50. The needle slider driven with the thumb 68 can be directed axially along the graduated region 60 to deploy the puncturing element 14, as particularly described below. The adjustable needle retainer 70 can be slid over the handle 50 and can be fixed to a plurality of positions on the graduated region 60 of the handle 50. Therefore, the adjustable needle retainer 70 can be adjusted to a first position on the region graduated 60, loosen, axially directed to a second position on the graduated region 60, and adjust to the second position to limit the movement of the needle operated slide with the thumb 68, and consequently the penetration depth of the puncture element 14. With Referring to Figures 1A-1 E, the piercing element 14 is preferably a needle assembly 62 that includes an elongated tubular body 63 having a prong distal tip 64 and a proximal securing fastener 66. The needle assembly 62 and / or the distal tip 64 are preferably formed from a shape memory alloy, such as Nitinol, which is pre-bent to improve the transverse deployment of the distal tip 64. The The distal tip 64 can be inserted into the needle entry port 54 and directed distally through the needle lumen 36 until the securing fastener 66 engages with the thumb operated needle slider 68 on the handle 50. thumb operated needle 68 can be secured to needle assembly 62, for example with radially extending ball locks in needle lumen 36 from thumb operated needle slider 68 (not shown), to control movement axial of the needle assembly 62. Preferably, the needle assembly 62 includes a drug delivery lumen 72 that extends from the safety fastener 66 to an outlet 74 in the distal tip 64. The outlet 74 may be a single opening for directing the fluid distally beyond the distal tip 64, or may include a plurality of openings having a predetermined exit pattern. For example, as shown in Figure 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 toward the tissue region. Preferably, the distal tip 64 also has a gauge diameter small enough so 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 into the vessel 102 after removing the distal tip 64. Alternatively, as shown in Figure 5B, the needle assembly 62 may include dual lumens 78a, 78b extending between a multiple line on the proximal end (not shown) to two adjacent output ports 74a74b. A dual lumen needle assembly may be useful for delivering a radiographic agent or other compound through a lumen in combination with a drug in the other. Preferably the dual lumens can allow two drugs to be independently injected, which can then react with each other within the selected tissue region, as will be appreciated by those skilled in the art. 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 of a conductive material such as platinium, 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 element 63 to the safety fastener 66 of the needle assembly 62. An electric current source may be coupled to the conductor for improve the absorption of the drug by the tissue region. For example, the distal tip 64 can facilitate electroporation, ie energize the distal tip 64 can create microscopic pores in the surrounding tissue to increase the penetration of the drug therein. With respect to the image element 18, in a first preferred embodiment best seen in FIG. 2, an intravascular ultrasound device ("IVUS") 80 is provided. A conventional ultrasound transducer 82 is provided on the distal end 84 of the IVUS device 80 which faces an image plane substantially normal to the longitudinal axis 22. The ultrasound transducer 82 or a reflector on the IVUS device 80 (not shown) can rotate about the longitudinal axis 22 to provide ultrasonic images in slices a along the image plane in a conventional manner, or alternatively, an in-phase disposition of ultrasound transducers may be provided to take images along a plane substantially normal to the longitudinal axis 22, as will be appreciated by those skilled in the art. Additional information on the use of an IVUS device to image tissue and other surrounding markers from within a blood vessel can be found in "Transvenous Coronary Ultrasound Imaging - A Novel Approach to Visualization of the Coronary Arteries" by Sudhir et al., Whose Description is expressly incorporated herein by reference.

During use, the transvascular catheter system 10 can be used to deliver a drug to a selected remote tissue region within the body of a patient in the following manner. The catheter 12 can be inserted percutaneously into a blood vessel in a conventional manner, while the needle assembly 62 remains retracted within the needle lumen 36, ie while the distal tip 64 is placed within the needle lumen 36 proximal to the baffle 48. The distal portion 30 of catheter 12 can be steered endovascularly to a vessel location adjacent to a remote tissue region for which treatment is selected. For example, in a preferred method shown in Figures 2 and 3A, catheter 12 can be directed through the venous system of the patient to a coronary vein 102 adjacent a coronary artery 100 selected for treatment. In another preferred method shown in Figures 6 and 3B, catheter 12 can be directed to a location within a coronary vein 102 adjacent to a selected ischemic region 220 of myocardium 112 for drug delivery. Once the desired endovascular location is achieved, the catheter 12 can be oriented to the selected tissue region using ultrasound images with the IVUS 80 device, external images, such as fluoroscopy or both. With reference to Figures 2 and 3A, the IVUS device 80 used to orient the system 10 to deliver a drug in a coronary artery 100 from a nearby coronary vein 102 is shown. The distal portion 30 of the catheter 12 is steered endovascularly through the venous system, for example on a guide wire 86, until it is within the coronary vein 102 and adjacent the selected coronary artery 100. The ultrasound transducer 82 can be operated to provide a cross-sectional image of the region, which is Illustratively shown in Figure 3A. The resulting image assists the user in orienting the catheter 12 with respect to the tissue surrounding the vein 102, for example to identify markings such as the pericardium 109, the endocardium 111, the erdium 113, and / or the heart chamber 110. In addition , because the rods 38, 40 are opaque to the ultrasound transducer 82 (not shown in FIG. 3A), produce artifacts 104, 106 in the image, thus providing orientation of the distal portion 30 of the catheter 12 with respect to the surrounding myocardium 112 and the selected coronary artery 100. Particularly, due to the triangular arrangement of the rods 38, 40, their artifacts 104, 106"point" circumferentially in the direction of the periphery 20 corresponding to the location of the peripheral aperture 34, and consequently in the direction toward which the distal tip 64 of the needle assembly 62 will deploy from the catheter 12. The catheter 12 can rotate about its longitudinal axis 22 to rotate the p distal orifice 30, as seen by artifacts 104, 106, until it can be seen that the distal tip 64 of needle assembly 62, i.e. artifact 104, is directed toward the selected coronary artery 100.

The resulting ultrasound image can also be scaled, allowing the user to measure the distance to the selected target region from the catheter 12, and in this way determine the exact distance that the distal tip 64 of the needle assembly 62 will need to address and reach the selected tissue region. The needle retainer 70 on the handle 50 can be loosened, adjusted along the graduated region 60, and then fixed to a predetermined position corresponding to the exact distance. Once the catheter 12 is properly oriented and the needle retainer 70 is adjusted to the predetermined position, the distal tip 64 of the needle assembly 62 can be deployed from the catheter 12 to penetrate the wall 103 of the vessel location 102 and enter to the selected tissue region 100. Preferably, the thumb-operated needle slider 68 is directed distally by the user, thereby directing the distal tip 64 against the baffle 48 and causing the distal tip 64 to tilt radially outwards as it exits the peripheral aperture 34. Due to the secured position of the needle retainer 70 on the handle 50, the thumb operated needle slider 68 can be rapidly advanced distally until it engages the needle retainer 70, thereby puncturing the wall 103 of the vein 102 and supplying the distal tip 64 at the exact distance, i.e., exactly within the selected target region of the artery 100. Alternatively, it would be convenient to pull on the target, i.e. pass a predetermined distance beyond the selected target region. , and then slowly back the distal tip 64 until it reaches the selected tissue region. A drug can 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 outlet 74 at distal tip 64. Distal tip 64 can be pushed back toward needle lumen 36 and catheter 12 withdrawn from the patient in a conventional manner. Before delivering the drug, a "mapping" procedure can be used to ensure that the drug is delivered as desired in the specific tissue region selected for treatment. For example, a radiographic agent can be delivered through the outlet 74 at the distal tip 64. The flux of the radiographic agent can 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 in the selected tissue region, the drug can be introduced, thus possibly avoiding the poor supply of what are known as expensive drugs. Alternatively, a radiographic agent and the like can be mixed with the drug to track the flow of the drug within the body, particularly with respect to the selected tissue region. Now with reference to Figure 6, there is shown another preferred embodiment of a transvascular catheter system 10 for delivering a drug to a remote tissue region 220 within myocardium 112. Several of the elements are similar to those previously described and as a consequence have the same reference numbers and will not be described further. The system 10 of this embodiment includes a drug delivery element, primarily a drug delivery catheter 214, which can be deployed from the distal portion 30 of the catheter 12, preferably in combination with the piercing element 14. The piercing element 14 preferably includes a solid needle assembly or guide wire assembly 162, without a lumen but similar to the previously described needle assembly 62, over which the drug delivery catheter 214 can be deployed. The guide wire assembly 162 may include an anchor tip (not shown) for securing the distal tip 164 of the guidewire assembly 162 to the tissue region 220 and / or facilitating the introduction of instruments, such as the delivery catheter. of drug 214, to tissue region 220. Drug delivery catheter 214 may include a porous balloon 218 for introducing the drug in a predetermined pattern within tissue region 220, and generally includes a plurality of extending lumens. between its proximal portion (not shown), and a distal portion 222. The drug delivery catheter 214 preferably has a guide wire lumen 224 so that the drug delivery catheter 214 can be delivered in the region of tissue 220 over the guide wire assembly 162, and also has a drug delivery lumen (not shown) that communicates with a portion, for example, 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 toward the tissue region 220. During use, catheter 12 can be introduced percutaneously into a blood vessel 102 and oriented relative to the selected tissue region 220 (see Fig. 3B). The guide wire assembly 162 can be deployed transvascularly to access the selected tissue region 220, similar to the previously described procedure. The drug delivery catheter 214 can be advanced over the guidewire assembly 162 to enter tissue region 220. The balloon 218 can be inflated, expanding it from a collapsed condition around the drug delivery catheter 214 to an enlarged condition that has contact with the surrounding tissue 220. The balloon 218 can be inflated simply by introducing a drug through the drug delivery lumen, which can be filtered through the porous region 226 and passed to the tissue region 220. Alternatively, the catheter 214 can include a separate inflation lumen (not shown) through which an inflation medium such as saline can 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 another alternative, the drug delivery element can be a flexible, thin catheter that is left to serve as a "permanent" transcutaneous access catheter, as particularly described below.

In other alternatives, the drug delivery catheter 214 and / or guidewire assembly 162 may include an electrode or other element (not shown) to increase the penetration of the drug delivered into the tissue region. For example, an internal heating element (not shown) can be provided inside the balloon 218 to heat the fluid therein and / or the surrounding tissue 220, which can increase the absorption of the drug delivered into the tissue. Successively, an electrode (not shown) can be provided on or inside the balloon 218 that can be coupled to an external electrode (not shown). Direct current can then be applied between the electrodes to iontophoretically direct drugs from the drug delivery catheter 214 to the surrounding tissue 220. In a further alternative, the distal tip 164 of the guide wire assembly 162 can be formed of an electrically conductive material as gold or platinum, or may include an electrode in a portion thereof (not shown), which may be coupled to an external source of electrical current by a conductor (not shown) extending proximally through the guidewire assembly 162. In this manner, a transvascular catheter system 10 according to the present invention can be used to deliver a drug directly and accurately in a selected remote tissue region in a single dose or bolus. Alternatively, the system can be used for a sustained delivery by holding 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 the selected tissue region for an extended period. For example, the needle assembly 62 or the infusion catheter 214 can be used to inject a matrix material into a tissue region that can slowly diffuse a drug in that region. Alternatively, a stent or similar structure can be delivered within the tissue region, the structure including a drug therein that can be subsequently removed. In addition, to provide a sustained supply and / or series of treatments with a drug, a permanent catheter (not shown) can be left within the selected tissue region. For example, the transvascular catheter system 10 can be introduced into a blood vessel, and the puncture element 14, for example the needle assembly 62 or the guide wire assembly 162 can be oriented and deployed within a selected tissue region, such as a region of interstitial tissue or other blood vessel. A guidewire (not shown) can be advanced within the tissue region, and possibly fixed in place. The transvascular catheter 12 can be removed from the blood vessel, leaving the guidewire, and a thin flexible catheter (not shown), which can be an infusion catheter similar to that described above or simply a single delivery port device, can be traced on the guide wire inside the tissue region and leave it there. The guidewire can then be removed, and the proximal end (not shown) of the thin and flexible catheter can be attached to the patient, for example, placed in port or secured (for example, using a port assembly as described below) depending on the duration of the therapy. The distal end of the permanent catheter can then remain in place within the tissue region, possibly over a long period, to provide access when necessary. Alternatively, with reference to Figure 7, the transvascular catheter system 10 may include a port 350 assembly that can be implanted. The port assembly 350 includes a body 352 that can be implanted above or below the skin of the patient, and one or more seals 354. The body includes a hollow bell 356 the interior of which communicates with the seal 354 that can Attach to the transvascular catheter system 10, such as the proximal end 24 of the catheter 12 or preferably a permanent catheter (not shown). For example, the catheter 12 shown in Figure 1 can be introduced percutaneously into the cardiovascular system of a patient, and the distal portion 30 can be advanced within the selected vessel, wherein the distal tip 64 of the needle assembly 62 (not shown in Figure 7) can be advanced within the selected remote tissue region, similar to the methods described above. The handle 50 (not shown in Figure 7) can then be removed from the proximal end 24 and replaced with the port assembly 350 so that the bell 356 can communicate with the lumen of the needle 36, the IVUS 32 lumen and / or a lumen of drug supply in the permanent catheter. The port assembly 356 can then be fixed or otherwise implanted in an accessible region of the patient's body (not shown). When it is desired to have access to the tissue region, an instrument such as a needle, an infusion device, a sensor or the like (not shown) can be directed towards the seal 354 to communicate with the drug delivery element extending towards the selected tissue region. For example, during a growth factor or gene therapy it is often desired to subject the selected tissue region to compounds, such as angiogenic growth factors, for long periods. The implantable system of the present invention facilitates such sustained treatment by allowing access to the tissue region as often as necessary to maintain a desired level of growth factor in the selected tissue region. Referring now to Figure 8, another preferred embodiment of a transvascular catheter system 10 according to the present invention is shown, which can be used to create a reservoir of drugs 224 within a selected tissue region 220 itself for provide a sustained supply. A catheter 12, similar to that described above, can be introduced endovascularly into a blood vessel 102 until the distal portion 30 is adjacent to the tissue region 220. The distal tip 64 of the needle assembly 62 can be oriented and used to puncture the wall 103 of vessel 102 and enter tissue region 220 using methods similar to those described above. An ablation device 230, such as a radiofrequency (RF) device, a laser device and the like, can be advanced in the needle assembly 62 within the tissue region 220. One or more electrodes 232 or similar elements in the device ablation 230 can be activated to create a cavity 224 within tissue region 220 in a manner known to those skilled in the art. The ablation device 230 can then be removed, and a drug can be introduced into the cavity 224 to create a reserve of drug in continuous contact with the surrounding tissue 220, thereby providing a sustained delivery while the surrounding tissue 220 absorbs the drug slowly. As an alternative to tissue ablation, a non-porous balloon catheter (not shown) can be advanced in the needle assembly 62 within tissue region 220. The balloon can be inflated to its enlarged condition to make contact and displace the surrounding tissue 220 and, thus, create a cavity 224. No further treatment of tissue 220 will be necessary to create cavity 224, particularly in ischemic tissue that is substantially non-flexible compared to healthy tissue and is unlikely to be expand to cover the cavity 224. Also within the spirit of the present invention are other devices, such as mechanical cutting, extraction or other instruments, which can also be used to remove tissue to create the cavity 224 when advancing in the needle assembly 62 within the weaving region 220, as those skilled in the art will appreciate. In addition, it would be desirable to inject a sealant or matrix material, such as collagen or a filament structure (e.g., drug-impregnated structure material) into cavity 224 or passage 223 that extends between blood vessel 102 and the cavity. 224. Although the distal tip 64 may be small enough to create a self-sealing passage 223, advancement of instruments, such as the drug delivery catheter 214 of Figure 6, may dilate the passage 223, which may result in leakage of the drug in the passageway 23 to the blood vessel 102 from the cavity 224. To substantially reduce the risk of this occurring, a matrix material, sealant, or filament (not shown) may be injected into the cavity 224 or step 223, for example through a lumen in the drug delivery element 214 or the needle assembly 62 before or while withdrawing from the cavity 224. In an alternative embodiment shown in Figure 5A, the transvascular catheter system 10 may include a plurality of needle assemblies 62, similar to the single needle assembly described above, for use 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 rods of the orientation element of the "cage" structure (not shown in Figure 5A). In particular, it is desirable to have access to a region of extended tissue, for example that extends substantially parallel to a vessel, especially within the myocardium. With a multi-needle intravascular catheter system, a single device can be delivered into a vessel and oriented. The needle arrangement can be deployed to sequentially or simultaneously inject one or more drugs into the extended tissue region, thereby providing a selected path pattern. 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 a picture element may be provided in a manner similar to those described above. Instead of a guide wire assembly or needle, 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). The osmotic surface preferably has a predetermined relationship with the targeting element, so that the osmotic surface can be directed circumferentially to the selected region of tissue, for example a specific portion of a vessel wall and / or a tissue region further. away from the glass wall. The catheter may include a balloon or other structure that can expand and which can press the osmotic surface in direct contact with the vessel wall to further facilitate delivery. A drug, possibly included within the osmotic surface itself or in a chamber below the osmotic surface, can then be delivered with or without iontophoresis or other assisted delivery mechanism. With reference to Figure 13, the systems and methods of the present invention can also be used to provide downstream access of a stenotic or occluded region of a blood vessel, for example to treat a coronary artery or a region of ischemic tissue of the myocardium. of descending flow of an occluded coronary artery. First, a downstream location of an occluded section 404 of a coronary artery 400 should be selected for its treatment, and a transvascular catheter device (not shown) inserted percutaneously into the venous system and advanced until it reaches a coronary vein 402 adjacent to the selected artery 400. A gap passage 406 can be created between the coronary vein 402 and the coronary artery 400, and a guide wire 410 can be advanced through the gap passage 406 to the coronary artery 400. The guidewire 410 can be substantially fixed within the coronary artery 400, for example including the distal end of the guide wire 410 in the wall of the coronary artery 400. coronary artery 400 (not shown). Further details on the systems and methods for performing the interstitial or transvascular procedures between the venous and arterial systems can be found in the co-pending applications with serial numbers 08 / 730,327 and 08 / 730,496, both filed on October 11, 1996, the descriptions of which are expressly incorporated herein by reference.

A transvascular catheter system 10 similar to that described above can then be advanced over the guidewire 410 along the venous system, through the interstitium passage 406 and into the coronary artery 400 down the occluded region 404, thereby that the plaque is not altered or modifies in any way the flow through the arterial system. It will be apparent to those skilled in the art that the transvascular catheter system 10 that is used to deliver the drug can also be used to create the interstitial passage 406. The artery 400 itself can then be treated, for example, using the assembly of needle 62 of figure 1 or drug delivery catheter 214 of figure 6. A drug can be delivered to lumen 408 of artery 400, within vessel wall 412 and / or surrounding tissue 414. In addition, a or more drug stores (not shown) can be created within the surrounding tissue 414, most preferably within the tissue of the myocardium adjacent to the coronary artery, to receive a drug that can absorb the surrounding tissue 414 over an extended period. 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 stabilization balloons (not shown) in the distal portion 30, for example proximate the peripheral opening 34. An inflation lumen may be provided in the catheter 12 to allow a means of inflation , for example saline, which will be introduced into the stabilization balloon to substantially fix the catheter 12 at the desired location within the blood vessel, ie 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. In addition, one or more of the elements of the system may include a sensor to take important information for the treatment of the selected tissue region. For example, a pressure sensor may be provided in 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 inspect the pressure at or near the supply site. The drug delivery element may also include a flow measurement sensor, allowing accurate measurement of the amount of drug delivered to the selected tissue region. Other feedback elements can also be provided, for example, a thermocoupler or other temperature sensor can be provided in the systems, including iontophoresis electrodes or ablation devices to inspect the amount of heat that is experienced in the tissue during a procedure. Alternatively, as shown in Figure 5D, the needle assembly 62 or other component may include a feedback element 79 for measuring a physiological condition. For example, an EKG end may be included in the distal tip or otherwise delivered within the selected tissue region, thereby allowing to inspect electrical events within the heart during drug delivery. During treatment, for example, a drug can be delivered in a tissue region to a desired condition, such as until the tissue becomes non-tachycardic or until tachycardia is induced. 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 due to its predetermined relationship with the periphery of the catheter and the drug delivery element. The image element preferably provides the radial component by detecting the ratio of the orientation element to the selected remote location (for example the distance between these), or signals in known relationships with the selected remote location. Once the selected remote location within the reference frame is known, the drug delivery element can be directed to the selected remote location to accurately deliver a drug. In another aspect of the present invention, Figures 9A-9D and 10 show a preferred embodiment of an implantable reservoir device 400 that can be used to provide a sustained delivery of a drug to a surrounding tissue of a blood vessel, preferably within a coronary vein 102 adjacent to ischemic tissue of myocardium 112. Backup device 400 includes a substantially cylindrical frame 402 adapted to expand between a collapsed condition to insert it into a blood vessel and an enlarged condition to be coupled to a wall 103 of blood vessel 102 and defining a longitudinal axis 404. The frame 402 has sufficient flexibility to expand between the collapsed and enlarged conditions during use without the substantial risk of failure or fatigue, even being rigid enough to fix the reserve device 400 within the blood vessel 102 Preferably, the frame 402 is flexibly 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 of a woven wire mesh, for example, of a shape memory alloy such as nitinol, stainless steel, platinum, polymers or other plastics and similar. The frame 402 may be woven in a cross structure, a sinusoidal structure, or may include a pair of expandable rings connected by spacers to retain the axially spaced rings. A flexible membrane 408 is attached to the frame 402, preferably on the outside of the frame 402 so that the membrane 408 can improve a fluid tight seal when pressed against the wall 103 of the glass 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 must be substantially flexible, and may be resilient in case of preferring a tension on the membrane 408. the frame, or plastic if a small initial diameter is preferred. Preferred materials include dacron and PTFE, which may also be immersed in silicone. The membrane 408 includes a porous region 418 that is preferably located along at least a portion of the periphery 412 of the membrane 408. The porous region 418 may be a permeable or semipermeable material bonded or otherwise attached to segments not permeable membrane 408. Alternatively, the entire membrane 408 can be formed of a non-permeable material with holes formed through non-uniform areas to define the porous region 418. Also, as shown in Figures 9B and 9C, at less one of the end panels 416 can be traversed, that is, it can be penetrated by a needle 432, but automatically resealed, to facilitate the filling or in-situ filling of the stock 410, preferably having a concave shape to facilitate the Needle penetration 432. Alternatively, reservoir 410 may be pre-filled with a drug, possibly together with an anticoagulant compound or other drug. this, before delivering it to blood vessel 422. In addition, the drug and the pore size of the porous region 418 may have a predetermined ratio so that the drug permeates or flows through the porous region 418 in the surrounding tissue with a predetermined flow speed. During use, the reserve device 400 is delivered percutaneously into a blood vessel in its collapsed condition using a delivery device, for example within a lumen of a delivery or cover catheter adapted to receive the reserve device 400. Alternatively, the frame 402 may include a control bell at one end (not shown) that can be clamped and compressed radially inwardly to collapse the frame 402. Once the reserve device 400 is within a blood vessel adjacent to the region For example, the coronary vein 112 adjacent to the selected tissue region 112, the reserve device 400 is used from a delivery device, for example using a plunger within the lumen of the suction catheter (not shown). Preferably, the frame 402 automatically expands to its elongated condition, thereby substantially anchoring the device 400 in position within the vessel 102. The frame 402 can also create a fluid-tight seal with the wall 103 of the vessel 102, to prevent the supplied fluid escapes through the periphery 412 flowing down into the vessel 102. If the reservoir 410 is empty during deployment, for example, to prevent rupture of the membrane 408 when the frame 402 is collapsed, an element of Drug delivery can be introduced into the beaker 102 to fill the reservoir 410. For example, as shown in Figs. 9C and 9D, an injection device 430 including a cover 434 covering a hollow needle 432 can be delivered endovascularly, or the delivery catheter used to supply the reserve device 400 may include an additional drug delivery needle lumen. The needle 432 can be used to penetrate the traversable end region 416, where the reservoir 410 can be filled by introducing the drug through the needle 432. The reserve device 400 can remain in the vessel 102 for a substantial period, possibly hours or days, allowing the drug to be absorbed slowly within the vessel wall and preferably the surrounding tissues. In addition, the drug delivery element, for example the covered hollow needle can be reintroduced into the vessel 423 to fill the reservoir 410, for example using a port assembly that can be implanted in a manner similar to that shown in the figure 7. Alternatively, the reserve device 400 may include an electrode (not shown) to allow iontophoresis or other improved delivery. A catheter including a conductor (not shown) can be inserted into the vessel 102, coupled with the electrode, and subsequently energized by an external source of electric current (not shown) for this purpose. In an alternative embodiment, which is shown in Figure 11, the reserve device 400 can provide an endovascular "pump" for a delivery delivery of a drug over time. In this embodiment, the reserve device 400 includes a septum panel 420 that divides the reserve 410 into first and second regions 410a, 410b. The first end panel 414 of the membrane 408 is an osmotic membrane and the first reservoir 410a is filled with a fluid absorbing compound. The porous region 418 of the membrane 408 communicates only with the second reservoir 410b, which is filled with a drug in situ or before use. When the reserve device 400 is used within a vessel (not shown), using a procedure similar to that just described, the compound in the first reservoir 410a begins to flow slowly and osmotically from within the lumen of the vessel. When this happens, the septum panel 420 is forced to expand towards the second end panel 416, thereby applying a force within the second reservoir 410b, which "pumps" or otherwise encourages the drug to flow out of the region. porous 418 and preferably towards the vessel wall. In other arrangements, instead of a septum panel 420, a cylindrical septum may be provided, creating a first internal reservoir and a second reservoir surrounding the first reservoir (not shown). The area of one or both end panels in contact with the first internal reservoir can be provided from an osmotic material, thereby creating a similar flow of a porous region on the periphery of the membrane in communication with the second annular reservoir. Other shapes and configurations of the reserve device 400 can also be provided that can be deployed and substantially fixed adjacent the selected tissue region. In addition, a drug reservoir device similar to those described can be delivered directly into the tissue, for example, using one of the transvascular catheter systems described above, as will be apparent to those skilled in the art. In a preferred mode that is shown in the figure 12, a system including a pair of endovascular locking devices 500 can be used to create a stock of drug 508a within a blood vessel 112 itself, ie between the blockers 500 and the wall 103a 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, in a manner similar to that described above. However, the membrane 504 is preferably non-permeable, although alternatively a permeable periphery (not shown) can be provided to improve the surface area through which the drug can be directed towards the vessel wall 103. To create the reserve 508a, the first blocker 500a is used 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 reserve device 400. A drug in the lumen of the vessel 108a, and the second blocker 500b is used within the vessel 102, thereby encapsulating the drug within the lumen 108a between the blockers 500a, 500b.

Alternatively, the drug may be delivered to the reservoir 508a after both blockers 500 are used and fixed within the vessel 102. For example, the second blocker 500b may include a traversable end panel 514 at one end, and an open interior that You can communicate directly with the 108th reservation. In this way, an injection needle device (not shown) can be used to inject the drug through the traversable end panel 514 and into the reservoir 508a in situ. It has been clinically determined that one or more segments of the venous system, even within the coronary system, may be occluded for extended periods without adversely affecting the performance of the coronary system. In this way a reserve system that can be implanted in accordance with the present invention can be used to create a reserve within a coronary vein without substantially interfering with the flow of blood back from the myocardium. Then the vessel wall and the surrounding tissue can absorb a drug within the reservoir to treat the selected tissue regions adjacent to the reservoir site. Additionally, it has been clinically determined that occlusion and complete closure of the coronary venous system will not harm the normal operation of the heart. The endocardial veins can take at least a portion of the extra return vein. In addition, within the next thirty minutes of complete occlusion, the Tebesian system, which includes capillaries, veins, and porous tissue that form the myocardium, can replace the venous system and return one hundred percent of the blood back from the myocardium. In this manner, the reserve devices according to the present invention can be deployed in one or more regions within the coronary venous system without the substantial risk of presenting side effects on the coronary blood flow or damaging the tissues of the coronary system. Although the invention is susceptible to various modifications and alternative forms, specific examples thereof have been shown in the figures and are described in detail herein. However, it should be understood that the invention is not limited by the particular forms or methods described, on the contrary, the invention must cover all modifications, equivalents and alternatives that fall within the spirit and scope of the appended claims.

Claims

NOVELTY OF THE INVENTION CLAIMS 1. - A system for delivering a drug to a tissue region within the body of a patient, the system comprising: a catheter having a proximal portion and a distal portion adapted to be inserted into a blood vessel, and defining a periphery and a longitudinal axis; an orientation element on the distal portion in a circumferential relationship with the periphery of the catheter to provide a peripheral orientation of the distal portion near the longitudinal axis; and a drug delivery element on the distal portion for delivering a drug in a predetermined direction with respect to the longitudinal axis, the drug delivery element being aligned with the peripheral orientation of the orientation element.
2. The system according to claim 1, further characterized in that the drug delivery element comprises a deployable needle from the distal portion.
3. The system according to claim 2, further characterized in that the needle is deployable substantially radially from the distal portion.
4. The system according to claim 3, further characterized by comprising a control mechanism in the proximal portion of the catheter attached to the needle to deploy the needle at a precise distance radially from the distal portion, where the needle can be deployed Precisely to a selected region remote from the catheter within a reference frame including a peripheral component and a radial component.
5. The system according to claim 3, further characterized by comprising an image element adjacent to the orientation element to detect the relationship of the orientation element with respect to the selected region, thus providing the peripheral component and the component radial of the selected region within the frame of reference.
6. The system according to claim 1, further characterized in that the drug delivery element comprises an osmotic surface in a portion of the periphery aligned with the peripheral orientation of the orientation element.
7. A system for delivering a drug in a region of tissue within the body of a patient, the system comprises: a catheter having a proximal portion and a distal portion adapted to be inserted into a blood vessel, and defining a periphery and a longitudinal axis; a puncturing element deployable from the distal portion in a predetermined circumferential relationship with the periphery of the catheter, and including a distal tip adapted to penetrate a wall of a blood vessel to access a tissue region farther from the blood vessel wall; a drug delivery element in the distal portion for delivering a drug to the tissue region; and an orientation element in the distal portion in a predetermined relationship with the periphery of the catheter and the puncture element.
8. The system according to claim 7, further characterized in that it comprises an image element adjacent to the orientation element for detecting the location of the orientation element with respect to the tissue region.
9. The system according to claim 8, further characterized in that the image element comprises an ultrasound transducer.
10. The system according to claim 8, further characterized in that the catheter includes a lumen extending from the proximal portion toward the distal portion to receive the imaging element therein.
11. The system according to claim 7, further characterized in that it comprises: a handle in the proximal portion; and a control mechanism in the handle attached to the piercing element to advance the piercing element from the distal portion.
12. The system according to claim 7, further characterized in that it comprises a peripheral opening in a predetermined circumferential location on the periphery of the distal portion through which the puncture element can be deployed. 13. - The system according to claim 12, further characterized in that the catheter includes a needle lumen communicating with the peripheral opening to receive the puncture element through it. 14. The system according to claim 13, further characterized in that the needle lumen includes a baffle element adapted to direct the distal tip substantially transversely with respect to the longitudinal axis when the puncture element is deployed. 15. The system according to claim 7, further characterized in that the puncture element comprises a needle and wherein the drug delivery element comprises a lumen within the needle. 16. The system according to claim 15, further characterized in that the needle includes an exit port arrangement for providing a predetermined flow pattern of fluid within the region of tissue accessed by the needle. 17. The system according to claim 15, further characterized in that the needle includes a plurality of lumens that extend through it to independently introduce a plurality of drugs. 18. The system according to claim 7, further characterized in that at least a portion of the piercing element comprises an electrically conductive material coupled to a proximal end of the piercing element for coupling the piercing element to an electrical current source. 19. The system according to claim 7, further characterized in that the pricking element comprises a plurality of deployable needles from predetermined locations in the distal portion to provide a selected trajectory pattern for the drug delivery element. 20. The system according to claim 7, further characterized in that it comprises an implantable port assembly that includes a bell that can be attached to the drug delivery element and a penetrable seal that provides a fluid tight seal with the supply element. of drug, the implant port assembly being implanted in the patient's body to provide long-term access to the tissue region. 21. The system according to claim 7, further characterized in that the drug delivery element comprises a permanent catheter useful in combination with the puncture element to the tissue region. 22. The system according to claim 7, further characterized in that the pricking element comprises a guide wire, and wherein in addition the drug delivery element is deployable on the guide wire. 23. - The system according to claim 22, further characterized in that the drug delivery element comprises an infusion catheter. 24. The system according to claim 22, further characterized in that the drug delivery element comprises an infusion balloon. 25. The system according to claim 22, further characterized in that the guide wire includes a fixing tip for fixing the guide wire in the tissue region. 26. The system according to claim 22, further characterized in that the drug delivery element includes a fixation tip for securing the drug delivery element in the tissue region. 27. The system according to claim 7, further characterized in that the drug delivery element includes a first electrode therein adapted to be electrically coupled to a second electrode, where direct current is directed between the first and second electrodes. a drug from the drug delivery element is iontophoretically directed from the drug delivery element to the second electrode. 28. The system according to claim 27, further characterized in that the second electrode can be attached to a surface region of the patient under treatment. 29. - The system according to claim 7, further characterized in that the drug delivery element comprises an osmotic surface in the distal portion of the catheter. 30. The system according to claim 7, further characterized in that it comprises a feedback sensor in the drug delivery element or the puncture element. 31.- The system according to claim 30, further characterized in that the feedback sensor comprises an element for detecting a physiological condition in the tissue region. 32. The system according to claim 30, further characterized in that the feedback sensor comprises an EKG terminal. 33.- A system for delivering a drug to a region of tissue within the body of a patient, the system comprising: a catheter having a proximal portion and a distal portion adapted to be inserted into a blood vessel, and defining a periphery and a longitudinal axis; a deployable needle from the distal portion having a drug delivery lumen therein for delivering drugs therethrough, an orientation element on the distal portion in a predetermined relationship with the needle; and an image element adjacent to the orientation element for detecting the location of the orientation element with respect to the region of tissue that is surrounding the distal portion. 34. - The system according to claim 33, further characterized in that the catheter includes a needle lumen extending from the proximal portion toward the peripheral opening at a predetermined circumferential location on the periphery of the distal portion through which the The needle can be used, and the orientation element has an asymmetric configuration aligned with the peripheral opening at the periphery. The system according to claim 34, further characterized in that the orientation element comprises a plurality of rods extending axially along the distal portion. 36.- The system according to claim 34, further characterized in that one of the plurality of rods is provided at the location in direct axial alignment with the peripheral opening. 37.- The system according to claim 34, further characterized in that the orientation element comprises a radiopaque marker. 38.- The system according to claim 37, further characterized in that the radiopaque marker comprises a pair of markers arranged opposite each other in the periphery. 39.- A system for creating a reservoir in a tissue region within the body of a patient to receive a drug therein, the system comprising: a catheter having a proximal portion and a distal portion adapted to be inserted into a blood vessel , and defining a periphery and a longitudinal axis; a guidewire assembly deployable from the distal portion in a predetermined circumferential relationship with the periphery of the catheter; an orientation element on the distal portion in a predetermined relationship with the guide wire assembly, the orientation element being detectable by an imaging element for detecting the location of the orientation element with respect to a region of extravascular tissue surrounding the portion distal and a deployable tissue ablation device in combination with the lead wire guide to form a cavity in the extravascular tissue region. 40. The system according to claim 39, further characterized in that it comprises an image element adjacent to the orientation element to detect the location of the orientation element with respect to a region of extravascular tissue surrounding the distal portion. 41. A reserve device for providing a sustained supply of a drug within the cardiovascular system of a patient, comprising: an elongate frame adapted to expand between a collapsed condition to insert into a blood vessel and an enlarged condition for coupling a wall of the blood vessel, the frame defining a longitudinal axis and a periphery; and a flexible membrane attached to the frame and defining a reservoir therein, the membrane including a porous region. 42. - The device according to claim 41, further characterized in that the porous region of the membrane is arranged along the periphery of the frame. 43.- The device according to claim 41, further characterized in that the frame is deviated towards an enlarged condition. 44. The device according to claim 41, further characterized in that the porous region comprises a semipermeable material. 45.- The device according to claim 41, further characterized in that it comprises a drug within the reserve adapted to pass through the porous region of the membrane. 46.- The device according to claim 45, further characterized in that it comprises an anti-coagulant compound within the reserve. 47. The device according to claim 41, further characterized in that an injection device can penetrate an end region of the membrane to facilitate on-site filling of the reserve. 48. The device according to claim 41, further characterized in that it comprises a septum that divides the reserve into first and second reservation regions. 49. - The device according to claim 48, further characterized in that the membrane includes an osmotic region in communication with the first reserve region. 50.- The device according to claim 49, further characterized in that the porous region of the membrane communicates with the second reserve region. 51.- A method for delivering a selected drug to a selected tissue region within the body of a patient with a catheter having a deployable pricking element, a drug delivery element and an orientation element on a distal portion thereof, the method comprises: the percutaneous introduction of the distal portion of the catheter into a blood vessel; the direction of the distal portion endovascularly to a vessel location adjacent to the selected tissue region; the orientation of the pricking element towards the selected tissue region; the deployment of the pricking element to access the selected tissue region; and the delivery of a drug with the drug delivery element to the selected tissue region. 52. The method according to claim 51, wherein the blood vessel also comprises a vein. 53. The method according to claim 51, wherein the blood vessel further comprises a coronary vein, and the selected tissue region comprises myocardial tissue or a coronary artery. 54. - The method according to claim 51, further comprising the step of orientation includes the step of displaying the orientation element. The method according to claim 54, wherein in addition the orientation element has a predetermined circumferential relationship near a periphery of the catheter with respect to the puncture element. 56. The method according to claim 54, wherein the catheter further includes an image element adjacent to the orientation element, and the step of creating an image includes the step of operating the image element. 57. The method according to claim 56, further comprising the image element comprising an ultrasound transducer, and the step of operating the image element includes the step of obtaining an image including the region of tissue selected along the length of the image. plane substantially normal towards a longitudinal axis of the catheter. 58. The method according to claim 51, further comprising the needle element comprising a needle, and wherein the deployment step includes penetrating the wall of a blood vessel and entering the tissue region with a distal tip of the needle. the needle. 59. The method according to claim 51, further comprising the step of making a map of the tissue region selected before the step of delivering a drug. 60. - The method according to claim 59, wherein the step of making a map includes the introduction of a radiographic agent in the selected tissue region. 61.- The method according to claim 51, wherein the delivery step includes the step of deploying the drug delivery element in combination with the puncture element. 62. The method according to claim 61, wherein the drug delivery element comprises an infusion catheter. 63. The method according to claim 62, wherein the step of inflating a porous balloon in the infusion catheter is included in the delivery step. 64.- The method according to claim 51, wherein it further comprises the steps of: supplying an ablation element in the tissue region; and activating the ablation element to create a drug pool within the tissue region. The method according to claim 64, wherein the step of supplying the ablation element includes the step of advancing the ablation element on the puncture element within the tissue region. 66.- A method for creating a reservoir of fluid within an extravascular tissue region for a sustained delivery of a drug using a catheter having a guidewire and an orientation element on a distal portion thereof, the method comprising the steps of: introducing percutaneously the distal portion of the catheter into a blood vessel; directing the distal portion endovascularly to a vessel location adjacent to the tissue region; Orient the guide wire to the tissue region; deploying the guidewire in the tissue region; and forming a drug pool within the tissue region. 67.- The method according to claim 66, wherein the blood vessel also comprises a vein. 68.- The method according to claim 66, wherein the blood vessel also comprises a coronary vein and the extra vascular tissue region comprises myocardial tissue. 69. The method according to claim 66, wherein it further comprises the step of introducing a drug into the drug pool. The method according to claim 66, wherein in addition the step of forming a drug reservoir includes the steps of supplying an ablation element in the tissue region and activating the ablation element to create the drug reservoir. 71. The method according to claim 66, wherein it further comprises the step of introducing a sealant into the drug reservoir to seal the drug reservoir from the vessel location. 72. The method according to claim 66, wherein further the step of forming a drug reservoir includes the step of removing a portion of the tissue region. 73.- A method for creating a reservoir of drug within a blood vessel for delivering a drug to a region of tissue adjacent to the blood vessel, the method comprising the steps of: advancing a first endovascular blocker in a condition collapsed throughout from the blood vessel to a location adjacent to the tissue region; expanding the first endovascular blocker to an enlarged condition, thereby sealing the blood vessel at the location of fluid flow along the blood vessel; advancing a second endovascular blocker in a condition collapsed along the blood vessel to the location; expanding the second endovascular blocker to an enlarged condition, thereby further sealing the blood vessel at the location of fluid flow along the blood vessel; and introducing a drug into the blood vessel adjacent to the first endovascular blocker. 74. The method according to claim 73, wherein further the step of expanding the second endovascular blocker includes the step of deploying the second endovascular blocker adjacent to the first endovascular blocker, thereby defining a reservoir of drug within the blood vessel. between the first and second endovascular blockers. 75. - The method according to claim 73, wherein in addition the introduction step includes the step of introducing a drug into the drug pool. 76. The method according to claim 75, wherein the blood vessel also comprises a vein. 77. The method according to claim 75, wherein the blood vessel further comprises a coronary vein, and wherein the tissue region comprises myocardial tissue or coronary artery. 78.- A method for providing access to a selected tissue region within a patient's body from a blood vessel using a transvascular catheter having a deployable puncture element and an orientation element on a distal portion thereof, the method comprising: the percutaneous introduction of the distal portion of the transvascular catheter into a blood vessel; directing the distal portion endovascularly to a vessel location adjacent to the selected tissue region; orienting the pricking element towards the selected tissue region; unfolding the pricking element to access the selected tissue region; advancing a flexible catheter in the selected tissue region; and removing the transvascular catheter from the body. 79. The method according to claim 78, wherein further comprises the additional step of advancing a guidewire within the selected tissue region. 80. The method according to claim 79, wherein further the step of advancing a flexible catheter comprises tracking the flexible catheter over the guidewire in the selected tissue region. 81. The method according to claim 78, further comprising the additional step of attaching a proximal end of the flexible catheter to a surface location of the patient's body. 82. The method according to claim 78, comprising the additional step of delivering a drug through the flexible catheter within the selected tissue region. 83. The method according to claim 78, further characterized in that the blood vessel comprises a vein. 84. The method according to claim 78, wherein the blood vessel comprises a coronary vein and wherein the selected tissue region comprises myocardial tissue or a coronary artery. SUMMARY OF THE INVENTION A transvascular system (10) is described for delivering a drug to a tissue region, from a blood vessel, such as a coronary vein, which includes a catheter (12) having a distal portion (26) with puncture elements (14), orientation (16), drug delivery (62), and imaging (18); the pricking element (14) is deployed to penetrate the vessel wall to access the tissue region; the orientation element (16), for example a "cage" includes a plurality of rods (38, 40), and / or radiopaque marker having a predetermined relationship with the location of the orientation element (16) with respect to the region of fabric for orienting the pricking element (14); the catheter (12) is inserted percutaneously into the vessel, the puncture element 14 is oriented towards the tissue region, the puncture element (14) is used to access the tissue region, and the drug is delivered to the region of tissue. tissue; an ablation device (230) can also be deployed to create a cavity in the tissue region to receive the drug, or a permanent catheter (214) can be advanced and left in the tissue region; an implanted reserve device (350) is also described, which further has an included membrane (354) on an expandable frame (352) defining a reservoir, and includes a porous region; the reserve device can be deployed, expanded within a blood vessel and filled in place or pre-filled with a drug that passes through the porous region; alternatively, an endovascular blocking pair can be used to isolate a section of a blood vessel that can be filled with a drug that can be absorbed by the surrounding tissue. PG / HL / eos * sff * aom * rcp * kra * ald * yac * asg * igp * cgm * P00 / 1250F