Abstract:
Apparatus and methods for delivering a therapeutic or diagnostic agent into extravascular tissue surrounding a body passageway is provided comprising a catheter having a sheath, a tubular member, and a plurality of hollow needles on a distal end of the tubular member. The tubular member is selectively movable between delivery position, wherein the plurality of hollow needles are retracted within the sheath, and an extended position, wherein the plurality of hollow needles extend beyond a distal endface of the sheath to pierce and penetrate extravascular tissue. The catheter also includes a balloon for applying pressure to seal puncture wounds created by the hollow needles.

Description:
FIELD OF THE INVENTION 
     The present invention relates to apparatus and methods for delivering a therapeutic or diagnostic agent into extravascular tissue. More particularly, the present invention provides a catheter for delivering therapeutic or diagnostic materials to cardiac tissue using the cardiac vasculature. 
     BACKGROUND OF THE INVENTION 
     A number of techniques have been developed to treat occlusive diseases of the heart, such as atherosclerosis. For example, stenosis of the coronary arteries typically is treated using bypass grafting techniques. More recently, minimally-invasive techniques, such as percutaneous transluminal angioplasty and atherectomy, have been developed that use catheter-based systems to disrupt or remove a stenosis. Techniques such as transmyocardial revascularization (“TMR”) also have been developed, in which a high-energy laser is used to ablate a matrix of channels in the myocardial tissue to enhance perfusion. 
     More recently, attempts at stimulating revascularization of cardiac tissue have focused on the use of the angiogenic factors. For example, Schumacher et al., “Induction of Neoangiogenesis in Ischemic Myocardium by Human Growth Factors,”  Circulation  97:645-650 (1998), report that intraoperative injection of fibroblast growth factor (FGF-I) into the myocardium of 20 patients suffering from stenosis of the internal mammary artery/left anterior descending coronary artery resulted in the development of new capillary vessels radiating outward from the injection point in 4 days. 
     By comparison, however, Fleischer et al., “One-Month Histologic Response of Transmyocardial Laser Channels With Molecular Intervention,”  Ann. Thorac. Surg.,  62:1051-8 (199), report that a single dose of vascular endothelial growth factor (VEG-F), administered intraoperatively at the time of laser TMR, showed no significant increase in myocardial vascularity. It was hypothesized that longer residence of the VEG-F may be required to stimulate angiogenesis. 
     In view of the foregoing, it would be desirable to provide methods and apparatus for percutaneously injecting therapeutic agents, such as drugs or angiogenic growth factors, into myocardial tissue to promote revascularization. 
     It also would be desirable to provide methods and apparatus for percutaneously injecting diagnostic agents, such as radio-isotopes or contrast agents, into myocardial tissue to enhance diagnosis of cardiac ischemia. 
     Apparatus and methods are known for injecting pharmacological agents into the walls of vessels, and surrounding tissue, to reduce restenosis following the use of minimally-invasive techniques, such as angioplasty. For example, angioplasty balloons often injure a large percentage of the endothelium that they contact, and the healing response may itself lead to recurrence of the stenosis. Methods and apparatus therefore have been developed for injecting drugs, such as anti-platelet, anti-coagulant, anti-proliferative and/or anti-inflammatory drugs, into the wall of a treated vessel, or adjacent tissue, to discourage restenosis. 
     For example, U.S. Pat. No. 5,464,395 to Faxon et al. describes a system for delivering therapeutic or diagnostic agents to tissue surrounding a vessel. A needle cannula having a tissue-piercing tip is extended from a delivery catheter to penetrate a selected distance into tissue surrounding the vessel to inject a therapeutic or diagnostic agent. The device includes a balloon for dilating the vessel prior to extending the needle cannula. If multiple needle cannulas are used, each needle cannula requires a separate lumen and must be individually positioned within the tissue to be treated. 
     U.S. Pat. No. 5,693,029 to Leonhardt describes a catheter having a plurality of fixed-length needle assemblies that are selectively extended to pierce the walls of a lumen and inject a therapeutic agent. The therapeutic agent is delivered to the needle assemblies via a common channel. The catheter includes a balloon that is inflated to deploy the needle assemblies, and a retraction mechanism that retracts the needle assemblies once the balloon is deflated. 
     The foregoing devices have a number of disadvantages that limit the utility of those devices for delivering therapeutic or diagnostic agents in the heart. For example, each needle cannula in the Faxon device must be separately deployed and positioned; consequently, the use of multiple needle cannulas may be both time consuming and laborious. Similarly, because the Leonhardt device employs relatively short fixed-length needle assemblies, that device cannot be used for administering a therapeutic or diagnostic agent at various depths within the myocardium. In addition, the retraction mechanism used in the Leonhardt device inherently poses risks to the patient&#39;s health should that mechanism fail. 
     It therefore would be desirable to provide methods and apparatus for administering a therapeutic or diagnostic agent at multiple sites in extravascular tissue, but that does not require time consuming and laborious in-situ assembly. 
     It also would be desirable to provide methods and apparatus for administering a therapeutic or diagnostic agent at multiple sites in extravascular tissue at various depths. 
     SUMMARY OF THE INVENTION 
     In view of the foregoing, it is an object to provide methods and apparatus for percutaneously injecting a therapeutic agent, such as drug or angiogenic growth factor, into myocardial tissue to promote revascularization. 
     It is another object of this invention to provide methods and apparatus for percutaneously injecting a diagnostic agent, such as a radio-isotope or contrast agent, into myocardial tissue to enhance diagnosis of cardiac ischemia. 
     It is a further object of the present invention to provide methods and apparatus for administering a therapeutic or diagnostic agent at multiple sites in extravascular tissue without requiring time consuming and laborious in-situ assembly. 
     It is a still further object of this invention provide methods and apparatus for administering a therapeutic or diagnostic agent at multiple sites in extravascular tissue at various depths. 
     These and other objects of the present invention are accomplished by providing a catheter for percutaneously delivering a therapeutic or diagnostic agent to the heart comprising a sheath, a tubular member slidably disposed within the sheath, and a plurality of hollow needles coupled to the tubular member. The plurality of hollow needles have a delivery position, wherein the plurality of hollow needles are retracted within the sheath, and an extended position, wherein the plurality of hollow needles extend beyond a distal endface of the sheath and curve outwardly to penetrate extravascular tissue. 
     In a preferred embodiment, the catheter is adapted to be disposed in the coronary venous vasculature to inject a therapeutic or diagnostic agent at selected depths into the myocardium. The catheter preferably includes a balloon disposed on the outer sheath that may be used to apply pressure to seal the injection sites after a therapeutic or diagnostic agent is injected. Methods of using the catheter of the present invention also are provided. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     Further features of the invention, its nature and various advantages will be more apparent from the accompanying drawings and the following detailed description of the preferred embodiments, in which: 
     FIG. 1 is a side view of an illustrative embodiment of a catheter system constructed in accordance with the present invention; 
     FIGS. 2A and 2B are, respectively, a cross-sectional view of the distal end of the catheter of FIG. 1, and an end view taken along view line  2 B— 2 B of FIG. 2A, in the delivery position; 
     FIGS. 3A and 3B are, respectively, a cross-sectional view of the distal end of the catheter of FIG. 1, and an end view taken along view line  3 B— 3 B of FIG. 3A, in the extended position; and 
     FIGS. 4A,  4 B and  4 C illustrate methods of using the catheter of FIG. 1 to inject a therapeutic or diagnostic agent into extravascular tissue. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The present invention relates generally to apparatus and methods for administering a therapeutic or diagnostic agent to extravascular tissue, especially the heart. Although the invention is described hereinafter as particularly useful for administering a therapeutic and diagnostic agent to the heart, the methods and apparatus of the present invention advantageously may be used for administering therapeutic or diagnostic agents to other organs and vessels. 
     Referring to FIG. 1, illustrative catheter  10  constructed in accordance with the present invention is described. Catheter  10  includes outer sheath  11  having proximal end  12  coupled to handle  13  and distal end  14  having inflatable balloon  15 . Handle  13  includes distal portion  16  joined to outer sheath  11 , and proximal portion  17 , which is engaged by threads  18  with distal portion  16 . Syringe  19 , containing a therapeutic or diagnostic drug to be injected into a patient&#39;s tissue, is coupled to proximal portion  17  at hub  20 . Guidewire  21  extends through hub  20  and out of the distal end of catheter  10 . Catheter  10  preferably is 30 cm or longer, and is adapted to be percutaneously and transluminally inserted into a vessel of the patient&#39;s vasculature, such as the coronary venous vasculature. 
     Referring now also to FIGS. 2A and 2B, tubular member  25  is arranged for sliding movement in outer sheath  11 , and has a proximal end coupled to handle member  17  and distal end  26  having endcap  27 . Endcap  27  has a plurality of hollow needles  28  affixed to distal endface  29 . Inner member  30  is disposed coaxially within tubular member  25  to form annular lumen  31 . Inner member  30  includes lumen  32 , through which guide wire  21  is slidably disposed. Tubular member  25  and inner member  30  are coupled to proximal portion  17  of handle  13  so that when proximal portion  17  is rotated within distal portion  16  of handle  13 , tubular member  25  and inner member  30  are extended or retracted a predetermined distance. Inflation lumen  33  couples balloon  15  to a source of inflation medium, such as a syringe (not shown), via handle  13 . 
     Outer sheath  11 , tubular member  25  and inner member  30  preferably comprise a material commonly used in catheter construction, such as polyethylene, polyvinyl chloride or polyurethane. In addition, tubular member  25  may include ring  34 , formed of a layer of radio-opaque marker material, such as gold, disposed near endcap  29 . Radio-opaque ring  34  may be employed to assist in orienting catheter  10  so that the distal end of tubular member  25  is aligned with a desired treatment site in the patient&#39;s vasculature. 
     Annular lumen  31  extends from the proximal end of catheter  10 , where it is coupled to syringe  19 , to endcap  29  at distal end  14 . Hollow needles  28  protrude longitudinally from distal endface  29 , and are in fluid communication with annular lumen  31 . Hollow needles  28  preferably comprise a resilient material, such as nickel titanium or stainless steel, and are biased to curve outwardly away from the longitudinal of catheter  10  when extended beyond distal endface  36  of outer sheath  11 . 
     Hollow needles  28  each have non-coring tip  35  and opening  37  and a lumen that communicates with annular lumen  31 . Hollow needles  28  are designed to readily pierce tissue, to enable injection of a therapeutic or diagnostic agent into extravascular tissue. In accordance with one aspect of the present invention, hollow needles  28  are disposed in a semi-circular pattern, as illustrated in FIG.  2 B. This arrangement ensures that when the catheter is inserted and properly oriented, for example, in the coronary sinus or great cardiac vein, the needles will extend only into the myocardium, and not puncture the circumference of the vessel adjacent the pericardial sac. Alternatively, hollow needles  28  may be arranged in a different pattern, for example to cover more or less of the circumference of endcap  29 , depending upon the intended application of catheter  10 . 
     Still referring to FIGS. 2A and 2B, when tubular member  25  is retracted proximally, for example, by rotating proximal portion  17  of handle  13  relative to distal portion  16 , hollow needles  28  are retracted into outer sheath  11 . When retracted in outer sheath  11 , hollow needles  28  are closely bunched together, and assume a delivery position substantially parallel to a longitudinal axis of outer sheath  11 . In the delivery position, outer sheath  11  prevents tips  32  from puncturing the patient&#39;s vasculature during insertion and withdrawal of catheter  10 . 
     With respect to FIGS. 3A and 3B, catheter  10  is shown with hollow needles  28  in the extended position. The extended position may be attained, for example, by rotating proximal portion  17  of handle  13  relative to distal portion  16 , so that tubular member  25  is translated in the distal direction. As hollow needles  28  extend beyond distal endface  36  of outer sheath  11 , hollow needles curve outwardly away from the longitudinal axis of the catheter, due to the bias of the needles. Thus, as tubular member  25  slides in the distal direction, hollow needles  28  curve radially away from endcap  29  to pierce the vessel wall and surrounding tissue. 
     Advantageously, catheter  10  enables a clinician to adjust the depth to which tips  32  of hollow needles  28  are deployed by controlling relative motion between tubular member  25  and outer sheath  11  using handle  13 . For example, handle  13  may include gradations that provide correspondence between relative motion of handle portions  16  and  17  and extension of hollow needles  28 . In addition, because hollow needles  28  communicate with annular lumen  31 , catheter  10  permits a therapeutic or diagnostic agent to be injected in a relatively widespread pattern without repeatedly repositioning the catheter. 
     Referring now to FIGS. 4A to  4 B, methods of using a catheter constructed in accordance with the present invention are described. Catheter  10  is first inserted percutaneously and transluminally into a patient&#39;s vessel V under fluoroscopic guidance. For example, if it is desired to inject an angiogenic growth factor or other bioactive agent, e.g., FGF-I or VEG-F, into the myocardium, catheter  10  may be advanced along guide wire  21  via a femoral vein, the inferior vena cava and the right atrium into the coronary sinus. 
     Radio-opaque ring  34  may be used to orient distal end  14  of catheter  10  adjacent a desired treatment site. Specifically, catheter  10  may be rotated so that when hollow needles  28  are extended from outer sheath  11 , all of the needles pierce the epicardium, and few or none pierce the opposing vessel wall (i.e., adjacent the pericardial sac). 
     Once distal end  14  is properly positioned adjacent the myocardium, handle  13  is operated to translate tubular member  25  in the distal direction to extend hollow needles  28 . As hollow needles  28  extend beyond distal endface  36  of outer sheath  11 , the hollow needles begin to curve outwardly, so that tips  32  pierce the epicardium and myocardium adjacent to vessel V a first predetermined depth. Syringe  19  then is operated to inject therapeutic or diagnostic agent A into the tissue to form pockets P. 
     Handle member  13  may then be operated a second time to further extend tubular member  25 , thereby causing hollow needles  28  to further penetrate into the tissue, as shown in FIG.  4 B. Syringe  19  may then be actuated a second time to inject therapeutic or diagnostic agent A into the tissue to form additional pockets P′. Accordingly, handle  13  may be actuated to control the depth of penetration of hollow needles  28  to inject a therapeutic or diagnostic agent at a series of locations along a single needle track. 
     Once injection of the therapeutic or diagnostic agent is completed along a particular needle track, handle  13  is operated to withdraw tubular member  25  proximally into outer sheath  11 , thereby causing hollow needles  28  to be retracted from the tissue and back into outer sheath  11 . Once hollow needles  28  are fully retracted within outer sheath  11 , catheter  10  may be removed from the patient or repositioned at another treatment site. 
     Alternatively, as illustrated in FIG. 4C, catheter  10  may be advanced over guide wire  21  so that balloon  15  is positioned adjacent puncture wounds W formed by deployment of hollow needles  28 . Balloon  15  then may be inflated via inflation lumen  33  to apply a low pressure to puncture wounds W for a short interval of time, e.g., a few minutes, to seal the wounds and prevent therapeutic or diagnostic agent A from migrating along the needle track into vessel V. Balloon  15  then is deflated and catheter  10  may be removed from the patient or re-positioned at another treatment site for further injections. 
     Although preferred illustrative embodiments of the invention are described above, it will be apparent to one skilled in the art that various changes and modifications may be made therein without departing from the invention, and the appended claims are intended to cover all such changes and modifications that fall within the true spirit and scope of the invention.