Abstract:
The present invention provides a deflectable catheter-based system for assisting in the delivery of therapeutic agents, cellular materials and the like to one or more sites in a target body tissue. The system provides for one or more injections to a predetermined needle insertion depth with a single core needle that can be advanced and retracted from the tip of the catheter. The catheter assembly includes a handle subassembly having a mechanism for setting and limiting the depth of insertion of the needle, a slide for moving the injection needle between retracted and extended positions, a return spring for biasing the needle to the retracted position, and a modified pulley mechanism for compensating for catheter shaft compression when the catheter is deflected.

Description:
BACKGROUND OF THE INVENTION 
     The present invention pertains to the field of catheter-based delivery systems. Particularly, it relates to an intravascular apparatus for delivering pharmacological or biological materials. More particularly, it involves a deflectable injection catheter for introducing therapeutic agents, such as cell cultures, growth factors, angiogenic agents, and the like, from within a chamber of the heart into damaged myocardium. 
     Coronary disease is the most prevalent cause of death in the United States. A heart attack, or myocardial infarction, occurs when coronary artery blockages severely restrict or deprive the heart muscle of blood flow. Blood supply which is greatly reduced or blocked for more than a transitory period of time can result in a significant loss of functioning heart muscle. The heart muscle cells, or cardiomyocytes, that die following a heart attack cannot be replaced by the body under normal conditions, because heart muscle cells are incapable of effective regeneration after injury or infarction. Instead, as a result of the healing phase after a heart attack, a scar is formed in the affected region of the heart. 
     This fibrous scar tissue cannot contract, does not contribute to heart function, and causes the rest of the heart to work harder and overcompensate for the nonfunctioning portion. As the uninjured regions of the heart become overburdened, a progressive deterioration can occur culminating in congestive heart failure. 
     Treatment options for damaged heart muscle and resulting end-stage heart failure include drug therapy, revascularization of the damaged tissue, mechanical circulatory assist devices, ventriculotomy, and heart transplantation. 
     Drug therapy is precluded in a number of refractory patients, generally only treat symptoms and has a limited effect on the progression of the disease. Transplant is limited by a shortage of donor hearts and need for continuous immunosupression. 
     Moreover, most of the above approaches involve highly invasive surgical procedures, with cardioplegic arrest and cardiopulmonary bypass. 
     What is needed is a method and means for delivering therapeutic agents to such patients in a minimally invasive procedure. More preferably, the need exists for percutaneous, localized delivery of therapeutic and pharmacological agents. 
     Catheter systems have been proposed for myocardial revascularization, via drilling or boring channels in the myocardium, such as by laser or needle, and, possibly, deposition of angiogenic substances within the channels created as an adjunct thereto. Such devices, however, raise performance and safety issues. 
     Specifically, precise control of the depth of the channel into the myocardium so as not to pierce the epicardium. More specifically, prior deflectable injection catheters exhibit shrinkage in the catheter shaft due to compression thereof when the catheter is deflected. This can change the relative position of the needle and the catheter shaft leading to inaccurate readings on the depth of needle insertion into the tissue to be treated. 
     Also, without a retraction default mechanism such prior catheter systems can cause injury to the endocardium from the instruments used to drill or bore the channels, or during advancement and delivery to the target location from these instruments. Further, a catheter capable of accessing more difficult areas of the heart is advantageous to achieving full benefit of the procedure. Additionally, minimal resistance to the flow of the agents or materials being deposited is desirable. 
     BRIEF SUMMARY OF THE INVENTION 
     The invention presents a system for delivery of therapeutic agents and/or cellular-based matter into body tissue. And, more specifically, a deflectable catheter-based method and apparatus for injecting such agents and materials directly into damaged or injured muscle tissue. 
     Accordingly, the present invention provides a catheter system for precise and controlled delivery of therapeutic agents and cellular materials to one or more sites in target body tissue. These agents and materials can be in aqueous form, microspheres suspended in solution, gels, pellets or any other media, whether in solid or fluid form, capable of delivery through the inner lumen of the catheter. 
     The delivery system includes a distal shaft, a proximal handle assembly and inner core member. The handle assembly has a mechanism for setting and limiting the depth of insertion of the inner core member or injection needle, a slide for moving the injection needle between retracted and extended positions, a return spring for biasing the inner core member to the retracted position. In a further preferred embodiment, a modified pulley mechanism is incorporated for compensating for catheter shaft compression when the catheter is deflected. 
     In its most specific form, it is a further object of the present invention to provide a catheter-based delivery system for assisting in the percutaneous delivery and controlled injection of myogenic cells (myoblasts, myotubes, young muscle fiber cells), angiogenic substances, growth factors, drugs and other therapeutic agents to a desired endoventricular treatment site. The system provides for multiple injections to a predetermined needle insertion depth with a single core needle that can be advanced and retracted from the tip of the catheter. 
     In a further aspect of the invention, the delivery system is designed to perform with an inner core member having a sufficiently large inner diameter to minimize resistance to the flow of media through the inner core member and so as not to subject the media being injected to high pressures. 
     In another aspect of the invention, the injected media can include a radiopaque material. This is especially useful in situations where multiple injections in a spaced apart pattern are contemplated. Although, however, a radiopaque marker can be used with single injections also. 
     Further features and advantages of the invention will become apparent from the following detailed description taken with the accompanying drawings. 
    
    
     
       BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS 
       The invention is illustrated in the drawings in which like reference numerals and characters designate the same or similar elements throughout the figures of which: 
         FIG. 1  depicts a general view of the entire deflectable microimplant-delivery system; 
         FIG. 1A  is a view through cross section A—A of the distal working length of the catheter assembly; 
         FIG. 1B  is a view through cross section B—B of the proximal working length of the catheter assembly; 
         FIG. 2A  depicts a cross section view of the distal portion of the handle assembly with the distal working length of the catheter in a substantially non-deflected mode; 
         FIG. 2B  depicts a cross section view of the distal portion of the handle assembly with the distal working length of the catheter in a deflected mode; 
         FIG. 3  shows a detailed cross section view of the proximal portion of the handle assembly; 
         FIG. 4  is a cross section of the entire catheter assembly in a non-deflected position showing the relative position of the inner core member and the catheter; 
         FIG. 5  is a cross section of the entire catheter assembly with the distal end in a deflected position indicating the relative position of the inner core member, with respect to the distal end of the catheter, remaining substantially unchanged; and 
         FIG. 6  is a cross section of the entire catheter assembly with the catheter shaft in a deflected position and the inner core member in an extended position. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The present invention relates to a deflectable catheter assembly including a distal shaft section, a proximal handle subassembly and an inner core member for delivery of therapeutic agents, cellular-based materials, or a combination thereof, to diseased, injured or defective tissue. The following description is presented to enable one of ordinary skill in the art to make and use the invention and is provided in the context of a patent application and its requirements. Various modifications to the embodiments described will be readily apparent to those skilled in the art and the generic principles herein may be applied to other embodiments. Thus, the present invention is not intended to be limited to the embodiments shown but is to be accorded the widest scope consistent with the principles and features described herein. 
     An overall view of the deflectable microimplant delivery system  10  is given in  FIG. 1 . This catheter apparatus includes shaft or working length (that portion of the catheter apparatus which physically enters the patient)  20  and handle assembly  30 . 
       FIG. 1  also shows the deflection knob  32 , inner core advancement control member  42 , insertion depth gauge  54 , inner core depth control knob  52 , injection port  56  and sheath port  58 , all of which will be explained in more detail below with reference to  FIGS. 2A ,  2 B and  3 . 
       FIG. 1A  is a cross section through the distal portion of working length  20 . This distal working length admits to an outer shaft with a multi-lumen section comprising a first inner lumen within which is the inner core member or needle assembly  22 , a second lumen containing pull wire  24 , which is fixed at its distal end to the distal portion of shaft  20 , and a third lumen housing ribbon  26 . When the pull wire  24  is tensioned, by distal advancement of the deflection knob  32 , the distal end of the shaft  20  is deflected (as better seen in  FIG. 2B ). 
     In a preferred embodiment, ribbon  26  exists only in the distal portion of the shaft  20  as can be seen in a comparison between  FIG. 1A  and  FIG. 1B  (which is a cross section through the proximal portion of working length  20 ). The ribbon  26  assists in returning the distal tip of the catheter shaft to the substantially non-deflected position when deflection knob  32  is retracted proximally. Furthermore, ribbon  26  assists in the torquing and tracking of the distal portion of the working length  20  and in deflection thereof. The ribbon  26  also enhances pushability of the delivery system while maintaining integrity of the distal portion of the working length  20 . Ribbon  26  can me made from any suitable material such as stainless steel, cobalt-chromium alloys, polymers and the like. 
       FIGS. 2A and 2B  indicate the working length  20  of the catheter system along with a longitudinal cross section through the distal portion of the handle assembly  30 . Pull wire  24  traverses a groove in pulley member  36  and is fixed at its proximal end to deflection rod  34 . Pulley  36  is fixed to pulley base  35 . In the embodiment shown, pulley base  35  is not fixed to the distal handle housing. But the pulley base  35  may be secured with respect to the handle assembly with, for example, mechanical fasteners, such as a set screw, or adhesives or the like. 
     When the deflection knob  32  is advanced distally, as shown in  FIG. 2B , it places the pull wire  24  in tension, thereby causing the distal end of the shaft  20  to deflect. The pulley  36  is employed to substantially maintain the relative position of the inner core member  22  with respect to the distal end of shaft  20  when the shaft  20  is deflected (as better shown in  FIG. 5 ). And pulley  36  also lessens the risk of the inner core member  22  from advancing out of, or retracting in from, the distal end of shaft  20  when the shaft  20  is manipulated during delivery to the site to be treated. Without the advantage of the pulley member  36 , it has been found that, depending on the design of the handle assembly, the distal tip of the inner core member  22  can be caused to extend beyond, or retreat proximally, from the distal end of the shaft  20  unintentionally. And therefore, the relative position of the inner core member  22  with respect to the distal end of shaft  20  when the shaft  20  is deflected can vary leading to inaccurate insertion depths of the inner core member  22 , without such advantage. 
       FIG. 3  shows the details of the proximal end of the handle assembly  30 . This portion of the handle assembly  30  includes seal housing  38  surrounding the inner core member  22 , slide member  40 , insertion knob or inner core member advancement control  42 , return spring  46 , internal flange  48 , depth stop member  50 , depth knob or inner core insertion depth control  52 , depth indicator or insertion depth gauge  54 , injection port  56 , and sheath port  58 . 
     Insertion knob  42  is fixed to and slides with slide member  40 . Slide member  40  can comprise a one piece unit or include a second proximal element  44  (as shown), for ease of manufacturing, which is fixed to the slide member  40  by, for example, mechanical fasteners, adhesives and the like. Insertion depth gauge  54 , which is fixed to depth stop member  50 , gives a visual indication of the maximum depth of insertion of inner core member  22 . Inner core insertion depth control  52  sets the position of the insertion depth gauge  54 . More specifically, rotation of depth knob  52 , which threadingly engages depth stop  50 , axially translates depth stop member  50  and depth indicator  54 , therefore limiting maximum distal axial movement of inner core member  22  by limiting the maximum distal axial travel, in the embodiment shown, of second proximal slide element  44 , which is fixed to the slide member  40 , which is in turn fixed to insertion knob  42 . 
     Injection port  56  is used to inject various therapeutic treatments such as myogenic cells, bone marrow derived stem cells, endothelial cells, cardiomyocytes, angiogenic growth factors, drugs or any combination thereof. Sheath port  58  is used to flush the lumen containing the inner core member  22 . 
     In summary, the inner core insertion depth control  52  sets the maximum distance that the inner core member  22 , slide member  40  and insertion knob  42  can travel. That maximum distance is indicated on the depth gauge  54 . Inner core advancement control  42  is advanced manually against the bias of return spring  46 . Return spring  46  has its distal end seated in abutting fashion to flange  48  formed on the inside of the handle assembly  30 . The return spring  46  acts to retract the inner core member  22  when pressure is released on the insertion knob  42 . When the inner core member  22  is advanced distally of the tip of shaft section  20  and into the desired treatment site, therapeutic agents can then be delivered through the injection port  56 . 
       FIG. 4  depicts a cut away view of the entire microimplant delivery system in the non-deflected mode with the inner core member in the retracted position. 
       FIG. 5  is similar to  FIG. 4  except that the catheter apparatus is indicated in a deflected mode with the inner core member remaining in the retracted position. 
       FIG. 6  is a view similar to  FIG. 5  except that the inner core member is now shown in an extended position. 
     By way of example, and not by way of limitation, the present invention is embodied in a deflectable microimplant delivery system  10  for treating regions of the myocardium damaged by myocardial infarction. In this embodiment, the system is introduced into the patient&#39;s vascular system through a major vessel in a manner and using techniques well known to those of ordinary skill in this art. With specific example to treating a regin or regions of the left ventricle, the system is introduced into the femoral artery, advanced up through the descending aorta, over the aortic arch, down the ascending aorta, through the aortic valve and into the left ventricle. 
     Using known imaging modalities, such as magnetic resonance, intracardic echocardiography, ultrasound, transesophogeal echocardiography, transthoracic echocardiography, fluoroscopy and the like, the location of the distal tip of the catheter shaft  20  within the left ventricle can be verified. Once manipulated to a region adjacent an infarct zone in the left ventricle, the catheter shaft  20  is deflected, by deflection knob  32 , as depicted in  FIG. 5 , such that the distal tip is disposed against a site on the endocardial surface of the left ventricle. The maximum depth of insertion of the inner core member into the myocardium, if not having been previously set, is set via rotation of the insertion depth control knob  52 . Inner core advancement control member  42  is then manipulated to move the inner core member  22  towards an extended position, as shown in  FIG. 6 , piercing through the endocardium and into the myocardium. In the embodiment shown in  FIGS. 4–6 , the inner core member  22  is provided with a beveled or skived tip to facilitate piercing of the endocardium through and into the myocardium. The desired therapeutic solution is then injected through the injection port and the inner core member into the myocardium. A number of injections may be performed at or around the infarct zone or the catheter can be repositioned to treat other areas of the left ventricle. 
     Other than the specific example given above, the deflectable microimplant delivery system described above can be used to inject therapeutic agents and cellular-based materials into any other chamber of the heart, such as by venous approach, for example femoral vein or internal jugular vein, or into almost any body tissue requiring treatment or repair. Including, for example, the kidneys, liver, brain, gastrointestinal tract, esophagus, and vascular system. 
     A deflectable catheter assembly with a working length section and a handle subassembly for delivery of one or more therapeutic agents and/or cellular-based therapies has been disclosed. Although the present invention has been described in accordance with the embodiments shown, one of ordinary skill in the art will readily recognize that there could be variations to the embodiments and those variations would be within the spirit and scope of the present invention. 
     For example, the inner core member and/or the distal portion of the catheter shaft could be designed to cause the inner core member to deflect at an angle oblique to the distal tip of the catheter shaft. This could allow for a longer track for the implanted media, with more therapeutic media being implanted with less risk of leakage of the therapeutic media. Moreover, this modification could also reduce the risk or likelihood of the inner core member piercing or passing completely through the organ or tissue to be treated. 
     Moreover, inner core member  22  can be drawn from a single piece of hypotubing or be formed as a multi-piece assembly. More specifically, needle assembly  22  can comprise a proximal hypotube portion, a distal skived hypotube section, with an intermediate polyimide tubing bonded at its proximal end to the proximal hypotube portin and at its distal end to the skived hypotube section. The latter described multi-section needle assembly enhances the overall deliverablity of the deflectable delivery system. 
     Additionally, the microimplant delivery system can be used to introduce a host of cellular matter to the treatment site, which can include myogenic cells, vascular endothelial growth factors, fibroblast growth factors, bone marrow derived stem cells, endothelial cells, cardiomyocytes or any combination of these or other biological or therapeutic agents. 
     Also, the catheter apparatus can be used as a tool for transmyocardial revascularization. In this manner the catheter apparatus, for example, could be used to form channels into the myocardium with or without the deposition of angiogenic enhancing substances such as vascular endothelial growth factors and fibroblast growth factors.