Patent Abstract:
A system is disclosed, for administering a therapeutic agent locally and to a depth within cardiac tissue. An elongate, flexible catheter contains a flexible electric conductor and supports at its distal end an implantable electrode incorporating a penetrating element, typically a fixation helix or a linear needle that penetrates cardiac tissue as the electrode is implanted. A therapeutic agent is delivered through the electrode, to the cardiac tissue surrounding the penetrating element. The electrode can act as a sensor to monitor an electrical condition of the surrounding cardiac tissue and to control delivery of the agent responsive to the sensed electrical condition. Several embodiments feature a distal reservoir adjacent the electrode, for effecting transient deliveries of the therapeutic agent in minute quantities. Other embodiments are disclosed for providing sustained deliveries of agents.

Full Description:
[0001]     This is a divisional of copending prior application Ser. No. 10/101,301, filed Mar. 19, 2002 as a divisional of application Ser. No. 09/260,641 (now U.S. Pat. No. 6,358,247), filed Mar. 2, 1999 as a divisional of application Ser. No. 08/816,850 (now U.S. Pat. No. 6,086,582), filed Mar. 13, 1997. 
     
    
     FIELD OF THE INVENTION  
       [0002]     This invention relates to site specific delivery of therapeutic agents, structures and catheter systems to achieve site specific delivery of therapeutic agents, and means for implanting and using these systems to enable delivery of therapeutic agents to the body. More specifically, this invention relates to delivery of pharmacological agents to specific regions of the heart at a depth within the heart wall.  
       BACKGROUND OF THE INVENTION  
       [0003]     It is possible to identify particular sites within the myocardium which may benefit from local drug release therapy. Examples of problematic tissue which may benefit form local drug release therapy are ischemic sites and arrhythmogenic sites. Different means and methods for delivering agents to these sites will be disclosed in detail.  
         [0000]     Ischemic Sites  
         [0004]     Ischemic tissue is characterized by limited metabolic processes which cause poor functionality. The tissue lacks oxygen, nutrients, and means for disposing of wastes. This hinders the normal functioning of the heart cells or myocytes in an ischemic region. If an ischemic, or damaged, region of the heart does not receive enough nutrients to sustain the myocytes they are said to die, and the tissue is said to become infarcted. Ischemia is reversible, such that cells may return to normal function once they receive the proper nutrients. Infarction is irreversible.  
         [0005]     Non-invasive systemic delivery of anti-ischemic agents such as nitrates or vasodilators allows the heart to work less by reducing vascular resistance. Some vascular obstructions are treated by the systemic delivery of pharmacological agents such as TPA, urokinase, or antithrombolytics which can break up the obstruction. Catheter based techniques to remove the vascular obstructions such as percutaneous transluminal coronary angioplasty (PTCA), atherectomy devices, and stents can increase myocardial perfusion. More drastic, but very reliable procedures such as coronary artery bypass surgery can also be performed. All of these techniques treat the root cause of poor perfusion.  
         [0006]     It should be noted that these therapies are primarily for the treatment of large vessel disease, and that many patients suffer from poor perfusion within smaller vessels that cannot be treated with conventional therapies.  
         [0007]     The delivery of angiogenic growth factors to the heart via the coronary arteries by catheter techniques, or by implantable controlled release matrices, can create new capillary vascular growth within the myocardium. Recent work has shown substantial increases in muscular flow in a variety of in vivo experimental models with growth factors such as Tumor Angiogenic factor (TAF), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and acidic fibroblast growth factor (aFGF). The methods of delivering these agents to the heart include implantable controlled release matrices such as ethylene vinyl acetate copolymer (EVAC), and sequential bolus delivery into the coronary arteries. Recently similar techniques have been attempted in peripheral vessels in human patients with the primary difficulty being systemic effects of the agents delivered.  
         [0008]     U.S. Pat. No. 5,244,460 issued to Unger describes a method of introducing growth factors over time by delivering them through fluid catheters into the coronary arteries, but this does not result in efficient delivery of these agents to the ischemic tissue. If these or other agents are delivered to the coronary artery, a region of tissue that is equivalent to that supplied by the artery will receive the therapeutic agents. This may be substantially more tissue than is in need of local drug delivery therapy. Further, if a vessel is occluded, the growth factors will act in the tissue which the coronary arteries successfully perfuse. As the underlying problem of ischemic tissue is poor perfusion, excess growth factor must be delivered in order to obtain the desired effects in the poorly perfused tissue. Further, growth factors may cause unwanted angiogenesis in tissues where inappropriately delivered. The cornea is described by Unger as such a location, but perhaps more critical is inappropriate delivery of these factors to the brain. Further, placement of delivery devices within these coronary arteries as Unger describes tends to obstruct these arteries and may augment occlusive thrombosis formation. There is a significant need for minimizing the amount of growth factors for introducing angiogenesis by delivering these agents only to the site where they are most needed.  
         [0009]     There are complications with clinically acceptable procedures where special devices for delivering agents to ischemic tissue will be useful. After opening vessels using PTCA, the vessels often lose patentcy over time. This loss of patentcy due to re-stenosis may be reduced by appropriate pharmacological therapy in the region of the artery. There is a need for new techniques that will enable pharmacological therapy to reduce the incidence of restenosis. Arrhythmogenic sites Cardiac arrhythmias are abnormal rhythmic contractions of the myocardial muscle, often introduced by electrical abnormalities, or irregularities in the heart tissue, and not necessarily from ischemic tissue. In a cardiac ablation procedure, the arrhythmogenic region is isolated or the inappropriate pathway is disrupted by destroying the cells in the regions of interest. Using catheter techniques to gain venous and arterial access to the chambers of the heart, and possibly trans septal techniques, necrotic regions can be generated by destroying the tissue locally. These necrotic regions effectively introduce electrical barriers to problematic conduction pathways.  
         [0010]     U.S. Pat. No. 5,385,148 issued to Lesh describes a cardiac imaging and ablation catheter in which a helical needle may be used to deliver fluid ablative agents, such as ethanol, at a depth within the tissue to achieve ablation. Lesh further describes a method of delivering a pharmacological agent to the tissue just before performing the chemical ablation procedure to temporarily alter the conduction of the tissue prior to performing the ablation. Such temporary alteration of tissue has the advantage of allowing the physician to evaluate the results of destructive ablation in that region prior to actually performing the ablation. This method of ablation has the advantage that the ablative fluid agents are delivered to essentially the same tissue as the temporary modifying agents. However, with ablative fluid agents it is difficult to control the amount of tissue which is destroyed—especially in a beating heart, and ablative RF energy is in common use because of its reproducible lesions and ease of control. There is a need for an ablation catheter that uses a single structure within the heart wall for both temporary modification of tissue conductivity by delivery of therapeutic agents at a depth within the tissue, and delivery of RF energy.  
         [0011]     U.S. Pat. No. 5,527,344 issued to Arzbaecher and incorporated by reference herein, describes a pharmacological atrial defibrillator and method for automatically delivering a defibrillating drug into the bloodstream of a patient upon detection of the onset of atrial arrhythmias in order to terminate the atrial arrhythmias. By delivering agents to a blood vessel, Arzbaecher requires systemic effects to be achieved in order to terminate the atrial arrhythmias. The advantages of local drug delivery are absent from the system described. There is a need for a system and method to transiently treat atrial arrhythmias by local delivery of pharmacological agents which affect the excitation of the cardiac tissue locally.  
         [0012]     Many patents describe systems for delivering anti inflammatory agents to the endocardial surface of the heart. Such surface delivery is less viable for regions at a depth within the tissue. Further, because of the volume of fluid moving by the inner surfaces of the heart, higher concentrations may be required at the surface to counteract the effects of dilution. These higher doses result in greater likelihood of problematic systemic effects from the therapeutic agents. Delivering agents within the tissue will minimize the dilution of agents, and decrease the possibility of the agents being delivered to inappropriate sites. This is particularly important with growth factors whose systemic affects are not well documented, just as it is important for antiarrhythmic agents whose pro-arrhythmia systemic effects have been recognized. There is a need for a means to deliver agents to ischemic and arrhythmogenic sites within the myocardium.  
         [0013]     To deliver substances at a depth within the heart, U.S. Pat. Nos. 5,447,533 and 5,531,780 issued to Vachon describe pacing leads having a stylet introduced anti inflammatory drug delivery dart and needle advanceable from the distal tip of the electrode. U.S. Pat. No. 5,002,067 issued to Berthelson describes a helical fixation device with a groove to provide a path to introduce anti-inflammatory drug to a depth within the tissue. U.S. Pat. No. 5,324,325 issued to Moaddeb describes a myocardial steroid releasing lead whose tip of the rigid helix has an axial bore filled with a therapeutic medication such as a steroid or steroid based drug. None of these patents provides a means for site specific delivery of agents as all applications of the drug delivery systems are at the location selected for pacing. None of these provides a means or method for delivering agents to ischemic or infarcted tissues. Only Vachon and Moaddeb provide a means for effectively delivering the anti-inflammatory agents to a depth within the myocardium. U.S. Pat. No. 5,551,427 issued to Altman describes a catheter system capable of delivering drugs to the heart at a depth within the heart tissue.  
         [0014]     U.S. Pat. No. 5,431,649 issued to Mulier describes a hollow helical delivery needle to infuse the heart tissue with a conductive fluid prior to ablation to control the lesion size produced. The system does not have drug delivery capabilities.  
         [0015]     None of the prior art includes the use of macromolecular controlled release matrices such as ethylene vinyl acetate copolymer to deliver agents with large molecular weights to a depth within the heart tissue.  
       OBJECTS AND ADVANTAGES  
       [0016]     In general it is an object of the present invention to provide a biocompatible drug delivery catheter which will improve the ability to deliver drugs to a depth within the heart tissue.  
         [0017]     Another object of the invention is the delivery of growth factors to a depth within the heart tissue over an extended period of time to increase collateral flow in poorly perfPat.uised tissue.  
         [0018]     Yet another object of the invention is to provide a permanently implantable system that will enable transient delivery of pharmacological agents to a depth within the heart tissue such that cardiac arrhythmias may be terminated.  
         [0019]     It is also an object of the invention to provide a combination drug delivery and ablation catheter that will enable a region of the heart tissue to be modified pharmacologically prior to performing RF ablation at a depth within the heart tissue.  
         [0020]     It is a further object of the invention to provide catheters with implantable osmotic pumps at their distal ends that deliver pharmacological agents to a depth within the myocardium.  
         [0021]     Another object of the invention is to provide catheters with controlled release matrices at their distal ends that deliver pharmacological agents to a depth within the heart tissue.  
         [0022]     A further object of the invention is to provide catheters with fluid pathways from proximally located reservoirs which may deliver fluids to a depth within the myocardium, with an electrical conductor to sense the heart so an external device may determine when to deliver pharmacological therapy to a depth within the heart tissue.  
         [0023]     A further object of the invention is to provide catheters with fluid pathways from proximally located reservoirs which may deliver fluids to a depth within the myocardium, with a high conductivity electrical conductor capable of delivering RF therapy to the heart from the metallic structure used to deliver drugs to the heart.  
         [0024]     Yet another object of the invention is to provide catheters with a means to clear the agents from a catheter and replace them with other agents.  
         [0025]     Further objects and advantages of this invention will become apparent from a consideration of the drawings and ensuing description. 
     
    
     DESCRIPTION OF THE DRAWINGS  
       [0026]      FIG. 1   a  is a partial cross sectional view of a drug delivery catheter.  
         [0027]      FIG. 1   b  is a cross sectional view of the proximal portion of a dual lumen drug delivery catheter.  
         [0028]      FIG. 1   c  is a partial cross sectional view of the distal portion of a drug delivery catheter with a hollow fixation helix.  
         [0029]      FIG. 2  is a partial cross sectional view of the distal portion of a drug delivery catheter with a short needle located in the axis of the helical fixation device.  
         [0030]      FIG. 3   a  is a partial cross sectional view of the distal portion of a drug delivery catheter which incorporates an osmotic pump.  
         [0031]      FIG. 3   b  is a partial cross sectional view of the distal portion of a drug delivery catheter which incorporates an osmotic pump.  
         [0032]      FIG. 4  is a partial sectional view of a distal portion of a drug delivery catheter.  
         [0033]      FIG. 5   a  is a partial sectional view of the distal portion of a drug delivery catheter with a rate control barrier.  
         [0034]      FIG. 5   b  shows a partially sectioned view of the distal portion of a drug delivery catheter with a second lumen for stylet use during implantation.  
         [0035]      FIG. 5   c  is a transverse section of the catheter in  FIG. 5   b.    
         [0036]      FIG. 6  is a partial sectional view of a subcutaneous injection port, and a drug delivery catheter.  
         [0037]      FIG. 7  is a partial sectional view of the distal end of a drug delivery catheter.  
         [0038]      FIG. 8  is a partial sectional view of a filled helical drug delivery fixation means.  
         [0039]      FIG. 8   a  is a transverse section of the fixation means in  FIG. 8 .  
         [0040]      FIG. 9  is a partial sectioned view of the distal end of a drug delivery catheter.  
         [0041]      FIG. 10   a  is a partial sectioned view of a drug delivery catheter with a nitinol transient delivery means.  
         [0042]      FIG. 10   b  is a partial cross sectional view of the distal portion of drug delivery catheter with a vapor pressure transient delivery means. 
     
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS  
       [0043]     New concepts for delivering agents for the treatment of heart failure, ischemia, arrhythmias, and restenosis are disclosed. The main embodiments consist of transvenous or transarterial catheter delivery techniques for delivering agents directly to a chosen site within the heart at a depth within the heart tissue. Hollow helical delivery devices, needle delivery devices, and implantable controlled release matrices may be inserted such that metabolic agents, anti ischemic agents, growth factors, antiarrhythmic agents, anti-inflammatory agents anti-proliferative agents, gene therapy preparations, and combinations of these agents may be delivered directly to the tissue that can benefit most from these agents.  
         [0044]     These drug delivery structures may be made from different materials depending upon whether the device is to be used chronically or acutely. For example, metal components in the preferred implantable embodiments, formed of a Platinum Iridium alloy consisting of ninety percent Platinum and ten percent Iridium, typically are replaced with 316L surgical stainless steels in the acute embodiments. Likewise implantable grades of silicone and polyurethane are replaced with polyurethanes, polyolefins, fluoropolymers, nylon, and the like in the acute uses of the devices. Herein the term catheter is used to describe both chronically and acutely implantable systems.  
         [0045]      FIG. 1   a  shows a first cardiac drug delivery catheter with a sectional view of the proximal end. A pin  2  is shown mechanically crimped at a crimp  6  to an electrically conductive helical coil  8 . Crimp  6  is typically covered by a compliant polymer molding  4  which may form a seal with a catheter port on a drug delivery reservoir or pumping means  16 . Such a reservoir, shown schematically, may be implanted subcutaneously or located outside the patient. A line  18  represents a fluid coupling of reservoir  16  to lumen  12 , which enables delivery of fluid treatment agents from the reservoir to fixation end  24 . Further molding  4  and a catheter body or sheath  14  may have external sealing rings to provide fluid tight seals with such ports. Pin  2  connects to an internal tubing  10  with a lumen  12  which extends the entire length of the catheter to the distal end  22  and allows for fluid agents to be delivered through a fluid pathway in fixation end  24 . The catheter body or sheath  14 ,  20 , and  22  covers the coil  8  along the entire length of the delivery system distal to crimp  4  such that rotation of pin  2  or crimp  4  relative to proximal catheter body  14  rotates coil  8  within catheter body  14 ,  20 , and  22  and deploys fixation mechanisms at fixation end  24 . The central lumen  12  in some embodiments may also be used to pass a stylet for use during implantation to facilitate the implantation procedure.  
         [0046]     The catheter shown in  FIG. 1   a  is made of permanently implantable materials, it has electrical continuity from end to end for sensing cardiac activity, it has a lumen for conveying fluidic agents along its length, and a hollow fixation means for delivering fluidic agents to a depth within the heart tissue.  
         [0047]     Further as to the sensing of cardiac activity, a monitor and control device  26  is electrically coupled to pin  2  through a line  28 , thus to enable a sensing of highly localized cardiac electrical activity at device  26 . Cardiac activity can be recorded at device  26 , e.g. stored in a memory chip (not shown). Further, sensed cardiac activity may be employed to provide controlling signals to reservoir  16  through a line  30 , e.g. to. initiate or terminate the supplying of a fluid agent from the reservoir, responsive to sensing a predetermined activity or condition in cardiac tissue proximate fixation end  24 . The materials selected are suited for permanent implantation to provide for transient drug delivery driven by a proximal reservoir and energy source. For example, catheter body  14 ,  20 , and  22  is an implant grade polyurethane or silicone, and the distal fixation mechanism at fixation end  24  is a platinum iridium alloy. The catheter has a single electrode to facilitate implantation by sensing the electrical potential at the implant site. This combination achieves the advantages of ease of implantation, and delivery of fluidic agents to a depth within the heart from a proximally located reservoir.  
         [0048]     In another embodiment, the monitor and control device  26  is not required. Instead, reservoir  16  pumps at a low, constant rate, supplying infusing agents to a depth within the myocardium, thus to locally apply selected agents, such as angiogenic growth factors, at a steady rate over an extended period, e.g. one week.  
         [0049]      FIG. 1   b  shows another embodiment of the proximal end of a catheter delivery system in which a stylet lumen  66  is provided for insertion of a stylet. Such an additional lumen may be useful to prevent contamination of an inner drug delivery tubing  62  during implantation. Inner tubing  62  is connected to a pin  52  at a connection  56 , which may be performed simply by pulling tubing  62  over pin  52  at connection  56 . An electrically conductive coil  60  surrounds tubing  62  and may be rotated relative to outer jacket or catheter body  58  of the delivery system. After implantation using a stylet in stylet lumen  66 , pharmacological agents may be delivered to the heart by a fluid pathway defined by a delivery system lumen  64 . In this specific embodiment, crimp  54  which connects pin  52  and coil  60  is not overmolded, and a single set of seals  70  are shown molded over the proximal end of catheter body  58 . Seals  70  prevent migration of fluids into the catheter after connection with a catheter port in a drug delivery reservoir or pumping means. In one embodiment, the distal end of the drug delivery catheter shown in  FIG. 1   b  would be the distal embodiment shown in  FIG. 5   b.    
         [0050]      FIG. 1   c  shows a partial cross sectional view of the distal portion of a delivery catheter which is to be implanted endocardially by the appropriate venous or arterial access. Here, a simple pathway for fluid to pass from a subcutaneous reservoir or delivery pump (not shown) through a deployable helical needle is provided. Helical coil  102  is multifilar, but could be single filar as well. The number of filars can be varied to determine the flexibility of the catheter as well as the coil&#39;s ability to transmit torque to fixation helix  114 . The fixation helix is screwed into the heart by turning a coil  102  inside an outer catheter body  106 . A fixed structure  130 , on the inner wall of the catheter body  106 , facilitates advancement and retraction of the fixation helix  114  by forcing the helical fixation structure  114  to advance from the distal end of the catheter when the central helical coil  102  and tube for drug delivery  104  are rotated counterclockwise. Fixed structure  130  is typically formed from a radio opaque material to assist the implanting physician in identifying when fixation helix  114  has been deployed. Fixed structure  130  also will retract the fixation helix  114  from the heart wall when the coil  102  is rotated clockwise. These directions could be reversed by varying the direction of the winding of the fixation helix  114 . The helical coil  102  which provides torque to implant the fixation helix  114  is welded or crimped to a coupling structure or torque delivery structure  110  at a coil to torque delivery structure connection  128 . Here, the coil is shown crimped at connection  128 . Proximal stop  124 , and distal stop  112  are raised portions on the inside of the catheter body  106 , and prevent the fixation helix  114  from being extended or retracted too far. A fluid path is provided from the proximal end of the catheter (not shown) by tube for drug delivery  104  which connects to the tube fitting  126  of the hollow fixation helix  114 . The hollow fixation helix  114  may have a number of small holes or helix apertures  116 ,  118 ,  120 ,  122  along its length where it is penetrated into the heart tissue. These holes provide a means for delivering agents into the heart tissue at a depth within the tissue. Helix tip  132  is sharp to facilitate penetration of the heart tissue, and acts as a fuPat.rther opening for the agents to migrate from the tissue. In some embodiments the helix apertures may be on only the distal portion of the helix to minimize the possibility of agents being delivered within the heart chambers. In other embodiments, the helix apertures are not present to maximize the structural integrity of the fixation helix. Where this is the case, agents are delivered to the heart from the aperture at the hollow helix tip  132 . The fixation helix  114  is rigidly attached to the torque delivery structure  110  to provide means for advancement when coil  102  is rotated.  
         [0051]      FIG. 1   c  shows a means for delivering agents by a fluid path to a depth within the heart tissue, to provide a wide variety of agents by way of a fluid pathway to a depth within the tissue from a proximally located reservoir. Helix  114  acts as an electrode, with electrical energy being transmitted along helical coil  102  to and from fixation helix  114  by way of electrically conductive torque delivery structure  110 . It can be viewed as the distal end of the implantable catheter whose proximal end is shown in  FIG. 1   a  or  FIG. 1   b . In one embodiment, the device of  FIG. 1  could be used for chronic delivery of antiarrhythmic agents to alter local conduction either continuously, or on demand based upon the signals sensed through fixation helix  114 . Such algorithms have been described for pharmacological atrial defibrillation by Arzbaecher in U.S. Pat. No. 5,527,344. In other embodiments agents for a variety of disease states may be continuously infused by the fluid pathway to a specific site within the myocardium. The proximal end of the catheter may be connected to a drug pumping mechanism or to a proximally located reservoir. Such proximal devices may be implanted or located outside the patient. Access to implantable proximal devices for refilling agents is achieved with a subcutaneous port.  
         [0052]     Transient delivery of pharmacological agents based upon demand requires the presence of electrical conductors along the length of the drug delivery catheter to monitor the electrical action of the heart, e.g. the heart rate as indicated by a time-dependent voltage. Delivering of agents upon demand locally alters the conduction or automaticity of the cardiac tissue and allows for the arrhythmia to be treated. Only a small amount of drug is required to treat a specific location within the tissue, which has substantial benefits. Small doses of antiarrhythmic agents minimize the need to refill the proximally located reservoir; and reduce the systemic effects from large drug doses as well as the effects of the agents on normally functioning cardiac tissue. In one application of this embodiment, the device is implanted in the right atrium at a location determined to be most likely to terminate a patients supraventricular arrhythmia. A subcutaneous infusion pump is triggered by the electrical activity of the heart, and a very small region of tissue receives local drug delivery for a preprogrammed duration. A small region of heart is then modified such that cardiac excitation wavefronts are altered by the tissue treated. This provides substantial advantages to patients. Typical of the drugs delivered are antiarrhythmic agents such as those described in U.S. Pat. No. 5,551,427 issued to Altman.  
         [0053]     In another embodiment, the device in  FIG. 1   c  is an acute catheter made of nonimplantable materials. Catheter body  106  is formed of polyurethane or a fluoropolymer such as ETFE or PTFE; helical fixation structure  114 , and torque delivery structure  110  are made of Titanium or 316L stainless steel. Such a catheter is used for acute ablation procedures in which antiarrhythmic agents are delivered to temporarily alter the conduction of the heart at the site of the implanted helix. Electrical mapping and stimulation measurements are made to determine if the region is appropriate to be ablated. If the region is not appropriate the device is removed and repositioned. If the region treated by the antiarrhythmic agents which affect tissue conduction is desired to be ablated, RF energy is delivered from the electrically active helix to a large surface electrode, such as that used in electrocautery. Such an electrode is shown schematically in  FIG. 1 a  as a patch electrode  32  that can be in contact with the patient&#39;s skin outside the body. A conductor  34  electrically couples electrode  32  with monitor and control device  26 , whereby device  26  is employed in a known manner to utilize a circuit including conductors  28  and  34 , electrode  32 , pin  2 , crimp  6 , coil  8  and a fixation element at the distal end of the coil, to generate an RF current through tissue between the fixation element and electrode  32 . The region ablated is that near the surface of the implanted helix. The helical coil  102  is highly conductive to enable RF energy to be conducted to the distal fixation structure to allow ablation of the region immediately at the fixation structure. Such a high conductivity coil can be formed from a number of wires wrapped in parallel in which each wire has a high conductivity silver core jacketed by an MP35N non corrosive alloy. This catheter provides for both temporary modification of tissue conductivity by delivery of therapeutic agents to a depth within the tissue, and delivery of RF energy from the same structure.  
         [0054]      FIG. 2  shows another distal portion of a delivery catheter for endocardial placement. The operation is similar to that just described. However, here the fixation structure  202  is solid and does not provide a fluid path for delivery of agents. The fluid pathway is instead provided by a centrally located hollow needle  204 . Apertures could also be made along the needle to provide more exposure to the tissue within the heart wall. Fluid agents flow through connecting tube  104 , inside the hollow needle  204 , and out through apertures in the surface (not shown) and the needle tip  206 . Agents are delivered via the needle to a depth within the tissue. Thus, needle  204  provides a tissue penetrating element distinct from the fixation element, whereas in  FIG. 1   c  the penetrating element and fixation element are the same, i.e. helix  114 . The solid fixation structure  202  advances in the same manner as described in  FIG. 1 , and may be rigidly attached to the torque delivery structure  110  by a weld  208 . Other methods of connection are possible. The primary advantage of this design is that the solid helical fixation structure  202  is structurally more robust than that of the hollow structure shown in  FIG. 1   c . This facilitates implantation of the structure.  
         [0055]     Other embodiments which incorporate osmotic pumps, controlled release matrices, membrane barriers, and catheter based transient delivery means increase the ability to control the delivery of agents to a depth within the heart tissue. They have substantial advantages in delivering agents such as growth factors and gene therapy preparations in that very small amounts of the agents are effective, the delivery is controlled over time, and the agents are delivered to a depth within the heart.  
         [0056]      FIG. 3   a  shows an osmotic pump located at distal end of a catheter to drive therapeutic agent into heart tissue using a needle  318 . Alternatively a hollow helix fluid transport system as described can be employed. Agents may be delivered via the fluid pathway previously described, through the check valve  302 , and into the drug volume or drug reservoir  304 . After the drug reservoir  304  is full, agents migrate out the needle tip  320 , and apertures  322 . Reservoir  304  may be loaded before, during, or after implantation from the proximal end of the drug delivery catheter. Once advanced into the heart tissue, diffusion of a liquid across the semipermeable membrane  312  occurs because of an osmotic salt  310 . As this salt expands with hydration, pressure is exerted against the flexible barrier  306  and the rigid osmotic pump housing  308 . The expansion constricts the drug volume  304 . As check valve  302  is closed to reverse flow, the agents are forced through the delivery structure and into the heart wall. The pathway to needle tip  320  includes proximal needle apertures  316  and proximal needle opening  324  within the reservoir  304 . The rigid support  314  supports the fixation helix and the needle delivery structure.  
         [0057]     Placing an osmotic pump directly at the site where agents are delivered has the benefit of limiting the amount of agent in the system. In devices where the agent in the filling tube can be removed, the site specific osmotic pump does not require a long length of tubing filled with pharmacological agent. This may be particularly useful for agents whose systemic effects are undesirable or unknown. To deliver agents by a fluid pathway along the length of a catheter system requires a length of tubing to be filled with the appropriate agent. Although minimizing the cross sectional area of such a tube reduces excessive amounts of agents, putting the pump at the site for delivery eliminates the problem. Placing the osmotic device at the end of the catheter tube provides the advantageous means for follow-up delivery after the pump has delivered all of the agents in the reservoir  304 . Further, only a very small amount of agent is required and the osmotic pump is placed on a catheter at the site for delivery. A catheter based osmotic pump as in  FIG. 3   a  may be filled proximally after implant, and agents may be altered during delivery. Such delivery techniques have substantial advantages for macromolecules such as growth factors and genetic material. Further, they may allow for very controlled delivery of microsphere or micelle encapsulated agents.  
         [0058]     The drug reservoir  304  can contain either a solution or a solid formulation in a semipermeable housing with controlled water permeability. The drug is activated to release in solution form at a constant rate through a special delivery orifice (e.g. either  316  or  322 ). The release of drug molecules or encapsulated drug molecules from this type of controlled release drug delivery system is caused by osmotic pressure and controlled at a rate determined by the water permeability and the effective surface area of the semipermeable housing as well as the osmotic pressure gradient. Devices which use hydrodynamic pressure gradients are similar except the semipermeable membrane is replaced by an opening, and the osmotic salt is replaced by an absorbent and swellable hydrophilic laminate.  
         [0059]      FIG. 3   b  shows a partially sectional view of another embodiment of the distally located osmotic pump. Here a check valve  402  is located at the proximal end of a needle  404  which extends through drug volume or reservoir  304 . Needle  404  provides more structural stability to the drug delivery device and guarantees a fluid pathway to the delivery needle tip  320  even after the osmotic action has driven all of the agent out of the drug volume  304 . Further, a section of a seal  406  is shown attached to the inside of the catheter body. Osmotic pump housing  308  is moveably contained within seal  406 , which acts to prevent migration of fluids into the catheter body.  
         [0060]      FIG. 4  shows another embodiment of a cardiac drug delivery system. Here the fixation mechanism consists of a needle  484  with apertures  486  that penetrates the myocardium and is held in place by barbs  466 . In a chronic implant barb  466  may be composed of either a rigid metallic alloy or a biodegradable polymer. If a biodegradable material is used, long term tissue attachments will maintain fixation with the heart, and the barb  466  will not cause undue trauma should the drug delivery system need to be explanted.  
         [0061]     In addition,  FIG. 4  shows a multilumen catheter and valve system for the filling of reservoir  462 . Agents are delivered along the fluid path defmed by a filling lumen  452  in a bitumen tubing  450  such that unidirectional check valve  456 , shown here as a ball check valve, is opened allowing agents to flow through lumen  458  of tube  460  and out the distal end of tube  480 . The ball check valve has a sphere in a generally conical tube which allows unidirectional flow by obstructing the smaller diameter fluid pathway to reverse flow and not obstructing the larger diameter circular pathway of the open flow direction in various embodiments it could be replaced with a reed check valve, a hinged plate check valve, or the equivalent. After the reservoir  462  is filled, the fluid will open check valve  472  and flow out clearing lumen  468  in bitumen tube  450 . This filling action will force ball check valve  470  closed. After filling, the remaining agent in the bitumen tube may be cleared by delivering sterile distilled water, which may contain anticoagulants such as heparin to assure long term patentcy of the catheter lumens, to clearing lumen  468 . This clearing fluid will force check valve  472  closed, and check valve  470  open such that agents may be flushed from the bitumen tube and replaced with the distilled water or other flushing agents. If the system is chronically implanted, such a bitumen tube and series of valves would allow one to fill the reservoir  462  and clear the bitumen tube  450  after implant. Further, because the distal end of the tube  480  allows for filling of the reservoir  462  from the distal end, agents may be changed merely by filling via filling lumen  452  which will force the existing agents out through proximal reservoir exit  474 , through valve  472  and clearing lumen  468 . If the proximal end of such a bilumen delivery system were connected to a dual port subcutaneous reservoir (not shown) agents would be injected into one port while withdrawn from the second port.  
         [0062]     In this delivery catheter, the distal housing also acts as an osmotic delivery system with semi permeable membrane  496 , hydrophilic salt or agent  476 , and flexible polymer barrier  464  allowing for controlled delivery of agents over a period of time. After the expiration of the osmotic energy source, agents may be delivered via the fluid pathway by an external pumping means if desired. The valve housing  454  houses the three unidirectional valves  456 ,  470 , and  472 , and provides tube fittings  488  and  490  for connection to the bitumen tubing. This valve housing  454  is also attached by a crimp  494  to the coil  492 . This structure is assembled from the separate components and combined. Alternatively, separate valves could be fit into openings in a simpler metallic form, and the whole mechanically and hermetically attached to the rigid osmotic pump housing  478 . Rigid support  482  is fixed to needle  484 , and may also have structural elements which enter into the region of the hydrophilic salt, and possibly attach to the valve housing  454 .  
         [0063]      FIG. 5   a  shows partially in section an embodiment where a membrane or rate controlling barrier  506  stands between the agent reservoir  502  and the apertures  518  in the proximal end of the delivery needle  520  which would allow the agents to be delivered to the distal end of the delivery needle  524 , and through the apertures  522 . The needle could be replaced with a hollow helical delivery device as shown in  FIG. 1   c  if desired. An optional controlled release structure  508  provides chronic delivery of agents to the implant site. As this agent diminishes, new agents can be provided through the connecting tube and check valve  402 , such that rate of release is governed by control barrier  506 . Barrier  506  is shown here with substantial thickness, but it could be formed of a simple membrane, a membrane reinforced with a substantially porous structure, such as a laminate of expanded polytetrafluoroethylene (ePTFE), or any other structure which could be used to govern the rate of drug delivery to the side of the barrier connected by a fluid pathway to the tissue to be treated. The design of the control release barrier would be customized for the agents to be delivered and may be intentionally designed to specify a rate of delivery substantially different from that which the optional control release structure  508 . Needle plug  516  prevents flow through the needle lumen, while maintaining a rigid axial support, and could be formed of an inert polymer or metallic material. Rigid support  510  acts to support axial location of needle  524  and may be a mechanical base for the helical fixation means. Controlled release structure  508  could be composed of a macromolecular controlled release matrix such as EVAC housing a growth factor such as TAF, bFGF, or aFGF.  
         [0064]     In another preferred embodiment of  FIG. 5   a , controlled release structure  508  would be left out and the space would be filled with pharmacological agents and act as a reservoir for acute delivery immediately after implantation. The fluid path for subsequent agents would then include tubing  104 , check valve  402 , proximal needle  512  and proximal apertures  514  into agent reservoir  502 , contained by drug reservoir housing  504 . The fluid agent then passes through rate control barrier  506  into the fluid reservoir.  
         [0065]     In other embodiments of  FIG. 5   a , the control barrier  506  could be electrically activated to allow rapid delivery of positive pressure and agent delivery from one side to the other. In this electrically activated embodiment, the optional control release structure or acute reservoir  508  could merely deliver agents acutely to preserve the viability of the fluid pathway for the time when therapy is deemed necessary. Acute delivery of antithrombolytics and anti-inflammatory agents would limit blockages and tissue inflammation resulting from the implantation of the structure in the heart wall and improve the ability of a transient system to deliver agents quickly and effectively to the region within the tissue. An electrically controlled barrier could be fashioned much like any electrically controlled microvalve.  
         [0066]      FIG. 5   b  is a partially sectional view of the drug delivery system described in  FIG. 5   a  which incorporates a separate stylet lumen  552  within the same catheter body  550 . Such a stylet lumen accommodates a removable wire element to allow the implanting physician to control the shape of the device to guide it to the appropriate site. This additional lumen  552  allows the drug delivery tubing to travel the length of the coil in its own lumen  554 . Although shown here as a continuous part of catheter body  550 , stylet end stop  556  usually is attached as a separate component.  FIG. 5   c  shows the diameter of stylet lumen  552  to be substantially smaller than lumen  554 . These lumens may change depending upon the requirements for different applications. Such an additional lumen for stylet use could easily be combined with any of the drug delivery systems presented here. This additional lumen will prevent the lumen of the drug delivery tubing  104  from getting obstructed with body fluids during stylet use, prevent damage to tubing  104  by the stylet, and allow the materials of both stylet and tubing  104  to be chosen without regard to the requirements of the other.  
         [0067]      FIG. 6  is a partially sectioned view of one preferred embodiment of a subcutaneous reservoir structure  626  and a drug delivery catheter  628 . Subcutaneous reservoir structure  626  may be connected to the proximal end of the delivery catheters shown. Subcutaneous reservoir structure  626  consists of a housing  602  whose reservoir  606  may be filled with a fluid pharmacological agent. The agent is introduced by transcutaneous injection into the reservoir  606  through the polymer injection barrier  604 . This barrier is typically composed of silicone rubber such that it creates a seal after removal of the filling needle. In addition, the housing  602  is typically constructed of titanium, polyurethane, or other known rigid biocompatible and nonreactive materials.  
         [0068]      FIG. 6  shows a means for connecting the drug delivery catheter to the subcutaneous reservoir, a constant pressure pumping means, or automatic infusion pump. Subcutaneous reservoir structure  626  has a port  610  which accepts the proximal end of delivery catheter  628  such that the region of separation  622  between the crimp structure  620  and proximal end of the jacket body  614  is completely within port  610 . This prevents fluids from entering the separation  622  which allows the coil and inner tubing  624  to rotate relative to the jacket body  614  for advancement of fixation structure  616  and needle delivery system  618 . After the proximal end is inserted into port  610  of subcutaneous reservoir structure  626 , a set screw may be advanced within threads  608  to secure the catheter in position by applying force to pin  612 . This set screw connection to the pin is common in devices used to deliver electrical therapy to the heart, and could be used to perform an electrical connection to the fixation means  616  or needle  618  in order to sense the electrical activity of the tissue. This electrical signal could be monitored by devices with algorithms similar to those designed to deliver electrical therapy to the heart, except that instead of electrical therapy they introduce pharmacologic therapy.  
         [0069]      FIG. 7  shows another embodiment of an acute drug delivery system. The catheter body  702  houses a lumen  704  for fluid transport of therapeutic agents and a lumen  706  for stylet use during implantation. Lumen  704  travels the length of the delivery catheter and connects to needle delivery structure  714 . During implantation through the vasculature, blood soluble coating  710 , e.g. as in U.S. Pat. No. 4,827,940 issued to Mayer, completely protects the vasculature from the sharp elements of the fixation helix  712  and the needle delivery structure  714 . Blood soluble coatings such as sugars may be used. After the appropriate heart chamber is accessed, the physician waits for the coating  710  to dissolve. The coating may be combined with a radio opaque material such as barium sulfate to identify better when this has been accomplished. After the coating  710  has dissolved, the physician implants the fixation helix  712  by rotating the entire catheter about its own axis. Torque is delivered from the catheter body  702  to the fixation helix  712  by the embedded portion  708  of the fixation helix. This embedded region can be manufactured using molding and bonding technology. The principle advantage of this device is the small cost of manufacturing such a simple design with no moving parts.  
         [0070]      FIG. 8  shows a hollow fixation helix  802  with apertures  804  along its length.  FIG. 8   a  shows the hollow helix to be filled with a second material  810 . Second material  810  in the preferred embodiment is a controlled release polymer matrix filled with a therapeutic agent for extended delivery of agents through apertures  804  in fixation helix  802 . In one embodiment the controlled release matrix is comprised of silicone rubber and the agent to be delivered is lidocaine. In another embodiment the agent may be amiodorone HCL. In another embodiment, the controlled release matrix is EVAC and the agent is aFGF. Other variations are also possible. After implantation of the structure within the heart wall by penetration of helix tip  808 , the rest of the helix is rotated such that all apertures  804  are within the tissue. Agents then migrate from the controlled release matrix to the tissue in which it is implanted. Such a controlled release matrix filling of the hollow core which penetrates the heart could be pursued with other penetrating structures as well.  
         [0071]      FIG. 9  shows a drug delivery system with VEGF in an EVAC matrix  908  housed in a reservoir defined by cylinder  906 , and ends  904  and  914 . In the preferred embodiment, these are nonpermeable, although in other embodiments permeability may be desirable. End  904  acts both to transmit torque to fixation helix  916 , but also as a stop for a stylet (not shown) which may be used during implantation down the coil lumen  902 . After implantation of the drug delivery catheter, body fluids migrate through apertures in distal needle  920  and into a reservoir through a proximal region  912  of the needle and dissolve pharmacological agents in acute dosage  910  which may be present to counter inflammation associated with implantation. Over time, growth factors are delivered via needle  920  to a depth within the heart. Note that the absence of a tube for agent delivery enables stylet use during implantation. In variations on this embodiment, other controlled release means could be housed within a semi permeable structure that would allow increased fluid transport to assist in delivery of agents through needle  920  to a depth within the heart wall.  
         [0072]      FIG. 10   a  shows another drug delivery catheter in which agents may be delivered transiently to a depth within the tissue. Here, helical coil consists of four coradial wires which are electrically isolated from one another by a layer of insulation. The electrical insulation allows a current pathway to be defined which allows current to flow through electrical connection  1018  from two of the coradial wires and into Nitinol thermally activated shape memory ribbon or band  1020 , which wraps around flexible polymer barrier  1010  as shown in section. Current flowing through Nitinol ribbon  1020  completes its circuit to the other two coradial wires at electrical connection  1002  to torque delivery structure  1004  via conduction through a connection to support structure  1012  which is electrically connected to needle  1028 . Insulating structure  1032  separates the two electrical connection regions on torque delivery structure  1004  and allows current to pass through ribbon  1020 . If the electrical resistance of the Nitinol is sufficiently high, ohmic heating causes a constricting shape change upon the flexible polymer barrier  1010 . Contained within flexible polymer barrier  1010  is a partially porous polymer controlled release matrix structure  1022  such as silicone rubber containing lidocaine, which upon compression by the Nitinol ribbon, forces agents out of the controlled release matrix  1022  and into the needle  1028  within the reservoir  1026 , then out the distal region  1016  of the needle into the heart.  
         [0073]      FIG. 10   b  shows another transient drug delivery structure in which a reservoir contains a fluid whose vapor pressure provides the energy to delivery therapeutic agents. As in  FIG. 10   a , the different filars in the helical coil, such as filar  1068 , are electrically insulated from one another such that two independent electrical connections may be made at a crimp  1050  and a crimp  1072  which are separated from each other by electrically insulating barrier  1070 . The electrical connections made at crimp  1050  and  1072  have an electrical path between them which is defined by resistive heating element  1052  which passes through a reservoir  1056 . Within reservoir  1056  is a fluid gas mixture which provides a constant pressure at human body temperature via a plate  1058  to a drug matrix  1060 . If drug matrix  1060  is a substantially porous controlled release matrix, the pores surrounding the matrix will be filled with relatively high concentration of agents in fluids. As electrical energy is delivered along the two independent electrical conductors to resistive heating element  1052 , the temperature of the fluid within reservoir  1056  increases. As reservoir housing  1066  and support structure  1064  are rigid and noncompliant, this increases the pressure within reservoir  1056  to cause expansion of bellows  1054  and apply pressure to the controlled release matrix  1060 . This forces the concentrated fluid from within the porous controlled release matrix into proximal end of needle delivery system  1074  and out through the distal end of the needle into the heart wall. Such vapor pressure energy sources have been used in infusion pumps such as an infusion pump available from Infusaid of Norwood, MA. However, that system has not been implanted on a catheter, nor does that pressure system provide a thermal element to increase the temperature within the charging fluid and thus deliver the pressure transiently. In addition to the porous matrix, there is a soluble anti-thrombogenic and anti inflammatory agent for use in acute dosage form  1062  which surrounds proximal length of needle  1074 , while still leaving the end free for agent administration. Such acute dosage forms may be very useful for guaranteeing the long term outcome of such controlled delivery systems by minimizing the response of the tissue to the trauma of implantation.  
         [0074]     A method for delivering therapy using a combined drug delivery ablation catheter proceeds as follows. Initially the arrhythmogenic site is located using techniques common to those in the field of cardiac electrophysiology. The delivery system is inserted into the appropriate site within the heart by the internal or external jugulars, cephalic vein, subclavian vein, femoral artery, or the other vascular delivery routes. Then, the drug delivery structure is implanted at the arrhythmogenic site supply an appropriate agent for altering the local conduction properties. After implantation, agents are delivered and the effect on the arrhythmogenic site is evaluated by electrical techniques such as mapping. If the location is appropriate, and the agents appear to terminate the critical arrhythmia, RF energy is delivered to the tissue by way of the same structure used to deliver the agents to the heart. If the position is inappropriate and the local pharmacological agents do not correct for the arrhythmia, the device is repositioned, and the procedure repeated.  
         [0075]     A method for transient treatment of supraventricular arrhythmias using a chronically implantable transient drug delivery catheter proceeds as follows. After electrophysiologists have specified the appropriate region for implantation based upon the patient&#39;s cardiac electrical action, a catheter is implanted at this site to deliver antiarrhythmic agents at a depth within the heart transiently, as well as to sense the electrical activity near the device. The catheter is then connected to an external controller and power source, which determines suitability of therapy and delivers energy to a device such as those described in  FIGS. 10   a  and  10   b  for transient delivery of pharmacological agents, or to a device such as that shown in  FIG. 1   c  coupled to a proximally located pumping means. The device then senses cardiac activity through the surface of the drug delivery structure. When the heart experiences an arrhythmic event, the controller identifies the event and activates the energy source which delivers the drug to the heart. This drug modifies the selected area of tissue and either terminates the arrhythmia, or substantially reduces the magnitude of the required electrical therapy. If the arrhythmia does not terminate, the pump may deliver a secondary dosage, or trigger an external electrical therapy device. If no arrhythmia is sensed, the device is maintained in a monitoring mode.  
         [0076]     Thus the different embodiments of the invention provide a means to effectively deliver agents at a depth within the myocardium to provide a new means for delivering pharmacological therapy to specific locations within the heart. These delivery systems will allow therapies for ischemic tissue, arrhythmogenic sites, and other cardiac disease to be delivered over an extended period of time through a chronic implant, or rapidly over a short period of time during an acute procedure. They enable controlled delivery of small amounts of macromolecular agents such as growth factors, transient drug delivery to the tissue for treating cardiac arrhythmias, and may be used with other cardiac devices.  
         [0077]     Many other variations are possible. For example, the flow of liquid agents maybe driven by implantable infusion pumps with a variety of energy sources, and the device could be made from different biocompatible materials. Other examples include distally located electrically activated piezoelectric crystals as energy sources for drug delivery, and distally located ultrasound transducers for implantation using ultrasound imaging. In addition, in the embodiments where unipolar sensing through the drug delivery structure is insufficient, it is a simple task to add another electrode to enable bipolar sensing.  
         [0078]     Catheters with a straight cylindrical lumen from one end to the other could be used with a thin bundle of optical fibers passed through the lumen to photoablatively create channels within the heart for improving the flow of pharmacological agents within the heart. In other variations, the thin optical fiber could be replaced with a thin RF electrode structure which could literally burn channels within the tissue. Such procedures could be viewed as a combined transmyocardial revascularization (TMR) and drug delivery. For example, after a catheter is implanted and agents are delivered to minimize reflow damage to the heart, simple TMR could be introduced with a centrally placed optical fiber. Subsequent to the TMR, angiogenic growth factors could be introduced.  
         [0079]     In other embodiments, the devices described may be used for acute delivery of metabolic agents, and anti-ischemic agents to poorly perfused tissue just prior to introducing reflow. The agents improve the health of the poorly perfused tissue and minimize the amount of reflow injury introduced by the white blood cells. In another embodiment the devices described may be used to deliver specific antiarrhythmic agents over a time course of days to weeks while physicians determine whether an implantable system is appropriate. In a another embodiment, the catheters described may be used to deliver gene therapy at a depth in the diseased myocardium over a period of days to weeks.  
         [0080]     Further, the delivery of the agents could be performed with appropriately modified catheter shapes such that curves are located to effect a certain position within the heart. Such curves in a catheter could be molded into place, or held in place by plastic deformation of the helical coil in the region it is desired. Such curved structures may provide improved access to certain regions within the right atrium, left atrium, right ventricle and left ventricle.  
         [0081]     Further, the implantable versions of the different catheters could have their fixation mechanisms coated with radioactive agents such as Phosphorous 32 to emit beta radiation for the minimization of tissue growth on the fixation structures. This has particular advantages for catheters meant to be implanted for durations longer than a few days, to be removed after the therapy has been delivered.  
         [0082]     Further, acute embodiments of this device could incorporate standard sensor technologies for measuring pH and P 02 within the heart chamber or even within the myocardium, and mapping electrodes could be placed along the distal portion of the catheter body to facilitate implantation relative to measured electrical signals through the myocardium.  
         [0083]     Accordingly, the scope of the invention should be determined not by the embodiments illustrated, but by the appended claims and their legal equivalents.

Technology Classification (CPC): 0