Abstract:
Catheter devices, systems and methods wherein linear electrode arrays are disposed on catheters that penetrate through tissue such that the electrodes of the array may be used to sense properties of surrounding tissue or body fluid. The invention is useable for various purposes, including the delivery of a substance, article or device to a specific target location within the body of a human or animal subject.

Description:
FIELD OF THE INVENTION  
       [0001]    The present invention relates generally to methods and apparatus for medical treatment and more particularly to catheter devices, systems and methods wherein linear electrode arrays are disposed on catheters that penetrate through tissue such that the electrodes of the array may be used to sense properties of surrounding tissue or body fluid. 
       BACKGROUND 
       [0002]    Targeted Substance Delivery 
         [0003]    In a variety of situations it is desirable to deliver therapeutic or diagnostic substances (e.g., drugs, biologics, cells, genes, fillers, tissue adhesives, etc.), articles (e.g., implants, beads, coils, pellets, etc.) or devices (e.g., guidewires, sensors, etc.) to specific locations within body of a human or animal subject. Examples of target locations to which substances, articles and/or devices may be delivered include: organs, body lumens, myocardial tissue, infarcted or necrotic tissue, brain tissue skeletal muscle, nerves, blood vessel walls, tumors and other normal or pathological tissues. Also, in some instances, it may be desirable to advance a catheter into or adjacent to a previously implanted device (e.g., a refillable drug delivery reservoir, a prosthetic device, a fluid filled implant, etc.)to deliver a substance (e.g., a refill quantity of a drug or fluid, a lubricant, a filler material, etc.), article (e.g., a small battery or other item) or some ancillary apparatus (e.g., a power supply wire, etc.) to that previously implanted device. 
         [0004]    Some catheters and implantable substance delivery devices (e.g., drug eluting stents) have been used to indirectly deliver drugs or substances to specific target locations within the body by releasing the drug within the lumen of a nearby blood vessel and allowing the drug to diffuse through the blood vessel wall or distribute through downstream capillaries, to the desired target location. 
         [0005]    The prior art has also included catheter devices that may be used for delivering substances, articles or devices directly into interstitial target locations by guided advancement of a penetrating catheter into the lumen of a blood vessel and subsequently advancing a penetrator such as a hollow needle from the catheter, into or through the wall of the blood vessel in which the catheter is positioned and through any intervening tissue to the target site. The desired substance, article or device may then be delivered. 
         [0006]    Particular interest has developed in methods for controlled or targeted delivery of substances such as drugs (e.g., chemotherapeutic agents), gene therapy compositions (e.g., plasmids, viral vectors genetically modified cells, naked DNA), biological factors (e.g., angiogenic factors, nerve growth factors, other cell growth factors other proteins), monoclonal antibodies, or specific cell types (e.g., stem cells or other progenator cells, pancreatic islet cells, dopamine secreting neurons, endothelial cells, myocardial cells, other myocytes, etc) into interstitial target locations for the purpose of treating diseases such as myocardial ischemia, solid tumor types of cancer, parkansonism, diabetes, etc. 
         [0007]    Specifically, in the treatment of myocardial ischemia, research has indicated that introduction of certain angiogenic substances into ischemic areas of myocardium may result in therapeutic angiogenesis in patients who suffer from clinically significant coronary artery disease. Generally speaking, the term “angiogenesis” refers to the creation of new capillaries and/or blood vessels within the parenchyma of an organ, within a tumor or within an area of tissue (e.g., myocardium). Angiogenesis is believed to occur as a multi-step process in which endothelial cells focally degrade and invade through their own basement membrane, migrate through interstitial stroma toward an angiogenic stimulus, proliferate proximal to the migrating tip, organize into blood vessels, sand reattach to newly synthesized basement membrane. The term “therapeutic angiogenesis” generally refers to the administration of angiogenic substances or treatments to promote creation of new blood vessels or capillaries in tissues that previously lacked sufficient blood flow. 
         [0008]    Various approaches have heretofore been used for delivery of angiogenic substances into the myocardium. One approach is the use a tissue penetrating device, such as a laser, to create penetration tracts or transmyocardial (TMR) channels which extend from either the epicardial (outer) surface or endocardial (inner)surface of the heart into the myocardium, and to then inject quantities of angiogenic substances into those TMR channels. Examples of this approach are described in U.S. Pat. Nos. 5,925,012 (Murphy-Chutorian, et al.), 5,999,678 (Murphy-Chutorian, et al.) and 6,106,520 (Laufer, et al.). 
         [0009]    Catheters Having Electrodes for Sensing Properties of Tissue 
         [0010]    Various electrophysiological diagnostic catheters have been known in the prior art. A typical electrophysiological diagnostic catheter comprises a flexible catheter that may be advanced through coronary blood vessels and/or chambers of the heart while one or more electrodes on the catheter are used to sense electrophysiological signals in tissue surrounding the particular coronary blood vessel in which the catheter is positioned. The electrophysiological signals sensed by the catheter-mounted electrode(s) are then used to map the electrophysiological activity in regions of the myocardium of interest and to diagnose arrhythmogenic foci or lesions in conduction pathways that may be repaired by electrical ablation therapy. Examples of commercially available electrophysiological catheters useable for mapping and diagnosis include but are not limited to the TORQR® series fixed curve diagnostic catheters, MARINR® series coronary sinus diagnostic catheters, SOLOIST™ series fixed curve diagnostic catheters, and STABLEMAPR™ diagnostic catheters (Medtronic Corporation, Minneapolis, Minn.) and the Biosense-Webster fixed curve catheters, CRISTA CATH deflectable diagnostic catheters, HALO XP 20 pole deflectable mapping catheters and LASSO circular mapping catheters (Johnson &amp; Johnson, New Brunswick, N.J.). 
         [0011]    The electrophysiological diagnostic and mapping catheters of the prior art have not typically been used to penetrate through tissues, but rather are designed to move within blood vessel lumens and chambers of the heat without penetrating into surrounding tissues. 
         [0012]    There remains a need in the art for the development of new catheters that are capable of penetrating or advancing through tissue, are capable of providing information about the surrounding environment for the purpose of delivering substances, articles or devices to specific interstitial target locations. 
       SUMMARY OF THE INVENTION 
       [0013]    In accordance with the present invention there is provided a catheter that incorporates a linear electrode array that is useable to sense properties of tissue or body fluid into which the catheter is advanced. In general, such catheter device comprises i) an elongate catheter body (rigid or flexible) having a lumen and a distal end that penetrates through tissue, ii) a linear electrode array (e.g., a plurality of electrodes arranged in a row at spaced apart locations) on or in the catheter body, such electrode array being operative to sense a property of tissue or body fluid and to generate signals in response to the sensed property and iii) a display apparatus for displaying indicia of the sensed property. The property of tissue or body fluid sensed by the electrodes may be any desired electrical, chemical, thermal, physiological or other property. In some embodiments, the electrodes will sense electrophysiological signals within tissue, thereby distinguishing tissues of different types and/or distinguishing between healthy tissue (e.g., normal myocardial, brain or other tissue) and diseased tissue (e.g., ischemic, necrotic or infarcted areas of the myocardium, brain or other tissue). 
         [0014]    Further in accordance with the invention, there is provided a system for delivering a substance, article or device to a desired target location within the body of a human or animal subject. In general, such system comprises a linear electrode array equipped catheter of the type summarized in the immediately preceding paragraph in combination with another tissue penetrating catheter device. The other tissue penetrating catheter device is positionable within a body lumen (e.g., a blood vessel, urethra, lymphatic or other natural or man made luminal structure within the body) and a tissue penetrating member (e.g., a hollow needle or wire having a sharp tip) is advancable from the catheter to a first location outside of the body lumen in which the catheter is positioned. The linear electrode array equipped catheter device is then advanceable through or over the tissue penetrating member such that the linear electrode array equipped catheter device will advance into tissue or body fluid and the electrodes of the linear electrode array will sense a property of that tissue or body fluid. 
         [0015]    In some embodiments, as described herein, the other tissue penetrating catheter may incorporate orientation apparatus (e.g., imageable markers, sensors, on board imaging apparatus, etc.) for determining the rotational orientation of the catheter and/or the expected trajectory or path on which the tissue penetrating member will advance such that the operator may adjust the position and/or rotational orientation of the other tissue penetrating catheter within the body lumen to substantially ensure that subsequent advancement of the tissue penetrating member will cause the tissue penetrating member to advance to the intended first location (e.g., in the direction of the target location) and not some other location. 
         [0016]    Examples of tissue penetrating catheters that incorporate such orientation apparatus include but are not limited to those described in U.S. Pat. Nos. 5,830,222 (Makower), 6,068,638 (Makower), 6,159,225 (Makower), 6,190,353 (Makower, et al.), 6,283,951 (Flaherty, et al.), 6,375,615 (Flaherty, et al.), 6,508,824 (Flaherty, et al.), 6,544,230 (Flaherty, et al.), 6,579,311 (Makower), 6,602,241 (Makower, et al.), 6,655,386 (Makower, et al.), 6,660,024 (Flaherty, et al.), 6,685,648 (Flaherty, et al.), 6,709,444 (Makower), 6,726,677 (Flaherty, et al.) and 6,746,464 (Makower), the entire disclosure of each such United States patent being expressly incorporated herein by reference. 
         [0017]    Still further in accordance with the invention, there is provided a method for delivering a substance, article or device to a target location within the body of a human or animal subject. This method generally comprises the steps of i) providing a linear electrode array equipped catheter device as summarized above; ii) inserting the linear electrode array equipped catheter device into the subject&#39;s body and advancing it through tissue or body fluid such that the electrodes of the linear electrode array will sense a property of the tissue or body fluid and the display apparatus will display indicia of the property sensed by each electrode, iii) determining on the basis of the indicia displayed by the display device when the catheter body is positioned such that introduction of the substance, article or device through the lumen of the catheter body will result in delivery of the substance, article or device to the target location and iv) delivering the substance, article or device through the lumen of the catheter body to the target location. 
         [0018]    In some applications of this method, another tissue penetrating catheter device may be initially positioned within a body lumen and a penetrator may be advanced from that intraluminal catheter to a fist location outside of the body lumen in which that catheter is positioned. Thereafter, the linear electrode array equipped catheter is advanced through or over that tissue penetrator, through intervening tissue, and to the intended target location using information provided by the linear electrode array to determine when the linear electrode array equipped catheter is properly positioned for delivery of the intended substance, article or device. 
         [0019]    Further aspects, details and embodiments of the present invention will be understood by those of skill in the art upon reading the following detailed description of the invention and the accompanying drawings. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0020]      FIG. 1  is a perspective view of one embodiment of a linear electrode array-equipped delivery catheter of the present invention. 
           [0021]      FIG. 1A  is side view of a system of the present invention comprising the linear electrode array-equipped delivery catheter of  FIG. 1  in combination with a transluminal tissue penetrating catheter having a penetrator through which the linear electrode array-equipped delivery catheter is advanced. 
           [0022]      FIG. 2  is an enlarged view of Region  2  of  FIG. 1A . 
           [0023]      FIG. 3  is an enlarged schematic diagram of one example of a signal processing and display apparatus to which the linear electrode array-equipped delivery catheter of the present invention may be attached. 
           [0024]      FIG. 4  shows a diagram of a human subject in whom the catheter system of  FIG. 2  has been inserted and positioned to perform a procedure wherein a therapeutic or diagnostic substance is delivered to a target location within the myocardium of the subject&#39;s heart. 
           [0025]      FIG. 4A  is an enlarged view of the heart of the human subject shown in  FIG. 4 . 
           [0026]      FIGS. 4B-4C  are transmural sectional views through region  4 B of  FIG. 4A  showing steps in a method for delivering an substance, article or device to a target location within the myocardium of the subject&#39;s heart using the system of  FIG. 1A . 
           [0027]      FIGS. 4D-4E  are transmural sectional views through region  4 B of  FIG. 4A  showing steps in a method whereby the linear electrode array equipped catheter of the present invention may be used to distinguish between different regions of the heart (e.g., myocardium, endocardium, ventricle). 
       
    
    
     DETAILED DESCRIPTION 
       [0028]    The following detailed description, the accompanying drawings are intended to describe some, but not necessarily all, examples or embodiments of the invention. The contents of this detailed description and accompanying drawings do not limit the scope of the invention in any way. 
         [0029]      FIGS. 1 and 2  show a linear electrode array equipped catheter device  10  and system  13  of the present invention. The linear electrode array equipped catheter device  10  comprises an elongated, flexible catheter body  24  having a lumen that terminates distally at an open distal end  42 . A linear array of electrodes  50  is mounted on or in the catheter body  24 , generally parallel to the longitudinal axis of the catheter body  24 . In this embodiment the linear array of electrodes  50  comprises seen electrodes  50 . The distal-most electrode (i.e., Electrode #1) is located about 2 mm from the distal end  42  of the catheter body  24  and the distal end  42  of the catheter body  24 . A proximal hub member  25  is attached to the proximal end of the catheter body  24 . A port/Luer connector is formed on the proximal end of hub  25  in communication with the catheter lumen such that a syringe  26  or other apparatus may be attached to the port/Luer connector  55  and used to deliver a substance, article or device in a distal direction through the lumen of the catheter body  24  and out of the open distal end  42  or, alternatively to facilitate aspiration or withdrawal in the proximal direction of a substance, article or device. 
         [0030]    A connector cable  54  also extends from the proximal hub  25  and terminates in a connector  56 , such as a plug, to connect the linear array of electrodes  50  to a power source/display device  52 . In some embodiments, the electrodes  50  may be operative to sense electrophysiological signals in tissue and the power source/display device  52  may provide current to the electrodes  50  and may receive, process and display indicia of the electrophysiological signals sensed by each electrode. For example, as seen in  FIG. 3 , the power source/display device  52  may provide a separate display indicator for each electrode in the array to display qualitative or quantitative indicia of electrophysiological signals being sensed by each electrode at any given point in time. For example, in the example of  FIG. 3 , a separate indicator light  53  is provided for each of the seven electrodes. Each indicator light  53  emits light when some predetermined type, frequency or intensity of electrophysiological signal is being sensed by that electrode. 
         [0031]    In some embodiments, the individual indicator lights  53  may emit differing colors or intensity of light to indicate quantitative variations in the strength, frequency, wave form or some other parameter of the electrophysiological signal being received by that electrode. In the example shown in  FIG. 3 , the indicator lights  53  associated with electrodes  1 ,  2 ,  3  and  4  are illuminated, thereby indicating that electrophysiological signals meeting some predetermined criteria are being sensed in tissue adjacent to those electrodes while the indicator lights  53  associated with more distally positioned electrodes  5 ,  6  and  7  are not illuminated thereby indicating that no electrophysiological signals meeting predetermined criteria are being sensed by those electrodes. If the predetermined criteria were defined so as to select for electrophysiological signals associated with non-infarcted myocardium, this would indicate that electrodes  1 ,  2 ,  3  and  4  are currently positioned within non-infarcted myocardial tissue while the more distally located electrodes  5 ,  6  and  7  are positioned within infarcted myocardial tissue. Thus, if a therapeutic substance (e.g., an angiogenic agent, myocytes, myoblasts, etc.) were to be injected through the catheter  10  while it is in its current position, the substance would be delivered into the infarcted myocardium. 
         [0032]    In other embodiments, the indicator lights  52  may be programmed to indicate the types of tissue or body fluid that is in contact with each electrode  50  at the present time. In this regard, for example, each indicator light may emit red light when the electrode  50  associated with that indicator light  53  is within myocardial tissue, green light when the electrode  50  associated with that indicator light  53  is within endocardial tissue and blue light when the electrode  50  associated with that indicator light  53  has advanced into a chamber of the heart so as to be surrounded by blood. Moreover, it is to be appreciated that indicator lights  53  as shown in  FIG. 3  are just one of many possible indicator types that may be incorporated into the display device  52 . For example, in some embodiments, the display  52  may provide a plurality of screens (or a single divided screen) that shows actual electrophysiological waveforms as received by each electrode  50 . Alternatively, as a further example, the display  52  may provide a series of bar indicators to indicate the relative intensity of the electrical signal being sensed by each electrode  50 . 
         [0033]    As shown in  FIG. 1A , the linear electrode array equipped catheter device  10  may optionally be used in combination with a transluminal tissue penetrating catheter  13  which comprises an elongated catheter body  12  having a distal end DE, laterally deployable tissue penetrator  30  that advances laterally out of side port  41  formed in catheter body  12 . This tissue penetrator  30  may comprise a hollow needle having a lumen through which the linear electrode array equipped catheter  30  is advanceable. This tissue penetrator  30  may be formed of any suitable material, such as elastic or superelastic material (e.g., nickel-titanium allow) and may be biased to a curved configuration, as shown. 
         [0034]    A handpiece  14  is provided on the proximal end of the catheter body  12 , as shown in  FIG. 1 . The tissue penetrator  30  is moveable between a retracted position where it is substantially retracted within the catheter body  12  and an extended position wherein it has been longitudinally advanced out of side port  41  such that it extends on a trajectory or path away from the catheter body  12 . The handpiece  14  comprises an advancement/retraction knob  15  which may be pushed in the distal direction to advance the penetrator  30  from its retracted position to its extended position and pulled in the proximal direction to retract the penetrator  30  from its extended position to its retracted position. An adjustable stop member  17  limits the extent of distal advancement of the advancement/retraction knob  15 , thereby controlling the length from the side port  32  to the distal tip of the penetrator  30  when the penetrator  30  is fully extended. 
         [0035]    In the particular embodiment shown in the drawings, a proximal side arm  22  is connected to the proximal end of the lumen of the tissue penetrator  30  such that the catheter body  24  of the linear electrode array equipped catheter device  10  may be inserted therethrough and advanced out of the open distal end of the penetrator  30  as seen in  FIG. 1A . In some applications, an optional guidewire GW may be inserted through the lumen of the penetrator  30  and the body  24  of the linear electrode array equipped catheter device  10  may then be advanced over such guidewire GW. 
         [0036]    In the depicted embodiment of the intraluminal penetrating catheter  13  has an opening at its distal end and a through lumen that extends from a port  16  on the handpiece  14 , through the catheter body  12  and through such open distal end of the catheter body  12 . A guidewire GW may pass through this lumen for over-the-wire advancement of this catheter device  13 . It will be appreciated that, in some alternative embodiments, the lumen may terminate proximally in a side opening in the catheter body  12 , thereby providing a rapid exchange type guidewire lumen. Also in the embodiment shown, an infusion port  18  is optionally formed on the handpiece  14  in communication with the through lumen such that an infusion apparatus  20  (e.g., a syringe, intravenous tube, pump, injector, etc.) may be used to infuse fluid (e.g., saline solution, radiographic contrast medium, etc.) may be used to infuse fluid (e.g., saline solution, radiographic contrast medium, etc.) through lumen and out of the open distal end of the tip member  46 . A valve (e.g., a Tuohi-Borst valve) may be provided on proximal port  16  to secure a guidewire GW when desired and/or to form a fluid tight seat at proximal port  16  when fluid is being infused through infusion port  18 . 
         [0037]    Typically, the penetrator  30  will be advanced to a first location. Such first location will typically be between the body lumen in which the penetrating catheter  13  is positioned and the intended target location to which the desired substance, article or device is to be delivered. As explained in the summary of the invention provided above, some embodiments of eh intraluminal tissue penetrating catheter  13  may incorporate orientation apparatus (e.g., imageable markers, sensors, on board imaging apparatus, etc.) for determining the rotational orientation of the catheter and/or the expected trajectory or path on which the tissue penetrating member will advance such that the operator may adjust the position and/or rotational orientation of the other tissue penetrating catheter within the body lumen to substantially ensure that subsequent advancement of the tissue penetrating member will cause the tissue penetrating member to advance to the intended first location (e.g., in the direction of the target location) and not some other location. In such embodiments, the orientation apparatus may be used to position and rotationally orient that catheter body  12  within the body lumen so that subsequent advancement of the penetrator  30  will cause the penetrator to move in the direction of the intended target location instead of some other unintended direction. 
         [0038]    After the penetrator  30  has been advanced to the first location, the catheter body  24  of the linear electrode array equipped catheter device  10  is advanced distal end first through the lumen of the penetrator  30  and further through tissue lying beyond the distal end of the penetrator  30 , until it has reached the target location. The distal end  42  of the catheter body  24  is capable of penetrating through tissue. In some embodiments, the distal end  42  of the catheter body  24  may comprise a discrete tissue penetrating distal tip member such as those described in copending United States Published Patent Application No. 200/0173440 (Ser. No. 11/279,771) entitled  Microcatheter Devices And Methods For Targeted Substance Delivery  filed on Apr. 14, 2006 and U.S. Pat. No. 6,602,241, the entire disclosures of which are expressly incorporated herein by reference. In some embodiments, outlet opening(s) may be formed in the side wall of the catheter body  24  instead of or in addition to the opening formed in the distal end  42 . 
         [0039]      FIGS. 4-4C  show an example of a procedure in which the system shown in  FIG. 1A  is used to deliver a substance, article or device to a target location within the myocardium of the heart of a human subject. As shown, the catheter body  12  of the transluminal tissue penetrating catheter  13  is percutaneously introduced into a femoral blood vessel and advanced, transluminally, through the vasculature to a position within a coronary blood vessel CV located near the intended target location TL. Thereafter, as seen in  FIG. 4B , after the penetrating catheter body  12  has been properly positioned and rotationally oriented, the penetrator  30  is advanced through the wall of the coronary blood vessel CV and through a portion of the myocardium M to a first location that is between the coronary blood vessel CV and the target location TL. 
         [0040]    As seen in  FIG. 4C , the linear electrode array equipped catheter  10  is advanced out of the distal end of the penetrator  30 , through myocardial tissue and into the target location. As this catheter  10  is advanced, the electrodes  50  will sense electrophysiological signals and the operator may use the sensed signals as indicated on the display device  52  to determine when the distal end  42  of the catheter body  24  has entered the target location. For example, if the target location is a myocardial infarct, the operator may slowly advance the catheter body  24  until the distal most electrode(s)  50  (i.e., electrode #1 or possibly a plurality of the distal-most electrodes) sense(s) little or no electrophysiological signals, thereby indicating that the distal end  42  of the catheter body  24  has entered the necrotic zone within the infarct. The remaining electrodes will indicate electrophysiological activity consistent with healthy myocardium located between the coronary vessel CV and the infarcted target location TL. A desired substance (e.g., myoblasts, myocytes, angiogenic agents, etc.) may then be delivered through the lumen of catheter  10  directly in to the infarct. 
         [0041]      FIGS. 4D and 4E  illustrate the manner in which the electrodes  50  may be used to distinguish between tissue types as may be desired when attempting to position the catheter body  24  at a specific location, measure myocardial wall thickness or for other purposes. In the example of  FIG. 4D , the catheter body  24  has been advanced through the myocardium M into the endocardium E. As a result, the distal most electrode(s)  50  (i.e., electrode #1 or possibly a plurality of the distal most-electrodes) will sense electrophysiological signals of endocardial tissue while the remaining electrodes  50  will sense electrophysiological signals of myocardial tissue. 
         [0042]    In the example of  FIG. 4E , when the catheter body  24  is further advanced such that its distal end  42  is within the ventricle V of the heart, the distal most electrode(s)  50  (i.e., electrode #1 or possibly a plurality of the distal most-electrodes) will sense electrophysiological signals indicative of blood within the ventricular chamber, the electrodes located midway along the catheter body  50  (e.g., electrodes #3 and 4) will sense electrophysiological signals indicative of endocardium E and the remaining proximal electrodes (e.g., electrodes #5, 6 and 7) will sense electrophysiological signals of myocardium M. 
         [0043]    In applications where a substance is to be delivered through catheter  10 , examples of the types of substances that may be so delivered include but are not limited to: contrast agents or other agents that provide an enhanced image of the target site, traceable substances that may be used to determine the rate at which the substance distributes away from or is otherwise inactivated at the target site or other pharmacokinetic or biodistributive parameters or variables, drugs, proteins, cells (e.g., stem cells, nerve cells, progenator cells, myoblasts, myocytes, secretory cells, pancreatic islet cells, dopamine secreting cells, endothelial cells, hepatocytes, cloned cells, cells grown in cell culture, genetically modified cells, and combinations thereof), angiogenic substances (e.g., vascular endothelial growth factor (VEGF), fibroblast growth factors (FGF), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF) or scatter factor, heparin combined with an adenosine receptor agonist, nerve cell growth factor (NGF), and combinations thereof), other agents that increase vascularity of an ischemic target site, myogenic substances, neurogenic substances, genes, gene therapy compositions, genetic material in combination vectors (e.g., viruses), stem cells of a type that will mature in situ into a type of cell that is currently deficient, substances that promote the growth of myocytes in tissue that is necrotic or characterized by a lack of living myocytes, secretory cells that secrete a substance (e.g., dopamine, insulin, a particular neurotransmitter) that is deficient, step F comprises insulin secreting cells, glial cell line-derived neurotropic factor (GDNF), nerve growth factor, neuro-immunophilin ligand, poly ADP-Ribose polymerase, and combinations thereof. 
         [0044]    In applications where an article is to be delivered through catheter  10 , examples of the types of articles that may be so delivered include but are not limited to; substance eluting implants, radioactive implants, embolic members, markers, radiopaque markers, etc. 
         [0045]    In applications where a device is to be delivered through catheter  10 , examples of the types of articles that may be so delivered include but are not limited to; catheters, cannulae, guidewires, wires, electrodes, sensors, microreservoirs, implantable devices, substance eluting or delivering devices, etc. 
         [0046]    It is to be appreciated that the invention has been described hereabove with reference to certain examples or embodiments of the invention but that various additions, deletions, alterations and modifications may be made to those examples and embodiments without departing from the intended spirit and scope of the invention. For example, any element or attribute of one embodiment or example may be incorporated into or used with another embodiment or example, unless to do so would render the embodiment or example unsuitable for its intended use. Also, where the steps of a method or process are described, listed or claimed in a particular order, such steps may be performed in any other order unless to do so would render the embodiment or example not novel, obvious to a person of ordinary skill in the relevant art or unsuitable for its intended use. All reasonable additions, deletions, modifications and alterations are to be considered equivalents of the described examples and embodiments and are to be included within the scope of the following claims.