Abstract:
A therapy delivery and/or diagnostic device includes a layer of a catalytic agent, having nitrite reductase and/or nitrate reductase, or nitrosothiol reductase activity. The catalytic layer converts nitrate/nitrate or nitrosothiols to nitric oxide when in contact with blood.

Description:
TECHNICAL FIELD  
       [0001]     The present invention relates to implantable therapy delivery and/or diagnostic devices and more particularly to such devices that include a blood-contacting surface adapted to generate nitric oxide (NO).  
       BACKGROUND  
       [0002]     Cardiac rhythm management (CRM) systems often employ a therapy delivery and/or diagnostic device coupled to a surface of a patient&#39;s heart via one or more medical electrical leads. Typically the one or more leads include electrodes for both stimulating the heart and sensing electrical activity of the heart. Alternatively, or in addition to the electrodes, leads may include means for sensing physiological parameters, such as pressure or blood oxygen content, and/or means for therapeutic and/or diagnostic fluid infusion.  
         [0003]     After a period of time, implanted devices become encapsulated by fibrotic tissue, the process begun in part by thrombus generation at blood-contacting surfaces of the implanted device. Implantable materials including means to release NO in order to simulate antithrombogenic properties of endothelial cells have been generally proposed for incorporation in a host of medical devices. It is desirable to incorporate such a material into a device in order to keep active surfaces of the device free from encapsulation, which may inhibit function of the device, and/or to increase ease of chronic explant of the devices.  
         [0004]     Although embodiments of the present invention are described in the context of cardiac implants, it should be recognized that the scope of the invention includes any implantable medical device including blood-contacting surfaces.  
     
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0005]     The following drawings are illustrative of particular embodiments of the invention and therefore do not limit its scope, but are presented to assist in providing a proper understanding of the invention. The drawings are not to scale (unless so stated) and are intended for use in conjunction with the explanations in the following detailed description. The present invention will hereinafter be described in conjunction with the appended drawings, wherein like numerals denote like elements, and:  
         [0006]      FIG. 1  is a schematic rendering of an implanted exemplary CRM system, which may incorporate one or more embodiments of the present invention;  
         [0007]      FIG. 2  is a plan view of one of the devices included in the CRM system shown in  FIG. 1 ;  
         [0008]     FIGS.  3 A-C are plan views with partial sections of portions of devices according to some embodiments of the present invention;  
         [0009]     FIGS.  4 A-C are plan views with partial sections of portions of devices according to some alternate embodiments of the present invention;  
         [0010]      FIG. 5  is a radial section view of a device according to another embodiment of the present invention;  
         [0011]      FIG. 6  is a plan view of another exemplary device which may incorporate one or more embodiments of the present invention;  
         [0012]      FIG. 7A  is a plan view with a partial section of a portion of a device according to another embodiment of the present invention;  
         [0013]      FIG. 7B  is a radial section view through section line A-A of the device shown in  FIG. 7A ;  
         [0014]      FIG. 8A  is a plan view with a partial section of a portion of a device according to another embodiment of the present invention; and  
         [0015]      FIG. 8B  is a plan view with a partial section of a portion of a device according to yet another embodiment of the present invention.  
     
    
     DETAILED DESCRIPTION  
       [0016]     The following detailed description is exemplary in nature and is not intended to limit the scope, applicability, or configuration of the invention in any way. Rather, the following description provides a practical illustration for implementing exemplary embodiments of the invention.  
         [0017]      FIG. 1  is a schematic rendering of an implanted exemplary CRM system, which may incorporate one or more embodiments of the present invention.  FIG. 1  illustrates the CRM system including a generator  1  to which a first device  12  and a second device  14  are coupled and extend therefrom into a patients vascular system to implant sites  15  and  13 , respectively, entering via a vascular entry site  11 . Means for coupling devices  12  and  14  to generator  1  are well known to those skilled in the art, one example of which is via an IS-1 connector  24 , illustrated in  FIG. 2 , inserted into a connector module port of generator  1 .  
         [0018]      FIG. 1  further illustrates first device  12  including a stimulating tip electrode  122  and a coil electrode  120 , which may either be an anode acting in conjunction with tip electrode  122  (cathode), a high voltage defibrillation electrode, or a combination of both; a fixation element  123 , in the form of tines, holds tip electrode  122  in contact with tissue at implant site  13 .  FIG. 2  is a plan view of device  14  illustrating an alternate fixation element composed of two preformed bends  143  which serve to hold device  14  at implant site  15  within a cardiac vein; either an electrode (not shown) or an infusion port (not shown) is positioned in proximity to a distal end  23  of device  14  in order to deliver therapy to implant site  15 .  
         [0019]     According to embodiments of the present invention a layer of catalytic agent capable of converting nitrite/nitrate or nitrosothiols to nitric oxide, when in contact with blood, is present on an outer surface of a polymeric layer overlaying a portion of device  12  in proximity to implant site  13  and/or device  14  in proximity to implant site  15 , wherein the portion in proximity to implant site  13 ,  15  is defined in conjunction with  FIG. 1  as any portion between vascular entry site  11  and implant site  13 ,  15 . ( FIG. 2  further illustrates device  14  including an anchoring sleeve  27  defining a point  21  along device  14  which may approximately correspond with vascular entry site  11  when device  14  is implanted.) The catalytic agent according to one embodiment is a biocatalytic agent and according to an alternate embodiment is a biomimetic agent; both agents are described by Batchelor et al. in U.S. Patent application 2002/0115559, which is incorporated by reference in its entirety herein. Batchelor et al. further describe means for attaching the catalytic agents to substrates, including adsorption, covalent bonding and the like. According to one embodiment, a portion of device  12  or  14 , in the form of a polyurethane outer sheath, is covered with a Cu(II)-complex doped film, which is formed in part from 132 mg polyurethane and 4 mg of Cu(II) metal ion ligand complex, a biomimetic agent.  
         [0020]     In addition to an outer layer of catalytic agent, some embodiments of the present invention further include a polymeric substrate/matrix underlying the layer of catalytic agent, which contains a reservoir of lipophilic salts or nitrite/nitrate or nitrosothiols that can leak to the catalytic layer; such is also described by Batchelor et al. in the aforementioned patent application. In the ensuing description, layers of catalytic agent and reservoirs in polymeric substrates, which are incorporated into various embodiments of the present invention, include any of those described in Batchelor et al.  
         [0021]     FIGS.  3 A-C are plan views with partial sections of portions of devices according to embodiments of the present invention.  FIG. 3A  illustrates a polymer layer  30 , for example an outer sheath, surrounding a first conductor  31  and a second conductor  32  extending therethrough; polymer layer  30  includes a layer of catalytic agent  35 , present on an outer surface thereof and forming an interface with a surrounding blood pool/stream  37 . Catalytic agent  35  may be present along an entire length of device  12  and or  14  ( FIG. 1 ), a discrete segment of the portion of device  12  and or  14  that extends within the vascular system, or a length of device  12  and or  14  extending from venous entry  11  approximately to implant site  15  or  13 , respectively. According to one embodiment of the present invention, polymer layer  30  forms a device body to carry conductors  31 ,  32 ; examples of materials forming layer  30  include silicone and polyurethane.  
         [0022]     FIGS.  3 B-C illustrate layer of catalytic agent  35  extending beneath coil electrode  320 ,  325 , which is mounted on the device body and coupled to conductor  32 ; either an end of coil  320 ,  325  extends inward through layer  30  to conductor  32  or conductor  32  extends outward to coil  320 ,  325  to be coupled, for example, by crimping, welding or other methods known to those skilled in the art. According to the embodiment illustrated in  FIG. 3B , coil electrode  320  overlays the outer surface of polymer layer  30 , while, according to the embodiment illustrated in  FIG. 3C , electrode  325  is embedded in polymer layer  30 . In either case, catalytic agent  35  can contact surrounding blood  37  in between turns of coil  320 ,  325  to convert nitrite/nitrate or nitrosothiols to nitric oxide. According to some embodiments, layer of catalytic agent  35  is only present on polymer layer  30  in that area corresponding to electrode  320 ,  325 , as illustrated, (or coil  120  illustrated in  FIG. 1 ) since this area is particularly susceptible to thrombus formation due to surface discontinuities caused by coil  320 ,  325 . Alternately, as previously described, catalytic agent  35  is further present along portions of polymer layer  30  extending away from coil  320 ,  325 ,  120 .  
         [0023]     FIGS.  3 A-C further illustrate polymer layer  30  including a bulk matrix or substrate  39  underlying layer of catalytic agent  35 . According to some embodiments of the present invention, as previously described, bulk matrix  39  includes a reservoir of lipophilic salts or nitrite/nitrate or nitrosothiols that can leak to catalytic layer  35 . Alternate embodiments are contemplated wherein the catalytic agent is dispersed throughout layer  30 , for example having been blended into bulk matrix  39  of layer  30  during an initial forming process or having been absorbed into bulk matrix  39  in a secondary process.  
         [0024]     FIGS.  4 A-C are plan views with partial sections of portions of devices according to alternate embodiments of the present invention.  FIG. 4A  illustrates a polymer layer  40  including layer of catalytic agent  35 , present on an outer surface thereof and forming an interface with surrounding blood  37 . In contrast to the embodiment illustrated in  FIG. 3A , polymer layer  40 , rather than forming a device body, as layer  30  does, is a separate element overlaying a device body  43 . Examples of materials forming layer  40  include silicone, polyurethane and PTFE. Layer  40  including catalytic agent  35  may extend along all or a portion of device  12  and or  14  ( FIG. 1 ). According to one embodiment, layer  40  extends up to coil electrode  120  and the outer surface of layer  40  is approximately isodiametric with an OD of coil  120 ; such a construction is described in commonly assigned U.S. Pat. No. 6,052,625, for example in conjunction with  FIGS. 3 and 9  of that patent, the descriptions of which are incorporated by reference herein. According to alternate embodiments, layer  40  including catalytic agent  35  underlies coil electrodes as is illustrated in FIGS.  4 B-C.  
         [0025]      FIG. 4B  illustrates a coil  420  mounted on device body  43  and overlaying the outer surface of layer  40 , while  FIG. 4C  illustrates a coil  425  mounted on device body  43  and embedded in layer  40 ; coil  420 ,  425  is coupled to conductor  42  in a manner previously described in conjunction with FIGS.  3 B-C. In either case, catalytic agent  35  can contact surrounding blood  37  in between turns of coil  420 ,  425  to convert nitrite/nitrate or nitrosothiols to nitric oxide. According to some embodiments, layer of catalytic agent  35  is only present on polymer layer  40  in that area corresponding to electrode  420 ,  425 , as illustrated, since this area is particularly susceptible to thrombus formation as was previously described in conjunction with FIGS.  3 B-C. Alternately, as previously described, catalytic agent  35  is further present along portions of polymer layer  40  extending away from coil  420 ,  425 .  
         [0026]     Although not labeled in FIGS.  4 A-C, polymer layer  40 , similar to layer  30 , includes a bulk matrix or substrate underlying layer of catalytic agent  35 . As previously described, according to some embodiments of the present invention the bulk matrix includes a reservoir of lipophilic salts or nitrite/nitrate or nitrosothiols that can leak to catalytic layer  35 ; and, according to alternate embodiments, the catalytic agent is dispersed throughout layer  40 .  
         [0027]     It should be noted that catalytic layer  35  illustrated in FIGS.  3 B-C and FIGS.  4 B-C may be formed on outer surfaces of layers  30  and  40 , respectively either before or after coil electrodes  320 ,  325  and  420 ,  425 , respectively, are mounted on the device bodies. Further, according to some embodiments, layer of catalytic agent  35  comprising a biomimetic agent, which is a metal ion ligand complex, is covalently attached to outer surfaces of coil electrodes  320 ,  325  and  420 ,  425 .  
         [0028]     Conductors  31 ,  41  and  32 ,  42 , according to some embodiments, include one or more electrically conductive wires, examples of which include, but are not limited to a cable formed of a plurality of MP35N wires and a coil formed of one or more MP35N wires. Conductors  31 ,  41  and  32 ,  42  of this type are electrically isolated from one another via insulative layers formed about each conductor  31 ,  41  and  32 ,  42  or according the embodiment illustrated in  FIG. 5 .  
         [0029]      FIG. 5  is a radial section view of a device according to another embodiment of the present invention.  FIG. 5  illustrates a device body  53  in the form of a multilumen tube including a first lumen  531  carrying a first conductor  51  and a second lumen  532  isolated from first lumen  531  and carrying a second conductor  52 .  FIG. 5  further illustrates a polymer layer  50  overlaying device body  53  and including layer of catalytic agent  35  on outer surface of layer  50 , similar to embodiments described in conjunction with FIGS.  4 A-C. According to other embodiments, layer  50  is not included and device body  53  is the polymer layer on which layer of catalytic agent  35  present, similar to embodiments described in conjunction with FIGS.  3 A-C.  
         [0030]      FIG. 5  further illustrates yet another embodiment wherein dashed lines represent a plurality of pores through which lipophilic salts or nitrite/nitrate or nitrosothiols leak to catalytic layer  35  from a reservoir held in a bulk matrix  59  of device body  53 . According to an alternate embodiment catalytic layer  35  is present on outer surface of device body  53 , rather than on outer surface of layer  50 , and is in communication with outer surface of layer  50  via the plurality of pores. Such embodiments of layer  50  including the plurality of pores may be formed, for example, from expanded-PTFE. Furthermore, according to yet another embodiment, layer  50  including the plurality of pores extends over a coil electrode, for example electrodes  320 ,  325 , the pores in this case allowing electrical conduction therethrough. It should be noted that, in yet another embodiment, layer  50 , including the plurality of pores and overlaying an electrode, may be replaced by a conductive polymer layer, which performs the similar function of allowing electrical conduction and includes a layer of catalytic agent  35  on an outer surface thereof.  
         [0031]      FIG. 6  is a plan view of another exemplary device, which may incorporate one or more embodiments of the present invention.  FIG. 6  illustrates a device body  63  extending from a connector  64  and carrying a first conductor  61  and a second conductor  62 , which electrically couple a sensor capsule  66  to contacts on connector  64 ; a tine fixation element  623 , positioned in proximity to sensor capsule  66 , is adapted to secure the device to an implant site.  FIG. 6  further illustrates a polymer layer  60  overlaying a portion of sensor capsule  66 ; sensor capsule includes an active surface  67 , which according to one embodiment is a diaphragm adapted to transmit blood pressure forces, one example of which is described in commonly assigned U.S. Pat. No. 5,564,434 which is incorporated by reference herein. According to some embodiments of the present invention polymer layer  60  includes a layer of catalytic agent adapted to convert nitrite/nitrate or nitrosothiols to NO, as previously described, which is attached to an outer surface of layer  60  surrounding sensor capsule active surface  67 . Thus, active surface  67 , due to NO production in surrounding blood, may be kept free of thrombotic attachments, which could hinder performance of surface  67 .  
         [0032]      FIG. 7A  is a plan view with a partial section of a distal portion of a device according to another embodiment of the present invention and  FIG. 7B  is a radial section view through section line A-A of  FIG. 7A .  FIG. 7A  illustrates a helical fixation element  73  extending from the distal portion and coupled to a conductor  71  extending within a polymer layer  70 , which includes layer of catalytic agent  35  attached to an outer surface thereof; element  73  is adapted to secure the device to an implant site and further serves as an electrode to stimulate tissue in proximity to the implant site. Element  73  along with other electrodes described herein may be formed from any appropriate material known to those skilled in the art, one example of which is platinum. According to embodiments of the present invention, catalytic agent  35  is adapted to convert nitrite/nitrate or nitrosothiols, in blood near implant site, to NO, as previously described. Furthermore, according to another aspect of the present invention, NO formed in proximity to an electrode-tissue interface may increase an electrical efficiency of the interface by inhibiting proliferative and/or inflammatory responses of tissue cells.  
         [0033]      FIG. 7A  further illustrates a polymeric plug  79 , which may be formed from polyurethane or silicone, held within polymer layer  70 , wherein, according to some embodiments, polymer plug  79  contains within its bulk matrix a reservoir of lipophilic salts or nitrite/nitrate or nitrosothiols that can leak to catalytic layer  35  in close proximity to implant site thereby increasing NO generation, which may further enhance an electrical stimulating interface between tissue and element  73  which is embedded therein at implant. Furthermore, element  73  may include a steroid coating, for example beclomethasone diproprionate, which also serves to enhance the electrical interface according to means well known to those skilled in the art of cardiac pacing. According to other embodiments, plug  79  includes catalytic layer  35 , which is exposed to blood  37  via a plurality of pores included in layer  70 , similar to that described in conjunction with  FIG. 5 .  
         [0034]      FIG. 8A  is a plan view with a partial section of a distal portion of a device according to another embodiment of the present invention.  FIG. 8A  illustrates a tine fixation element  823  in proximity to a tip electrode  822 , which is coupled to a conductor  81  and includes a layer of catalytic agent  36  comprising a biomimetic agent, which is a metal ion ligand complex, attached to an outer surface thereof, for example by covalent bonding. According to embodiments of the present invention, catalytic agent  36  is adapted to convert nitrite/nitrate or nitrosothiols, in blood  37  near implant site, to NO, in order to enhance an electrical interface between electrode  822  and tissue at the implant site, as previously described.  FIG. 8B  is a plan view with a partial section of a portion of a device according to yet another embodiment of the present invention.  FIG. 8B  illustrates a porous electrode  832  formed, for example, by a sintering process known to those skilled in the art and including layer of catalytic agent  36 ; electrode  832  contains a polymer plug  89 , which may be formed from polyurethane or silicone. According to the illustrated embodiment, polymer plug  89  holds within its bulk matrix a reservoir of lipophilic salts or nitrite/nitrate or nitrosothiols that can leak to catalytic layer  36 , through pores of electrode  832 , in close proximity to implant site thereby increasing NO generation, which may further enhance an electrical stimulating interface as was previously described in conjunction with FIGS.  7 A-B. According to an alternate embodiment, plug  89  holds a steroid which may elute over time through porous electrode  832 ; such a construction for steroid elution through a porous electrode is well known to those skilled in the art and may be modified to incorporate the alternate embodiment of plug  89 , which holds a reservoir of lipophilic salts or nitrite/nitrate or nitrosothiols. According to further embodiments a porous layer, such as that forming electrode  832 , overlays layer of catalytic agent  36 , which may be either incorporated into plug  89  or formed on electrode  822  illustrated in  FIG. 8A , such that agent  36  can contact surrounding blood  37  through the pores.  
         [0035]     In the foregoing detailed description, the invention has been described with reference to specific embodiments. However, it may be appreciated that various modifications and changes can be made without departing from the scope of the invention as set forth in the appended claims.