Patent Abstract:
An endoventricular injection catheter with integrated echocardiographic capability enables injections into heart tissue under visualization. The catheter includes an elongated body having a distal end and an imaging core arranged to be inserted into a heart. The imaging core is arranged to transmit ultrasonic energy and to receive reflected ultrasonic energy at the distal end to provide electrical signals representing echocardiographic images to enable cardiac visualization. The catheter further includes an injector carried on the elongated body with the imaging core. The injector is arranged to inject a therapeutic agent into tissue of the heart visualized by the imaging core.

Full Description:
PRIORITY CLAIM 
     The present application claims the benefit of U.S. Provisional Patent Application Ser. No. 61/228,057, filed Jul. 23, 2009, which application is incorporated herein by reference in its entirety. 
    
    
     BACKGROUND 
     The present invention generally relates to therapies for patients with heart dysfunction, such as congestive heart failure and other dysfunctions after a heart attack. The present invention more specifically relates to catheter-based therapies for heart dysfunction. The present invention also relates specifically to cell-based therapies for heart dysfunction. 
     In the United States, there are an estimated 7,750,000 adults that have survived a heart attack, or myocardial infarction. These myocardial infarctions often lead to congestive heart failure and potentially life threatening heart rhythm disorders. Cell-based therapy has emerged as an encouraging approach to rebuilding such damaged hearts. In particular, catheter-based transendocardial injection is considered a promising delivery mode. Examples of therapeutic agents comprise mesenchymal stem cells and skeletal myoblasts. 
     Effective catheter-based delivery of a therapeutic agent requires knowledge of the internal architecture of the left ventricle and the ability to position and orient the catheter in the left ventricular chamber. Furthermore, the ability to penetrate and inject a therapeutic agent into the myocardium is required, typically by means of an injection needle. It would be advantageous if an endoventricular injection catheter comprised integrated echocardiographic capabilities that enabled real-time image guidance to control depth of needle injection into left ventricular wall and prevent myocardial perforation. It would be further advantageous if the same catheter could be used to identify infarcted regions in order to indicate suitable injection sites. It would be still further advantageous if leakage of the therapeutic agent could be prevented following removal of the injection needle. It would be yet still further advantageous if the therapeutic agent could be delivered from a distal reservoir to minimize trauma to the therapeutic cells during delivery. 
     SUMMARY OF THE INVENTION 
     The invention provides an endoventricular injection catheter with integrated echocardiographic capability. The catheter comprises an elongated body having a distal end and an imaging core arranged to be inserted into a heart. The imaging core is arranged to transmit ultrasonic energy and to receive reflected ultrasonic energy at the distal end to provide electrical signals representing echocardiographic images to enable cardiac visualization. The catheter further includes an injector carried on the elongated body with the imaging core. The injector is arranged to inject a therapeutic agent into tissue of the heart visualized by the imaging core. 
     The elongated body may include a telescoping section to permit longitudinal positioning of the imaging core. The imaging core may be a mechanically rotating imaging core. 
     The catheter may further include a deflection system that causes the elongated body distal end to deflect in a desired direction. The deflection system may include a steerable guide sheath. The deflection system may alternatively include a deflection section sheath, a steering ring, at least one steering wire, and a deflection control knob. 
     The elongated body of the catheter may include a guide wire lumen for receiving a guide wire. The guide wire lumen may be at the distal end of the elongated body of the catheter. Alternatively, the guide wire lumen may extend along the elongated body of the catheter proximal to the distal end. 
     The elongated body may include an imaging core lumen and an outer circumferential surface. The imaging core lumen and the outer surface may define a substantially uniform wall thickness of the elongated body over a portion of the elongated body circumference. 
     The imaging core comprises a plurality of transducers. The catheter may further include a cannula lumen and the injector may include a cannula received by the cannula lumen and an injection needle within the cannula. The cannula may be formed of a super-elastic material. 
     The catheter may further include an injection system including the injector. The injection system may include a proximal handle. The injection handle may include injection controls for extending the cannula, advancing the injection needle, limiting advancement of the injection needle beyond the cannula, and torquing the cannula. The injection needle may include an end stop that limits advancement of the injection needle within the cannula. The injection system may further include a reservoir within the cannula and a plunger that forces therapeutic agent into the needle. 
     The injector may include a pair of injection needles. The injector may further comprise a fiber optic bundle and an ultraviolet light source for photocrosslinking an injected bioabsorbable polymer solution. 
     The invention further provides a method of providing image-guided transendocardial injection of a therapeutic agent into a left ventricular wall of a heart. The method includes the steps of providing an endoventricular injection catheter having integrated echocardiographic capability. The catheter may include an elongated body having a distal end and an imaging core arranged to be inserted into a heart. The imaging core may be arranged to transmit ultrasonic energy and to receive reflected ultrasonic energy at the distal end to provide electrical signals representing echocardiographic images to enable cardiac visualization. The catheter may further include an injector carried on the elongated body with the imaging core. The injector is arranged to inject a therapeutic agent into tissue of the heart visualized by the imaging core. The method further includes the steps of delivering the endoventricular injection catheter into the left ventricle of the heart, visualizing the left ventricular wall of the heart using the imaging core, identifying infarct regions of the left ventricle, and injecting a therapeutic agent into the visualized infarcted regions of the left ventricle using the injector. The method may include the further step of injecting a bioabsorbable agent with the injector to prevent back flow of the therapeutic agent. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The invention, together with further features and advantages thereof, may best be understood by making reference to the following descriptions taken in conjunction with the accompanying drawings, in the several figures of which like reference numerals identify identical elements, and wherein: 
         FIG. 1  illustrates use of catheter; 
         FIG. 2  shows a block diagram of an endoventricular injection catheter system with integrated echocardiographic capabilities; 
         FIG. 3  is a partial sectional view of a catheter embodying the invention; 
         FIG. 3A  is a sectional view taken along lines A-A of  FIG. 3 ; 
         FIG. 4  is a partial sectional view of the catheter of  FIG. 3  shown partially extended; 
         FIG. 5  is a partial sectional view of the distal end of the catheter of  FIG. 3  having an injection cannula and needle according to an aspect of the present invention; 
         FIG. 6  is a partial sectional view of another catheter embodying the present; 
         FIG. 7  is a partial sectional view of another catheter embodying the invention; 
         FIG. 7A  is a sectional view taken along lines A-A of  FIG. 7 ; 
         FIG. 7B  is a sectional view taken along lines B-B of  FIG. 7 ; 
         FIG. 7C  is a sectional view taken along lines C-C of  FIG. 7 ; 
         FIG. 8  is a partial sectional view of another catheter embodying the invention shown deflected; 
         FIG. 9  is a sectional view of still another catheter embodying the invention; 
         FIG. 10  is a sectional view of still another catheter embodying the invention; 
         FIG. 11  is a sectional view of still another catheter embodying the invention; 
         FIG. 12  is a partial sectional view of the distal end of another catheter embodying the invention; 
         FIG. 13  is a partial sectional view of the distal end of another catheter embodying the invention; 
         FIG. 14  is a side view of an imaging core of another catheter having multiple transducers according to further aspects of the invention; 
         FIG. 15A  is a top view of an injection system embodying the invention; 
         FIG. 15B  is a side view of the injection system of  FIG. 15A ; 
         FIG. 16A  is another top partial sectional view of injection system  FIG. 15A  showing the internal elements thereof in greater detail; 
         FIG. 16B  is a partial sectional side view of the injection system of  FIG. 16A ; 
         FIG. 17  is a sectional view of the distal tip of an injection cannula and an injection needle with side ports and a closed end according to further aspects of the invention; 
         FIG. 18A  is a sectional view of the distal tip of another injection needle with side ports and an opened end according to further aspects of the invention; 
         FIG. 18B  is a perspective view of the distal tip of an injection needle with an opened end according to further aspects of the invention; 
         FIG. 19  is a sectional view of the distal tip of an injection cannula and an injection needle with an end stop according to aspects of the invention; 
         FIG. 20  is a perspective view of the distal tip of an injection needle having a dual injection needle according to further aspects of the invention; 
         FIG. 21  is a perspective view of the distal tip of a dual injection needle with a fiber optic bundle according to further aspects of the invention; 
         FIG. 21A  is a sectional view taken along lines A-A of  FIG. 21 ; 
         FIG. 22  is a partial sectional view of still another catheter embodying the invention; 
         FIG. 23A  is a top view of another injection system proximal handle embodying the invention; 
         FIG. 23B  is a side view of the injection system of  FIG. 23A ; 
         FIG. 24A  is another partial sectional top view of the injection system of  FIG. 23A  showing the internal elements thereof in greater detail; 
         FIG. 24B  is a partial sectional side view of the injection system of  FIG. 24A ; 
         FIG. 25  is a flow diagram illustrating processing stages for image guidance of transendocardial injections according to aspects of the invention; 
         FIG. 26  is a flow diagram illustrating processing stages for identifying an infarct region; and 
         FIG. 27  is a flow diagram illustrating processing stages for calculating tissue classifiers according to further aspects of the invention. 
     
    
    
     DETAILED DESCRIPTION OF THE EMBODIMENTS 
       FIG. 1  shows a cut-away illustration of a heart having therein an endoventricular injection catheter  2  having integrated echocardiographic capabilities delivered via a steerable guide sheath  4 . The steerable guide sheath  4  is delivered percutaneously from a femoral arterial site to the aorta  6  and through the aortic valve  8  into the left ventricle  10 . The catheter  2  comprises a mechanically rotating imaging core  12 , an injection cannula  402 , and an injection needle  404 .  FIG. 1  illustrates how the steerable guide sheath  4  and endoventricular injection catheter  2  can be used to inject a needle into a region of interest  14  in the left ventricular wall under echocardiographic guidance. 
       FIG. 2  shows a high-level block diagram of the endoventricular injection catheter system comprising the endoventricular injection catheter  2  with integrated echocardiographic capabilities, an injection control system  20 , a patient interface module  22 , and console  24 . The injection control system  20  is mechanically coupled to the catheter  2 . The patient interface module is electrically and mechanically coupled to the catheter. The patient interface module  22  further provides electrical isolation of the patient from the system. The patient interface module  22  may take the form as described for example in additional detail in U.S. patent application Ser. No. 12/633,278 by Moore et al., the complete disclosure of which is hereby incorporated herein by reference. The patient interface module  22  and console  24  are coupled by analog and digital signal lines. The console  24  controls operation of the patient interface module  22  and the imaging aspect of the catheter  2 . The console  24  may further display images. The endoventricular injection catheter system may be employed to advantage to provide, for example, image guidance of transendocardial injection of therapeutic agents such as cell-based solutions to heart attack victims. 
     Referring to  FIG. 3 , it shows an endoventricular injection catheter with integrated echocardiographic capability  2  embodying aspects of the present invention. The catheter  2  comprises a first proximal housing  30 , a telescoping section  32 , a second proximal housing  33 , a proximal section  34 , a distal section  36 , an imaging core  12 , and an injection system  400 . The endoventricular injection catheter  2  may be used in combination with a steerable guide sheath  4  ( FIG. 1 ) wherein the catheter  2  is disposed within the steerable guide sheath  4  as illustrated in  FIG. 1 . The catheter length may be generally between 100 cm and 150 cm, more particularly, for example, between 110 cm and 120 cm. The diameter of the catheter proximal section  34  may generally be between 8 F and 18 F, as for example approximately 10 F. The diameter of the catheter distal section  36  may be between 6 F and 10 F, as for example about 8 F. 
     The first proximal housing  30  mates to the patient interface module (not shown) via engagement pins  41  and couples mechanical energy to the drive cable  40  and electrical energy into a transmission line  42  disposed within the drive cable  40  that is electrically connected to the ultrasonic transducer  44 . A saline flush port  43  enables acoustic coupling from the ultrasonic transducer  44  to the exterior of the distal section  36 . For additional description of the first proximal housing  30 , reference may be had for example, to U.S. patent application Ser. No. 12/336,441 by Moore the complete disclosure of which is hereby incorporated herein by reference. 
     The telescoping section  32  enables longitudinal translation of the imaging core  12  with respect to the catheter sheaths. The telescoping section  32  includes an outer supporting member  46 , an inner tubular member  48 , and a primary inner member  50  that slides into the inner tubular member  48 . The telescoping section further includes an end cap  52  and an end stop  54  that is bonded to the distal end of the inner tubular member  48 . The inner tubular member  48  is bonded to the proximal housing  30 . The supporting member  46  and the primary inner member  50  are bonded to the second proximal housing  33 . The end cap  52  includes a groove  53  that provides a connection point for controlled movement of the telescoping section  32 . The end stop  54  prevents the supporting member  46  and primary inner member  50  from disengaging the inner tubular member  48  when the telescoping section is fully extended. The telescoping section length is generally between 1 cm and 5 cm, more particularly between 2 cm and 3 cm. The primary inner member  50  is formed of a biocompatible material such as polyetheretherketone (PEEK) or stainless steel. The primary inner member  50  has an inner diameter typically between 0.075″ and 0.100″. The supporting member  46  is also formed of a biocompatible material such as PEEK or stainless steel. Further description of such a telescoping section may be found, for example, in U.S. patent application Ser. No. 12/336,441 by Moore, the complete disclosure of which is hereby incorporated herein by reference. 
     The proximal section  34  includes a secondary member  58 , an imaging core lumen  60 , and an injection cannula lumen  62 . A cross-sectional view of the proximal section  34  is illustrated in  FIG. 3A . The proximal section  34  further includes an exit port  64  for the injection cannula. The secondary member  58  is formed of a biocompatible flexible material such as PEEK and has an outer diameter generally between 8 F and 18 F, more particularly approximately 10 F. The imaging core lumen  60  diameter may be between 0.075″ and 0.100″. The injection cannula lumen  62  diameter may be between 0.030″ and 0.037″, sufficient to pass an injection cannula of size typically between 20 gauge to 22 gauge. 
     The distal section  36  includes a distal sheath  66 , a flushing exit port  68 , an atraumatic tip  70 , and an imaging core lumen  61 . The distal sheath  66  is formed of a biocompatible flexible material such as polyethylene or other thermoplastic polymer that minimizes acoustic loss. The atraumatic tip  70  is formed of a low durometer material such as polyether block amide (Pebax®) or blend of Pebax grades such as Pebax 63D and 40D. The imaging core lumen  60  diameter may be between 0.075″ and 0.100″. 
     The imaging core  12  includes a drive cable  40 , a transducer housing  72 , an ultrasonic transducer  44 , and a transmission line  42  disposed within the drive cable  40 . The imaging core is electrically and mechanically coupled by a connector  74  to the patient interface module. The electrical coupling enables sending and receiving of electrical signals along the transmission line  42  to the ultrasonic transducer  44 . The mechanical coupling enables rotation of the imaging core  12 . The drive cable  40  may be formed of a stainless steel round-wire coil with a coil outer diameter in the range 0.070″ to 0.180″, more particularly approximately 0.105″ for a 10 F distal sheath profile. The elongation and compression of the drive cable during acceleration must be minimized to insure accurate positioning. The drive cable should also minimize non-uniform rotation of the imaging core. The transducer housing  72  is described in additional detail in U.S. patent application Ser. No. 12/330,308 by Zelenka and Moore, the complete disclosure of which is hereby incorporated herein by reference. 
     The ultrasonic transducer  44  includes at least a piezoelectric layer and may further include conductive layers, at least one matching layer, and a backing layer. The ultrasonic transducer  44  may further include a lens. Design and fabrication of ultrasonic transducers for imaging catheters are known to those skilled in the art. The ultrasonic transducer generally operates over frequency ranges of 5 MHz to 60 MHz, more particularly between 10 MHz to 30 MHz. 
     The injection system  400  comprises an injection cannula  402  and an injection needle (not shown) disposed within the injection cannula  402 . The injection cannula  402  may be formed of a biocompatible superelastic material such as a nickel-titanium (or Nitinol) alloy that can take a curved shape. The cannula size is generally between 20 gauge and 24 gauge, more particularly approximately 22 gauge. The distal tip of the injection cannula  402  can be treated to be echogenic to facilitate ultrasound image guidance. 
       FIG. 4  illustrates the endoventricular injection catheter  2  of  FIG. 3  with the telescoping section  32  in a partially extended position. The first proximal housing  30  and imaging core  12  which are fixedly attached to each other are shown translated relative to the telescoping section  32 , the second proximal housing  33 , and the proximal sheath  34 . Telescoping imaging catheters enable the imaging core  12  to translate longitudinally through the imaging core lumen  60  while the proximal sheath  34  and distal sheath (not shown) remain fixed in position. As described herein, the imaging core  12  can translate longitudinally through the imaging core lumen  60 . The position of the imaging core  12  when the telescoping catheter  32  is in an un-extended state is as shown in  FIG. 3 . The distance of travel of the imaging core  12  between the un-extended position and the fully-extended position within the length of the inner tubular member is limited by end stop  54 . As mentioned elsewhere herein, the end cap  52  facilitates controlled movement of the telescoping section  32  and the end stop  54  prevents the supporting member  46  and primary inner member  50  from disengaging the inner tubular member  48  when the telescoping section is fully extended. 
       FIG. 5  illustrates the distal end of the embodiment of  FIG. 3  for echocardiographic guidance of the injection cannula  402  and an injection needle  404 . The injection cannula  402  is shaped to facilitate image-guided delivery of the injection needle  404  to a specific site of interest. The optimal bend angle for image guidance of transendocardial injections can be determined empirically. An endoventricular injection catheter with integrated echocardiographic capabilities provides real-time image guidance during needle injection into the left ventricular wall and facilitates prevention of myocardial perforation. 
     Referring now to  FIG. 6 , another endoventricular injection catheter  102  with integrated echocardiographic capabilities embodying the invention is shown. The endoventricular injection catheter  102  comprises a proximal housing  132 , a proximal member  134 , a distal sheath  136  and an injection system  138 . The longitudinal position of the imaging core  112  remains fixed relative to the catheter sheaths  134 ,  136  because no telescoping section is included. A non-telescoping catheter may be advantageous because of reduced complexity and manufacturing cost in applications wherein longitudinal positioning of the imaging core  112  is not critical. 
     Referring to  FIG. 7 , another alternative embodiment of an endoventricular injection catheter  202  with integrated echocardiographic and deflection capabilities embodying the invention is shown. The endoventricular injection catheter  202  includes the first proximal housing  30 , the telescoping section  32 , a second proximal housing  233 , a proximal section  234 , a deflection section  235 , a distal section  236 , the imaging core  12 , the injection system  400 , and a deflection control system  239 . An advantage of an endoventricular injection catheter with a deflection capability is a steerable guide sheath is not required for delivery and positioning of the catheter. The catheter length may be generally between 100 cm and 150 cm, more particularly between 110 cm and, for example 120 cm. The diameter of the proximal section  234  may be generally between 8 F and 18 F, more particularly, for example, approximately 10 F. The diameter of the distal section  236  may be generally between 6 F and 10 F, more particularly, for example, approximately 8 F. 
     The first proximal housing  30  mates to the patient interface module (not shown) via engagement pins  41 . It couples mechanical energy to the drive cable  40  and electrical energy into a transmission line  42  disposed within the drive cable  40  that is electrically connected to the ultrasonic transducer  44 . 
     The telescoping section  32 , as previously described enables longitudinal translation of the imaging core  12  with respect to the catheter sheaths. The telescoping section  32  includes the outer supporting member  46 , the inner tubular member  48 , and the primary inner member  50  that slides into the inner tubular member  48 . The telescoping section further includes the end cap  52  and an end stop  54  that is bonded to the distal end of the inner tubular member  48 . The inner tubular member  48  is bonded to the proximal housing  30 . The supporting member  46  and the primary inner member  50  are bonded to the second proximal housing  33 . The end cap  52  includes a groove  53  that provides a connection point for controlled movement of the telescoping section  32 . The end stop  54  prevents the supporting member  46  and primary inner member  50  from disengaging the inner tubular member  48  when the telescoping section is fully extended. The telescoping section length may be generally between 1 cm and 5 cm, more typically between 2 cm and 3 cm. The primary inner member  50  may be formed of a biocompatible material such as polyetheretherketone (PEEK) or stainless steel. The primary inner member  50  an inner diameter typically between 0.075″ and 0.100″, for example. The supporting member  46  may also be formed of a biocompatible material such as PEEK or stainless steel. 
     The second proximal housing  233  includes a guide wire lumen  263 , an imaging core lumen  265 , and an injection cannula lumen  267 . The second proximal housing  233  further includes a deflection control knob  278  that is bonded to steering wires  280 , 282 , as by welding, brazing, or soldering, for example. The second proximal housing  233  may be formed of a biocompatible rigid material. The guide wire lumen  263  diameter may be between 0.015″ and 0.037″, sufficient, for example, to pass 0.014″, 0.018″ and 0.035″ guide wires. The imaging core lumen  265  diameter may be between 0.075″ and 0.100″. The injection cannula lumen  267  diameter may be between 0.030″ and 0.037″, sufficient, for example, to pass an injection cannula of size generally between 20 gauge to 22 gauge. The second proximal housing  233  is bonded to the primary inner member  50  and a secondary member  258  of the proximal section  234 . 
     Referring now to  FIG. 7A  along with  FIG. 7 , the proximal section  234  includes the secondary member  258  and multiple lumens. The multiple lumens include an imaging core lumen  260 , a guide wire lumen  261 , an injection cannula lumen  262 , and two steering wire lumens  284 , 286 . The proximal section further includes an exit port  264  for the injection cannula. The secondary member  258  may be formed of a biocompatible flexible material such as PEEK and may have an outer diameter generally between 8 F and 18 F, more particularly approximately 10 F, for example. The diameter of the imaging core lumen  260  may be between 0.075″ and 0.100″. The diameter of the guide wire lumen  261  may be between 0.015″ and 0.037″, sufficient, for example, to pass 0.014″, 0.018″ and 0.035″ guide wires. The diameter of the steering wire lumen  284 ,  286  may be between 0.008″ and 0.014″, sufficient, for example, to pass a steering wire having a diameter of between 0.006″ and 0.012″, for example. The diameter of the injection cannula lumen  262  may be between 0.030″ and 0.037″, sufficient, for example, to pass an injection cannula of size between 20 gauge to 22 gauge, for example. 
     Referring now to  FIG. 7B  along with  FIG. 7 , the deflection section  235  includes a deflection section sheath  288 , reinforcement coil  290 , a steering ring  292 , and multiple lumens. The deflection section sheath  288  may be formed of a low durometer material such as an olefin. Olefins facilitate bonding to the proximal section  234  and distal section  236 . The use of a low durometer material further insures that the catheter bends in the deflection section  235 . The multiple lumens include an imaging core lumen  294 , a guide wire lumen  291 , and two steering wire lumens  296 ,  298 . The diameter of the imaging core lumen  294  may be between 0.075″ and 0.100″. The diameter of the guide wire lumen  291  may be between 0.015″ and 0.037″, sufficient, for example, to pass 0.014″, 0.018″ and 0.035″ guide wires. The diameter of the two steering wire lumens  296 ,  298  may be between 0.008″ and 0.014″, sufficient, for example, to pass a steering wire having a diameter between 0.006″ and 0.012″, for example. 
     Referring now to  FIG. 7C  along with  FIG. 7 , the distal section  236  includes a distal sheath  266 , a flushing exit port  268 , an atraumatic tip  270 , an imaging core lumen  293 , and a guide wire lumen  295 . The distal section further includes an exit port  297  for the guide wire. The distal sheath  266  may be formed of a biocompatible flexible material such as polyethylene or other thermoplastic polymer that minimizes acoustic loss. The atraumatic tip may be formed of a low durometer material such as polyether block amide (Pebax®) or blend of Pebax grades such as Pebax 63D and 40D. The diameter of the imaging core lumen  293  may be between 0.075″ and 0.100″. The diameter of the guide wire lumen  295  may be between 0.015″ and 0.037″, sufficient, for example, to pass 0.014″, 0.018″ and 0.035″ guide wires. 
     The imaging core  12  includes a drive cable  40 , a transducer housing  72 , an ultrasonic transducer  44 , and the transmission line  42  disposed within the drive cable  40 . The imaging core is electrically and mechanically coupled by a connector  74  to the patient interface module. The electrical coupling enables sending and receiving of electrical signals along the transmission line  42  to the ultrasonic transducer  44 . The mechanical coupling enables rotation of the imaging core  12 . The drive cable  40  may be formed of a stainless steel round-wire coil having a coil outer diameter in the range 0.070″ to 0.180″, for example, approximately 0.105″ for a 10 F distal sheath profile. The elongation and compression of the drive cable during acceleration must be minimized to insure accurate positioning. The drive cable should also minimize non-uniform rotation of the imaging core. The transducer housing  72  is described in additional detail in U.S. patent application Ser. No. 12/330,308 by Zelenka and Moore the complete disclosure of which is hereby incorporated herein by reference. 
     The ultrasonic transducer  44  may include at least a piezoelectric layer and typically further comprises conductive layers, at least one matching layer, and a backing layer. The ultrasonic transducer  44  may further comprise a lens. Design and fabrication of ultrasonic transducers for imaging catheters are known to those skilled in the art. The ultrasonic transducer generally operates over frequency ranges of 5 MHz to 60 MHz, more typically between 10 MHz to 30 MHz. 
     The injection system  400  includes an injection cannula  402  and an injection needle (not shown) disposed within the injection cannula  402 . The injection cannula  402  may be formed of a biocompatible superelastic material such as a nickel-titanium (or Nitinol) alloy that can take a curved shape. The cannula size may be between 20 gauge and 24 gauge, more particularly approximately 22 gauge, for example. The distal tip of the injection cannula  402  can be treated to be echogenic to facilitate ultrasound image guidance. 
     The deflection system  239  generally includes deflection control means, at least one steering wire, and a steering ring. In accordance with this embodiment, the deflection system  239  includes a deflection control knob  278 , two steering wires  280 ,  282 , and a steering ring  292 . The steering wires may be formed of polytetrafluoroethylene (PTFE) coated stainless steel. The diameter of the steering wires  280 ,  282  may be between 0.006″ and 0.012″. The steering wires  280 ,  282  may be welded, brazed, or soldered to the steering ring  292 . The steering ring  292  may be formed of stainless steel and located toward the distal end of the deflection section  235 . The reinforcement coil  290  of the deflection section  235  prevents pinching of the imaging core lumen  294 . Alternatively, a reinforcement braid could be used in place of the reinforcement coil. The location of the injection cannula exit port  264  proximal to the deflection section  235  insures that the injection cannula  402  does not prevent deflection of the catheter.  FIG. 8  illustrates deflection of the distal end of the endoventricular injection catheter  202  when the deflection control knob  278  is rotated. 
     An over-the-wire imaging catheter sheath having variable thickness between the outer diameter and the imaging core lumen can lead to imaging artifacts. A distal section sheath  300  having an alternative imaging core lumen  302  as illustrated in  FIG. 9  provides a more uniform sheath thickness in the lower portion of the sheath which is relevant to the imaging direction. Another alternative embodiment of the distal section has an elliptical-shaped sheath  310  as illustrated in  FIG. 10  with an alternative imaging core lumen  312 . It also provides a more uniform sheath thickness in the lower portion of the sheath. Still another embodiment of the distal section is shown in  FIG. 11  wherein the distal sheath  320  provides for a still larger range of directions having a uniform sheath thickness.  FIG. 11  shows an alternate embodiment of the imaging core lumen  322 . 
     Short monorail tip catheter designs provide an alternative to over-the-wire catheter designs wherein a short monorail tip enables rapid exchange of the catheter in comparison to the over-the-wire design shown in  FIG. 7 . An advantage of rapid exchange catheters is that they typically have smaller overall profiles compared to over-the-wire catheters. Catheters having smaller profiles require smaller access sites, such as the femoral artery, which may in turn reduce bleeding complications. With a monorail design it is not necessary to have a guide wire lumen in the deflection control section, proximal section, deflection section, or distal sheath. The reduction in material can reduce the cost of manufacturing. 
       FIG. 12  illustrates an alternative embodiment of the distal section including a distal sheath  330  having an imaging core lumen  331 , a short monorail tip  332 , a flushing exit port  334 , and a guidewire lumen  336  for guidewire GW. The short monorail tip  332  is bonded to the distal sheath  330  wherein the imaging core lumen  331  is parallel to the guide wire lumen  336 . The wall thickness in the distal sheath  330  is uniform around the imaging core lumen  331 . Such a distal section including a monorail design is described, for example, in additional detail in U.S. patent application Ser. No. 12/547,972 by Zelenka the complete disclosure of which is hereby incorporated by reference. 
       FIG. 13  illustrates another alternative distal section embodiment including a distal sheath  340  having an imaging core lumen  341 , a short monorail tip  342 , a flushing exit port  344 , a guidewire lumen  346  for guidewire GW, and a support bar  348 . The support bar  348  can prevent collapse of the imaging core lumen  341  in cases of large deflections of the catheter. The support bar  348  is formed of a suitably rigid material such as stainless steel or PEEK. 
     An advantage of an imaging catheter with a mechanically rotating and translating imaging core is the ability to image a volume of interest without repositioning the catheter sheath. The imaging core can be longitudinally translated within the catheter sheath by means of an external translation device. A disadvantage of an imaging catheter with a mechanically rotating and translating imaging core for imaging moving structures such as the heart is that the rate at which a volume can be swept is relatively slow compared to cardiac motion velocities. Imaging cores comprising multiple transducer elements can reduce the time to image a volume of interest. 
       FIG. 14  illustrates an alternative embodiment of an imaging core  350  including a drive cable  352 , a first transducer housing  354 , a first ultrasonic transducer  356 , a first transmission line  358 , a second transducer housing  360 , a second ultrasonic transducer  362 , a second transmission line  364 , and a transducer housing coupling  366 . The first ultrasonic transducer  356  is seated in the first transducer housing  354  and is connected to the first transmission line  358 . The second ultrasonic transducer  362  is seated in the second transducer housing  360  and is connected to the second transmission line  364 . The facing direction of the second transducer housing  360  and second ultrasonic transducer  362  is 180° relative to the facing direction from the facing direction of the first transducer housing  354  and first ultrasonic transducer  356 . The first transducer housing  354  and second transducer housing  360  are mechanically connected by the transducer housing coupling  366 , generally a flexible coil. 
     The use of multiple transducers reduces the amount of time required to ultrasonically scan a volume. In an exemplary design, the first and second transducer housings  354 ,  360  and transducer housing coupling  366  can be fabricated from a single stainless steel hypotube. The first and second transducer housings  354 ,  360  provide rigid support to the first and second ultrasonic transducers  356 ,  362  by means of a fitted slot. The transducer housing coupling  366  is a spiral-cut section of the hypotube and balances axial rigidity to the first and second transducer assemblies with bending flexibility. The pitch of the spiral cut can be constant or can be varied depending upon the target stiffness characteristics. For example, the pitch may be decreased for more flexibility or increased for less flexibility. In an exemplary design, the first and second transducer housings  354 ,  360  may be approximately 0.155″ in length, the transducer housing coupling  366  may be approximately 0.235″ in length, and the transducer diameters may be 0.100″, for example. The pitch of spiral-cut coupling may be 0.040″ having 0.004″ kerfs. The alternative embodiment of an imaging core comprising multiple transducers is described in additional detail in U.S. patent application Ser. No. 12/633,278 by Moore et al. the complete disclosure of which is hereby incorporated by reference. 
     Referring now to  FIGS. 15A and 15B , the injection system  400  thereshown include an injection cannula  402 , an injection needle  404  disposed within the cannula  402 , and a proximal handle  410 . The injection system further includes a female Luer lock  412  and a connection tube  414 . The proximal handle  410  includes a cannula extension controller  416 , a maximum needle depth controller  420 , a needle injection controller  422 , and a torque device  426 . As described further above, the proximal handle can be adapted to extend the cannula, advance the injection needle, limit advancement of the injection needle beyond the cannula, and torque the cannula. The use of the maximum needle depth controller  420  and needle injection controller  422  in combination can further prevent perforation of the left ventricular wall and pericardial sac during injection. Mechanical design safeguards operate in combination with real-time echocardiographic guidance to prevent myocardial perforation. 
     The injection cannula  402  may be formed of a biocompatible superelastic material such as a nickel-titanium (or Nitinol) alloy that can take a curved shape. The cannula size may be between 20 gauge and 24 gauge, more particularly approximately 22 gauge, for example. The distal tip of the cannula can be treated to be echogenic to facilitate ultrasound image guidance. The needle  404  may be formed of stainless steel or a nickel-titanium alloy and may be between 24 gauge and 26 gauge in size. The needle  404  can be treated to be echogenic to facilitate ultrasound image guidance. A multiport manifold (not shown) can be connected to the female Luer lock  412  for delivery of therapeutic solutions, crosslinkable polymer solutions, and other fluids through the injection needle  404 . 
     Referring now to  FIGS. 16A and 16B  along with  FIG. 3 , an embodiment of the proximal handle  410  and the internal control mechanisms are illustrated. The segment of the cannula  402  inside the proximal handle  410  is slotted  403 . The cannula extension controller  416  is coupled to the cannula  402  by a first rigid member  428 . The cannula  402  can be extended beyond the exit port  64  of the injection cannula lumen  62  of the endoventricular injection catheter  2  by sliding the cannula extension controller  416  toward the torque device  426 . The maximum needle depth controller  420  is coupled to a stop plate  431  by a second rigid member  430 . The needle injection controller  422  is coupled to a needle injection support member  436  by a third rigid member  432 . The second and third rigid members  430 ,  432  extend through the slot  403  of the cannula  402 . The needle injection support member  436  extends the length of the cannula and is bonded to the injection needle  404 , as for example by welding or brazing. The stop plate  431  is disposed inside the slotted cannula  402  and outside the needle injection support member  436 . The maximum length that the injection needle  404  can extend beyond the distal end of the cannula  402  can be limited by the maximum needle depth controller  420 . The maximum needle depth controller  420  is used to adjust the distance between the stop plate  431  and the third rigid member  432  that is attached to the needle injection controller  422 . The injection needle  404  can be extended beyond the distal end of the injection cannula  402  by sliding the needle injection controller  422  toward the torque device  426 . The control mechanisms of the injection system  400 , including the cannula extension controller  416 , the maximum needle depth controller  420 , the needle injection controller  422 , and the torque device  426 , may be used in combination with real-time echocardiographic guidance to safely inject the needle at a site of interest. Real-time echocardiographic guidance provides visual feedback for primary prevention of myocardial perforation. The maximum needle depth controller  420  provides a proximal mechanical control as a secondary prevention to myocardial perforation. A syringe (not shown) that is filled with a therapeutic agent can be connected to the female Luer lock  412  and used for delivery of the therapeutic agent. The therapeutic agent passes through the connector tube  414 , a flexible tube  434 , and the injection needle  404  into the myocardium. The profile of the flexible tube  434  tapers from a size comparable to the connector tube  414  down to a size comparable to the injection needle  404 . 
     Referring now to  FIG. 17 , the distal tip of the injection cannula  402  and an embodiment of an injection needle  404  are shown. The needle  404  includes a closed, non-coring tip  405  with a primary bevel  470  and secondary bevel  472 . The needle further includes side flush ports  474  to distribute the therapeutic agent. An alternative embodiment of an injection needle  407  is shown in  FIGS. 18A and 18B  wherein the distal tip  408  of the needle is open. 
     Still another alternative embodiment of the injection needle is shown in  FIG. 19  wherein an injection needle  471  comprises an end stop  482 . The end stop  482  can be formed by several different methods including swaging or laser welding. The end stop  482  insures that the injection needle does not extend beyond a pre-determined maximum length beyond the cannula, as for example, approximately 6 mm. A maximum depth limiter at the proximal handle of the injection control system may not be sufficient, because the relative longitudinal position of the distal cannula tip and the distal needle tip can shift when traversing a curved path such as the aortic arch. The end stop  482  provides a safeguard in addition to safeguards provided by real-time echocardiographic guidance and a maximum depth limit controller that further mitigates accidental myocardial perforation by the injection needle. 
     Back leakage of the injected therapeutic agent can reduce the efficacy of the agent. Back leakage can be prevented by injection of a bioabsorbable polymer solution such as a poloxamer that gels as it reaches body temperature. The polymer solution can be administered simultaneously with the injection of the therapeutic solution. Alternatively, the polymer solution can be injected after the injection of the therapeutic agent. The same injection needle can be used for injection of the therapeutic agent and polymer solution. An alternative embodiment of the injection needle may take the form of a dual injection needle  484  as shown in  FIG. 20 . The first and second needles  486 ,  492  of the dual injection needle  484  are bonded along a line, as for example by laser welding. The therapeutic agent can be injected using needle  486  while the polymer solution can be injected using needle  492  for example. The dual injection needle  484  may be used in combination with a second connection tube and female Luer lock (not shown) at the injection system proximal handle connected to the second needle. 
     An alternative approach to prevent back leakage of the therapeutic agent is by use of a bioabsorbable photocrosslinkable hydrogel such as poly(ethylene glycol) (or PEG). The photocrosslinkable hydrogel may be administered simultaneously with or secondary to the therapeutic agent. Ultraviolet illumination of the hydrogel at the injection site initiates photocrosslinking and can be performed using a fiber optic bundle  464  as shown in  FIGS. 21 and 21A . The fiber optic bundle  464  runs the length of the injection needle and can be disposed above the bond line  466 . The proximal end of the fiber optic bundle may be coupled to an ultraviolet light source (not shown) including a lamp providing light having a long wavelength of, for example, 365 nm. 
     Still another concern regarding delivery of the therapeutic agent to a region of interest is potential trauma to the therapeutic cells during delivery through the injection needle from the proximal end to the distal end such that viability of the therapeutic agent is degraded. An alternative embodiment of an injection system  500  is shown in  FIG. 22  wherein the therapeutic agent can be loaded into a distal reservoir chamber  506  to minimize the length of the delivery path. The distal reservoir chamber  506  can be of sufficient volume for multiple injections. The size of a cannula lumen  662  can be increased by reducing the size of the drive cable  640  and imaging core lumen  660 . The size of a cannula lumen  662  can be further increased by increasing the catheter profile. 
     The proximal end of an injection needle  504  is bonded to the reservoir chamber  506 . The reservoir chamber can be loaded with the therapeutic agent by retracting the needle to its most proximal position that is determined by a proximal end stop  508  of the cannula  502 . When the reservoir chamber is at this loading position a reservoir chamber loading window  510 , cannula loading window  512 , and a proximal sheath loading window  664  can be aligned to enable loading of the therapeutic agent. The windows  510 ,  512 ,  664  may be pass-through holes or holes filled with a self-closing material such as silicone. A plunger  514  and plunger head  516  are advanced distal of the windows to further prevent any leakage of the therapeutic agent outside the reservoir chamber  506 . 
     The cannula  502  comprises a tapered distal section  520  with a flared tip  522 . The shoulder  524  of the tapered distal section  520  further prevents the injection needle  504  from extending beyond a pre-determined length, as for example, approximately 6 mm. A distal means to limit extension of the needle beyond the cannula may be necessary in situations wherein the relative longitudinal position of the distal cannula tip and the distal needle tip can shift when traversing a curved path such as the aortic arch. The flared tip  522  provides a blunt surface  523  to help stabilize the cannula against the left ventricular wall and prevent penetration of the cannula into the tissue. 
     Referring now to  FIGS. 23A and 23B , a still further injection system  500  includes the injection cannula  502 , the injection needle  504  disposed within the injection cannula  502 , and a proximal handle  530 . The proximal handle  530  comprises a cannula extension controller  536 , a maximum needle depth controller  540 , a needle injection depth controller  542 , a torque device  546 , and a distal reservoir plunger controller  548 . The maximum needle depth controller  540  is a proximal control to restrict the depth to which the needle  504  can extend beyond the distal tip of the cannula  502 . The needle injection depth controller  542  is arranged to vary the position of the needle distal tip relative to the cannula distal tip. The distal reservoir plunger controller  548  is used to dispense the therapeutic agent. 
     Referring to  FIGS. 24A and 24B  along with  FIG. 22 , the internal control mechanisms of proximal handle  530  are illustrated. The segment of the cannula  502  inside the proximal handle  530  has a slot  503 . The cannula extension controller  536  is coupled to the cannula  502  by a first rigid member  550 . The cannula  502  can be extended beyond the exit port  674  of the injection cannula lumen  662  of the endoventricular injection catheter  602  by sliding the cannula extension controller  536  toward the torque device  546 . The maximum needle depth controller  540  is coupled to a stop plate  554  by a second rigid member  552 . The needle injection controller  542  is coupled to a needle injection support member  558  by a third rigid member  556 . The distal reservoir plunger controller  548  is coupled to the distal reservoir plunger  514  by a fourth rigid member  550 . The second rigid member  552 , third rigid member  556 , and fourth rigid member  550  extend through the slot  503  of the cannula  502 . The needle injection support member  558  extends the length of the cannula  502  and is bonded to the injection needle  504 , by welding or brazing, for example. The stop plate  554  is disposed inside the slotted cannula  502  and outside the needle injection support member  558 . 
     The maximum length that the injection needle  504  can extend beyond the distal end of the cannula  502  can be limited by the maximum needle depth controller  540 . The maximum needle depth controller  540  is used to adjust the distance between the stop plate  554  and the third rigid member  556  that is attached to the needle injection controller  542 . The injection needle  504  can be extended beyond the distal end of the injection cannula  502  by sliding the needle injection controller  542  toward the torque device  546 . 
     The control mechanisms of the injection system  500 , including the cannula extension controller  536 , the maximum needle depth controller  540 , the needle injection controller  542 , and the torque device  546  may be used in combination with real-time echocardiographic guidance to safely inject the needle at a site of interest. Real-time echocardiographic guidance provides visual feedback for primary prevention of myocardial perforation. The maximum needle depth controller  540  provides a proximal mechanical control as a secondary prevention to myocardial perforation. The tapered distal section  520  of the cannula  502  provides a distal mechanical control as a tertiary prevention to myocardial perforation. The therapeutic agent can be delivered from the distal reservoir  506  through the needle  504  to the site of interest by use of the distal reservoir plunger controller  548 . 
       FIGS. 25 ,  26  and  27  are flow diagrams illustrating sets of processing stages for image guidance of transendocardial injections according to aspects of the invention.  FIG. 25  shows an exemplary set of processing stages for transendocardial injection of a therapeutic agent to an infarcted region in a left ventricular wall. The catheter is delivered to the left ventricular chamber in step  700  via a retrograde approach. The catheter is oriented to enable imaging of a region with a suspected infarct in step  702 . A set of baseline images are then acquired in step  704 . 
     The region of infarct is identified in step  706 . Referring now to  FIG. 26 , an exemplary set of processing stages to identify an infarct region is illustrated. Image data is first acquired in step  730 . Identification of the infarct region includes image segmentation in step  732  into blood and non-blood tissues, compensation of image data for imaging system and ultrasound transducer effects in step  734 , calculation of tissue classifiers in step  736 , and finally identification of infarct region in step  738 . Compensation of system and transducer effects mitigates range-dependent amplitude and frequency variations in the ultrasound signals that can degrade accuracy of tissue classification.  FIG. 27  shows an exemplary set of processing stages for calculation of tissue classifiers. The image data of interest are selected  750 . The integrated backscatter and slope-of-attenuation tissue parameters are calculated in steps  752  and  754 , respectively. Calculation of such tissue classifiers are known to those skilled in the art of ultrasound tissue classification. The process is repeated for all image data of interest as indicated by decision block  756 . Referring now to  FIG. 26 , the calculated tissue classifiers are used to identify the infarct region in step  738 . Infarcted tissue is known to have higher values of integrated backscatter and slope-of-attenuation. The ranges of tissue classifiers corresponding to infarcted tissue are determined empirically. 
     Referring back now to  FIG. 25 , the injection cannula is deployed and stabilized at the site of infarction in step  708 . The maximum depth limit for the injection needle is set in step  710 . The needle is then injected into the myocardium in step  712 . The therapeutic agent is injected into the myocardium in step  714 . The needle is removed from the injection site in step  716  and repositioned at a next injection site following decision block  718  as necessary. 
     While particular embodiments of the present invention have been shown and described, modifications may be made, and it is therefore intended to cover in the appended claims, all such changes and modifications which fall within the true spirit and scope of the invention as defined by those claims.

Technology Classification (CPC): 0