Abstract:
The disclosure pertains to a handle assembly for a left atrial appendage occlusion device delivery system and methods of use therefor. The handle assembly includes a leadscrew mechanism for smooth, low backlash control of a delivery catheter for the left atrial appendage occlusion device and manipulation segments which allow one hand operation of the handle assembly.

Description:
BACKGROUND 
       [0001]    Embolic stroke is the nation&#39;s third leading killer for adults, and is a major cause of disability. There are over 700,000 strokes per year in the United States alone. Of these, roughly 100,000 are hemorragic, and 600,000 are ischemic (either due to vessel narrowing or to embolism). The most common cause of embolic stroke emanating from the heart is thrombus formation due to atrial fibrillation. Approximately 80,000 strokes per year are attributable to atrial fibrillation. Atrial fibrillation is an arrhythmia of the heart that results in a rapid and chaotic heartbeat that produces lower cardiac output and irregular and turbulent blood flow in the vascular system. There are over five million people worldwide with atrial fibrillation, with about four hundred thousand new cases reported each year. Atrial fibrillation is associated with a 500 percent greater risk of stroke due to the condition. A patient with atrial fibrillation typically has a significantly decreased quality of life due, in part, to the fear of a stroke, and the pharmaceutical regimen necessary to reduce that risk. 
         [0002]    For patients who develop atrial thrombus from atrial fibrillation, the clot normally occurs in the left atrial appendage (LAA) of the heart. The LAA is a cavity which looks like a small finger or windsock and which is connected to the lateral wall of the left atrium between the mitral valve and the root of the left pulmonary vein. The LAA normally contracts with the rest of the left atrium during a normal heart cycle, thus keeping blood from becoming stagnant therein, but often fails to contract with any vigor in patients experiencing atrial fibrillation due to the discoordinate electrical signals associated with AF. As a result, thrombus formation is predisposed to form in the stagnant blood within the LAA. 
         [0003]    Blackshear and Odell have reported that of the 1288 patients with non-rheumatic atrial fibrillation involved in their study, 221 (17%) had thrombus detected in the left atrium of the heart. Blackshear J L, Odell J A., Appendage Obliteration to Reduce Stroke in Cardiac Surgical Patients With Atrial Fibrillation. Ann Thorac. Surg., 1996.61(2): 755-9.  Of the patients with atrial thrombus, 201 (91%) had the atrial thrombus located within the left atrial appendage. The foregoing suggests that the elimination or containment of thrombus formed within the LAA of patients with atrial fibrillation would significantly reduce the incidence of stroke in those patients. 
         [0004]    Pharmacological therapies for stroke prevention such as oral or systemic administration of warfarin or the like have been inadequate due to serious side effects of the medications and lack of patient compliance in taking the medication. Invasive surgical or thorascopic techniques have been used to obliterate the LAA, however, many patients are not suitable candidates for such surgical procedures due to a compromised condition or having previously undergone cardiac surgery. In addition, the perceived risks of even a thorascopic surgical procedure often outweigh the potential benefits. See Blackshear and Odell, above. See also Lindsay B D., Obliteration of the Left Atrial Appendage: A Concept Worth Testing, Ann Thorac. Surg., 1996.61(2):515. 
         [0005]    Despite the various efforts in the prior art, there remains a need for a minimally invasive method and associated devices for reducing the risk of thrombus formation in the left atrial appendage. 
       SUMMARY 
       [0006]    This disclosure pertains to a handle assembly for a left atrial appendage occlusion device delivery system comprising a first non-rotating catheter displacement component rotatably connected to a second rotatable catheter displacement component, said a first non-rotating catheter displacement component having a distal end adapted to operably connect to a delivery catheter for a left atrial appendage occlusion device, wherein the first non-rotating catheter displacement component and the second rotatable catheter displacement component further comprise a lumen therethrough, further wherein the second rotatable catheter displacement component portion of the lumen comprises an internally threaded segment; a first manipulation segment having a externally threaded tubular distal extension adapted to rotationally engage the internally threaded segment of the second rotatable catheter displacement component, said externally threaded tubular distal extension having a length; and a second manipulation segment reversibly coupled to the first manipulation segment, wherein the second manipulation segment has affixed thereto an elongate shaft adapted to slidably and rotatably pass through a lumen associated with the first manipulation segment, the lumen of the first non-rotating catheter displacement component and second rotatable catheter displacement component, and a connected delivery catheter for a left atrial appendage occlusion device, further wherein rotation of the second rotatable catheter displacement component relative to the first non-rotating catheter displacement component is adapted to displace the delivery catheter proximally relative to the elongate shaft by a distance at least equal to the length of the externally threaded tubular distal extension of the first manipulation segment. 
         [0007]    This disclosure also pertains to a method of using a handle assembly for a left atrial appendage occlusion device delivery system comprising connecting a handle assembly for a left atrial appendage occlusion device delivery system comprising: a first non-rotating catheter displacement component having a distal end adapted to operably connect to a delivery catheter for a left atrial appendage occlusion device; a second rotatable catheter displacement component; a first manipulation segment having an externally threaded tubular distal extension; and a second manipulation segment having affixed thereto an elongate shaft adapted to slidably and rotatably pass through a lumen associated with the first manipulation segment, a lumen to the first non-rotating catheter displacement component and second rotatable catheter displacement component, and a connected delivery catheter for a left atrial appendage occlusion device, to a delivery catheter for a left atrial appendage occlusion device at the distal end of the first non-rotating catheter displacement component of the handle assembly; positioning the distal end of the externally threaded tubular distal extension of the first manipulation segment proximate the distal end of the first non-rotating catheter displacement component such that a distal end of the elongate shaft extends beyond a distal end of the delivery catheter for a left atrial appendage occlusion device; reversibly attaching a left atrial appendage occlusion device to the distal end of the elongate shaft; withdrawing the left atrial appendage occlusion device into a distal end region of the delivery catheter for a left atrial appendage occlusion device adapted to contain a left atrial appendage occlusion device by moving the externally threaded tubular distal extension of the first manipulation segment proximally relative to the first non-rotating catheter displacement component and rotating the second rotatable catheter displacement component relative to the first non-rotating catheter displacement component. 
         [0008]    This disclosure further pertains to a second method of using a handle assembly for a left atrial appendage occlusion device delivery system comprising inserting a delivery catheter for a left atrial appendage occlusion device intravascularly into a patient, wherein the delivery catheter has operably attached to its proximal end a handle assembly for a left atrial appendage occlusion device delivery system comprising a first non-rotating catheter displacement component having a distal end adapted to operably connect to a delivery catheter for a left atrial appendage occlusion device; a second rotatable catheter displacement component; a first manipulation segment having an externally threaded tubular distal extension; and a second manipulation segment having affixed thereto an elongate shaft adapted to slidably and rotatably pass through a lumen associated with the first manipulation segment, a lumen to the first non-rotating catheter displacement component and second rotatable catheter displacement component, wherein the delivery catheter for a left atrial appendage occlusion device further includes a collapsed left atrial appendage occlusion device disposed within a distal end region thereof, further wherein the left atrial appendage occlusion device is releasably connected to the elongate shaft; advancing the delivery catheter for a left atrial appendage occlusion device intravascularly until the left atrial appendage occlusion device is positioned at least partially within a left atrial appendage; rotating the second rotatable catheter displacement component relative to the first non-rotating catheter displacement component to withdraw the distal end region of the delivery catheter for a left atrial appendage occlusion device from left atrial appendage occlusion device thereby deploying the left atrial appendage occlusion device within the left atrial appendage; uncoupling the second manipulation segment reversibly coupled to the first manipulation segment from the first manipulation segment; manipulating the second manipulation segment to detach the left atrial appendage occlusion device from the distal end of the elongate shaft; and removing the delivery catheter for a left atrial appendage occlusion device from the patient. 
     
    
     
       BRIEF DESCRIPTION OF DRAWINGS 
         [0009]      FIG. 1  illustrates a handle assembly for a left atrial appendage occlusion device delivery system in a first configuration. 
           [0010]      FIG. 2  illustrates the handle assembly of  FIG. 1  in longitudinal cross-section. 
           [0011]      FIG. 3  illustrates the handle assembly of  FIG. 1  in a second configuration in longitudinal cross-section. 
           [0012]      FIGS. 4A-4D  illustrates the indicated transverse cross-sections the handle assembly of  FIG. 1  in the second configuration. 
           [0013]      FIG. 5  illustrates a handle assembly for a left atrial appendage occlusion device delivery system as it may be used to deliver a left atrial appendage occlusion device. 
       
    
    
     DETAILED DESCRIPTION 
       [0014]    The following description should be read with reference to the drawings wherein like reference numerals indicate like elements throughout the several views. The drawings, which are not necessarily to scale, are not intended to limit the scope of the claimed invention. The detailed description and drawings illustrate example embodiments of the claimed invention. 
         [0015]    All numbers are herein assumed to be modified by the term “about.” The recitation of numerical ranges by endpoints includes all numbers subsumed within that range (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, and 5). 
         [0016]    As used in this specification and the appended claims, the singular forms “a”, “an”, and “the” include the plural referents unless the content clearly dictates otherwise. As used in this specification and the appended claims, the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise. 
         [0017]    It is noted that references in the specification to “an embodiment”, “some embodiments”, “other embodiments”, etc., indicate that the embodiment described may include a particular feature, structure, or characteristic, but every embodiment may not necessarily include the particular feature, structure, or characteristic. Moreover, such phrases are not necessarily referring to the same embodiment. Further, when a particular feature, structure, or characteristic is described in connection with an embodiment, it would be within the knowledge of one skilled in the art to effect such feature, structure, or characteristic in connection with other embodiments, whether or not explicitly described unless clearly stated to the contrary. 
         [0018]      FIGS. 1 and 2 , shows a handle assembly  10  for a left atrial appendage occlusion device delivery system in a first configuration. The handle assembly comprises a first non-rotating catheter displacement component  100  rotatably connected to a second rotatable catheter displacement component  110 , said a first non-rotating catheter displacement component  100  having a distal end adapted to operably connect to a delivery catheter (see element  160  of  FIG. 5 ) for known left atrial appendage occlusion devices (not shown). The connection between the handle assembly and the delivery catheter for a left atrial appendage occlusion device may be made by any of the devices known in the art for that purpose, such as a Luer connector, and may be made with intervening elements if desired. The first non-rotating catheter displacement component  100  is joined to the second rotatable catheter displacement component  110  in a manner which allows relative rotation without significant longitudinal translation. A non-limiting example of such a join will be discussed with reference to  FIG. 4C . 
         [0019]    In some embodiments, the distal end of the first non-rotating catheter displacement component  100  may be connected to a hemostasis seal  150  to be discussed in greater detail. In such embodiments, the delivery catheter for a left atrial appendage occlusion device  100  may be connected to the distal end of the hemostasis seal  150  by any of the devices known in the art for that purpose, such as a Luer connector, and may be made with intervening elements if desired. 
         [0020]    The first non-rotating catheter displacement component  100  may include a lumen, shared by proximal extension with the second rotatable catheter displacement component  110 . The lumen is adapted to receive a distal portion of a first manipulation segment  120  which comprises a distal end  126 , a externally threaded tubular distal extension  122 , and a tubular segment  124  affixed to a proximal end of the externally threaded tubular distal extension  122 . In some embodiments, the tubular segment  124  of first manipulation segment  120  includes an enlarged region  126  which facilitates manipulation of the handle during use. In other embodiments, the enlarged region  126  may be directly attached to the externally threaded tubular distal extension  122 . 
         [0021]    The externally threaded tubular distal extension  122  of first manipulation segment  120  is adapted to engage an internally threaded segment  116  of the second rotatable catheter displacement component  110  such that rotation of the second rotatable catheter displacement component  110  translates the first non-rotating catheter displacement component  100 , and the second rotatable catheter displacement component  110  rotatably joined thereto, relative to the first manipulation segment  120 . At least a portion of the lumen within the first non-rotating catheter displacement component  100  includes one or more keyways  102 , best seen in  FIGS. 4A-4D , which may engage one or more keys  128  associated with distal end  126  of first manipulation segment  120 . The key(s)  128  and keyway(s)  102  cooperate to prevent rotation of the first non-rotating catheter displacement component  100  relative to first manipulation segment  120  as second rotatable catheter displacement component  110  is rotated relative to the first non-rotating catheter displacement component  100  and first manipulation segment  120 . This allows an operator to grasp the first manipulation segment  120  with, for example the third and fourth fingers of one hand while rotating the second rotatable catheter displacement component  110  with the thumb and first finger of that hand for smooth retraction of the delivery catheter  160  (see  FIG. 5 ). Although only a single key and keyway  102  have been illustrated to avoid clutter, it will be appreciated that  2 ,  3 ,  4 , or more keyways  102  and corresponding keys  128  may be associated with first non-rotating catheter displacement component  100  and distal end  126  of first manipulation segment  120  respectively. 
         [0022]    First manipulation segment  120  may be initially reversibly coupled via a removable link  140  to a second manipulation segment  130  having affixed thereto an elongate shaft  132  (selectively omitted in  FIGS. 1-3  to avoid clutter) adapted to slidably and rotatably pass through a lumen associated with the first manipulation segment, the lumen of the first non-rotating catheter displacement component and second rotatable catheter displacement component, and a connected delivery catheter for a left atrial appendage occlusion device. The removable link  140  may be formed in any manner known in the art for that purpose. For example, the illustrated link  140  of  FIGS. 1-3  may be a friction-fit removable link or links ( 140 ). In other embodiments, the removable link may be formed as a frangible link. In yet other embodiments, the removable link may be provided by a bayonet connector or the like. 
         [0023]    The elongate shaft  132  may be releasably coupled at its distal end to a left atrial appendage occlusion device (not shown). In some embodiments, the distal end of elongate shaft  132  may be releasably connected to at its distal end to a left atrial appendage occlusion device by a threated segment. In other embodiments, the distal end of elongate shaft  132  may be releasably connected to at its distal end to a left atrial appendage occlusion device by other means known in in the art such as a soluble link, a magnetic link, and the like. 
         [0024]    As illustrated by the transition between  FIGS. 2 and 3 , rotation of second rotatable catheter displacement component  110  relative to first non-rotating catheter displacement component  100  and externally threaded tubular distal extension  122  of first manipulation segment  120  once the left atrial appendage is positioned within the left atrial appendage initially withdraws the delivery catheter for a left atrial appendage occlusion device, relative to elongate shaft  132  (not shown) affixed to second manipulation segment  130 , by a length equal to the length of the externally threaded tubular distal extension  122  thereby ejecting the left atrial appendage occlusion device within the left atrial appendage allowing it to expand, actively or passively depending upon the device design. 
         [0025]    If present, tubular segment  124  of first manipulation segment  120  allows the delivery catheter for a left atrial appendage occlusion device to be withdrawn an additional length. (See  FIGS. 3 and 5 .) The additional travel afforded by this further displacement of the delivery catheter for a left atrial appendage occlusion device relative to the elongate shaft  132  to which the left atrial appendage occlusion device is releasably coupled may serve several purposes. For example, displacing the delivery catheter for a left atrial appendage occlusion device relative to the left atrial appendage occlusion device may allow clearer visualization of the left atrial appendage occlusion device as it is deployed within the left atrial appendage, particularly if one or more of the left atrial appendage occlusion device, the elongate shaft, and the delivery catheter for a left atrial appendage occlusion device include one or more radiopaque or MRI imageable markers. The additional travel afforded by further displacement of the delivery catheter for a left atrial appendage occlusion device relative to the elongate shaft  132  may also facilitate anchoring the a left atrial appendage occlusion device by allowing it to be “tugged” relative to the left atrial appendage which may serve to seat or otherwise engage anchoring appendages, such as hooks or barbs, which may optionally be included in the left atrial appendage occlusion device. 
         [0026]    Turning to the cross-sectional views of an embodiment of the disclosed handle assembly found in  FIGS. 4A-4D ,  FIG. 4A  illustrates the distal end  126  of the externally threaded tubular distal extension  122  of first manipulation segment  120  in which key  128  engages keyway  102  of first non-rotating catheter displacement component  100 . In some embodiments, distal end  126  of the externally threaded tubular distal extension  122  of first manipulation segment  120  may be sized and adapted to ensure that the externally threaded tubular distal extension  122  of first manipulation segment  120  does not translate distally beyond the distal end of the first non-rotating catheter displacement component  100 . In other embodiments, distal end  126  of the externally threaded tubular distal extension  122  of first manipulation segment  120  may be sized and adapted to ensure that the externally threaded tubular distal extension  122  of first manipulation segment  120  does not translate proximally beyond the distal end of the internally threaded segment  116  of the second rotatable catheter displacement component  110 . As noted herein, some embodiments may employ more than one key and keyway if desired. Elongate shaft  132  is visible within the lumen of externally threaded tubular distal extension  122  of first manipulation segment  120  which in turn is located within the lumen of first non-rotating catheter displacement component  100 .  FIG. 4B  is similar; however the cross-section now passes through the externally threaded tubular distal extension  122 . 
         [0027]      FIG. 4C  passes through a join between first non-rotating catheter displacement component  100  and second rotatable catheter displacement component  110  which allows relative rotation without significant longitudinal translation. In this non-limiting embodiment, the join is formed by two flanges  112  attached to the first non-rotating catheter displacement component  100  and by one or more pins  114  affixed to the second rotatable catheter displacement component  110  and resting in the groove between the flanges  114 . 
         [0028]      FIG. 4D  illustrates a more proximal cross-section of the embodiment of  FIG. 3  in which the externally threaded tubular distal extension  122  of first manipulation segment has disengaged from the internally threaded segment  116  of the second rotatable catheter displacement component  110  thereby ensuring that the left atrial appendage occlusion device has been displaced from the distal end of the delivery catheter  160  for a left atrial appendage occlusion device and the delivery catheter for a left atrial appendage occlusion device has been further withdrawn relative to the elongate shaft  132 . Accordingly, the section depicted in  FIG. 4D  passes through tubular segment  124  of first manipulation segment  120 . 
         [0029]    As noted herein, in some embodiments, elements such as a hemostatic valve  150  may be inserted between the handle assembly  10  for a left atrial appendage occlusion device delivery system and the delivery catheter. As illustrated in  FIGS. 1-3 , a non-limiting hemostatic valve  150  has a seal  152 , a tubular seal displacing element  154 , and a fluid injection port  156 . In a first configuration of the seal  150  hemostatic valve  150  slidingly and rotatably receives elongate shaft  132  while preventing pressurized fluid introduced through fluid injection port  156  during flushing of the a left atrial appendage occlusion device delivery system prior to use from leaking through the handle. In a second configuration, tubular seal displacing element  154  may be advanced through the seal, for example by tightening a housing component, to provide a bushing-type fluid seal while reducing the frictional drag on the elongate shaft  132  thereby providing the operator with enhanced feel for forces acting on the left atrial appendage occlusion device during deployment. If desired, the tubular seal displacing element  154  may be advanced and withdrawn multiple times during a procedure, for example to minimize bleed-back, if it becomes desirable to withdraw the left atrial appendage occlusion device within the delivery catheter of a left atrial appendage occlusion device delivery system for repositioning. It will be appreciated that although the illustrated embodiment combines a hemostatic valve  150  and a fluid injection port  156  in a single unit, the elements may be provided separately. 
         [0030]    The structure and operation of the disclosed handle assembly for a left atrial appendage occlusion device delivery system may be further disclosed with reference to  FIG. 5  in which an exemplary handle assembly is used to deploy a known left atrial appendage occlusion device (not shown) from a delivery catheter  160  of left atrial appendage occlusion device delivery system. 
         [0031]    Prior to use, the disclosed handle assembly  10  may be prepared for use by positioning the distal end  126  of the externally threaded tubular distal extension  122  of first manipulation segment  120  at or near the distal end of a lumen associated with first non-rotating catheter displacement component  100  and the second rotatable catheter displacement component  110  such that the distal end of elongate shaft  132  affixed to second manipulation segment  130  extends distally beyond delivery catheter  160  for a left atrial appendage occlusion device. A known left atrial appendage occlusion device (not shown) may then be reversibly attached to the distal end of elongate shaft  132 . Linked first manipulation segment  120  and second manipulation segment  130  may then be withdrawn proximally to position externally threaded tubular distal extension  122  of first manipulation segment  120  adjacent internally threaded tubular distal extension  116  of second rotatable catheter displacement component  110 . The known left atrial appendage occlusion device may then be collapsed and withdrawn into the distal end of delivery catheter  160  for a left atrial appendage occlusion device by rotating second rotatable catheter displacement component  110  relative to first non-rotating catheter displacement component  100 , thereby engaging externally threaded tubular distal extension  122  of first manipulation segment  120  with internally threaded tubular distal extension  116  of second rotatable catheter displacement component  110 , and continuing to rotate first manipulation segment  120  until distal end  126  of the externally threaded tubular distal extension  122  of first manipulation segment  120  contacts a distal end of internally threaded tubular distal extension  116  of second rotatable catheter displacement component  110 . Prior to, during, and/or after withdrawing the known left atrial appendage occlusion device into the distal end of delivery catheter  160  for a left atrial appendage occlusion device, a lumen of the delivery catheter  160  for a left atrial appendage occlusion device may be flushed to remove air by supplying an appropriate fluid, such as saline, through flushing port  156  of optional hemostatic valve  150 . 
         [0032]    Once the left atrial appendage occlusion device delivery system has been prepared for use, the distal end of delivery catheter  160  for a left atrial appendage occlusion device may be inserted intravascularly into a patient in the conventional manner. The distal end of the delivery catheter  160  for a left atrial appendage occlusion device may then be advanced to the heart and further advanced trans-septally to at least partially enter the left atrial appendage. 
         [0033]    If desired, a tubular seal displacing element  154  may be advanced through the seal  152  of hemostasis seal  150 , if present, to reduce drag on elongate shaft  132  during manipulation of the left atrial appendage occlusion device thereby enhancing the operator&#39;s feel for the deployment forces. Rotation of the second rotatable catheter displacement component  110  relative to the first non-rotating catheter displacement component  100  until the externally threaded tubular distal extension  122  of first manipulation segment  120  passes distally through the internally threaded tubular distal extension  116  of second rotatable catheter displacement component  110  withdraws the delivery catheter  160  for a left atrial appendage occlusion device relative to the elongate shaft  132  and the left atrial appendage occlusion device, thereby deploying the left atrial appendage occlusion device within the left atrial appendage. The leadscrew mechanism provides mechanical advantage for easy, backlash-free smooth deployment of the left atrial appendage occlusion device. 
         [0034]    If desired, the first manipulation segment  120  may be further advanced distally relative to the first non-rotating catheter displacement component  100 , to allow the desired positioning of the left atrial appendage occlusion device within left atrial appendage to be confirmed by visualization of radiopaque or MRI imageable markers (not shown) associated with the delivery catheter  160  for a left atrial appendage occlusion device, the elongate shaft  132 , and/or the left atrial appendage occlusion device. If the initial positioning is deemed to be undesirable, the first manipulation segment  120  may be withdrawn proximally relative to the first non-rotating catheter displacement component  100  and the externally threaded tubular distal extension  122  of first manipulation segment  120  may be re-engaged with the internally threaded tubular distal extension  116  of second rotatable catheter displacement component  110  to allow the left atrial appendage occlusion device to be collapsed and withdrawn within the distal end of the delivery catheter  160  for a left atrial appendage occlusion device by rotation of second rotatable catheter displacement component  110 . In this manner, the left atrial appendage occlusion device may be repositioned as necessary. 
         [0035]    Once the left atrial appendage occlusion device is properly positioned within the left atrial appendage, the first manipulation segment  120  may be tugged by the operator to seat any anchoring elements such as hooks or barbs in the tissue of the left atrial appendage. The reversible coupling  140  between first manipulation segment  120  and second manipulation segment  130  may then be decoupled allowing second manipulation segment  130  and elongate shaft  132  to rotate relative to first manipulation segment  120  and delivery catheter  160  for a left atrial appendage occlusion device or otherwise be manipulated to releasably disconnect elongate shaft  132  from the deployed left atrial appendage occlusion device. If a hemostasis valve  150  including a tubular seal displacing element  154  is present between the first non-rotating catheter displacement component  100  and the delivery catheter  160  for a left atrial appendage occlusion device, tubular seal displacing element  154  may be withdrawn relative to seal  152 . The left atrial appendage occlusion device delivery system may then be removed from the patient. 
         [0036]    Although the illustrative examples described above relate to a left atrial appendage occlusion device delivery system, other uses for the disclosed handle system are also contemplated. In such an embodiment, the associated delivery catheter and the distal end of elongate shaft  132  may be modified to accommodate a different medical device such as a stent, stent graft, or aneurysm plug. 
         [0037]    Various modifications and alterations of this invention will become apparent to those skilled in the art without departing from the scope and principles of this invention, and it should be understood that this invention is not to be unduly limited to the illustrative embodiments set forth hereinabove. All publications and patents are herein incorporated by reference to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference.