Abstract:
A system for transplanting a bone plug from a donor site to a recipient site extracts the bone plug from the donor site, and then places a bone plug delivery device having a tip which is at least translucent and, preferably, clear over a tube containing the bone plug. The tip is then placed substantially over a pre-formed hole in the recipient site, whereafter the bone plug is forced from the tube, through the transparent tip, and into the pre-formed hole.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     The present application is a continuation of U.S. patent application Ser. No. 10/004,388 (now U.S. Pat. No. 6,767,354) filed on Oct. 23, 2001, which is a divisional application of U.S. patent application Ser. No. 09/118,680 (now U.S. Pat. No. 6,359,011) filed on Jul. 17, 1998, which are hereby incorporated by reference in their entireties 
    
    
     BACKGROUND OF THE INVENTION 
     The present invention is directed to methods and apparatus for harvesting and implanting bone plugs. The invention has particular utility in repairing damaged bone tissue, such as articular cartilage and underlying subchondral cancellous bone in the knee and other weight-bearing joints. 
     Weight-bearing joints, such as the knee, are particularly susceptible to injuries caused by friction between opposing bone surfaces. To understand the causes of such injuries, it is first necessary to understand the anatomy of a such a joint. In this regard,  FIG. 1  illustrates knee joint  10 . As shown in  FIG. 1 , knee joint  10  connects femur  12  to tibia  14  and fibula  18  via connective tissue  15  and  17  Interposed between opposing surfaces of femur  12  and tibia  14  are lateral and medial meniscus cartilages  21  and  23 , respectively. Condyles  22  at distal end  11  of femur  12  are supported by meniscus cartilages  21  and  23  on proximal end  13  of tibia  14 . Normally, distal end  11  of femur  12 , including condyles  22 , is covered by layer  28  of cartilaginous material which is about 5 mm thick. This layer  28  is called the articular cartilage. 
     Articular cartilage  28  forms a generally resilient pad which is fixed to distal surface  11  of femur  12  in order to protect femur  12  from wear and mechanical shock. When lubricated by fluid in knee joint  10 , articular cartilage  28  provides a surface which is readily slidable on the underlying surfaces of meniscus cartilages  21  and  23  or on proximal surface  13  of tibia  14  if one or both of meniscus cartilages  21  and  23  is partially or totally absent. Problems arise, however, if articular cartilage  28  becomes injured due to excessive near. For example, articular cartilage  28  can become torn or thin, or holes can develop therein. As a result of such injuries, osteochondritis and/or arthritis can develop, making movement of the joint painful In extreme cases, these conditions can result in disability if not treated. 
     Injuries of the foregoing type can be treated by replacing the joint, or portions thereof, with artificial materials. In some cases, however, it is possible to treat the injury by replacing only the bone tissue (i.e., the articular cartilage and/or underlying bone) at the site of the injury with a graft, or plug, from a healthy site. This option is preferable for a number of reasons. For example, surgery to transplant a bone plug is less invasive than that required for a joint replacement. In fact, bone plug transplant surgery is typically performed arthroscopically. Moreover, transplanting bone plugs leads to fewer post-operative complications, a shorter rehabilitation period, and better results overall, since it actually leaves patients with their original joint intact. 
     Surgical techniques for transplanting bone plugs typically involve removing the damaged bone tissue by drilling or cutting a hole at the site of the damage, and plugging this hole with a bone plug extracted from healthy bone tissue in the patient&#39;s body. This healthy tissue is generally extracted from non-load-bearing joints or surfaces in order to minimize patient substantial discomfort. 
     Surgical instruments are currently available which may be used to harvest or extract a bone plug from a donor site and, then, to implant it into a pre-formed hole at a recipient site. A conventional harvesting instrument typically includes a tube having a cutting edge at the distal end. To extract a plug, the instrument is driven into the bone at the donor site and then removed, taking with it a plug of healthy bone tissue. 
     The conventional instruments for harvesting bone plugs described above suffer from several drawbacks. For example, it is difficult to regulate the size (i.e., the length) of bone plugs extracted by them. Moreover, the bone plug tissue is sometimes unduly damaged or traumatized by excessive forces exerted during extraction or implantation. 
     Conventional instruments for implanting bone plugs also suffer from drawbacks. Generally, it is difficult to gauge the exact depth of plug insertion and, thus, to avoid slight protrusions or cavities. This problem is compounded in those instances where the donor and recipient sites do not have matching surface contours. 
     Thus, there exists a need for a bone plug harvesting apparatus which can be more easily used to remove plugs of bone, and which enables a surgeon to regulate the size of the bone plug being removed. In addition, there exists a need for a bone plug implantation apparatus which permits the plug to be implanted level and in proper alignment with the surrounding bone. 
     In view of the foregoing, an object of the invention is to provide improved methods and apparatus for harvesting and implanting bone plugs. 
     Another object is to provide such methods and apparatus as to permit the size of extracted plugs to be better regulated. 
     Still another object of the invention is to provide such methods and apparatus as to minimize trauma to the transplanted plugs. 
     Still another object is to provide such methods and apparatus as to facilitate accurate placement of bone plugs during implantation. 
     Yet still another object is to provide such methods and apparatus as to facilitate implantation in instances where the plugs or recipient sites have uneven contours. 
     BRIEF SUMMARY OF THE INVENTION 
     The present invention addresses the foregoing needs by providing, in one aspect, a bone plug implantation apparatus having a translucent and, preferably, a transparent or clear tip, through which the bone plug can be viewed during implantation. Unlike the prior art, inclusion of such a tip permits the surgeon to view the bone plug during implantation, thereby facilitating better placement, alignment and insertion of the plug into the donor site. 
     According to further aspects of the invention, the apparatus includes a “harvesting” tube which can be used to harvest the plug and which is used to hold the bone plug prior to implanting. The apparatus can also include a push rod that forces the bone plug into a pre-formed hole at the transplant site. The harvesting tube can include an aperture or recessed inner wall that reduces friction on the plug during implantation (and harvesting) and that, thereby, reduces undesirable compression of the plug. 
     According to further aspects of the invention, the tip has an inner diameter substantially equal to that of the hole into which the bone plug is transplanted. An outer diameter of the tip, however, can be greater than that of the hole. This larger outer diameter forms a shoulder upon which the tip can rest during implantation. The tip also covers the distal end of the harvesting tube and, hence, minimizes the damage that it might otherwise cause at the transplant site. 
     In still further aspects of the invention, the tip is rotatable relative to the harvesting tube. This facilitates rotation of the bone plug relative to the transplant site, e.g. so that their respective surfaces can be aligned and otherwise better fitted 
     According to still another aspect, the present invention provides an apparatus for harvesting plugs from bone tissue. The apparatus includes a harvesting tube, as described above, to which a cutting sheath is fitted. The sheath, which includes a cutting edge and a cutting tooth, can include markings on its outer surface so that the depth of insertion—and, therefore, the length of the bone plug—can be determined during harvesting. The harvesting tube can likewise include markings on its outer surface, e.g., adjacent the aforementioned window, so that the position and length of the plus can be more accurately determined after harvesting. 
     According to still another aspect, the present invention provides a method of transplanting a bone plug from a donor site to a recipient size. The method includes harvesting the bone plug from the donor site utilizing a bone plug harvesting apparatus as described above. The harvesting tube of the harvesting apparatus is fitted with a tip as described above to form a bone plug implantation apparatus, also as described above. The tip of the implantation apparatus is placed over a pre-formed hole at the recipient site and the bone plug is forced from the tube, through the transparent tip, and into the pre-formed hole. In related aspects of the invention, the tip is rotated prior to implantation to assure a better fit. 
     Still further aspects of the invention provide a drill guide for use in bone plug removal and replacement. The guide comprises a tip and a harvesting tube as described above. A drill bit is guided through the assembled tube/tip and is used to form a hole at the recipient site. Use of such an assembly as a drill guide can improve the integrity of the transplant, e.g., if the same (or similar) tube and tip are subsequently used during implantation of the plug. 
     This brief summary has been provided so that the nature of the invention may be understood quickly. A more complete understanding of the invention can be obtained by reference to the following detailed description of the preferred embodiments thereof in connection with the attached drawings. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       A more complete understanding of the invention may be attained by reference to the drawings, in which: 
         FIG. 1  shows the anatomy of a knee joint; 
         FIG. 2  shows a representative embodiment of a harvesting tube used in a bone plug harvesting apparatus in accordance with the present invention; 
         FIG. 2A  shows a top view of the apparatus shown in  FIG. 2 ; 
         FIG. 2B  shows a bone plug harvesting apparatus according to the invention. 
         FIGS. 3 and 4  show cutting teeth used in the apparatus of  FIG. 2B ; 
         FIGS. 5 through 10  depict a method for harvesting a bone plug using the apparatus shown in  FIG. 2B ; 
         FIGS. 11 through 13  show components of a bone plug implantation apparatus of the present invention; 
         FIG. 14  shows a bone plug implantation apparatus of the present invention: 
         FIG. 15  shows damaged bone tissue comprised of articular cartilage and underlying bone; 
         FIGS. 16 through 21  depict a method of implanting a bone plug using the apparatus shown in  FIG. 14 ; and 
         FIGS. 22-23  show drill guides according to the invention for forming bone holes. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       FIGS. 2 and 2B  are front views of a device  30  according to the invention for harvesting a plug of bone tissue (i.e., bone and/or articular cartilage) from a donor site. Illustrated device  30  is generally configured in the manner of the harvesting apparatus described in U.S. Pat. No. 6,017,348 the teachings of which are incorporated herein by reference. The harvesting device  30  incorporates improvements on the apparatus of that prior application, as described below and elsewhere herein. 
     The device  30  includes harvesting tube  31 , connector  32 , handle  33 , and cutting sheath  35 . As shown in  FIG. 2 , handle  33  is attached to proximal end  34  of tube  31  and is used to facilitate driving the distal end of the device into the donor site and rotating the device to remove the plug. Illustrated handle  33  can be rod-like in construction, as illustrated, or it can be of other configurations, such as a knurled knob, hexagonal nut, or the like. 
     A connector  32  disposed at the junction of handle  33  and tube  31  includes axial threads  36 , as illustrated, to facilitate affixing a cutting sheath or, alternatively, a delivery tip to the harvesting tube. Of course, connector  32  is not limited to the configuration shown in  FIG. 2  but, rather, can be of other configurations sufficient to support the uses described below. 
     Tube  31  is substantially cylindrical in shape and is made of surgical stainless steel or other material suitable to be driven into bone and used for plug extraction, as described below, Tube  31  has an inner bore  39  (see  FIG. 2B ) extending at least part way (and, preferable, all the way) along longitudinal axis A-A thereof (including through handle  33  and connector  32  as shown in  FIG. 2A ). The bore  39  has a diameter sized in accord with the bone plugs to be harvested. A tapered edge  41  at the distal end of the tube  31  facilitates movement of a bone plug (i.e., articular cartilage and/or underlying bone) into and out of inner bore  39 . 
     Referring to  FIG. 2B , device  30  also includes cutting sheath  35  that, too, is fabricated from surgical stainless steel or other suitable material. The sheath includes, at its distal end, tooth  43  and cutting edge  48 . An inner bore receives tube  31  in the manner shown in  FIG. 2B . The proximal end (e.g. the hub)  38  of sheath  35  includes threading or other structures for mating with corresponding threading  36  on connector  32 . 
     The outer surface of cutting sheath  35  may also include one or more markings  35   a, , as shown in  FIG. 2B , to facilitate determination of a depth to which tube  31  and cutting sheath  35  are inserted into bone tissue and, thereby, to facilitate estimating the length of a harvested bone plug. In preferred embodiments of the invention, there area plurality of such markings of cutting sheath  35 , each of which is separated by a predetermined distance which, in preferred embodiments of the invention is roughly 5 mm. 
     Tooth  43 , coupled (e.g., welded, clued or integrally formed) substantially at or near distal end  40  of sheath  35 , extends into inner bore  39  in a direction substantially orthogonal to cutting edge  48  as shown. By rotating the tube  31 , tooth  43  undercuts the bone within the bore  39  and, thereby, facilitates removal of the bone plug. Although a plurality of such teeth may be used in the present invention, preferred embodiments thereof include only one such tooth. 
       FIGS. 3 and 4  show front views of tube  31 , cutting sheath  35 , inner bore  39  and tooth  43  taken along ling B-B of  FIG. 2B  Referring to  FIG. 3 , tooth  43  is preferably rectangular in shape, though it may be of other configurations, e.g., triangular (as shown in  FIG. 4 ) The tooth  43  has a length which is roughly 1 16 to ¼ the diameter of inner bore  39 , with the most preferred length being roughly ⅕ of the diameter of inner bore  39 . 
     Turning back to  FIGS. 2 and 2B , tube  31  includes at least one recess  45  cut at least partway from an inner surface of tube  31  to an outer surface. This may comprise an indentation or, preferably, a window or aperture cut entirely through tube  31 . To avoid unduly weakening the tube  31 , recess  45  is spaced apart from its distal end. 
     Recess  45  is positioned so that at least a portion of it penetrates a patient&#39;s bone tissue during bone plug extraction. In this regard, the recess  45  reduces frictional contact between the bone plug and the inner surface of the tube  31 . This has the advantage of reducing undesirable compression of the plug during extraction and subsequent emplacement. Though the illustrated embodiment incorporates only a single recess  45 , those skilled in the art will appreciate that multiple recesses (e.g., windows) of varying (or the same) configuration may be used. 
     As further shown in the drawing, the outer surface of tube  31  may also include one or more markings, as shown in close-up view  46  in  FIG. 2 . In the illustrated embodiment, these markings are substantially similar to those contained on cutting sheath  35  and described above. When used in conjunction with a window-like recess  45 , these markings facilitate determination of the length and position of the bone plug. 
       FIGS. 5 to 10  depict the distal end of device  30  during a surgical procedure for harvesting a bone plug in accordance with the present invention. By way of overview, they show the driving of tube  31  and cutting sheath  35  into donor site  50 , the rotation of the tube to undercut the bone plug with tooth  43  and the removal of the tube  31  with the bone plug The surgical techniques shown in these drawings are typically performed arthroscopically using conventional equipment, although open surgical techniques may be used as well. 
     In detail,  FIG. 5  shows a close-up view of the distal end of device  30  (i.e., the distal end of cutting sheath  35  and the distal end of tube  31 ) prior to contact with donor site  50 . In this case, donor site  50  comprises bone tissue made up of both articular cartilage and underlying bone, such as the intracondylar notch or the periphery of the condyle. It should be noted, however, that the invention can also be used with cartilage-only and with bone-only sites, as well as with other appropriate bodily structures. 
       FIGS. 6 and 7  show penetration of device  30 —in particular, the distal end of tube  31  and cutting sheath  35 —into donor site  50 . Cutting edge  48  slices through donor site  50  to separate the bone plug  52  from surrounding tissue. Tapered edge  41  of tube  31  facilitates movement of bone tissue into inner bore  39  of tube  31 . 
     Once tube  31  has been driven into donor site  50  a desired depth, e.g., as determined from markings  35   a , the bone plug  52  is further separated from the surrounding tissue by rotating device  30  (and, more particularly, cutting sheath  35 ) to undercut the plug  52 , as shown in  FIG. 8 . Once rotated a complete (or near-complete) revolution, the distal end of device  30  is pulled from donor site, taking bone plug  52  with it. This is shown in  FIGS. 9 and 10 . 
     After extraction of the plug  52 , cutting sheath  35  is removed (e.g., unscrewed and removably slid from) tube  31 , leaving bone plug  52  in tube  31 . Bone plug  52  may then be implanted from tube  31  into a recipient site using the implantation apparatus shown in  FIG. 14 , the separate components of which are shown in  FIGS. 11 to 13 . 
     At the outset, the implantation apparatus includes a harvesting tube  31  similar and, preferably identical to that shown in  FIG. 2  and described above. For sake of completeness, that tube is redrawn in  FIG. 11 . 
     The implantation apparatus further includes a delivery tip  67  that facilitates transfer of the bone plug into a preformed hole in the recipient site. The tip  67 , which is attachably affixed to the distal end of the tube  31  is “at least translucent,” i.e., it is translucent or, preferably, transparent and, still more preferably, clear. In this regard, the tip  67  is preferably fabricated from surgical grade plastics, or the like. 
     Tip  67  can be affixed to tube  31 , via threading, friction fit or other known mechanism, so that its inner bore  101  is substantially aligned with inner bore  39  at the distal end of tube  31 . In the preferred embodiment, the tip is part of a one-piece, molded device which also includes a sheath-like portion—referred to below as proximal segment  66 —that slips over tube  31  and screws onto connector  32  (e.g., in the same manner as the cutting sheath discussed above) via connector  71 . Like tip  67 , the proximal segment  66  of the illustrated embodiment is also fabricated from materials that are at least translucent (and, preferably, clear). Together, the tip  67  and proximal segment  66  are referred to as delivery sheath  65 . 
     Of course, the invention is not limited to using a one-piece, molded device as its delivery sheath. For example, the delivery sheath can be a two-piece device comprised of a tip and a tube which fasten together, e.g., via screw threads or the like. 
     Referring to  FIG. 12 , proximal segment  66  has an inner bore  100  with a diameter substantially similar to, but somewhat larger than, an outer diameter  70  of tube  31 . This permits segment  66  to fit over tube  31  without substantial lateral play. Preferably, the connector  32  and/or connector  71  are mated to one another so as to permit rotation of the sheath  65  (and, more particularly, the tip  67 ) relative to the tube  31 . In the illustrated embodiment, the mating threads of corrector  32  and connector  71  permit it such rotation (e.g., via clockwise or counterclockwise motion of one relative to the other) Alternative embodiment may incorporate bearings, floating or sliding surfaces instead. 
     Tip  67  preferably has an inner bore  101  with a diameter that substantially corresponds to that of inner bore  39  of the distal end of harvesting tube  31 . In preferred embodiments, this also corresponds substantially to the inner diameter of the plug-receiving cavity at the recipient site. 
     The outer diameter of at least the distal end of the tip  67 , however, is preferably larger than the inner diameter of the cavity. The surface of the tip  67  at the distal end is preferably smooth, so as to prevent marring of the bone tissue surface, though it may include a friction-enhancing coating or structure (e.g., protrusions) to help maintain alignment of the bores  39  and  101  with the recipient cavity during the procedure. 
     The tip  67  and, more particularly, inner bore  101  has a length that permits at least a portion of the bone plug  52  to be seen during the implantation procedure. Thus, in preferred embodiments, the bore  101  has a length of 1 to 50 mm and, preferably, about 10 mm. Of course, the diameter of bore  101 , like that of the distal end of tube  31  and the recipient cavity, substantially matches the expected diameter of the bone plug  52 . 
     The junction of bores  100  and  101  forms a chamfered or flat shoulder adjacent to, or upon which, the distal end of tube  31  is disposed. This prevents the tube  31  and, particularly, its tapered distal end, from directly contacting, and potentially marring, the surface of the recipient site. In this regard, preferably, the distal end of tube  31  does not actually contact the shoulder. Instead, edge  41  is held just proximal of the shoulder (i.e., by connector  71  and threads  34 ) so as to permit transfer of a bone plug into the tip 
     Referring to  FIG. 13 , the illustrated implantation apparatus includes push rod  74  that slides, reciprocates or otherwise moves within inner bore  39  of tube  31  to push bone plug  52  through the tip  67  and into the recipient bore hole. To this end, the rod  74  is long enough and otherwise sized to permit complete evacuation of the plus from the bores  39  and  101 . The distal end of rod  74  is preferably sized and shaped (e.g., flat) to effect little or no damage to bone plug  52  during its contact therewith. To prevent the push rod from moving into tube  31 , the rod  74  preferably has a head  77  greater in diameter than inner bore  39 . 
     The following describes implantation of a bone plug into a recipient site using the implantation device shown in  FIGS. 11 to 14 . As before, this surgical technique is preferably performed arthroscopically using conventional equipment, although open techniques may be utilized as well. Implantation is generally performed in the manner described in the aforementioned incorporated-by-reference application, as modified to accommodate the improvements described herein. 
     To begin,  FIG. 15  shows a defect or damaged area  79  in articular cartilage  80  of the type amenable to repair using the method and apparatus of the present invention. Prior to implantation, the defect or damaged area is removed and a hole for the bone plug is formed. 
     This may be accomplished in a variety of ways known in the art. Preferably, however, the bone hole itself is formed using the harvesting tube  31  and/or delivery sheath  65  as a drill guide. More specifically, the tube  31  and sheath  65  (with substantially clear tip  67 ) are assembled and placed over the recipient site. A drill bit, having an outer diameter which is substantially the same as bore  39 , is then passed through bores  39  and  101  and applied to form a hole in the bone.  FIG. 23  shows drill bit  150  of drill  151  forming a bone hole in this manner. Alternatively, the tip of delivery sheath  65  alone may be used to form the bone hole  FIG. 22  shows drill bit  152  of drill  153  forming a bone hole in this manner In this regard, forming a bone hole using drill guides having a substantially clear tip facilitates formation of bone holes normal to the bone surface or at other desired angles. It also ensures better aliment between the bone plug implanting device and the hole at the recipient site. That is, because the drill bit can be viewed through the clear tip, it is possible to align the drill bit more accurately than has heretofore been possible. This step is, of course, performed prior to harvesting the replacement bone plug  52  or, alternatively, is performed using a harvesting tube  31  other than that in which a harvested plug  52  is contained. 
     Once the bone hole has been formed and the replacement bone plug has been harvested, the implantation apparatus is assembled by sliding the delivery sheath  65  over the harvesting tube  31 . The assembled apparatus is then placed so that the bore  101  substantially aligns with bone hole  87 , and so that edge  88  of tip  67  (i.e., that portion which surrounds the inner bore) rests on the surrounding bone tissue surface (i.e., on the articular cartilage covering the underlying bone). 
     If desired, the rod  74  may be used to move the bone plug  52  at least partially into tip  67  prior to placement of the implantation apparatus. Indeed, the bone plug  52  may be partially extruded, e.g., 1 mm to 2 mm, from the tip  67  to facilitate its alignment and insertion into the bone hole  87 . The bone plug  52 , moreover, can be rotated for better alignment with the hole. This may be accomplished by rotating the implantation device as a whole or, preferably, by rotating just the implantation sheath  65 . 
       FIG. 17  shows the beginning of the implantation process, with push rod  741  forcing bone plug  52  from the inner bore  39 , into tip  67  and just into bone hole  87 . As additional downward pressure is applied to push rod  74  bone plug  52  is forced further into the bone hole Once again, the plug  52  may be oriented before it is fully implanted. e.g., to obtain a better alignment to the bone surface contour, by rotating the implantation sheath  65  relative to the harvesting tube  31 . 
     In this latter regard, since tip  67  is clear, the surgeon is able to view at least part of, and preferably the entirety of, the plug  52  during implantation. In the example shown in  FIG. 18 , the surgeon will see that top surface  91  of bone plug  52  does not align with surface  94  of the recipient site. Accordingly, as shown in  FIG. 19 , the sheath  65  is rotated in the direction of arrow  95  for proper orientation. Once alignment has been achieved, the push rod  74  can be tapped to finalize the implant, as shown in  FIG. 20 . Thereafter, tube  31  and device  65  (including push rod  74 ) are removed from the site, as shown in  FIG. 21 . 
     In a preferred embodiment, bone plug  52  and corresponding bone hole  87  are sized for an interference fit, so as to reduce the chances that the bone plug will inadvertently dislodge from the bone hole. In this regard, although the bone plug preferably has an interference fit in the bone hole, several alternative methods are available for maintaining the bone plug in the bone hole. One such technique involves sewing sutures through peripheral edges of the articular cartilage adhering to the bone plug and the surrounding articular cartilage tissue. Alternatively, an adhesive layer (not shown) may be provided between bone plug  52  and bone hole  87 . This adhesive layer allows time for sufficient ingrowth of tissue from the surrounding environment so that bone plug  52  may become locked into place in bone hole  87 . Various bioadhesives are well known in the art, examples of which are fibrinogen and thrombin sealant (see, e.g., U.S. Pat. No. 5,067,964). 
     Bone-growth and cartilage-growth promoting chemical factors may also be added to the bone hole and/or to the implanted bone plug in order to promote rapid reconnection of the bone plug to the surrounding bone and articular cartilage. These bone-growth and cartilage-growth promoting chemical factors may include cartilage-derived colony-stimulating factor (“CDGF”) (see U.S. Pat. No. 5,376,636), various interleukins, colony-stimulating factor (“CSF”), osteopontin, platelet-derived growth factor (“PDGF”), and bone morphogenic protein (“BMP-1”). See also U.S. Pat. No. 5,372,503, the contents of which are hereby incorporated by reference into the subject application as if set forth herein in full. 
     The present invention has been described with respect to particular illustrative embodiments. It is to be understood that the invention is not limited to the above-described embodiments and modifications thereto, and that various changes and modifications may be made by those of ordinary skill in the art without departing from the spirit and scope of the appended claims.