Patent Publication Number: US-2005119695-A1

Title: Closure device and methods for making and using them

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS  
      This application is a continuation of application Ser. No. 10/435,104, filed May 9, 2003, which was a continuation-in-part of application Ser. No. 09/732,178, filed Dec. 7, 2000, now U.S. Pat. No. 6,719,777 entitled “Closure Device and Methods for Making and Using Them,” each of which are hereby expressly incorporated by reference. 
    
    
     FIELD OF THE INVENTION  
      The present invention relates generally to apparatus and methods for engaging tissue and/or closing openings through tissue, and more particularly to devices for closing a puncture in a blood vessel or other body lumen formed during a diagnostic or therapeutic procedure, and to methods for making and using such devices.  
     BACKGROUND  
      Catheterization and interventional procedures, such as angioplasty or stenting, generally are performed by inserting a hollow needle through a patient&#39;s skin and intervening tissue into the vascular system. A guide wire may then be passed through the needle lumen into the patient&#39;s blood vessel accessed by the needle. The needle may be removed, and an introducer sheath may be advanced over the guide wire into the vessel, e.g., in conjunction with or subsequent to a dilator. A catheter or other device may then be advanced through a lumen of the introducer sheath and over the guide wire into a position for performing a medical procedure. Thus, the introducer sheath may facilitate introducing various devices into the vessel, while minimizing trauma to the vessel wall and/or minimizing blood loss during a procedure.  
      Upon completing the procedure, the devices and introducer sheath may be removed, leaving a puncture site in the vessel wall. External pressure may be applied to the puncture site until clotting and wound sealing occur. This procedure, however, may be time consuming and expensive, requiring as much as an hour of a physician&#39;s or nurse&#39;s time. It is also uncomfortable for the patient, and requires that the patient remain immobilized in the operating room, catheter lab, or holding area. In addition, a risk of hematoma exists from bleeding before hemostasis occurs.  
      Various apparatus have been suggested for percutaneously sealing a vascular puncture by occluding the puncture site. For example, U.S. Pat. Nos. 5,192,302 and 5,222,974, issued to Kensey et al., describe the use of a biodegradable plug that may be delivered through an introducer sheath into a puncture site. When deployed, the plug may seal the vessel and provide hemostasis. Such devices, however, may be difficult to position properly with respect to the vessel, which may be particularly significant since it is generally undesirable to expose the plug material, e.g., collagen, within the bloodstream, where it may float downstream and risk causing an embolism.  
      Another technique has been suggested that involves percutaneously suturing the puncture site, such as that disclosed in U.S. Pat. No. 5,304,184, issued to Hathaway et al. Percutaneous suturing devices, however, may require significant skill by the user, and may be mechanically complex and expensive to manufacture.  
      U.S. Pat. No. 5,478,354, issued to Tovey et al., discloses a surgical fastener including an annular base having legs that, in a relaxed state, extend in a direction substantially perpendicular to a plane defined by the base and slightly inwards toward one another. During use, the fastener is fit around the outside of a cannula, thereby deflecting the legs outward. The cannula is placed in an incision, and the fastener is slid along the cannula until the legs pierce into skin tissue. When the cannula is withdrawn, the legs move towards one another back to the relaxed state to close the incision.  
      U.S. Pat. Nos. 5,007,921 and 5,026,390, issued to Brown, disclose staples that may be used to close a wound or incision. In one embodiment, an “S” shaped staple is disclosed that includes barbs that may be engaged into tissue on either side of the wound. In another embodiment, a ring-shaped staple is disclosed that includes barbs that project from the ring. Sides of the ring may be squeezed to separate the barbs further, and the barbs may be engaged into tissue on either side of a wound. The sides may then be released, causing the barbs to return closer together, and thereby pulling the tissue closed over the wound. These staples, however, have a large cross-sectional profile and therefore may not be easy to deliver through a percutaneous site to close an opening in a vessel wall.  
      Accordingly, devices for engaging tissue, e.g., to close a vascular puncture site, would be considered useful.  
     SUMMARY OF THE INVENTION  
      The present invention is directed to devices and methods for engaging tissue, e.g., to connect tissue segments together or to close and/or seal openings through tissue, such as in a wall of a body lumen. More particularly, the present invention is directed to vascular closure devices or clips for closing a puncture in a wall of a blood vessel formed during a diagnostic or therapeutic procedure, and to methods for making and using such devices.  
      In one aspect of the present invention, a device for engaging tissue includes a generally annular-shaped body defining a plane and disposed about a central axis extending substantially normal to the plane. The body may be movable from a substantially planar configuration lying generally in the plane towards a transverse configuration extending out of the plane. The body may also include a plurality of looped elements including alternating first and second curved regions that define an inner and outer periphery of the body, respectively, in the planar configuration. A plurality of tines or other tissue-engaging elements may extend from the first curved regions, and may be oriented towards the central axis in the planar configuration, and substantially parallel to the central axis in the transverse configuration. The device may be biased towards the planar configuration, e.g., to bias the tines towards the central axis.  
      The looped elements of the device may generally define an endless zigzag pattern, e.g., a sinusoidal pattern, extending about the central axis. The looped elements may facilitating deforming the device between the planar and transverse configurations, e.g., by distributing stresses through the device and minimizing localized stresses in the curved regions. In addition, the looped elements may be expandable between expanded and compressed states for increasing and reducing a periphery of the body in the transverse orientation, respectively. The looped elements may be biased towards one of the compressed and expanded states.  
      Adjacent tines of the device may have a first curved region disposed between them. The first curved region between adjacent tines may include a substantially blunt element extending towards the central axis. The blunt element may have a length shorter than lengths of the adjacent tines.  
      In addition or alternatively, the tines of the device may include first and second primary tines, having a first length and a second length, respectively, which may be the same as or different than one another. The first and second primary tines may be disposed on opposing first curved regions, and may be oriented substantially towards each other in the planar configuration. In the planar configuration, the first and second primary tines may at least partially overlap. The tines may also include one or more secondary tines having a length substantially shorter than the first and second lengths of the primary tines. The secondary tines may be disposed on either side of the first and second primary tines.  
      In another aspect of the present invention, a device for engaging tissue includes a generally annular-shaped body defining a plane and disposed about a central axis extending substantially normal to the plane. The body may be movable from a substantially planar configuration lying generally in the plane towards a transverse configuration extending out of the plane. A first primary tine, having a first length, may extend from the body towards the central axis in the planar configuration, and may be deflectable out of the plane when the body is moved towards the transverse configuration. A second primary tine, having a second length, may extend from the body towards the first tine when the body is in the planar configuration, and may be deflectable out of the plane when the body is moved towards the transverse configuration. The lengths of the first and second primary tines may cause the primary tines to at least partially overlap in the planar configuration. The body may be biased towards the planar configuration to bias the tines generally towards the central axis.  
      The device may include a set of secondary tines having a length shorter than the first and second lengths. The secondary tines may extend from the body towards the central axis in the planar configuration, and may be deflectable out of the plane when the body is moved towards the transverse configuration. In an exemplary embodiment, a secondary tine may be disposed on either side of the first primary tine, and a secondary tine may be disposed on either side of the second primary tine.  
      Optionally, adjacent tines may have a first curved region disposed between them. The first curved region between adjacent tines may include a substantially blunt element extending towards the central axis. The blunt element may have a length shorter than lengths of the adjacent tines.  
      Also, the device may include a plurality of looped elements disposed around a periphery of the body. The looped elements may generally define an endless zigzag pattern extending about the central axis. The first primary tine and the second primary tine may extend from looped elements disposed opposite one another. The looped elements may be expandable between expanded and compressed states for increasing and reducing a periphery of the body in the transverse orientation, respectively. The looped elements may be biased towards one of the compressed and expanded states.  
      In another aspect of the present invention, a method is provided for manufacturing a clip from an elastic material, such as a sheet of superelastic alloy, e.g., a nickel-titanium alloy (“Nitinol”). The components of the clip, e.g., a generally-annular body, optionally including looped elements, and/or tines, may be formed by removing portions from the sheet. The portions may be removed, e.g., by laser cutting, chemical etching, photo chemical etching, stamping, electrical discharge machining, and the like. The clip may be polished using one or more processes, such as electro-polishing, chemical etching, tumbling, sandblasting, sanding, and the like, and/or heat-treated to provide a desired finish and/or desired mechanical properties. Optionally, the body and tines may be coated with a therapeutic agent, e.g., a peptide coating and/or one or more clotting factors.  
      In addition or alternatively, the clip may be disposed in a planar configuration, e.g., upon forming the clip from the sheet, and heat treated to form a clip biased to the planar configuration. For example, the clip may be formed from a shape memory material, e.g., Nitinol, that may substantially recover the planar configuration when heated to a first predetermined temperature corresponding to an austenitic state, e.g., a temperature close to body temperature. The clip may be cooled to a second predetermined temperature corresponding to a martensitic state, e.g., a temperature at or below ambient temperature, and malleably manipulated.  
      For example, the clip formed from the sheet may be deformed to a transverse configuration, such as that described above, e.g., by loading the clip onto a mandrel or directly onto a delivery device. If the clip includes looped elements formed from the body, the looped elements may be biased upon heat treatment towards an expanded state, but may be malleably deformed to a compressed state upon cooling, e.g., to facilitate loading onto the delivery device. Alternatively, the clip may be formed from a superelastic material, e.g., Nitinol, such that the clip may be resiliently deformed to the transverse configuration and/or compressed state, yet may automatically attempt to resume its planar configuration and/or expanded state upon release from external forces.  
      In still another aspect of the present invention, a method for closing an opening in a wall of a body lumen is provided. The distal end of an elongate member may be advanced through an opening in a patient&#39;s skin, along a passage through tissue, and into the body lumen. A distal portion of an obturator may be positioned distally beyond the distal end of the elongate member along the passage within the body lumen. One or more expandable elements on the distal portion of the obturator may be expanded transversely. The obturator may be withdrawn from the passage until the expandable elements contact the wall of the body lumen, thereby providing a tactile indication of a location of the wall of the body lumen between the elongate member and the plurality of expandable elements of the obturator.  
      A clip may be advanced into the passage over the elongate member until tines of the clip penetrate the wall of the body lumen, the tines and the expandable elements on the obturator being angularly offset from one another such that the tines penetrate the wall at locations between the expandable elements. The obturator may be collapsed, and the elongate member and/or obturator may be withdrawn from the body lumen and passage, leaving the clip to substantially close the opening in the wall of the body lumen. When the elongate member is withdrawn, the tines may automatically at least partially move towards a planar configuration to substantially close the opening.  
      The tines of the clip may include primary tines and secondary tines. Here, advancing the clip may include puncturing the wall of the body lumen with the primary tines until tips of the primary tines enter the body lumen, and puncturing the wall of the body lumen with the secondary tines. The primary tines and the secondary tines may puncture the walls without contacting the expandable elements of the obturator.  
      Other objects and features of the present invention will become apparent from consideration of the following description taken in conjunction with the accompanying drawings. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       FIG. 1A  is a top view of a first embodiment of a clip including a plurality of tines in a planar orientation, in accordance with the present invention.  
       FIGS. 1B and 1C  are side views of the clip of  FIG. 1A , with the tines oriented substantially transversely from the planar orientation, in compressed and expanded states, respectively.  
       FIG. 2A  is a top view of a second embodiment of a clip including a plurality of tines in a planar orientation, in accordance with the present invention.  
       FIGS. 2B and 2C  are side views of the clip of  FIG. 2A , with the tines oriented substantially transversely from the planar orientation, in compressed and expanded states, respectively.  
       FIG. 3  is a top view of a third embodiment of a clip, in accordance with the present invention.  
       FIG. 4  is a top view of an embodiment of a clip having radiopaque markers thereon.  
       FIG. 5  is a top view of an embodiment of a clip having pockets for holding radiopaque markers therein.  
       FIG. 6  is a top view of another embodiment of a clip including stop elements, in accordance with the present invention.  
       FIG. 7  is a top view of yet another embodiment of a clip including stop elements, in accordance with the present invention.  
       FIG. 8  is a top view of still another embodiment of a clip including stop elements, in accordance with the present invention.  
       FIG. 9  is a side view of an apparatus, including an introducer sheath and an obturator, suitable for delivering a clip of the present invention.  
       FIGS. 10A-10D  are cross-sectional views of a blood vessel, showing a method for delivering a clip into a passage communicating with the vessel using the apparatus of  FIG. 9 .  
       FIG. 11A  is a top view of the blood vessel of  FIGS. 10A-10D , showing the orientation of the expandable elements of the obturator and openings produced by primary tines of the clip relative to an arteriotomy in the vessel.  
       FIG. 11B  is a top view of the blood vessel of  FIG. 11A , showing the arteriotomy being closed by the clip.  
       FIG. 12  is a top view of an embodiment of a clip having arcuate tines, in accordance with the present invention. 
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBOIDMENTS  
      Turning now to the drawings,  FIGS. 1A-1C  show a first preferred embodiment of a closure device or clip  10  for closing an incision, puncture, or other passage through tissue, e.g., communicating with a blood vessel or other body lumen (not shown). The clip  10  includes a body  12 , which may be generally annular in shape and surrounds a central axis  24 , and a plurality of tines  16  extending from the body  12 . As used herein, an “annular-shaped body” includes any hollow body, e.g., including one or more structures surrounding an opening, whether the body is substantially flat or has a significant thickness or depth. Thus, although an annular-shaped body may be circular, it may include other noncircular shapes as well, such as elliptical or other shapes that are asymmetrical about a central axis.  
      The body  12  may include a plurality of looped or curved elements  30  that are connected to one another to form the body  12 . Each looped element  30  may include an inner or first curved region  32  and an outer or second curved region  34 . In a preferred embodiment, the first and second curved regions  32 ,  34  are out of phase with one another and are connected alternately to one another, thereby defining an endless sinusoidal pattern. Alternatively, other generally zigzag patterns may be provided that repeat periodically, e.g., saw tooth or square tooth patterns (not shown), instead of a sinusoidal pattern, thereby defining inner and outer regions that alternate about the body  12 . When the clip  10  is in a substantially planar configuration, as shown in  FIG. 1A , the first curved regions  32  may define an inner periphery  36  of the body  12  and the clip  10 , and the second curved regions  34  may define an outer periphery  38 .  
      The plurality of tines  16  may be biased to extend generally inwardly, e.g., towards one another and/or towards the central axis  24 . The tines  16  may be disposed on the first curved regions  32 , and oriented toward the central axis  24  when the clip  10  is in the planar configuration. In a preferred embodiment, the tines  16  may be provided in pairs opposite from one another or provided otherwise symmetrically with respect to the central axis  24 .  
      The tines  16  may include a variety of pointed tips, such as a bayonet tip, and/or may include barbs (not shown) for penetrating or otherwise engaging tissue. For example, to increase the penetration ability of the clip  10  and/or to lower the insertion force required to penetrate tissue, each tine  16  may include a tapered edge (not shown) extending towards the tip along one side of the tine  16 . Alternatively, each tine  16  may be provided with a tapered edge on each side of the tine  16  extending towards the tip.  
      Additionally, as shown in  FIGS. 1A-1C , the tines  16  may be disposed on alternating first curved regions  32 . Thus, at least one period of a zigzag pattern may be disposed between adjacent tines  16 , which may enhance flexibility of the clip  10 , as explained further below.  
      As shown in  FIGS. 1B and 1C  (where opposite ends  33   a ,  33   b  are connected to one another), the body  12  and/or the tines  16  may be deflected such that the tines  16  extend transversely with respect to the plane defined in the planar configuration, thereby defining a transverse configuration for the clip  10 . Preferably, the tines  16  are oriented substantially parallel to the central axis  24  in the transverse configuration, as shown in  FIG. 1B . In the transverse configuration, the body  12  may have a generally annular shape defining a length, L.sub.1, that extends generally parallel to the central axis  24 , and corresponds generally to an amplitude of the zigzag pattern. Preferably, the body  12  is sufficiently flexible such that the clip  10  may assume a generally circular or elliptical shape (not shown), e.g., conforming to an exterior surface of a delivery device (not shown) used to deliver the clip  10 .  
      In a preferred embodiment, the tines  16  and/or body  12  are biased to move from the transverse configuration towards the planar configuration of  FIG. 1A . Thus, with the tines  16  in the transverse configuration, the tines  16  may penetrate and/or be engaged with tissue at a puncture site. When the clip  10  is released, the tines  16  may attempt to return towards one another as the clip  10  moves towards the planar configuration, thereby drawing the engaged tissue together and substantially closing and/or sealing the puncture site, as explained further below.  
      The looped elements  30  may distribute stresses in the clip  10  as it is deformed between the planar and transverse configurations, thereby minimizing localized stresses that may otherwise plastically deform, break, or otherwise damage the clip  10  during delivery. In addition, when the clip  10  is in the transverse configuration, the looped elements  30  may be movable between a compressed state, such as that shown in  FIG. 1B , and an expanded state, such as that shown in  FIG. 1C . Preferably, the looped elements  30  are biased towards the expanded state, but may be compressed to the compressed state, e.g., by constraining the clip  10 . Alternatively, only a portion of the looped elements  30  may be biased towards the expanded state, e.g., the first curved regions  32 , and/or the looped elements  30  may be biased towards the compressed state. Furthermore, the looped elements  30  reduce the force required to be exerted on the clip  10  to transition the clip  10  from the planar configuration to the transverse configuration before loading onto a delivery device (not shown).  
      With the clip  10  in the transverse configuration, the looped elements  30  may be circumferentially and/or radially compressed to the compressed state until the clip  10  defines a first diameter or circumference  26   a , such as that shown in  FIG. 1B . The clip  10  may be constrained in the compressed state, e.g., by loading the clip  10  onto a carrier assembly of a delivery device (not shown), as described further below. When released from the constraint, e.g., when deployed from the carrier assembly, the clip  10  may automatically expand towards the expanded state, such as that shown in  FIG. 1C , thereby defining a second diameter or circumference  26   b . Thus, the looped elements  30  may facilitate reducing the profile of the clip  10  during delivery, e.g., to facilitate introducing the clip  10  through a smaller puncture or passage. Once the clip  10  is deployed entirely from the delivery device, the looped elements  30  may resiliently expand as the clip  10  returns towards the planar configuration, as explained further below.  
      To manufacture the clip  10  (or, similarly, any of the other clips described herein), the body  12  and the tines  16  may be integrally formed from a single sheet of material, e.g., a superelastic alloy, such as a nickel-titanium alloy (“Nitinol”). Portions of the sheet may be removed using conventional methods, such as laser cutting, chemical etching, photo chemical etching, stamping, using an electrical discharge machine (EDM), and the like, to form the clip. The tines  16  may be sharpened to a point, i.e., tips may be formed on the tines  16  using conventional methods, such as chemical etching, mechanical grinding, and the like.  
      The clip  10  may be polished to a desired finish using conventional methods, such as electro-polishing, chemical etching, tumbling, sandblasting, sanding, and the like. Polishing may perform various functions depending on the method used to form the clip  10 . For a clip formed by laser cutting or using an EDM, polishing may remove heat affected zones (HAZ) and/or burrs from the clip. For a clip formed by photo chemical etching, polishing may create a smoother surface finish. For a clip formed by stamping, polishing may remove or reduce burrs from the bottom side of the clip, and/or may smooth the “roll” that may result on the topside of the clip from the stamping process.  
      In addition or alternatively, the clip  10  may be formed from a shape memory alloy, e.g., Nitinol, with the looped elements  30  formed initially in the compressed state and/or the clip  10  in the planar configuration. With the clip  10  deformed to the transverse configuration, the clip  10  may be expanded, e.g., by applying a force radially outwards against an inner surface of the clip  10 , thereby expanding the looped elements  30  to the expanded state. The looped elements  30  may then be heat treated, e.g., by heating the clip  10  to an austenitic state, to cause the looped elements  30  to “remember” the expanded state, as is known to those skilled in the art. It may also be necessary to further heat treat the clip  10  further, e.g., with the tines in the planar configuration to cause the body  12  and/or tines  16  to “remember” and be biased towards the planar configuration, as is known to those skilled in the art. The clip  10  may then be cooled, e.g., to a martensitic state, which may be at or close to ambient temperature, and manipulated, e.g., malleably deformed to the transverse configuration, for example, by loading the clip  10  onto a delivery device (not shown), as described below. Thus, if the clip  10  is subsequently heated to a predetermined temperature, e.g., at or below body temperature, the material may remember the planar configuration and/or expanded state and become biased towards them.  
       FIGS. 2A-2C  show another preferred embodiment of a closure device or clip  110  that includes a generally annular-shaped body  112  defining a plane and disposed about a central axis  124  extending through the plane. The body  112  preferably includes a plurality of looped elements  130  that are connected to one another to form the body  112 , similar to the previous embodiment. Each looped element  130  includes an inner or first curved region  132  and an outer or second curved region  134 . Similar to the previous embodiment, the first and second curved regions  132 ,  134  may form an endless sinusoidal pattern or other generally zigzag pattern. When the clip  110  is in a substantially planar configuration, as shown in  FIG. 2A , the first curved regions  132  may define an inner periphery  136 , and the second curved regions  134  may define an outer periphery.  
      Unlike the previous embodiment, the clip  110  includes a plurality of primary tines  114  and a plurality of secondary tines  116 . Each of the primary and secondary tines  114 ,  116  may include a variety of known pointed tips, similar to the previous embodiment.  
      Each of the primary tines  114  may have a length l.sub.1, although alternatively each of the primary tines  114  may have a different length than one another. The primary tines  114  may be disposed in one or more opposing pairs, e.g., on opposing first curved regions  132 , and may be oriented towards and/or across the central axis  124  in the planar configuration. In the planar configuration, the lengths l.sub.1 may be sufficiently long such that the primary tines  114  at least partially overlap one another, i.e., extend across the central axis  124  towards an opposing tine  114 . Therefore, the tips of the primary tines  114  may extend past the central axis  124  and/or the primary tines  114  in each pair may lie substantially parallel to each other when the clip  110  is in the planar configuration.  
      Each of the secondary tines  116  may be disposed on a first or inner curved region  132 , e.g., such that one or more secondary tines  116  may be provided between opposing pairs of primary tines  114 . Each of the secondary tines  116  may have a length l.sub.2 that is substantially less than the length l.sub.1 of the primary tines  114 .  
      Preferably, a secondary tine  116  is disposed on either side of each primary tine  114 . For example, the clip  110  shown in  FIGS. 2A-2C  has first and second primary tines  114 , and each of the first and second primary tines  114  has a secondary tine  116  on either side of it. Thus, the clip  110  may have a total of two primary tines  114  and four secondary tines  116 . Optionally, the secondary tines  116  may be disposed substantially symmetrically about the central axis  124 . The tines  114 ,  116  may be provided on every other first curved regions  132 . For example, a first curved region  132  having neither a primary tine  114  nor a secondary tine  116  may separate each adjacent tine, e.g., between two adjacent secondary tines  116 , or between a secondary tine  116  and a primary tine  114 .  
      As shown in  FIGS. 2B and 2C , the body  112  and/or the tines  114 ,  116  may be deflected such that they extend transversely with respect to the plane defined in  FIG. 2A . Preferably, the primary tines  114  and secondary tines  116  are oriented substantially parallel to the central axis  124  to define a transverse configuration, as shown in  FIG. 1B . In the transverse configuration, the body  112  has a generally annular shape defining a length, LE.sub.1, that extends generally parallel to the central axis  24 , and corresponds generally to an amplitude of the sinusoidal pattern. Preferably, the body  112  is sufficiently flexible such that the clip  110  may assume a generally circular or elliptical shape (not shown), e.g., conforming to an exterior surface of a delivery device (not shown).  
      The tines  114 ,  116  may be biased towards one another and/or towards the central axis  124 , i.e., due to the bias of the clip  110  towards the planar configuration of  FIG. 2A , similar to the previous embodiment. With the clip  110  in the transverse configuration, the clip  110  may be delivered such that the primary tines  114  entirely penetrate the wall of a blood vessel or other body lumen, while the secondary tines  116  only partially penetrate the wall due to their relative lengths, as explained further below.  
      The looped elements  130  may be expandable between a compressed state, as shown in  FIG. 2B , and an expanded state, as shown in  FIG. 2C , similar to the previous embodiment. Preferably, the looped elements  130  are biased to the expanded state, but may be resiliently compressed to the compressed state, e.g., by constraining the clip  110 .  
      Turning to  FIG. 3 , an alternative embodiment of a clip  210  is shown that includes a body  112  including looped elements  130 , and primary tines  114 , similar to the previous embodiment, but has no supplemental or secondary tines  116 . The reference numbers for elements of the clip  210  are consistent with like elements used for the clip  110 .  
      Any of the clips of the present invention may include one or more radiopaque markers or other markers visible using external imaging, such as fluoroscopy. For example, using the clip  110  of  FIGS. 2A-2C  as an example, the entire clip  110  may be coated with radiopaque material, which may be a high density material such as gold, platinum, platinum/iridium, and the like.  
      Alternatively, the clip  110  may be partially coated with radiopaque material by using masking techniques. For example, the entire clip  110  may first be coated with radiopaque material. The clip  110  may then be masked at locations where the radiopaque coating is desired. For example, the looped elements  130  of the clip  110  may be left unmasked during this process if it is desired to leave the looped elements  130  uncoated by radiopaque material. This may be desirable, e.g., to prevent radiopaque material from adversely affecting the flexibility of the looped elements  130 . The clip  110  may then be treated to remove the radiopaque material from the unmasked areas, in this example, the looped elements  130 . The masking may then be removed using conventional processes, leaving the rest of the clip  110  coated with radiopaque material.  
      Turning to  FIG. 4 , in another alternative, one or more discrete markers  102  may be provided at predetermined locations on the clip  110 . For example, high density or radiopaque material  102  may be crimped or otherwise secured onto opposing double looped or circular regions  130 . In another embodiment, shown in  FIG. 5 , a plurality of pockets  104  may be provided on the looped elements  130  into which high density plugs (not shown) may be bonded or otherwise secured. These various radiopaque markers may also be incorporated in any of the embodiments described herein.  
      Turning to  FIG. 6 , another embodiment of a clip  310  is shown that, similar to clip  110 , may include a plurality of looped elements  330  that interconnect to form a body  312 . Each looped element  330  may have a first or inner curved region  332  and a second or outer curved region  334 . Primary tines  314  may be disposed on opposing first curved regions  332 , which, optionally, may include a barb  302  thereon to enhance engagement with tissue. Secondary tines  316  may be provided on first curved regions  332  on either side of each primary tine  314 . In addition, a first curved region  332  without a tine  314 ,  316  may separate adjacent tines, as described above with regard to the previous embodiments.  
      The clip  310  also includes stop members  306  on one or more of the tines  314 ,  316 , e.g., adjacent the respective first curved region  332 . Each stop member  306  may be blunt-shaped, e.g., generally triangularly with an apex  307  of the stop member  306  extending from the first curved region  332 , and the tine  314 ,  316  extending from a wide or blunt base  307  of the stop member  306 . During use, the blunt bases  307  may limit penetration of the respective tines  314 ,  316  into tissue by reducing an effective length of the respective tine  314 ,  316 . For example, when the tines  314 ,  316  are driven into tissue, the tines  314 ,  316  may penetrate the tissue until the blunt bases  307  contact the tissue, whereupon the tines  314 ,  316  may be prevented from penetrating further into the tissue. Turning to  FIG. 7 , another embodiment of a clip  410 ( i ) is shown that includes a body  412 , a plurality of tines  414 , and a plurality of spring elements  440 ( i ) that interconnect between adjacent tines  414 . The body  412  includes outer curved regions  434  that extend between adjacent tines  414 , thereby defining an outer periphery for the clip  410 ( i ). The clip  410 ( i ) may be moveable between a substantially planar configuration such as that shown in  FIG. 7 , and a transverse configuration (not shown), and preferably is biased towards the planar configuration, similar to the previous embodiments.  
      In the embodiment shown, the spring elements  440 ( i ) generally are hollow diamond shaped elements, including curved inner regions  432 ( i ) oriented towards the central axis  424  of the body  412  when the clip  410 ( i ) is in the planar configuration. The spring elements  440 ( i ) may serve multiple purposes. First, the spring elements  440 ( i ) may bias the clip  410 ( i ), e.g., allowing the clip  410 ( i ) to at least partially expand resiliently. For example, when the clip  410 ( i ) is deflected into the transverse configuration (not shown), the spring elements  440 ( i ) may allow the tines  414  to be moved away from the central axis  424  and/or one another. Thus, during deployment, the tines  414  may be deflected radially outwardly or otherwise expanded to engage a larger area of tissue.  
      As the tines  414  are expanded, the spring elements  414 ( i ) may deform to become wider (along a dimension extending generally between the adjacent tines  414 ) and shorter (along a dimension extending generally parallel to the tines  414 ). Once a force causing the tines  414  to expand is removed, the spring elements  414 ( i ) may resiliently try to return towards their original shape, thereby pulling the tines  414  closer towards one another.  
      In addition, the curved inner regions  432 ( i ) of the spring elements  414 ( i ) may provide stops limiting penetration of the tines  414  into tissue, similar to the stop members described above. For example, when the clip  410 ( i ) is in the transverse configuration and the spring elements  414 ( i ) are expanded, the curved inner regions  432 ( i ) may be become more oblique, possibly becoming generally linear. Thus, when the tines  414  are driven into tissue, the curved inner regions  432 ( i ) may limit penetration of the tines  414 .  
      Finally, after the clip  410 ( i ) is deployed, e.g., the tines  414  are penetrated into tissue, the curved inner regions  432 ( i ) may return towards their original shape, and may pinch or otherwise engage tissue between the inner curved regions  432 ( i ) and the adjacent tines  414 . Thus, contracting the spring elements  440 ( i ) may enhance the ability of the clip  410 ( i ) to seal a puncture site, e.g., by pulling engaged tissue inwardly towards the central axis  424  of the clip  410 ( i ).  
      Turning to  FIG. 8 , an alternative embodiment of a clip  410 ( ii ) is shown that is substantially similar to the clip  410 ( i ) shown in  FIG. 7 , with the exception of the shape of the spring elements  440 ( ii ). Rather than diamond shaped elements, the spring elements  440 ( ii ) are looped elements generally defining a circular shape.  
      Turning now to  FIG. 12 , another preferred embodiment of a clip  710  of the present invention is illustrated. Similar to the previous embodiments, the clip  710  includes a generally annular-shaped body  712  that defines a plane. The body  712  is disposed about a central axis  724  that extends through the plane. The body  712  preferably includes a plurality of outer curved elements  730  that extend between adjacent tines  716  and are connected to each other to form the body  712 . When the clip  710  is in a substantially planar configuration, as shown in  FIG. 12 , the curved elements  730  define an outer periphery  738  of the clip  710 .  
      The tines  716  are curved or arcuately shaped and include distal tips  715  that extend toward the central axis  724  when the clip  710  is in the substantially planar configuration. Optionally, one or more of the tines  716  may include barbs  717 , similar to the previous embodiments. Preferably, the curve of the tines  716  are all in phase with one another such that the tines  716  spiral about the central axis  724 . This may allow a length of the tines  716  to be maximized for a given diameter of the body  712 .  
      For example, the tines  716  may have a length that is greater than a radius of the body  712  without the distal tips  715  of the tines  716  touching one another. Thus, due to the arcuate shape of each tine  716 , the tines  716  of clip  710  may be generally longer than the straight tines of the previous clips having comparable diameters. The tines  716  may, therefore, penetrate deeper into tissue than the tines of the other clips.  
      As with the previous embodiments, the body  712  and/or the tines  716  of clip  710  may be deflected until the tines  716  extend transversely with respect to the plane defined in the planar configuration, thereby defining a transverse configuration. In the transverse configuration, the tines  716  may be oriented substantially parallel to the central axis  724 . Additionally, as with the previous embodiments, the tines  716  and/or body  712  may be biased to move from the transverse configuration towards the planar configuration. The clip  710  may be delivered in substantially the same manner as will be described with respect to other clips of the present invention.  
      Any of the clips of the present invention may be coated with a substance that enhances hemostasis and/or healing of a blood vessel, e.g., by increasing a rate of regeneration of endothelium on the interior surface of the vessel, or by decreasing inflammatory response at the treatment site. In one embodiment, a suitable synthetic peptide coating may be applied to a clip to attract endothelial cells to the surface. An exemplary synthetic peptide coating may, for example, attach to the same cell binding sites as collagen. In another embodiment, a clip may be coated with a combination of clotting factors in order to promote hemostasis. For example, one side of the clip may be coated with Factor III and an endopeptidase, such as PTA, to accelerate the intrinsic clotting pathway. On the opposite side of the clip, a combination of a protein cofactor proaccelerin (Factor V) and an activated endopeptidase, such as serum prothrombin conversion accelerator (SPCA), cothromboplastin, and the like, may be applied to accelerate the extrinsic clotting pathway. The clips of the present invention may also be coated with any suitable hydrophilic polymer that swells in the presence of bodily fluids in order to reduce, minimize, or stop blood flow, thereby aiding the hemostasis process.  
      The clips of the present invention may be delivered using various apparatus and methods. An exemplary apparatus  500  suitable for delivering a clip of the present invention is shown in  FIG. 9 . Other suitable apparatus that may be used to deliver a clip of the present invention are disclosed in co-pending U.S. application Ser. No. 10/081,723, filed on the same day as the present application and entitled “Apparatus and Methods for Delivering a Closure Device” (attorney docket no. 262/280), which is assigned to the assignee of the present application. The disclosures of this application and any references cited therein are expressly incorporated by reference.  
      Generally, the apparatus  500  includes an introducer sheath  552 , and a housing or carrier assembly  554  slidably disposed on the sheath  552 . The sheath  552  includes a substantially flexible or semi-rigid tubular body  558  including a lumen  560  extending between its proximal and distal ends  562 ,  564 . The distal end  564  has a size and shape configured to facilitate insertion into a blood vessel, e.g., having a tapered tip for facilitating substantially atraumatic introduction through the passage and at least partially into the vessel. The lumen  560  has a size for inserting one or more devices therethrough, such as a catheter, guidewire, and the like (not shown). The sheath  552  also preferably includes one or more seals (not shown), such as a hemostatic valve, within the lumen  560  at or near the proximal end  562  that provides a fluid-tight seal, yet accommodates inserting one or more devices into the lumen  560  without fluid passing proximally from the sheath  552 .  
      Optionally, the sheath  552  may include a side port  566  that communicates with the lumen  560 , for example, to deliver fluids into the lumen  560 . Alternatively, or in addition, the side port  566  may be used to provide a “bleed back” indicator. An exemplary “bleed back” indicator and related methods of use are disclosed in co-pending application Ser. No. 09/680,837, filed Oct. 6, 2000, entitled “Apparatus and Methods for Positioning a Vascular Sheath,” which is assigned to the assignee of the present application. The disclosure of this application and any other references cited therein are fully incorporated by reference herein.  
      The apparatus  500  may also include a mechanical locator or obturator  600 , such as that disclosed in U.S. application Ser No. 10/081,723 (attorney docket no. 262/280), incorporated by referenced above, that may be part of an actuator assembly (not shown) that is attachable to the proximal end of the sheath  552 . Alternatively, the mechanical locator or obturator  600  may be a separate device that is insertable into the lumen  560 , e.g., through the actuator assembly. Generally, the obturator  600  is an elongate member including a distal tip  614  and a distal portion  616 . The distal tip  614  may be substantially soft and/or flexible such that the distal tip  614  may substantially atraumatically enter the vessel  590  (not shown, see  FIGS. 10A-10D ). The distal portion  616  generally includes one or more wings or other expandable elements  618  for providing tactile feedback, as described further below.  
      The carrier assembly  554  is slidably disposed on an exterior of the sheath  552 , and is configured for releasably carrying a clip  110  (shown in phantom), which may any of the clips described herein. The carrier assembly  554  may be substantially permanently attached to the sheath  552  and/or may be actuated from the proximal end  562  of the sheath  552 , for example, by the actuator assembly (not shown), to advance the clip  110  distally during deployment. Alternatively, the clip  110  may be carried by an actuator assembly, as disclosed in co-pending U.S. application Ser. No. 10/081,725, filed on the same day as the present application and entitled “Sheath Apparatus and Methods for Delivering a Closure Device,” which is assigned to the assignee of the present application (attorney docket no. 267/117). The disclosures of this application and any references cited therein are expressly incorporated herein by reference.  
      Turning to FIGS.  10 A-D, the apparatus  500  may be used to deliver the clip  110  to close and/or seal an incision, puncture, or other passage  592  that extends from a patient&#39;s skin  594 , through intervening tissue  596 , and into a wall  598  of a vessel  590  or other body lumen. Alternatively, the apparatus  500  may be used to deliver the clip  110  to engage tissue in other procedures, e.g., to connect tissue segments together or otherwise to secure tissue structures with respect to one another. For example, the apparatus  500  and clip  110  may be used to attach an anastomosis during a bypass procedure. It will be appreciated by those skilled in the art that the clip  110  and/or apparatus  500  may be useful in a variety of procedures.  
      As shown in  FIG. 10A , the sheath  552  may be inserted or otherwise positioned within the vessel  590 , i.e., through the passage  592 . The sheath  552  may be advanced over a guidewire or other rail (not shown) previously positioned through the passage  592  into the vessel  590  or advanced in conjunction with a pointed stylet directly through tissue using conventional procedures. Preferably, the vessel  590  is a peripheral vessel, such as a femoral, radial, or carotid artery, although other body lumens may be accessed using the sheath  552 , as will be appreciated by those skilled in the art.  
      The passage  592 , and consequently the sheath  552 , may be oriented at an angle “alpha” with respect to the vessel  590 , thereby facilitating introducing devices through the lumen  560  of the sheath  552  into the vessel  590  with minimal risk of damage to the vessel  590 . One or more devices, such as a guide wire, a catheter, and the like (not shown), may be inserted through the sheath  552  and advanced to a desired location within the patient&#39;s body. For example, the devices may be used to perform a therapeutic or diagnostic procedure, such as angioplasty, atherectomy, stent implantation, and the like, within the patient&#39;s vasculature.  
      After the procedure is complete, any devices used during the procedure may be removed from the sheath  552 , and the obturator  600  may be inserted into the lumen  560 . For example, the obturator  600  may be part of an actuator assembly (not shown), and may be advanced through the lumen when the actuator assembly is attached to the proximal end of the sheath  552 . Alternatively, the actuator assembly and obturator  600  may be coupled separately to the sheath  552 .  
      When the obturator  600  is fully inserted within the sheath  552 , the distal portion  616  of the obturator  600  may extend beyond the distal end  564  of the sheath  552 . In an alternative embodiment, the obturator  600  may be attached to an exterior surface (not shown) of the sheath  552 , for example, along a track, e.g., including cooperating slots, grooves, and the like (not shown) in the sheath  552  and obturator  600 .  
      Turning to  FIG. 10B , the expandable elements  618  on the distal portion of the obturator  600  may then be directed to their expanded configuration, for example, by activating a switch on the proximal end (not shown) of the obturator  600 . With the sheath  552  and obturator  600  coupled to one another, the sheath  552  and obturator  600  may be moved in conjunction with one another.  
      As shown in  FIG. 10C , the sheath  552  may be partially withdrawn from the vessel  590 , until the expandable elements  618  contact the wall  598  of the vessel  590 . Thus, the expandable elements  618  may provide a tactile indication of the position of the sheath  552  with respect to the wall  598  of the vessel  590 . In addition, the expandable elements  618  may assist in “presenting” the wall  598  of the vessel  590 , e.g., for receiving the clip  110 .  
      Generally, the clip  110  is carried by the carrier assembly  554  before the procedure. The clip  110  may be constrained in its transverse configuration on the carrier assembly  554 , and the carrier assembly  554  may be provided on or adjacent the proximal end of the sheath  552 . Because the tines, which may include primary and secondary tines  114 ,  116  may be biased towards one another, the tines  114 ,  116  may slidably contact an inner surface (not shown) of the carrier assembly  554  or an outer surface of the sheath  552 , thereby constraining the clip  110  in its transverse configuration.  
      Turning to  FIG. 10D , with the sheath  552  properly positioned, the carrier assembly  554  may then be actuated, for example, to advance the carrier assembly  554  distally over the sheath  552  to deliver the clip  110 . Preferably, the carrier assembly  554  may only be advanced a predetermined fixed distance relative to the distal end of the sheath  552 , and consequently, the expandable elements  618  of the obturator  600 , such that the clip  110  substantially engages the wall  598  of the blood vessel  590 . This predetermined distance may facilitate properly deploying the clip  110  with respect to the wall  598  of the vessel  590 , e.g., to prevent advancing the clip  110  too far, i.e., into the vessel  590 .  
      As the clip  110  is deployed from the carrier assembly  554 , the clip  110  may be expanded to an enlarged diameter. For example, a distal end of the carrier assembly  554  may include a ramped region (not shown) that may deflect the tines  114 ,  116 , and/or the body of the clip  110  radially outwardly. As the clip  110  is advanced over the ramped region, the tines  114 ,  116  may be deflected radially outwardly as they are being driven into the surrounding tissue, thereby engaging a larger region of tissue than if the tines  114 ,  116  had been maintained substantially axially.  
      Alternatively, the clip  110  may include expandable looped elements and/or spring elements (not shown), such as those described above, that may facilitate expanding the clip  110  as it is deployed from the carrier assembly  554  and/or the sheath  552 . For example, the looped elements of the clip  110  may be compressed when the clip  110  is loaded into the carrier assembly  554 , e.g., thereby allowing a relatively smaller profile carrier assembly  554  to be used. The clip  110  may automatically expand upon deployment from the carrier assembly  554  to engage a larger region of tissue surrounding the opening, such as an arteriotomy  591  in the wall  598  of the vessel  590  (see  FIG. 11A ).  
      Once the clip  110  is deployed entirely or otherwise released from the sheath  552 , the clip  110  may resiliently move towards its substantially planar configuration, such as that shown in  FIG. 1B .  
      During delivery of the clip  110 , radiopaque markers (not shown) on the clip  110 , the carrier assembly  554 , and/or the expandable members  618  may be monitored, e.g., using fluoroscopy, to facilitate observing and/or positioning the apparatus  500 . Thus, a relative position of the clip  110  with respect to the expandable elements  618 , and consequently to the wall  598  of the vessel  590 , may be ascertained before the clip  110  is deployed from the carrier assembly  554 .  
      Turning to  FIGS. 11A and 11B , in a preferred embodiment, the expandable elements  618  of the obturator  600  may be rotationally offset from the one or more tines  114  on the clip  110 . For example, if the clip  110  includes primary tines (such as those shown in  FIGS. 2A and 3 ), the obturator  600  and clip  110  may have a predetermined relative angular orientation about the central axis  124 . Preferably, the clip  110  is loaded onto the carrier assembly  554  in a predetermined angular orientation and the obturator  600  is receivable in the sheath  552  only in a predetermined angular orientation that is offset such that the tines  114 ,  116  are out of axial alignment with the expandable elements  618 , as shown in  FIG. 11A .  
      This predetermined rotational orientation may substantially minimize the possibility of the primary tines  114  contacting and/or damaging the expandable elements  618 . For example, with particular reference to  FIG. 11A , a preferred relative angular orientation of the clip  100  and obturator  600  is shown relative to an arteriotomy  591  in the wall  598  of the vessel  590 . Here, the expandable elements  618  are oriented to crisscross diagonally the arteriotomy  591  within the interior of the vessel  590 . Generally, because of the natural structure of the tissue in the wall of a vessel, an arteriotomy generally tends to adopt an elongate shape that extends transversely to the direction of flow (i.e., across the circumference of the vessel wall).  
      The primary tines  114  are oriented such that the primary tines  114  pierce the wall  598  of the vessel  590  on either side of the arteriotomy  591 , as shown. With the expandable elements  618  crisscrossing diagonally, risk of contact with the primary tines  114  is substantially reduced. Thus, the primary tines  114  may be sufficiently long to extend entirely through the wall  598  of the vessel  590  while avoiding the expandable elements  618 .  
      The expandable elements  618  may then be collapsed and/or withdrawn into the distal end  564  of the sheath  552 . As the clip  110  is released entirely from the sheath  552 , the primary tines  114  may partially overlap, as shown in  FIG. 11B , thereby pulling the arteriotomy  591  closed, similar to a single-thread suture. For example, the expandable elements  618  may be automatically collapsed immediately before or after the clip  110  is deployed from the carrier assembly  554  or when the carrier assembly  554  reaches its extreme distal position. Preferably, the distal portion  616  of the obturator  600  is collapsed and retracted into the sheath  554  after the primary tines  114  have pierced the wall  598  of the vessel  590 , but before the clip  110  is entirely released from the sheath  552 .  
      In addition, if the clip  110  includes secondary tines  116  (such as those shown in  FIG. 2A ), the secondary tines  116  may partially penetrate the wall  598  of the vessel  590  during deployment of the clip  110 . Preferably, the lengths of the secondary tines  116  are relatively short or stop members (not shown) may be provided that prevent the secondary tines  116  from piercing entirely through the wall  598 . When the clip  110  is released, the secondary tines  116  may pull the tissue inwardly, behaving somewhat similarly to a purse-string suture, to enhance closing the arteriotomy  591 .  
      Once the clip  110  is successfully deployed into the wall  598  of the vessel  590 , e.g., on either side of an arteriotomy  591 , the apparatus  500  may be withdrawn from the passage  592 . The entire apparatus  500  may be removed in one step, or alternatively, the obturator  600  may first be withdrawn from the sheath  552  before withdrawing the sheath  552 , thereby leaving the clip  110  in place to close the arteriotomy  591  and/or seal the passage  592 . In addition, if desired, a sealant or other material may be introduced into the passage  592  in conjunction with or separate from delivery of the clip  110  to further seal the passage  592 , as is known to those skilled in the art.  
      While the invention is susceptible to various modifications, and alternative forms, specific examples thereof have been shown in the drawings and are herein described in detail. It should be understood, however, that the invention is not to be limited to the particular forms or methods disclosed, but to the contrary, the invention is to cover all modifications, equivalents and alternatives falling within the spirit and scope of the appended claims.