Abstract:
A method that includes locating an opening in tissue by advancing a member through the opening in tissue and following locating the opening, deploying a medical device to aid with sealing the opening. The medical device includes a plurality of strut members forming a plurality of generally diamond-shaped openings, the plurality of strut member being configured to form an annular shaped structure with the generally diamond-shaped openings extending generally longitudinally relative to a longitudinal axis of the medical device. The medical device further includes a plurality of tissue engaging portions associated with the plurality of struts, each tissue engaging portion being disposed between adjacently positioned generally diamond-shaped openings.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This a continuation application of U.S. patnent application Ser. No. 11/396,141, filed 31 Mar. 2006, now U.S. Pat. No. 8,690,910, which is (i) a continuation-in-part application of U.S. patent application Ser. No. 10/787,073, filed Feb. 24, 2004, now U.S. Pat. No. 7,806,904, which is a continuation-in-part application of U.S. patent application Ser. No. 10/435,104, filed May 9, 2003, now U.S. Pat. No. 7,879,071, which is a divisional application of U.S. patent application Ser. No. 10/081,726, filed Feb. 21, 2002, now U.S. Pat. No. 6,623,510, which is a continuation-in-part application of U.S. patent application Ser. No. 09/732,178, filed Dec. 7, 2000, now U.S. Pat. No. 6,719,777, and (ii) is also a continuation-in-part application of U.S. patent application Ser. No. 10/335,075, filed Dec. 31, 2002, now U.S. Pat. No. 7,211,101, which is a continuation-in-part application of U.S. patent application Ser. No. 10/081,726, filed Feb. 21, 2002, now U.S. Pat. No. 6,623,510, which is a continuation-in-part application of U.S. patent application Ser. No. 09/732,178, filed Dec. 7, 2000, now U.S. Pat. No. 6,719,777, each of the disclosures of which, and any references therein, are incorporated herein in their entirety by this reference. 
     This continuation application also relates to U.S. application Ser. No. 09/732,178, filed Dec. 7, 2000, now U.S. Pat. No. 6,719,777; Ser. No. 10/081,726, filed Feb. 21, 2002, now U.S. Pat. No. 6,623,510; Ser. No. 10/335,075, filed Dec. 31, 2002; Ser. No. 10/081,723, filed Feb. 21, 2002, now U.S. Pat. No. 6,942,674; Ser. No. 10/081,717, filed Feb. 21, 2002; Ser. No. 10/356,214, filed Jan. 30, 2003 and Ser. No. 10/638,115, filed Aug. 8, 2003, the disclosures of which, and any references therein, are incorporated herein in their entirety by this reference. 
    
    
     BACKGROUND OF THE INVENTION 
     1. The 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. 
     2. The Relevant Technology 
     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 introduction of various devices into the vessel, while minimizing trauma to the vessel wall and/or minimizing blood loss during a procedure. 
     Upon completion of 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. 
     BRIEF 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 accordance with one aspect of the present invention, a device for closing an opening in a body lumen is provided that includes a generally annular-shaped body defining a plane, and a plurality of tissue engaging portions extending from the annular-shaped body substantially transversely with respect to the plane. In this embodiment, opposing tissue engaging portions, e.g., tines, are biased towards a substantially planar configuration lying in the plane. In one embodiment, the tissue engaging portions are biased towards one another, e.g., to close a puncture site or other opening through tissue. Alternatively, the tissue engaging portions may be biased away from one another. 
     In accordance with one aspect, the tissue engaging portions are integrally formed with the annular-shaped body, e.g., from a sheet of material, such as Nitinol or other superelastic alloy. The tissue engaging portions may be formed with the sheet of material in the substantially planar configuration. The tissue engaging portions may be deflected substantially transversely with respect to the plane to define a substantially transverse configuration. Alternatively, the device may be formed from an elongate wire or tube that may be wound to form an enclosed body. 
     In accordance with another aspect, the tissue engaging portions, e.g., tines, optionally including barbs, for penetrating tissue, may be disposed substantially symmetrically about a central axis. Alternatively, the tissue engaging portions may be disposed in opposing sets along a linear axis. 
     In accordance with another aspect of the present invention, a device for engaging tissue, e.g., to close an opening in a body lumen, is provided that includes a generally annular-shaped body defining a plane. A plurality of tissue engaging portions extend from the annular-shaped body substantially transversely with respect to the plane. In one embodiment, opposing tissue engaging portions of the device are biased towards a substantially planar configuration lying in the plane, as described above. 
     One or more expandable elements are disposed along a periphery of the annular-shaped body. The expandable elements are expandable between expanded and compressed states for increasing and reducing a peripheral dimension of the annular-shaped body, respectively. In one embodiment, the expandable elements may be an enclosed cell, e.g. a diamond-shaped cell, having a first width in the expanded state and a second width in the compressed state that is smaller than the first width. Alternatively, the expandable elements may be a zig-zag element or an arcuate element. The expandable elements can be biased to the expanded state, e.g., by appropriate heat treating of the expandable elements. Alternatively, the expandable elements may be biased to the compressed state. 
     In accordance with yet another aspect of the present invention, a clip, such as those described above, may be loaded on a delivery apparatus and used to close and/or seal an opening in a wall of a body lumen. The apparatus generally includes a sheath including proximal and distal ends defining a longitudinal axis there between. A housing is slidably disposed on the sheath, the housing including an annular cavity therein. A clip, such as those described above, is disposed within the cavity with the tissue engaging portions disposed substantially distally. 
     The housing can be actuable for advancing the clip distally towards the distal end of the sheath, e.g., to deploy the clip from the cavity. For example, the apparatus may include an actuator coupled to the housing, the actuator configured for advancing the housing distally to deploy the clip. The actuator includes a spring mechanism for biasing the housing distally upon activation of the actuator. In addition, the apparatus may include a locator element for positioning the distal end of the sheath, such as a bleed back lumen or a mechanical locator. 
     During use, the distal end of the sheath, with the housing and clip near its proximal end, may be positioned through a patient&#39;s skin along a passage and into a body lumen via an opening in the wall of the body lumen. One or more instruments may be introduced through the lumen of the sheath into the body lumen. A diagnostic or therapeutic procedure may be performed using the instruments at a location accessed via the body lumen. For example, the body lumen is a peripheral blood vessel, such as a femoral artery, and the procedure may include angioplasty, atherectomy, stent delivery, delivery of a therapeutic agent, and/or tissue ablation. 
     The sheath may be manipulated, for example, with the aid of a locator element, to position the distal end with respect to the opening, e.g., to ensure that the clip engages a wall of the body lumen or other tissue proximal to the opening and is not advanced into the body lumen itself. The housing is advanced distally into the passage, e.g., until the tissue engaging portions of the clip substantially engage the wall of the body lumen or other tissue proximal to the opening in the wall of the body lumen. In addition, or alternatively, the clip may be deployed from the housing, for example, by an ejector within the housing. The sheath may then be withdrawn from the body lumen and passage, leaving the clip in the passage. As the distal end of the sheath is withdrawn through the clip, the tissue engaging portions automatically at least partially move towards the planar configuration to pull the engaged tissue together and substantially close the opening. 
     In one embodiment, the clip automatically expands to an enlarged cross-section when the clip is deployed from the housing. Thus, the clip may be compressed to facilitate loading into the housing, and thereby provide a reduced profile for the clip. This may be useful to allow the clip to be delivered through a smaller puncture. 
     A method according to the present invention may include causing a clip or other closure element to engage tissue, e.g., muscle, fat, fascia, and the like, that is proximal to the body lumen. Thus, unlike previously known methods, which are directed to closing the wall of a blood vessel using clips or sutures, the present invention may include deploying a closure element in the passage to cause it to engage intermediate tissue between the patient&#39;s skin and the wall of the body lumen. When performed in this manner, the need to precisely position a closure element may be avoided as is required when engaging the wall of a vessel. Instead, the closure element may be located and delivered at a range of locations along the length of the passage yet still close and/or seal the passage. In effect, extra-vascular tissue is engaged to close the passage and thereby cause sealing of the wound. When the closure element is deployed, it can be planar, e.g., extending substantially parallel to the surface of the patient&#39;s skin, although not necessarily so. 
     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, which 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. 
     The present invention is also directed to methods for manufacturing tissue engaging clips in a manner in which a clip-precursor is first formed and such precursor is then reconfigured into the final shape of the clip. In one embodiment of the invention, a clip having an annular or hoop-shaped generally planar configuration with radially inwardly extending tines is manufactured by first forming a precursor with the tines extending radially outward and then reconfigured by inserting the precursor to its final shape with the tines extending radially inward and then heat setting the clip in this configuration. This permits the tines to be packed more closely together which enhances the sealing function of the clip and reduces the size of the clip&#39;s footprint. As will be explained in more detail herein, this manufacturing method overcomes the limitations of conventional methods in which the clip is manufactured in its final configuration. 
     In another embodiment, an annular or hoop-shaped planar clip precursor with radially inwardly extending tines is first manufactured in an oversize configuration and then has its lateral dimensions reduced to pack the tines closer together and to reduce the footprint of the clip and then heat set in that configuration. 
     The present invention is directed to vascular closure devices or clips having a design particularly suitable for closing a puncture in a wall of a blood vessel formed during a diagnostic or therapeutic procedure. According to 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 also includes 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 extend from the first curved regions, and are 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. 
     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 body or each other. 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. 
     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 any event, the primary tines of the clips of the present invention will be offset from the axis of symmetry of the loop from which they extend. The offsetting of the primary tines is achieved by simply relocating the primary tines which are directly attached to the loop to a location which is not on the axis of symmetry of the loop or providing an intermediate connecting element between the tines and the axis of symmetry of the curved region of the loop from which the tine extends. This connecting element is straight or linear, but may also be curved. The connecting element can be connected to a point or region on the axis of symmetry of the loop to enhance consistency of performance of the clip during deployment. The offsetting of the tines is believed to reduce any tendency to wander during deployment, which the tines might otherwise have. 
     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, or by the method disclosed in one or more of the incorporated by reference patents or patent applications. 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, which 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 clip may also be delivered to the desired site by using the apparatus and methods disclosed in U.S. patent application Ser. No. 10/356,214, filed Jan. 30, 2003 and Ser. No. 10/638,115, filed Aug. 8, 2003. The clip may also be manufactured according to the method set forth in U.S. patent application Ser. No. 10/335,075, filed Dec. 31, 2002. 
     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. 
     The present invention also relates to a method for closing an opening in a wall of a body lumen. The method can include advancing a distal end of an elongate member within the body lumen, the elongate member having a distal portion that assists in presenting the wall for receiving a clip having a plurality of tissue engaging portions having tips that point generally toward a central axis of the clip. Further, the method can include advancing the clip relative to the elongate member and the wall of the body lumen until the plurality of tissue engaging portions penetrate the wall of the body lumen. Optionally, the clip can be advanced until a distal end of the plurality of tissue engagement portions penetrate the wall but do not enter the body lumen. Stated another way, the method can include stopping advancement of the clip before the distal end of the plurality of tissue engagement portions enter the body lumen. Once the clip penetrates the wall, the elongate member can be withdrawn from the body lumen, leaving the clip to substantially close the opening in the wall of the body lumen. 
     According to another aspect, the method can include advancing a second elongate member relative to the elongate member, the clip slidably cooperating with the second elongate member. Withdrawing the second elongate member relative to the elongate member following penetration of the plurality of tissue engaging portions into the wall of the body lumen can enable the plurality of tissue engaging portions to automatically at least partially move towards a planar configuration to substantially close the opening. 
     The method can also related to closing a opening in a wall of a body lumen by (i) advancing a distal end of a first elongate member within the body lumen, the elongate member having a distal portion that assists in presenting the wall for receiving a clip having a plurality of tissue engaging portions symmetrically disposed about the clip, (ii) advancing the clip relative to the elongate member and the wall of the body lumen, as the distal portion of the elongate member assists with presenting the wall for receiving the clip, until the plurality of tissue engaging portions penetrate the wall of the body lumen, the tissue engaging portions and the distal portion of the elongate member being angularly offset from one another; and (iii) withdrawing the elongate member from the body lumen, leaving the clip to substantially close the opening in the wall of the body lumen. 
     To aid with positioning the clip relative to the wall, the method can further include positioning the distal portion of the first elongate member relative to the wall to assist in presenting the wall for receiving the clip to close the opening. In addition, the method can include moving the clip within a carrier assembly that moves relative to a second elongate member, toward the distal portion of the first elongate member until the clip deploys from within the carrier assembly. 
     Still another method of closing an opening in a wall of a body lumen can include advancing a distal end of a first elongate member within the body lumen, the elongate member having a distal portion that assists in presenting the wall for receiving a clip having a plurality of tissue engaging portions symmetrically disposed about the clip. The method can further include positioning a distal end of a second elongate member relative to the first elongate member, the second elongate member having a carrier assembly that receives the clip, and advancing the clip relative to the wall of the body lumen, as the distal portion of the first elongate member assists with presenting the wall for receiving the clip, until the plurality of tissue engaging portions penetrate the wall of the body lumen. Once the clip penetrates the wall, the method can include withdrawing the first elongate member and the second elongate member from the body lumen, leaving the clip to substantially close the opening in the wall of the body lumen. 
     These and other objects and features of the present invention will become more fully apparent from the following description and appended claims, or may be learned by the practice of the invention as set forth hereinafter. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       To further clarify the above and other advantages and features of the present invention, a more particular description of the invention will be rendered by reference to specific embodiments thereof which are illustrated in the appended drawings. It is appreciated that these drawings depict only typical embodiments of the invention and are therefore not to be considered limiting of its scope. The invention will be described and explained with additional specificity and detail through the use of the accompanying drawings in which: 
         FIG. 1A  illustrates a top view of a first embodiment of a clip including a plurality of tissue engaging portions in a planar orientation, in accordance with the present invention. 
         FIGS. 1B and 1C  illustrate side views of the clip of  FIG. 1A , with the tissue engaging portions oriented substantially transversely from the planar orientation, in reduced and expanded diameters, respectively. 
         FIG. 1D  illustrates a top view of the clip of  FIG. 1A  with the tines oriented substantially transversely from the planar orientation. 
         FIG. 2  illustrates a top view of another embodiment of a clip, in accordance with the present invention. 
         FIG. 3  illustrates a top view of another embodiment of a clip, in accordance with the present invention. 
         FIG. 4  illustrates a top view of another embodiment of a clip, in accordance with the present invention. 
         FIG. 5  illustrates a top view of another embodiment of a clip, in accordance with the present invention. 
         FIG. 6  illustrates a top view of the clip of  FIG. 5  with the clip unwound from its annular shape. 
         FIGS. 7A and 7B  illustrate top views of an alternative embodiment of the clip of  FIG. 5 , the clip shown unwound and including expandable elements shown in their expanded and compressed states, respectively. 
         FIGS. 8A and 8B  illustrate top views of another alternative embodiment of the clip of  FIG. 5 , the clip shown unwound and including expandable cells shown in their expanded and compressed states, respectively. 
         FIG. 9  illustrates a side view of an apparatus for delivering a clip, including an introducer sheath and an actuator assembly, in accordance with the present invention. 
         FIGS. 10A-10D  illustrates cross-sectional views of a blood vessel, showing a method for delivering a closure device into a passage communicating with the vessel such that the closure device engages the vessel wall. 
         FIGS. 11A-11D  illustrate cross-sectional views of a blood vessel, showing another method for delivering a closure device into a passage communicating with the vessel such that the closure device engages extra-vascular tissue proximal to the vessel wall. 
         FIG. 12  illustrates a top view of an alternative embodiment of a clip, in accordance with the present invention. 
         FIGS. 13-15  illustrate top views of additional embodiments of a clip, in accordance with the present invention. 
         FIG. 16A  illustrates a top view of another embodiment of a clip including a plurality of tines in a planar orientation, in accordance with the present invention. 
         FIGS. 16B and 16C  illustrate side views of the clip of  FIG. 16A , with the tines oriented substantially transversely from the planar orientation, in compressed and expanded states, respectively. 
         FIG. 17A  illustrates a top view of yet another embodiment of a clip including a plurality of tines in a planar orientation, in accordance with the present invention. 
         FIGS. 17B and 17C  illustrate side views of the clip of  FIG. 17A , with the tines oriented substantially transversely from the planar orientation, in compressed and expanded states, respectively. 
         FIG. 18  illustrates a top view of another embodiment of a clip, in accordance with the present invention. 
         FIG. 19  illustrates a top view of an embodiment of a clip having radiopaque markers thereon. 
         FIG. 20  illustrates a top view of an embodiment of a clip having pockets for holding radiopaque markers therein. 
         FIG. 21  illustrates a top view of another embodiment of a clip including stop elements, in accordance with the present invention. 
         FIG. 22  illustrates a top view of yet another embodiment of a clip including stop elements, in accordance with the present invention. 
         FIG. 23  illustrates a top view of still another embodiment of a clip including stop elements, in accordance with the present invention. 
         FIG. 24  illustrates a side view of an apparatus, including an introducer sheath and an obturator, suitable for delivering a clip of the present invention. 
         FIGS. 25A-25D  illustrate 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. 24 . 
         FIG. 26A  illustrates a top view of the blood vessel of  FIGS. 25A-25D , 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. 26B  illustrates Figure a top view of the blood vessel of  FIG. 26A , showing the arteriotomy being closed by the clip. 
         FIG. 27  illustrates a top view of an embodiment of a clip having arcuate tines, in accordance with the present invention. 
         FIGS. 28A and 28B  illustrate the before and after configuration of a clip manufactured according to one embodiment of this invention. 
         FIGS. 29A and 29B  illustrate the before and after-configuration of a clip manufactured according to another embodiment of the invention. 
         FIGS. 30A, 30   b , and  30 C illustrate alternate before and after-configurations of clips manufactured according to the method of this invention. 
         FIG. 31  illustrates a clip which, while generally planar, has tines which extend radially inwardly at an angle to the plane defined by the body. 
         FIGS. 32 and 33  illustrate clip precursors in which radially opposed primary tines have different lengths. 
         FIG. 34  illustrates one relationship between the grain orientation of a Nitinol sheet and the primary tines of a clip precursor. 
         FIG. 35A  illustrates a top view of a clip including a plurality of tines in a planar orientation, in which the primary tines are offset from the axis of symmetry of the loop from which they extend and are connected to a curved region of the loop by a straight connecting element in accordance with the present invention. 
         FIGS. 35B and 35C  illustrate side views of the clip of  FIG. 35A , with the tines oriented substantially transversely from the planar orientation, in compressed and expanded states, respectively. 
         FIG. 36  illustrates a clip according to the present invention in which the primary tines overlap with the body of the clip. 
         FIGS. 37A-37C  illustrates top views of clips in which the primary tines are offset from the axis of symmetry of the loop from which they extend by a connecting element which is at least partially curved. 
         FIG. 38  illustrates a clip in which the primary tines have different lengths. 
     
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     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. 
     Turning now to the drawings,  FIGS. 1A-1D  show a first embodiment of a closure device or clip  10  for closing an incision, puncture, or other passage communicating with a blood vessel or other body lumen (not shown). The clip  10  includes a peripheral body  12  and a plurality of tissue engaging portions  14 . Each tissue engaging portion  14  includes a pair of legs  16  terminating in a tine  18  configured for penetrating or otherwise engaging tissue. The tines  18  may include a variety of known pointed tips, such as a bayonet tip, and/or may include barbs (not shown) along an edge or planar surface of the tine  18 . The tissue engaging portions  14  are disposed substantially symmetrically about a central axis  24 . The body  12  also can include a plurality of expandable cells  20  that are connected by hinged regions  22  that also connect adjacent tissue engaging portions  14 . 
     In another embodiment, the body  12  and tissue engaging portions  14  are integrally formed from a single sheet of material, such as a superelastic alloy, such as a nickel-titanium (“Nitinol”) alloy. Portions of the sheet may be removed using conventional methods, such as laser cutting, chemical etching, and the like, to form the clip  10 .  FIG. 1A  shows the clip  10  with the tissue engaging portions  14  in a substantially planar configuration lying in a plane defined by the sheet. The clip  10  may include one or more radiopaque markers or other markers visible using external imaging, such as fluoroscopy. For example, the entire clip  10  may be coated with radiopaque material, or one or more discrete markers may be provided at predetermined locations on the clip  10 . 
     As shown in  FIGS. 1B and 1D , the tissue engaging portions  14  may be deflected such that they extend from the body  12  substantially transversely with respect the plane defined by the sheet. The tissue engaging portions  14  can be oriented substantially parallel to the axis  24  to define a transverse configuration, as shown in  FIG. 1B . Alternatively, the tissue engaging portions  14  may define an angle with respect to the axis  24 , as shown in  FIG. 1D . In the clip&#39;s transverse configuration, the body  12  has a generally annular shape, e.g., a hexagonal shape as shown in  FIG. 1D . The body  12  is sufficiently flexible such that the clip  10  assumes a generally circular or elliptical shape (not shown), e.g., conforming to an exterior surface of a delivery device (not shown) used to delivery the clip  10 . 
     The tissue engaging portions  14  can be biased from the transverse configuration towards one another, i.e., towards the planar configuration of  FIG. 1A . Thus, with the tissue engaging portions  14  in the transverse configuration, the tines  18  may be engaged with tissue, e.g. adjacent to a puncture site. When the clip  10  is released, the tissue engage portions  14  may attempt to return to the planar configuration, thereby drawing the engaged tissue together and substantially closing and/or sealing the puncture site. 
     In addition, the expandable cells  20  may be expandable from a compressed state, shown in  FIG. 1B , to an expanded state, shown in  FIG. 1C . The expandable cells  20  can be biased to the expanded state, but may be compressed to the compressed state, e.g., by constraining the clip  10 . In one embodiment, the clip  10  is formed with the expandable cells  20  in the expanded state. With the clip in its transverse configuration, the expandable cells  20  may be circumferentially and/or radially compressed to the compressed state such that the clip  10  defines a first diameter  26   a , shown in  FIG. 1B . The clip  10  may be constrained at the first diameter, e.g., by loading the clip  10  into a delivery device (not shown), as described further below. When released from the constraint, e.g., when deployed from the delivery device, the clip  10  may automatically expand to a second diameter  26   b , shown in  FIG. 1C . Thus, the expandable cells  20  may reduce the profile of the clip  10  during delivery, e.g., to facilitate introduction of the clip  10  through a smaller puncture or other passage. 
     In an alternative embodiment, the clip  10  may be formed from a shape memory alloy, e.g., Nitinol, with the expandable cells in the compressed state. With the clip  10  in 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 expandable cells  20  to the expanded state and expanding the clip  10  to the second diameter  26   b . The expandable cells  20  may then be heat treated to cause the expandable cells  20  to “remember” the expanded state, as is known to those skilled in the art. It may also be necessary to subsequently heat treat the clip  10  further, e.g. with the tissue engaging portions  14  in the planar configuration to cause the tissue engaging portions  14  to “remember” and be biased to the planar configuration, as is known to those skilled in the art. 
     Turning to  FIG. 2 , another embodiment of a clip  110  is shown that includes a peripheral body  112  and a plurality of tissue engaging portions  114 . Each tissue engaging portion  114  includes a pair of legs  116  terminating in a tine  118 . The tissue engaging portions  114  are disposed substantially symmetrically about a central axis  124 . The body  112  also can include a plurality of expandable cells  120  that are connected by hinged regions  122  that also connect adjacent tissue engaging portions  114 , similar to the first embodiment described above. 
     The tissue engaging portions  114  may be deflected such that they extend substantially transversely from the body  112  (not shown). The tissue engaging portions  114  may be oriented substantially parallel to the axis  124  to define a transverse configuration such that the body  112  has a generally annular shape. The tissue engaging portions  114  can be biased from the transverse configuration towards one another, i.e., towards the planar configuration of  FIG. 2 , similar to the previous embodiment. 
     The expandable cells  120  have a generally arcuate shape that may be expandable from a first width to a second wider width (not shown), behaving similarly to the diamond-shaped cells of the previous embodiment. Thus, the expandable cells  120  may be biased to the expanded state, but may be compressed to the compressed state, as described above. 
     Turning to  FIG. 3 , another embodiment of a clip  210  is shown that includes a peripheral body  212  including a plurality of arms  216  extending between tissue engaging portions or tines  214 ; expandable cells  220 , and hinged regions  222 . The clip  210  can be formed from a single sheet of material, similar to the embodiments described above, with the tines  214  biased to a planar configuration, as shown. The body  212  is deflectable to a transverse configuration (not shown) such that the tines  212  are oriented substantially transversely with respect to the plane of the sheet. The body  212 , and particularly the arms  216 , are sufficiently flexible such that the clip  210  may assume a generally annular shape in the transverse configuration, e.g., to facilitate loading of the clip  210  onto a delivery device (not shown). 
     The expandable cells  220  are substantially enclosed loops that may at least partially open from a compressed state (shown in  FIG. 2 ), to an expanded state (not shown). The loops can be biased to the expanded state, similar to the embodiments described above, thereby allowing the clip  210  to assume a reduced diameter and an expanded diameter. 
     Turning to  FIG. 4 , another embodiment of a clip  310  is shown, that is similar to the embodiment shown in  FIG. 3 , except that the clip  310  includes only two expandable cells  320 . The expandable cells  320  are still disposed in a substantially symmetrical arrangement to facilitate expansion of the clip  310  in a generally uniform manner. As will be appreciated by those skilled in the art, a clip in accordance with the present invention may have a variety of configurations, including two or more tissue engaging portions or tines, and including one or more expandable cells (or optionally no expandable cells). The tissue engaging portions and/or expandable cells can be arranged in a substantially symmetrical configuration, for example, about a central axis. 
     Turning to  FIG. 5 , another embodiment of a clip  410  is shown that includes a peripheral body  412  and a plurality of tissue engaging portions  414  terminating in tines  418 . The clip  410  may be formed from a single sheet of material, such as Nitinol, similar to the embodiments described above. 
     Alternatively, as shown in  FIG. 6 , the clip  410  may be formed from an elongate wire  430 , e.g., a solid rod or hollow tube, such as a length of hypotube. The tube  430  can be semi-rigid or flexible, thereby accommodating deflection of the clip  410  between its planar and transverse configurations, as described further below. The tube  430  may be bent and tines  418  may be formed therein using conventional methods. Alternatively, tines  418  may be formed separately and attached to the tube  430 , for example, by welding. The tube  430  may then be wound into an enclosed loop and the ends  432 ,  434  may be connected together, e.g., by welding, to provide a clip  410 , such as that shown in  FIG. 5 . 
     In this embodiment, the tissue engaging regions  414  are disposed in opposing sets along an axis of symmetry  424  extending between looped regions  426 , defining a substantially planar configuration. The tissue engaging portions  414  may be directed substantially transversely with respect to a plane defined by the planar configuration, but can be biased to return towards the planar configuration, similar to the embodiments described above. 
     In an alternative embodiment, shown in  FIGS. 7A and 7B , the regions  426 ′ between the tissue engaging portions  414  include expandable elements  420 , having a zig-zag shape, that are expandable between a compressed state and an expanded state. Thus, when the tube  412 ′ is wound to form a clip (not shown), the zig-zag elements  420  are disposed at the looped regions  426 ′ of the clip. The zig-zag elements  420  have a first width w 2  in the compressed state ( FIG. 7B ) and a second width w 2  in the expanded state that is larger than the first width ( FIG. 7A ). In a further alternative embodiment, shown in  FIGS. 8A and 8B , the expandable elements are substantially enclosed cells  420 ′, optionally having a diamond shape. Thus, similar to the embodiments described above, the expandable elements or cells allow the clip  410 ″ to assume first and second diameters. 
     Turning to  FIG. 9 , an apparatus  50  is shown that may be used to deliver a clip, such as any of the embodiments described above. Generally, the apparatus  50  includes an introducer sheath  52 , and a housing  54  slidably disposed on the sheath  52 . The sheath  52  includes a substantially flexible or semi-rigid tubular body  58  including a lumen  60  extending between its proximal and distal ends  62 ,  64 . The distal end  64  has a size and shape 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  60  has a size for accommodating insertion of one or more devices therethrough, such as a catheter, guidewire, and the like (not shown). The sheath  52  also can include a seal (not shown), such as a hemostatic valve, within the lumen  60  at or near the proximal end  62  that provides a fluid-tight seal, yet accommodates insertion of one or more devices into the lumen  60  without fluid passing proximally from the sheath  52 . 
     Optionally, the sheath  52  may include a side port  66  that communicates with the lumen  60 , for example, to allow the infusion of fluids into the lumen  60 , through the sheath  52 . Alternatively, or in addition, the side port  66  may be used to provide a “bleed back” indicator, such as that disclosed in U.S. Pat. No. 6,626,918, entitled “Apparatus and Methods for Positioning a Vascular Sheath,” which is assigned to the assignee of the present invention, and the disclosures of which, and any references therein, are incorporated herein in their entirety by this reference. Alternatively, the apparatus  50  may include a mechanical locator (not shown), such as that disclosed in U.S. Pat. No. 6,780,197, filed on the same day with U.S. Pat. No. 6,719,777, entitled “Apparatus and Method for Delivering a Closure Device,” the disclosures of which, and any references therein, are incorporated herein in their entirety by this reference. 
     The housing  54  is slidably disposed on an exterior of the sheath  52 , the housing  54  configured for releasably holding the clip  10 , e.g., within an annular cavity therein (not shown). The housing may be substantially permanently attached to the sheath  52  or, alternatively, the housing  54  may be attachable to the sheath  52 , e.g., using an outer sleeve (not shown). This outer sleeve may have the housing thereon, and the sleeve may be advanced over the sheath  52 , and coupled thereto at any time during its use. Exemplary embodiments of a housing for use with an apparatus in accordance with the present invention are disclosed in U.S. Pat. Nos. 6,197,042, 6,461,364, and 6,391,048, the disclosures of which, and any references therein, are incorporated herein in their entirety by this reference. 
     The housing  54  is actuable from the proximal end  62  of the sheath  52 , for example, by a housing actuator assembly (not shown), for advancing the clip  10  distally during deployment. A rod, cable, or other control wire (not shown) may couple the housing  54  to the actuator assembly. The housing actuator assembly may be detachable from the sheath  52 , e.g., to facilitate introduction of devices into the lumen  60 . In one embodiment, the actuator may be biased to advance the housing  54  upon activation. Thus, when activated, the housing  54  may be advanced towards the distal end of the sheath  52  to deploy the clip  10 . 
     Turning to  FIGS. 10A-10D , the apparatus  50  may be used to deliver a clip  10 , e.g., to close and/or seal an incision, puncture, or other passage  92  that extends from a patient&#39;s skin  94  through intervening tissue  96 , and a wall  98  of the vessel  90 . Alternatively, the apparatus  50  may be used to deliver any of the clips disclosed herein to engage tissue in other procedures, e.g., to connect tissue segments together or otherwise to secure tissue structures engaged by the clip with respect to one another. For example, the apparatus and clip may be used to attach an anastomosis during a bypass procedure. It will be appreciated by those skilled in the art that a clip and/or apparatus in accordance with the present application may be useful in a variety of procedures, including tubal ligations, and the like. 
     Generally, the clip  10  is pre-loaded in the housing  54  before the procedure. The clip  10  may be constrained in its substantially transverse configuration and then introduced over the distal end  64  of the sheath  52  and into the cavity or otherwise loaded in the housing  54 . Because the tissue engaging portions (not shown) of the clip  10  are biased to a planar configuration, they may engage an inner wall (not shown) of the housing  54  or an outer surface of the sheath  52 , thereby constraining the clip  10  in its transverse configuration. Alternatively, the clip  10  may be directed over the distal end  64  of the sheath  62 , thereby causing the tissue engaging portions to deflect transversely from the planar configuration towards a substantially axial or distal configuration. 
     As shown in  FIG. 10A , the sheath  52  may be inserted or otherwise positioned within the blood vessel  90 , i.e., through the passage  92 . The sheath  52  can be provided with the housing  54  in its proximal position, e.g., without the housing actuator assembly (not shown) attached. Alternatively, the housing actuator assembly may be provided attached to the sheath  52  as long as the lumen  60  may be accessed. In a further alternative, the housing  54  may be provided separately from the sheath  62  with the clip  10  preloaded therein. For example, the housing  54  may be provided on an elongate member, such as a tubular or U-shaped sleeve (not shown), that may be advanced over and coupled to the sheath  52  at any time before deployment of the clip  10 . The housing actuator may be coupled to the sleeve and/or may be attachable to the sleeve. 
     The sheath  52  may be advanced over a guidewire or other rail (not shown) previously positioned through the passage  92  into the blood vessel  90  using a conventional procedure. The blood vessel  90  can be a peripheral vessel, such as a femoral, radial, or carotid artery, although other body lumens may be accessed using the sheath  52 , as will be appreciated by those skilled in the art. 
     The passage  92 , and consequently the sheath  52 , may be oriented at a substantially acute angle “alpha” with respect to the vessel  90 , thereby facilitating introduction of devices through the lumen  60  of the sheath  52  into the vessel  90  with minimal risk of damage to the vessel  90 . One or more devices, such as a guide wire, a catheter, and the like (not shown), may be inserted through the sheath  52  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, the device(s) may be removed from the sheath  52 . The sheath  52  may be manipulated to position the distal end  64  with respect to the opening  92 , e.g., to ensure that the housing  54  is advanced to properly deploy the clip  10  in the wall  98  of the vessel  90 . Bleed back or mechanical locators may be used to facilitate this positioning. 
     As shown in  FIG. 10B , with the sheath  52  properly positioned, the housing  54  may be actuated, for example, to advance the housing  54  distally into the passage  92  to deliver the clip  10 . Movement of the housing  54  with respect to the distal end  64  of the sheath  52  can be limited, e.g., by the actuator assembly. Thus, the housing  54  may only be advanced a fixed distance such that the clip  10  substantially engages the wall  98  of the blood vessel  90 , e.g., until the tines  18  penetrate but do not pass completely through the wall  98 . Once the clip  10  is successfully deployed within the passage  92 , i.e., into the wall  98  of the vessel  90 , the apparatus  50  may be withdrawn from the passage  92 . 
     In addition, as the clip  10  is deployed from the housing  54 , the clip  10  may expand radially to an enlarged diameter (not shown), for example, if the clip  10  includes expandable elements (not shown), such as those described above. Thus, the clip  10  may be compressed into the housing  54 , e.g., thereby allowing a smaller profile housing  54  to be used. The clip  10  may be expanded upon deployment to engage a larger area of tissue adjacent the opening in the wall  98  of the vessel  90 . 
     As shown in  FIG. 10C , as the distal end  64  of the sheath  52  is withdrawn proximally from around the clip  10 , the tines  18  of the clip  10  are free to return towards the planar configuration. Thus, the tines  18  begin automatically to move from a substantially axial configuration to a less transverse configuration. Because the tines  18  are engaged to the tissue, however, they may not return completely to the planar configuration. Because of the bias to the planar configuration, however, the tines  18  automatically pull the tissue together, thereby closing and/or sealing the passage  92 , as shown in  FIG. 10D . In addition, if desired a sealant or other material may be introduced into the passage  92  in conjunction with or separate from delivery of the clip  10  to further seal the passage  92 , as is known to those skilled in the art. 
     Turning to  FIGS. 11A-11C , another method is shown in which the apparatus  50  may be used to deliver a clip  10 , e.g., to engage intervening tissue  96  to close and/or seal an incision, puncture, or other passage  92  that extends from a patient&#39;s skin  94  through the intervening tissue  96 , to a wall  98  of the vessel  90 . As shown in  FIG. 11A , the sheath  52  may be inserted or otherwise positioned within the blood vessel  90 , i.e., through the passage  92 . One or more devices (not shown) may be inserted through the sheath  52  to perform a procedure within the patient&#39;s body. After the procedure is complete, the device(s) may be removed from the sheath  52 , and the sheath  52  may be manipulated to position the distal end  64  within the passage  92 . 
     Turning to  FIG. 11B , with the sheath  52  properly positioned, the housing  54  may be actuated, for example, to advance the housing  54  distally into the passage  92  to deliver the clip  10  to a location between the patient&#39;s skin  94  and the vessel wall  98 . The clip  10  may be deployed from the housing  54 , thereby substantially engaging fascia or other intervening tissue  96  with the tines  18 . Once the clip  10  is successfully deployed within the passage  92 , the apparatus  50  may be withdrawn from the passage  92 . 
     As shown in  FIG. 11C , as the distal end  64  of the sheath  52  is withdrawn proximally from around the clip  10 , the tines  18  of the clip  10  are free to return towards the planar configuration. Because of the bias to the planar configuration, the tines  18  automatically pull the tissue together, thereby closing and/or sealing the passage  92 , as shown in  FIG. 10D . 
     In a further alternative, shown in  FIG. 12 , a clip  450  may be provided that includes a first set of tines  418  having a first length l 1 , and a second set of tines  419  having a second length l 2  substantially shorter than the first length l 1 . During use, similar to one of the methods described above, the clip  450  may be deployed such that the first set of tines  418  penetrate into and/or engage the wall of a blood vessel or other body lumen (not shown), while the second set of tines  418  engage extra-vascular tissue, i.e., tissue between the vessel wall and the patient&#39;s skin. Thus, the clip  450  may simultaneously close both the opening in the vessel wall and the passage through the intervening tissue. 
     Turning to  FIG. 13 , another embodiment of a clip  510  is shown for engaging tissue, in accordance with the present invention. The clip  510  includes a peripheral body  512  and a plurality of tissue engaging portions  514 . Each tissue engaging portion  514  includes a pair of legs  516  terminating in a tine  518  configured for penetrating or otherwise engaging tissue. The tissue engaging portions  514  are disposed substantially symmetrically about a central axis  524 . The body  512  also can include a plurality of expandable cells  520  that are connected by hinged regions  522  that also connect adjacent tissue engaging portions  514 , the cells  520  behaving similar to the embodiments described above. 
     In another embodiment, the body  512  and tissue engaging portions  514  are integrally formed from a single sheet of material, such as a Nitinol, similar to the embodiments described above. The clip  510  is shown in a relaxed state with the tissue engaging portions  514  disposed radially outward in a substantially planar configuration. Similar to the previous embodiments, the tissue engaging portions  514  may be deflected such that they extend from the body  512  substantially transversely with respect the plane defined by the sheet (similar to  FIG. 1B ). 
     The tissue engaging portions  514  can be biased from the transverse configuration away from one another, i.e., towards the planar configuration. Thus, with the tissue engaging portions  514  in the transverse configuration, the tines  518  may be engaged with tissue. When the clip  510  is released, e.g., from within a delivery device, the tissue engage portions  514  may attempt to return to the planar configuration, thereby securing the tissue with respect to the clip  510 . 
     In addition, the clip  510  may include expandable cells  520  that are expandable from a compressed state to an expanded state (similar to  FIG. 1C ), similar to the previous embodiments. The expandable cells  520  can be biased to the expanded state, but may be compressed to the compressed state, e.g., by constraining the clip  510 . Alternatively, any of the clips described herein may be biased to the compressed state but may be expanded to the expanded state, e.g., by constraining the clip over a sheath or other elongate member. 
     Turning to  FIG. 14 , yet another embodiment of a clip  610  is shown that includes a peripheral body  612  and a plurality of tissue engaging portions  614  terminating in tines  618 . The clip  610  may be formed from a single sheet of material, such as Nitinol or may be formed from a wire, rod or tube (not shown), similar to the embodiments described above. The tissue engaging regions  614  are disposed in opposing sets oriented away from one another along an axis of symmetry  624 , defining a substantially planar configuration. 
     The tissue engaging portions  614  may be directed substantially transversely with respect to a plane defined by the planar configuration, for example, by loading the clip  614  into a housing or lumen of a delivery device (not shown). The tissue engaging portions  614  can be biased to move away from one another, i.e., towards the planar configuration. In an alternative embodiment, the looped regions  626  or other regions of the body  612  may include expandable elements (not shown), e.g., having a zig-zag shape, a diamond shape, and the like. 
     Turning to  FIG. 15 , still another embodiment of a clip  710  is shown that includes a peripheral body  712  and a plurality of tissue engaging portions  714  terminating in tines  718 . The clip  710  is similar to the previous embodiment, except that the tissue engaging regions  714  are disposed in opposing sets along an axis of symmetry  724 , but are oriented in a common direction. The tissue engaging portions  714  may be directed substantially transversely with respect to a plane defined by the planar configuration. The tissue engaging portions  714  can be biased to return towards the planar configuration shown. In an alternative embodiment, the looped regions  726  or other regions of the body  712  may include expandable elements (not shown), e.g., having a zig-zag shape, a diamond shape, and the like, similar to the previous embodiments. 
     The clip  710  may be constrained on a delivery apparatus (not shown), similar to that described above, such that the tissue engaging portions  714  are all directed substantially transversely, and optionally distally, to facilitate their engagement into tissue during deployment, as will be appreciated by those skilled in the art. Unlike previous embodiments, which may close tissue around an opening, this embodiment may be useful when it is desired to maintain the relative position of tissue being engaged by the clip  710 . 
     Turning now to the drawings,  FIGS. 16A-16C  show another embodiment of a closure device or clip  810  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  810  includes a body  812 , which may be generally annular in shape and surrounds a central axis  824 , and a plurality of tines  818  extending from the body  812 . 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  812  may include a plurality of looped or curved elements  828  that are connected to one another to form the body  812 . Each looped element  828  may include an inner or first curved region  832  and an outer or second curved region  34 . In another embodiment, the first and second curved regions  832 ,  834  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  812 . When the clip  810  is in a substantially planar configuration, as shown in  FIG. 16A , the first curved regions  832  may define an inner periphery  836  of the body  812  and the clip  810 , and the second curved regions  834  may define an outer periphery  838 . 
     The plurality of tines  818  may be biased to extend generally inwardly, e.g., towards one another and/or towards the central axis  824 . The tines  818  may be disposed on the first curved regions  832 , and oriented toward the central axis  824  when the clip  810  is in the planar configuration. In another embodiment, the tines  818  may be provided in pairs opposite from one another or provided otherwise symmetrically with respect to the central axis  824 . 
     The tines  818  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  810  and/or to lower the insertion force required to penetrate tissue, each tine  818  may include a tapered edge (not shown) extending towards the tip along one side of the tine  818 . Alternatively, each tine  818  may be provided with a tapered edge on each side of the tine  818  extending towards the tip. 
     Additionally, as shown in  FIGS. 16A-16C , the tines  818  may be disposed on alternating first curved regions  832 . Thus, at least one period of a zigzag pattern may be disposed between adjacent tines  818 , which may enhance flexibility of the clip  810 , as explained further below. 
     As shown in  FIGS. 16B and 16C  (where opposite ends  833   a ,  833   b  are connected to one another), the body  812  and/or the tines  818  may be deflected such that the tines  818  extend transversely with respect to the plane defined in the planar configuration, thereby defining a transverse configuration for the clip  810 . The tines  818  can be oriented substantially parallel to the central axis  824  in the transverse configuration, as shown in  FIG. 16B . In the transverse configuration, the body  812  may have a generally annular shape defining a length, L 1 , which extends generally parallel to the central axis  824 , and corresponds generally to an amplitude of the zigzag pattern. The body  812  can be sufficiently flexible such that the clip  810  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  810 . 
     In another embodiment, the tines  818  and/or body  812  are biased to move from the transverse configuration towards the planar configuration of  FIG. 16A . Thus, with the tines  818  in the transverse configuration, the tines  818  may penetrate and/or be engaged with tissue at a puncture site. When the clip  810  is released, the tines  818  may attempt to return towards one another as the clip  810  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  828  may distribute stresses in the clip  810  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  810  during delivery. In addition, when the clip  810  is in the transverse configuration, the looped elements  828  may be movable between a compressed state, such as that shown in  FIG. 16B , and an expanded state, such as that shown in  FIG. 16C . The looped elements  828  can be biased towards the expanded state, but may be compressed to the compressed state, e.g., by constraining the clip  810 . Alternatively, only a portion of the looped elements  828  may be biased towards the expanded state, e.g., the first curved regions  832 , and/or the looped elements  828  may be biased towards the compressed state. Furthermore, the looped elements  828  reduce the force required to be exerted on the clip  810  to transition the clip  810  from the planar configuration to the transverse configuration before loading onto a delivery device (not shown). 
     With the clip  810  in the transverse configuration, the looped elements  828  may be circumferentially and/or radially compressed to the compressed state until the clip  810  defines a first diameter or circumference  826   a , such as that shown in  FIG. 16B . The clip  810  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  810  may automatically expand towards the expanded state, such as that shown in  FIG. 16C , thereby defining a second diameter or circumference  826   b . Thus, the looped elements  828  may facilitate reducing the profile of the clip  810  during delivery, e.g., to facilitate introducing the clip  10  through a smaller puncture or passage. Once the clip  810  is deployed entirely from the delivery device, the looped elements  828  may resiliently expand as the clip  810  returns towards the planar configuration, as explained further below. 
     To manufacture the clip  810  (or, similarly, any of the other clips described herein), the body  812  and the tines  818  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  818  may be sharpened to a point, i.e., tips may be formed on the tines  818  using conventional methods, such as chemical etching, mechanical grinding, and the like. 
     The clip  810  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  810 . 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  810  may be formed from a shape memory alloy, e.g., Nitinol, with the looped elements  828  formed initially in the compressed state and/or the clip  810  in the planar configuration. With the clip  810  deformed to the transverse configuration, the clip  810  may be expanded, e.g., by applying a force radially outwards against an inner surface of the clip  810 , thereby expanding the looped elements  30  to the expanded state. The looped elements  828  may then be heat treated, e.g., by heating the clip  10  to an austenitic state, to cause the looped elements  828  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  810  further, e.g., with the tines in the planar configuration to cause the body  812  and/or tines  818  to “remember” and be biased towards the planar configuration, as is known to those skilled in the art. The clip  810  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  810  onto a delivery device (not shown), as described below. Thus, if the clip  810  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. 17A-17C  show another embodiment of a closure device or clip  910  that includes a generally annular-shaped body  912  defining a plane and disposed about a central axis  9124  extending through the plane. The body  912  can include a plurality of looped elements  928  that are connected to one another to form the body  912 , similar to the previous embodiment. Each looped element  928  includes an inner or first curved region  932  and an outer or second curved region  934 . Similar to the previous embodiment, the first and second curved regions  932 ,  934  may form an endless sinusoidal pattern or other generally zigzag pattern. When the clip  910  is in a substantially planar configuration, as shown in  FIG. 17A , the first curved regions  932  may define an inner periphery  936 , and the second curved regions  934  may define an outer periphery. 
     Unlike the previous embodiment, the clip  910  includes a plurality of primary tines  916  and a plurality of secondary tines  918 . Each of the primary and secondary tines  916 ,  918  may include a variety of known pointed tips, similar to the previous embodiment. 
     Each of the primary tines  914  may have a length l 1 , although alternatively each of the primary tines  914  may have a different length than one another. The primary tines  914  may be disposed in one or more opposing pairs, e.g., on opposing first curved regions  932 , and may be oriented towards and/or across the central axis  924  in the planar configuration. In the planar configuration, the lengths l 1  may be sufficiently long such that the primary tines  914  at least partially overlap one another, i.e., extend across the central axis  924  towards an opposing tine  914 . Therefore, the tips of the primary tines  914  may extend past the central axis  924  and/or the primary tines  914  in each pair may lie substantially parallel to each other when the clip  910  is in the planar configuration. 
     Each of the secondary tines  916  may be disposed on a first or inner curved region  932 , e.g., such that one or more secondary tines  916  may be provided between opposing pairs of primary tines  914 . Each of the secondary tines  916  may have a length 1.sub.2 that is substantially less than the length l 1  of the primary tines  914 . 
     A secondary tine  916  can be is disposed on either side of each primary tine  914 . For example, the clip  910  shown in  FIGS. 17A-17C  has first and second primary tines  914 , and each of the first and second primary tines  914  has a secondary tine  916  on either side of it. Thus, the clip  910  may have a total of two primary tines  914  and four secondary tines  916 . Optionally, the secondary tines  916  may be disposed substantially symmetrically about the central axis  924 . The tines  914 ,  916  may be provided on every other first curved regions  932 . For example, a first curved region  932  having neither a primary tine  914  nor a secondary tine  916  may separate each adjacent tine, e.g., between two adjacent secondary tines  916 , or between a secondary tine  916  and a primary tine  914 . 
     As shown in  FIGS. 17B and 17C , the body  912  and/or the tines  914 ,  916  may be deflected such that they extend transversely with respect to the plane defined in  FIG. 17A . The primary tines  914  and secondary tines  916  can be oriented substantially parallel to the central axis  924  to define a transverse configuration, as shown in  FIG. 16B . In the transverse configuration, the body  912  has a generally annular shape defining a length, LE 1 , which extends generally parallel to the central axis  924 , and corresponds generally to an amplitude of the sinusoidal pattern. The body  912  can be sufficiently flexible such that the clip  910  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  914 ,  916  may be biased towards one another and/or towards the central axis  924 , i.e., due to the bias of the clip  910  towards the planar configuration of  FIG. 17A , similar to the previous embodiment. With the clip  910  in the transverse configuration, the clip  910  may be delivered such that the primary tines  914  entirely penetrate the wall of a blood vessel or other body lumen, while the secondary tines  916  only partially penetrate the wall due to their relative lengths, as explained further below. 
     The looped elements  928  may be expandable between a compressed state, as shown in  FIG. 17B , and an expanded state, as shown in  FIG. 17C , similar to the previous embodiment. The looped elements  928  can be biased to the expanded state, but may be resiliently compressed to the compressed state, e.g., by constraining the clip  910 . 
     Turning to  FIG. 18 , an alternative embodiment of a clip  1010  is shown that includes a body  912  including looped elements  930 , and primary tines  914 , similar to the previous embodiment, but has no supplemental or secondary tines  916 . The reference numbers for elements of the clip  1010  are consistent with like elements used for the clip  910 . 
     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  910  of  FIGS. 17A-17C  as an example, the entire clip  910  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  910  may be partially coated with radiopaque material by using masking techniques. For example, the entire clip  910  may first be coated with radiopaque material. The clip  910  may then be masked at locations where the radiopaque coating is desired. For example, the looped elements  928  of the clip  910  may be left unmasked during this process if it is desired to leave the looped elements  928  uncoated by radiopaque material. This may be desirable, e.g., to prevent radiopaque material from adversely affecting the flexibility of the looped elements  928 . The clip  910  may then be treated to remove the radiopaque material from the unmasked areas, in this example, the looped elements  928 . The masking may then be removed using conventional processes, leaving the rest of the clip  910  coated with radiopaque material. 
     Turning to  FIG. 19 , in another alternative, one or more discrete markers  902  may be provided at predetermined locations on the clip  910 . For example, high density or radiopaque material  902  may be crimped or otherwise secured onto opposing double looped or circular regions  928 . In another embodiment, shown in  FIG. 20 , a plurality of pockets  904  may be provided on the looped elements  928  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. 21 , another embodiment of a clip  1110  is shown that, similar to clip  910 , may include a plurality of looped elements  1128  that interconnect to form a body  1112 . Each looped element  1128  may have a first or inner curved region  1132  and a second or outer curved region  1134 . Primary tines  1114  may be disposed on opposing first curved regions  1132 , which, optionally, may include a barb  1102  thereon to enhance engagement with tissue. Secondary tines  1116  may be provided on first curved regions  1132  on either side of each primary tine  1114 . In addition, a first curved region  1132  without a tine  1114 ,  1116  may separate adjacent tines, as described above with regard to the previous embodiments. 
     The clip  1110  also includes stop members  1106  on one or more of the tines  1114 ,  1116 , e.g., adjacent the respective first curved region  1132 . Each stop member  1106  may be blunt-shaped, e.g., generally triangularly with an apex  1107  of the stop member  1106  extending from the first curved region  1132 , and the tine  1114 ,  1116  extending from a wide or blunt base  1107  of the stop member  1106 . During use, the blunt bases  1107  may limit penetration of the respective tines  1114 ,  1116  into tissue by reducing an effective length of the respective tine  1114 ,  1116 . For example, when the tines  1114 ,  1116  are driven into tissue, the tines  1114 ,  1116  may penetrate the tissue until the blunt bases  1107  contact the tissue, whereupon the tines  1114 ,  1116  may be prevented from penetrating further into the tissue. 
     Turning to  FIG. 22 , another embodiment of a clip  1210 ( i ) is shown that includes a body  1212 , a plurality of tines  1214 , and a plurality of spring elements  1240 ( i ) that interconnect between adjacent tines  1214 . The body  1212  includes outer curved regions  1234  that extend between adjacent tines  414 , thereby defining an outer periphery for the clip  1210 ( i ). The clip  1210 ( i ) may be moveable between a substantially planar configuration such as that shown in  FIG. 22 , and a transverse configuration (not shown), and can be biased towards the planar configuration, similar to the previous embodiments. 
     In the embodiment shown, the spring elements  1240 ( i ) generally are hollow diamond shaped elements, including curved inner regions  1232 ( i ) oriented towards the central axis  1224  of the body  1212  when the clip  1210 ( i ) is in the planar configuration. The spring elements  1240 ( i ) may serve multiple purposes. First, the spring elements  1240 ( i ) may bias the clip  1210 ( i ), e.g., allowing the clip  410 ( i ) to at least partially expand resiliently. For example, when the clip  1210 ( i ) is deflected into the transverse configuration (not shown), the spring elements  1240 ( i ) may allow the tines  1214  to be moved away from the central axis  1224  and/or one another. Thus, during deployment, the tines  1214  may be deflected radially outwardly or otherwise expanded to engage a larger area of tissue. 
     As the tines  414  are expanded, the spring elements  1214 ( i ) may deform to become wider (along a dimension extending generally between the adjacent tines  1214 ) and shorter (along a dimension extending generally parallel to the tines  1214 ). Once a force causing the tines  1214  to expand is removed, the spring elements  1214 ( i ) may resiliently try to return towards their original shape, thereby pulling the tines  1214  closer towards one another. 
     In addition, the curved inner regions  1232 ( i ) of the spring elements  1214 ( i ) may provide stops limiting penetration of the tines  1214  into tissue, similar to the stop members described above. For example, when the clip  1210 ( i ) is in the transverse configuration and the spring elements  1214 ( i ) are expanded, the curved inner regions  1232 ( i ) may be become more oblique, possibly becoming generally linear. Thus, when the tines  1214  are driven into tissue, the curved inner regions  1232 ( i ) may limit penetration of the tines  1214 . 
     Finally, after the clip  1210 ( i ) is deployed, e.g., the tines  1214  are penetrated into tissue, the curved inner regions  1232 ( i ) may return towards their original shape, and may pinch or otherwise engage tissue between the inner curved regions  1232 ( i ) and the adjacent tines  1214 . Thus, contracting the spring elements  1240 ( i ) may enhance the ability of the clip  1210 ( i ) to seal a puncture site, e.g., by pulling engaged tissue inwardly towards the central axis  1224  of the clip  1210 ( i ). 
     Turning to  FIG. 23 , an alternative embodiment of a clip  1210 ( ii ) is shown that is substantially similar to the clip  1210 ( i ) shown in  FIG. 22 , with the exception of the shape of the spring elements  1240 ( ii ). Rather than diamond shaped elements, the spring elements  1240 ( ii ) are looped elements generally defining a circular shape. 
     Turning now to  FIG. 27 , another embodiment of a clip  1510  of the present invention is illustrated. Similar to the previous embodiments, the clip  1510  includes a generally annular-shaped body  1512  that defines a plane. The body  1512  is disposed about a central axis  1524  that extends through the plane. The body  1512  can include a plurality of outer curved elements  1528  that extend between adjacent tines  1516  and are connected to each other to form the body  1512 . When the clip  1510  is in a substantially planar configuration, as shown in  FIG. 27 , the curved elements  1528  define an outer periphery  1538  of the clip  1510 . 
     The tines  1516  are curved or arcuately shaped and include distal tips  1515  that extend toward the central axis  1524  when the clip  1510  is in the substantially planar configuration. Optionally, one or more of the tines  1516  may include barbs  1517 , similar to the previous embodiments. The curve of the tines  1516  can all be in phase with one another such that the tines  1516  spiral about the central axis  1524 . This may allow a length of the tines  1516  to be maximized for a given diameter of the body  1512 . 
     For example, the tines  1516  may have a length that is greater than a radius of the body  1512  without the distal tips  1515  of the tines  1516  touching one another. Thus, due to the arcuate shape of each tine  1516 , the tines  1516  of clip  1510  may be generally longer than the straight tines of the previous clips having comparable diameters. The tines  1516  may, therefore, penetrate deeper into tissue than the tines of the other clips. 
     As with the previous embodiments, the body  1512  and/or the tines  1516  of clip  1510  may be deflected until the tines  1516  extend transversely with respect to the plane defined in the planar configuration, thereby defining a transverse configuration. In the transverse configuration, the tines  1516  may be oriented substantially parallel to the central axis  1524 . Additionally, as with the previous embodiments, the tines  1516  and/or body  1512  may be biased to move from the transverse configuration towards the planar configuration. The clip  1510  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  1300  suitable for delivering a clip of the present invention is shown in  FIG. 24 . Other suitable apparatus that may be used to deliver a clip of the present invention are disclosed in U.S. Pat. No. 6,942,674, which is assigned to the assignee of the present application, the disclosures of which, and any references therein, are incorporated herein in their entirety by this reference. 
     Generally, the apparatus  1300  includes an introducer sheath  1352 , and a housing or carrier assembly  1354  slidably disposed on the sheath  1352 . The sheath  1352  includes a substantially flexible or semi-rigid tubular body  1358  including a lumen  1360  extending between its proximal and distal ends  1362 ,  1364 . The distal end  1364  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  1360  has a size for inserting one or more devices therethrough, such as a catheter, guidewire, and the like (not shown). The sheath  1352  also can include one or more seals (not shown), such as a hemostatic valve, within the lumen  1360  at or near the proximal end  1362  that provides a fluid-tight seal, yet accommodates inserting one or more devices into the lumen  1360  without fluid passing proximally from the sheath  1352 . 
     Optionally, the sheath  1352  may include a side port  1366  that communicates with the lumen  1360 , for example, to deliver fluids into the lumen  1360 . Alternatively, or in addition, the side port  1366  may be used to provide a “bleed back” indicator. An exemplary “bleed back” indicator and related methods of use are disclosed in U.S. Pat. No. 6,626,918, which is assigned to the assignee of the present application, the disclosures of which, and any references therein, are incorporated herein in their entirety by this reference. 
     The apparatus  1300  may also include a mechanical locator or obturator  1400 , such as that disclosed in U.S. application Ser. No. 10/081,723, now U.S. Pat. No. 6,942,674, the disclosures of which, and any references therein, are incorporated herein in their entirety by this reference, that may be part of an actuator assembly that is attachable to the proximal end of the sheath  1352 . Alternatively, the mechanical locator or obturator  1400  may be a separate device that is insertable into the lumen  1360 , e.g., through the actuator assembly. Generally, the obturator  1400  is an elongate member including a distal tip  1414  and a distal portion  1416 . The distal tip  1414  may be substantially soft and/or flexible such that the distal tip  1414  may substantially atraumatically enter the vessel  1390  (not shown, see  FIGS. 25A-25D ). The distal portion  1416  generally includes one or more wings or other expandable elements  1418  for providing tactile feedback, as described further below. 
     The carrier assembly  1354  is slidably disposed on an exterior of the sheath  1352 , and is configured for releasably carrying a clip  910  (shown in phantom), which may any of the clips described herein. The carrier assembly  1354  may be substantially permanently attached to the sheath  1352  and/or may be actuated from the proximal end  1362  of the sheath  1352 , for example, by the actuator assembly (not shown), to advance the clip  910  distally during deployment. Alternatively, the clip  910  may be carried by an actuator assembly, as disclosed in co-pending U.S. application Ser. No. 10/081,725, now U.S. Pat. No. 6,749,621, 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, the disclosures of which, and any references therein, are incorporated herein in their entirety by this reference. 
     Turning to  FIGS. 25A-D , the apparatus  1300  may be used to deliver the clip  910  to close and/or seal an incision, puncture, or other passage  1392  that extends from a patient&#39;s skin  1394 , through intervening tissue  1396 , and into a wall  1398  of a vessel  1390  or other body lumen. Alternatively, the apparatus  1300  may be used to deliver the clip  910  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  1300  and clip  910  may be used to attach an anastomosis during a bypass procedure. It will be appreciated by those skilled in the art that the clip  910  and/or apparatus  1300  may be useful in a variety of procedures. 
     As shown in  FIG. 25A , the sheath  1352  may be inserted or otherwise positioned within the vessel  1390 , i.e., through the passage  1392 . The sheath  1352  may be advanced over a guidewire or other rail (not shown) previously positioned through the passage  1392  into the vessel  1390  or advanced in conjunction with a pointed stylet directly through tissue using conventional procedures. The vessel  1390  can be a peripheral vessel, such as a femoral, radial, or carotid artery, although other body lumens may be accessed using the sheath  1352 , as will be appreciated by those skilled in the art. 
     The passage  1392 , and consequently the sheath  1352 , may be oriented at an angle “alpha” with respect to the vessel  1390 , thereby facilitating introducing devices through the lumen  1360  of the sheath  1352  into the vessel  1390  with minimal risk of damage to the vessel  1390 . One or more devices, such as a guide wire, a catheter, and the like (not shown), may be inserted through the sheath  1352  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  1352 , and the obturator  1400  may be inserted into the lumen  1360 . For example, the obturator  1400  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  1352 . Alternatively, the actuator assembly and obturator  1400  may be coupled separately to the sheath  1352 . 
     When the obturator  1400  is fully inserted within the sheath  1352 , the distal portion  1416  of the obturator  1400  may extend beyond the distal end  1364  of the sheath  1352 . In an alternative embodiment, the obturator  1400  may be attached to an exterior surface (not shown) of the sheath  1352 , for example, along a track, e.g., including cooperating slots, grooves, and the like (not shown) in the sheath  1352  and obturator  1400 . 
     Turning to  FIG. 25B , the expandable elements  1418  on the distal portion of the obturator  1400  may then be directed to their expanded configuration, for example, by activating a switch on the proximal end (not shown) of the obturator  1400 . With the sheath  1352  and obturator  1400  coupled to one another, the sheath  1352  and obturator  1400  may be moved in conjunction with one another. 
     As shown in  FIG. 25C , the sheath  1352  may be partially withdrawn from the vessel  1390 , until the expandable elements  1418  contact the wall  1398  of the vessel  1390 . Thus, the expandable elements  1418  may provide a tactile indication of the position of the sheath  1352  with respect to the wall  1398  of the vessel  1390 . In addition, the expandable elements  1418  may assist in “presenting” the wall  1398  of the vessel  1390 , e.g., for receiving the clip  910 . 
     Generally, the clip  910  is carried by the carrier assembly  1354  before the procedure. The clip  910  may be constrained in its transverse configuration on the carrier assembly  1354 , and the carrier assembly  1354  may be provided on or adjacent the proximal end of the sheath  1352 . Because the tines, which may include primary and secondary tines  914 ,  916  may be biased towards one another, the tines  914 ,  916  may slidably contact an inner surface (not shown) of the carrier assembly  1354  or an outer surface of the sheath  1352 , thereby constraining the clip  910  in its transverse configuration. 
     Turning to  FIG. 25D , with the sheath  1352  properly positioned, the carrier assembly  1354  may then be actuated, for example, to advance the carrier assembly  1354  distally over the sheath  1352  to deliver the clip  910 . The carrier assembly  1354  may only be advanced a predetermined fixed distance relative to the distal end of the sheath  1352 , and consequently, the expandable elements  1418  of the obturator  1400 , such that the clip  910  substantially engages the wall  1398  of the blood vessel  1390 . This predetermined distance may facilitate properly deploying the clip  910  with respect to the wall  1398  of the vessel  1390 , e.g., to prevent advancing the clip  910  too far, i.e., into the vessel  1390 . 
     As the clip  910  is deployed from the carrier assembly  1354 , the clip  910  may be expanded to an enlarged diameter. For example, a distal end of the carrier assembly  1354  may include a ramped region (not shown) that may deflect the tines  914 ,  916 , and/or the body of the clip  910  radially outwardly. As the clip  910  is advanced over the ramped region, the tines  914 ,  916  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  914 ,  916  had been maintained substantially axially. 
     Alternatively, the clip  910  may include expandable looped elements and/or spring elements (not shown), such as those described above, that may facilitate expanding the clip  910  as it is deployed from the carrier assembly  1354  and/or the sheath  1352 . For example, the looped elements of the clip  910  may be compressed when the clip  910  is loaded into the carrier assembly  1354 , e.g., thereby allowing a relatively smaller profile carrier assembly  1354  to be used. The clip  910  may automatically expand upon deployment from the carrier assembly  1354  to engage a larger region of tissue surrounding the opening, such as an arteriotomy  1391  in the wall  1398  of the vessel  1390  (see  FIG. 26A ). 
     Once the clip  910  is deployed entirely or otherwise released from the sheath  1352 , the clip  910  may resiliently move towards its substantially planar configuration, such as that shown in  FIG. 26B . 
     During delivery of the clip  910 , radiopaque markers (not shown) on the clip  910 , the carrier assembly  1354 , and/or the expandable members  1418  may be monitored, e.g., using fluoroscopy, to facilitate observing and/or positioning the apparatus  1300 . Thus, a relative position of the clip  910  with respect to the expandable elements  1418 , and consequently to the wall  1398  of the vessel  1390 , may be ascertained before the clip  910  is deployed from the carrier assembly  1354 . 
     Turning to  FIGS. 26A and 26B , in another embodiment, the expandable elements  1418  of the obturator  1400  may be rotationally offset from the one or more tines  914  on the clip  910 . For example, if the clip  910  includes primary tines (such as those shown in  FIGS. 17A and 18 ), the obturator  600  and clip  910  may have a predetermined relative angular orientation about the central axis  924 . The clip  910  can be loaded onto the carrier assembly  1354  in a predetermined angular orientation and the obturator  600  is receivable in the sheath  1352  only in a predetermined angular orientation that is offset such that the tines  914 ,  916  are out of axial alignment with the expandable elements  1418 , as shown in  FIG. 26A . 
     This predetermined rotational orientation may substantially minimize the possibility of the primary tines  914  contacting and/or damaging the expandable elements  1418 . For example, with particular reference to  FIG. 26A , a relative angular orientation of the clip  910  and obturator  1400  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  914  are oriented such that the primary tines  914  pierce the wall  1398  of the vessel  1390  on either side of the arteriotomy  1391 , as shown. With the expandable elements  1418  crisscrossing diagonally, risk of contact with the primary tines  914  is substantially reduced. Thus, the primary tines  914  may be sufficiently long to extend entirely through the wall  1398  of the vessel  1390  while avoiding the expandable elements  618 . 
     The expandable elements  1418  may then be collapsed and/or withdrawn into the distal end  1364  of the sheath  1352 . As the clip  910  is released entirely from the sheath  1352 , the primary tines  914  may partially overlap, as shown in  FIG. 26B , thereby pulling the arteriotomy  1391  closed, similar to a single-thread suture. For example, the expandable elements  1418  may be automatically collapsed immediately before or after the clip  910  is deployed from the carrier assembly  1354  or when the carrier assembly  1354  reaches its extreme distal position. The distal portion  1416  of the obturator  1400  can be collapsed and retracted into the sheath  1354  after the primary tines  914  have pierced the wall  1398  of the vessel  1390 , but before the clip  910  is entirely released from the sheath  1352 . 
     In addition, if the clip  910  includes secondary tines  916  (such as those shown in  FIG. 17A ), the secondary tines  916  may partially penetrate the wall  1398  of the vessel  1390  during deployment of the clip  910 . The lengths of the secondary tines  916  can be relatively short or stop members (not shown) may be provided that prevent the secondary tines  916  from piercing entirely through the wall  1398 . When the clip  910  is released, the secondary tines  916  may pull the tissue inwardly, behaving somewhat similarly to a purse-string suture, to enhance closing the arteriotomy  1391 . 
     Once the clip  910  is successfully deployed into the wall  1398  of the vessel  1390 , e.g., on either side of an arteriotomy  1391 , the apparatus  1300  may be withdrawn from the passage  1392 . The entire apparatus  1300  may be removed in one step, or alternatively, the obturator  1400  may first be withdrawn from the sheath  1352  before withdrawing the sheath  1352 , thereby leaving the clip  910  in place to close the arteriotomy  1391  and/or seal the passage  1392 . In addition, if desired, a sealant or other material may be introduced into the passage  1392  in conjunction with or separate from delivery of the clip  910  to further seal the passage  1392 , as is known to those skilled in the art. 
     According to another aspect, the clips described herein can be manufactured in various manners. These clips can be useful for engaging tissue so as to connect tissue segments together or to close and/or seal openings through tissue such as a puncture wound in a body lumen. These clips may be used by deforming them from their generally planar configuration such that the tines are pointing in a direction generally transverse to the plane, holding the clip in this deformed condition, deploying the clip proximal to the tissue to be engaged and removing the deforming force such that the clip engages the tissue and attempts to return to its original generally planar configuration. The methods and apparatus disclosed in the above-mentioned U.S. patent application Ser. Nos. 10/081,726 and 09/732,178, now U.S. Pat. Nos. 6,623,510 and 6,719,777 can be used to deploy the clips of the present invention to engage tissue and close or seal an opening. 
     In such use, the deformation of the clip causes the tines to be directed generally axially away from the body of the clip and it is the elastic property of the deformed clip which causes it to attempt to return to its original generally planar configuration. The body of the device may comprise a series of looped elements which generally define an endless zigzag pattern, e.g., a sinusoidal pattern, extending about a central access. The looped elements are believed to facilitate 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 another embodiment of the present invention, a clip precursor is first formed from a sheet of material, such as a superelastic alloy, such as a nickel-titanium alloy (“Nitinol”) alloy. The property of superelasticity and of certain alloys which possess that property is disclosed in U.S. Pat. No. 4,665,906, the disclosures of which, and any references therein, are incorporated herein in their entirety by this reference. This forming can be done by removing portions of the material by cutting, chemical etching, laser cutting, photochemical etching, stamping, electrical discharge machining and the like to produce a precursor such as that shown in  FIG. 28A  which has radially outward extending tines. The precursor can then be polished using one or more processes such as electropolishing, tumbling, sand blasting, sanding and the like or such polishing can be done as a final step after the clip is formed. Forming of a precursor in this manner does not require working to tolerances as close as those which would be required if the clip was to be manufactured in its final configuration shown in  FIG. 28B  because the radially outwardly extending tines of the precursor shown in  FIG. 28A  are easily accessible by the forming tool whereas attempting to directly form the clip with radially inwardly extending tines which are closely spaced requires difficult high precision metal cutting. Thus, manufacture of a precursor which is then reconfigured to final clip shape permits the achievement of closer spacing between the elements of the final clip than would otherwise be achievable with conventional methods. 
     The precursor  1610  comprises a hoop-shaped planar body  1611  which has outwardly extending primary (longer) tines  1612  and secondary (shorter) tines  1613 . For example, the primary trials may be 0.070 to 0.105 inches in length and the secondary tines may be 0.025 to 0.035 inches in length. Each of the tines terminates in a point  1614 . When the precursor  1610  has been reconfigured into clip  1616  shown in  FIG. 28B , the tines  1612  and  1613  become the tissue engaging portions of the clip. The tines may be sharpened or given a shape, e.g., barbs (not shown), while the device is in the precursor state. The body  1611  may compromise connecting links such as loops  1615 . These links may have any suitable shape provided that such shape does not interfere with inversion of the precursor  1610 . 
     The precursor  1610  is then inverted to reconfigure it into the shape of clip  1616 . In this embodiment in which the precursor is formed from a sheet of nickel-titanium alloy, the inverted precursor is then heat set, e.g., by heating to a temperature of 510° C., and then quenched to cool to room temperature. The clip  1616  will now be in the austenitic state. 
     Heat setting and quenching are essential to successful practice of the invention with superelastic alloys. As explained in more detail in U.S. Pat. No. 4,665,906, the disclosures of which, and any references therein, are incorporated herein in their entirety by this reference, a superelastic alloy such as nickel-titanium exists in two states, the austenitic state and the martensitic state. Such alloys will initially be in the austenitic state, e.g., when the precursor is formed. However, when the precursor is inverted to take the shape of the final clip, the stress experienced by the alloy during the inversion will cause the alloy to be partially or wholly converted to the martensitic state. Such a martensitic state is commonly referred to as stress-induced martensite. Such martensite structure has the property of superelasticity and the inverted precursor would revert to its original shape if not held in the inverted configuration. 
     Since, if the inverted precursor was left in the martensitic state, it would want to elastically revert to its original uninverted state, it must be converted back to austenite. Thus, heating and quenching are required to convert the inverted precursor from the martensitic state to the austenitic state such that the clip is stable in its planar configuration as shown in  FIG. 28B  and will retain that configuration. 
     The times and temperatures for heat setting of superelastic alloys of various compositions can be determined from existing literature or can be determined empirically without any difficulty. The clips are small in size and the heating and quenching may be done with any conventional heating and quenching equipment. For example, once inverted, the inverted precursor can be held in that configuration and placed in a fixture which will hold it in the inverted configuration during heat setting. 
     When clips are manufactured according to the present invention, the space between the tines may actually be eliminated, i.e., after inverting the precursor, the tines may be in contact with each other, in either a side-by-side or an over-and-under relationship. The number, length and spacing of the tines may be varied according to the desires of the manufacturer. Furthermore, while use of a planar precursor is a convenience in manufacturing, a planar configuration is not required. For example, the precursor could be bent along a diameter or major or minor axis of the precursor and could be heat set in such a bent configuration. Alternatively, the clip, while generally planar, may have the tines extending at an acute angle to the plane defined by the body as shown in  FIG. 31  in which the body  1611  and tines  1612  are shown. Furthermore, manufacturing from a sheet of material is a convenience, but other manufacturing techniques, including joining of components such as the tines to the body, can be accomplished by welding, brazing, or other known methods of joining materials. In such cases, one or more of such components may be circular in cross-section or tubular in configuration. 
     Still further, the clip need not be fabricated from a single material, e.g., the tines may be manufactured from a different material than the body. In such cases, a portion of the clip such as the tines may be bioabsorbable provided that the final clip is capable of elastic recovery after being deformed. An advantage of the present invention is that it permits the production of clips with tines that are 30 to 40% or more longer than those which could be made with prior direct cutting methods, because there is no limit on the length of the tine which is formed on the precursor. Thus, after the precursor is inverted, the tines may overlap the annular body. 
     In the alternative embodiment of this invention illustrated in  FIGS. 29A and 29B , the precursor  1620  is manufactured in an expanded oversize configuration to provide space for removing material from a sheet of material, such as a superelastic alloy, such as nickel-titanium, by conventional methods such as cutting, chemical etching, photochemical etching, stamping, electric discharge machining, laser cutting or the like. 
     The precursor  1620  is reconfigured by imposing radially inwardly directed force on body  1621  such that precursor  1620  takes a smaller planar shape such as one of those shown in  FIG. 29B . The precursor  20  has a planar body  1621 , tines  1622  and  1623  having points  1624  and such tines are connected by links  1625  as previously described with regard to  FIG. 28A . The reconfigured precursor is then heat set and quenched as described above to complete the manufacture of clip  1626 . 
     Clips of still other configurations can be manufactured in the manner of clip  1626  by starting with a differently shaped precursor such as precursor  1630  shown in  FIG. 30A . Precursor  1630  can be reconfigured by being subjected to radially inward deforming forces as shown in  FIG. 30B  or by opposed laterally inward forces as shown in  FIG. 30C . In each case, the planar body  1631  having tines  1632  and  1633  with points  1634  and links  1635  will be caused to take a smaller dimension and will be heat set as described above to form clips  1636  and  1637 . Clips manufactured according to the method of the present invention can have a multitude of configurations other than those shown in  FIGS. 28B, 29B, and 30C and 30D . For example, the configurations shown in U.S. patent application Ser. Nos. 09/732,178 and 10/081,726, now U.S. Pat. Nos. 6,719,777 and 6,623,510, could be manufactured according to the present invention. 
     It has been found that Nitinol sheet is stronger in one direction than in others, which may be the result of crystal orientation in the Nitinol. The clip precursors can be formed such that the primary tines are aligned with the strongest orientation of the Nitinol. It has been found, as shown in  FIG. 7 , that the greatest strength of the primary tines is achieved if those tines are transverse to the grain orientation of the Nitinol. Thus,  FIG. 34  illustrates clip precursor  1660  having primary tines  1661  as the precursor would be cut from sheet  1662 . The grain orientation of sheet  1662  is shown by the double-headed arrow  1663 . Typically, a plurality of precursors  1660  would be cut from the same sheet, each with its primary tines transverse to the grain orientation of the sheet. In addition, even if clips are formed directly without using precursors, it is desirable that their primary tines be transverse to the grain orientation. 
     The clips of the present invention may have primary or secondary tines which have the same or different lengths and the tines may be straight or curved. For example, radially opposed tines may have one tine at “12 o&#39;clock” which is longer than the opposing tine at “6 o&#39;clock.” Exemplary configurations of clip precursors with primary tines of different length are shown in  FIGS. 32 and 33 . In  FIG. 32 , clip precursor  1640  is shown with a primary tine  1641  which is shorter than primary tine  1642 . Similarly, in  FIG. 33 , a clip precursor is shown which has a primary tine  1651  which is shorter than primary tine  1652 . 
     The clips of the present invention may also be delivered using the apparatus and methods described in U.S. patent application Ser. No. 10/081,723, filed Feb. 21, 2002, now U.S. Pat. No. 6,942,674, which is assigned to the assignee of the present application, the disclosures of which, and any references therein, are incorporated herein in their entirety by this reference. Similarly, the apparatus and methods disclosed in U.S. patent application Ser. No. 10/081,717, filed Feb. 21, 2002, now U.S. Pat. No. 6,695,867, which is assigned to the Assignee of the present application, the disclosures of which, and any references therein, are incorporated herein in their entirety by this reference. 
     Other features can be added to the clips including radio-opaque markers, and/or porous surfaces to promote tissue ingrowth or the clip may be coated in whole or in part with a bioabsorbable material and/or coated with a material containing a substance which is delivered to the patient for therapeutic, diagnostic or other purposes. Such coatings may comprise peptides, clotting factors or other materials designed to benefit the patient. 
     While the principal object of the present invention is to provide a manufacturing method which facilitates the production of clips having a small footprint, the present invention can also be used to make clips of larger dimensions since, no matter what methods are used to cut the precursor from a sheet of material, the ease of manufacture of even larger size clips is facilitated. Thus, the advantages of the present invention may be realized with regard to clips having larger sizes and clips having a variety of configurations. 
     Turning now to the drawings,  FIGS. 35A-35C  show another embodiment of a closure device or clip  1710  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  1710  includes a body  1712 , which may be generally annular in shape and surrounds a central axis  1724 , a plurality of primary tines  1714  and a plurality of secondary tines  1716  extending from the body  1712 . 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  1712  includes a plurality of looped or curved elements  1728  that are connected to one another to form the body  1712 . Each looped element  1728  may include an inner or first curved region  1732  and an outer or second curved region  1734 . In another embodiment, the first and second curved regions  1732 ,  1734  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  1712 . 
     The plurality of tines  1714  and  1716  may be biased to extend generally inwardly, e.g., towards one another and/or towards the central axis  1724 . The tines  1714  and  1716  may be disposed on the first curved regions  1732 , and oriented toward the central axis  1724  when the clip  1710  is in the planar configuration. The primary tines  14  are offset from the axis of symmetry  1737  of the loops from which they extend and are connected to a first curved region  1732  by a straight connecting element having a longer side  1735  and a shorter side  1736 . In another embodiment, the tines  14  and  1716  may be provided in pairs opposite from one another or provided otherwise symmetrically with respect to the central axis  1724 . 
     The tines  1714  and  1716  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  1710  and/or to lower the insertion force required to penetrate tissue, each primary tine  1714 , as shown in  FIG. 35A  as element  1718 , and each secondary tine  1716  may include a tapered edge (not shown) extending towards the tip along one side of the tine  1714  or  1716 . Alternatively, as shown in  FIGS. 35A-35C , each tine  1714  or  16  may be provided with a tapered edge on each side of the tine  1714  or  1716  extending towards the tip. 
     Additionally, as shown in  FIGS. 35A-35C , the tines  1714  and  1716  may be disposed on alternating first curved regions  1732 . Thus, at least one period of a zigzag pattern may be disposed between adjacent tines  1714  and  1716 , which may enhance flexibility of the clip  1710 , as explained further below. 
     As shown in  FIGS. 35B and 35C  (where opposite ends  1733   a ,  1733   b  are connected to one another), the body  1712  and/or the tines  1714  and  1716  may be deflected such that the tines  1716  extend transversely with respect to the plane defined in the planar configuration, thereby defining a transverse configuration for the clip  1710 . The tines  1714  and  1716  can be oriented substantially parallel to the central axis  1724  in the transverse configuration, as shown in  FIG. 35B . In the transverse configuration, the body  1712  may have a generally annular shape defining a length, LE 1 , that extends generally parallel to the central axis  1724 , and corresponds generally to an amplitude of the zigzag pattern. The body  1712  can be sufficiently flexible such that the clip  1710  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  1710 . 
     In another embodiment, the tines  1714  and  1716  and/or body  1712  are biased to move from the transverse configuration towards the planar configuration of  FIG. 35A . Thus, with the tines  14  and  16  in the transverse configuration, the tines  1714  and  1716  may penetrate and/or be engaged with tissue at a puncture site. When the clip  1710  is released, the tines  1714  and  1716  may attempt to return towards one another as the clip  1710  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  1728  may distribute stresses in the clip  1710  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  1710  during delivery. In addition, when the clip  1710  is in the transverse configuration, the looped elements  1728  may be movable between a compressed state, such as that shown in  FIG. 35B , and an expanded state, such as that shown in  FIG. 35C . The looped elements  1728  can be biased towards the expanded state, but may be compressed to the compressed state, e.g., by constraining the clip  1710 . Alternatively, only a portion of the looped elements  1728  may be biased towards the expanded state, e.g., the first curved regions  1732 , and/or the looped elements  1728  may be biased towards the compressed state. Furthermore, the looped elements  1728  reduce the force required to be exerted on the clip  1710  to transition the clip  1710  from the planar configuration to the transverse configuration before loading onto a delivery device (not shown). 
     With the clip  1710  in the transverse configuration, the looped elements  1728  may be circumferentially and/or radially compressed to the compressed state until the clip  1710  defines a first diameter or circumference  1726   a , such as that shown in  FIG. 35B . The clip  1710  may be constrained in the compressed state, e.g., by loading the clip  1710  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  1710  may automatically expand towards the expanded state, such as that shown in  FIG. 35C , thereby defining a second diameter or circumference  1726   b . Thus, the looped elements  1728  may facilitate reducing the profile of the clip  1710  during delivery, e.g., to facilitate introducing the clip  1710  through a smaller puncture or passage. Once the clip  1710  is deployed entirely from the delivery device, the looped elements  1728  may resiliently expand as the clip  1710  returns towards the planar configuration, as explained further below. 
     To manufacture the clip  1710  (or, similarly, any of the other clips described herein), the body  1712  and the tines  1714  and  1716  may be integrally formed from a single sheet of material, e.g., a superelastic alloy, such as 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, or the method disclosed in U.S. patent application Ser. No. 10/335,075, filed Dec. 31, 2002, to form the clip. The tines  1714  and  1716  may be sharpened to a point, i.e., tips may be formed on the tines  1714  and  1716  using conventional methods, such as chemical etching, mechanical grinding, and the like. 
     The clip  1710  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  1710 . 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  1710  may be formed from a shape memory alloy, e.g., Nitinol, with the looped elements  1728  formed initially in the compressed state and/or the clip  1710  in the planar configuration. With the clip  1710  deformed to the transverse configuration, the clip  1710  may be expanded, e.g., by applying a force radially outwards against an inner surface of the clip  1710 , thereby expanding the looped elements  1728  to the expanded state. The looped elements  1728  may then be heat treated, e.g., by heating the clip  1710  to an austenitic state, to cause the looped elements  1728  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  1710  further, e.g., with the tines in the planar configuration to cause the body  1712  and/or tines  1714  and  1716  to “remember” and be biased towards the planar configuration, as is known to those skilled in the art. The clip  1710  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  1710  onto a delivery device (not shown), as described below. Thus, if the clip  1710  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. 
     Each of the primary tines  1714  may have a length l 1 , although alternatively, as shown in  FIG. 35A , each of the primary tines  1714  may have a different length than one another. The primary tines  1714  may be disposed in one or more opposing pairs, e.g., on opposing first curved regions  1732 , and may be oriented towards and/or across the central axis  1724  in the planar configuration. In the planar configuration, the lengths l 1  may be sufficiently long such that the primary tines  1714  at least partially overlap one another, i.e., extend across the central axis  1724  towards an opposing tine  1714 . Therefore, the tips of the primary tines  1714  may extend past the central axis  1724  and/or the primary tines  14  in each pair may lie substantially parallel to each other when the clip  1710  is in the planar configuration. 
     Each of the secondary tines  16  may be disposed on a first or inner curved region  32 , e.g., such that one or more secondary tines  16  may be provided between opposing pairs of primary tines  14 . Each of the secondary tines  16  may have a length l 2  that is substantially less than the length l 1  of the primary tines  14 . 
     A secondary tine  1716  can be disposed on either side of each primary tine  1714 . For example, the clip  1710  shown in  FIGS. 35A-35C  has first and second primary tines  1714 , and each of the first and second primary tines  1714  has a secondary tine  1716  on either side of it. Thus, the clip  1710  may have a total of two primary tines  1714  and four secondary tines  1716 . Optionally, the secondary tines  1716  may be disposed substantially symmetrically about the central axis  1724 . The tines  1714 ,  1716  may be provided on every other first curved regions  1732 . For example, a first curved region  1732  having neither a primary tine  1714  nor a secondary tine  1716  may separate each adjacent tine, e.g., between two adjacent secondary tines  16 , or between a secondary tine  16  and a primary tine  1714 . 
     With the clip  1710  in the transverse configuration, the clip  1710  may be delivered such that the primary tines  1714  entirely penetrate the wall of a blood vessel or other body lumen, while the secondary tines  1716  only partially penetrate the wall due to their relative lengths, as explained further below. 
     As shown in  FIG. 35A , primary tines  1714  are connected to curved regions  1732  by linear regions  1735  and  1736  which are of different lengths. Thus, primary tines  1714  are offset from the axis of symmetry  1737  of the loops having the curved regions to which they are attached. The offsetting of primary tines is also disclosed in parent application Ser. No. 10/335,075, filed Dec. 31, 2002, which discloses the use of curved configurations to connect the primary tines to the curved regions of the clip. It has been found desirable to use linear, or straight, regions, as shown as elements  1735  and  1736  in  FIG. 35A  to connect the primary tines  1714  of the present invention to the curved regions  1732 . 
       FIG. 36  illustrates a clip of the same general type as that of  FIG. 35A , but in a somewhat different embodiment in which primary tines  1714   a  overlap body  1712  at locations comprising first curved regions  1732 . 
       FIGS. 37A-37C  illustrate various designs of clips configured according to the present invention in which the primary tines, which are offset from the axis of symmetry of the loop from which they extend, are connected directly to a first curved region or are connected to the curved region by extending one side of the curved region to form one side of the primary tine and connecting the other side of the primary tine with a curved connecting element. 
     Turning to  FIGS. 37A-37C  in more detail,  FIG. 37A  illustrates clip  1826  has body  1821 , primary tines  1822 , secondary tines  1823  and loops  1825 . Each loop has an axis of symmetry such as that indicated by  1827 . The tines are provided with point  1824 . In this embodiment, the primary tines  1822  are offset from the axis of symmetry of the loop from which they extend and are connected directly to the first curved section of such loop. 
     In  FIG. 37B , the clip  1936  has body  1931  having primary tines  1932  and secondary tines  1933  is illustrated. The body  1931  is provided with loops  1935  and the primary tines  1932  comprise a first side  1937  which is an extension of a side of the loop  1938  from which tine  1937  extends and another side  1939  which is connected directly to the loop from which it extends. The primary tines are offset from the axis of symmetry, indicated by  1940  of the loop from which they extend. 
     The clip of  FIG. 37C  is similar in some respects to the clip of  37 B, but is generally elliptical in shape rather than generally circular in shape. Thus, clip  2037  comprises body  2031  which has loops  2035 , primary tines  2032 , secondary tines  2033  which tines have points  2034 . In this embodiment, the primary tines  2032  extend beyond the innermost reach of the first curved regions which are opposite the first curved regions from which the primary tines extend. The primary tines are offset from the axis of symmetry  2038  of the loop from which they extend. The primary tines of the clip of  FIG. 37C  are connected to the loops from which they extend in the same manner as those of  FIG. 37B . 
       FIG. 38  illustrates a clip  2110  in which the primary tines  2114  and  2116  are of different lengths. The primary tines  2114  and  2116  are offset from the axis of symmetry  2130  of the loop from which they extend and are connected to the loop in the same manner as the primary tines of  FIG. 37B . 
     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  1710  of  FIGS. 35A-35C  as an example, the entire clip  1710  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  1710  may be partially coated with radiopaque material by using masking techniques. For example, the entire clip  1710  may first be coated with radiopaque material. The clip  1710  may then be masked at locations where the radiopaque coating is desired. For example, the looped elements  1728  of the clip  1710  may be left unmasked during this process if it is desired to leave the looped elements  1728  uncoated by radiopaque material. This may be desirable, e.g., to prevent radiopaque material from adversely affecting the flexibility of the looped elements  1728 . The clip  1710  may then be treated to remove the radiopaque material from the unmasked areas, in this example, the looped elements  1728 . The masking may then be removed using conventional processes, leaving the rest of the clip  1710  coated with radiopaque material. 
     In another alternative, one or more discrete markers may be provided at predetermined locations on the clip  1710 . For example, high density or radiopaque material may be crimped or otherwise secured onto opposing double looped or circular regions  1728 . In another embodiment, a plurality of pockets may be provided on the looped elements  1728  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. 
     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. 
     As described herein, the clips of the present invention may be delivered using various apparatus and methods. Suitable apparatus that may be used to deliver a clip of the present invention are disclosed in U.S. application Ser. No. 10/081,723, filed on Feb. 21, 2002, now U.S. Pat. No. 6,942,674, and entitled “Apparatus and Methods for Delivering a Closure Device” and in U.S. application Ser. No. 10/356,214, filed Jan. 30, 2003, and Ser. No. 10/638,115, filed Aug. 8, 2003, and Ser. No. 10/081,725, filed Feb. 2, 2001, now U.S. Pat. No. 6,749,621, which are assigned to the assignee of the present application, the disclosures of which, and any references therein, are incorporated herein in their entirety by this reference. 
     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. For example, and not by way of limitation, the features and structures of one clip can be used with any other clip described herein. Similarly, the structures and methods useable to deploy a clip can be used to deploy other clips, including, but not limited to, those clips described herein.