Abstract:
A method of performing a treatment for gastroesophagheal reflux disease (GERD) includes providing a distal end of a shaft of a medical instrument with a proximally facing end effector having a laterally offset clevis defining a shaft-clevis plane and opposing mutually rotatable jaws proximally directed and laterally displaced relative to a longitudinal axis of the shaft. The jaws hold parts of a two-part fastener, respectively, and are offset and separated from the shaft. Significantly, the jaws operate in a plane at an angle to the shaft-clevis plane. The shaft is inserted with the proximally facing end effector through the esophagus in a first direction. The shaft is retracted in a second direction substantially opposite the first. The end effector contacts a stomach wall at a location near the esophagus and the stomach wall is manipulated with the end effector.

Description:
BACKGROUND OF THE INVENTION 
   1. Field of the Invention 
   The invention relates to surgical fasteners, endoscopic surgical instruments, and procedures. More particularly, the invention relates to surgical fasteners, endoscopic instruments, and procedures for the transoral plication and fastening together of portions of the stomach for the treatment of GERD. 
   2. State of the Art 
   Gastroesophageal reflux disease (GERD) or persistent heartburn is caused by an improper relaxation of the lower esophageal sphincter (LES) that allows the frequent regurgitation of acidic stomach contents into the esophagus. If left untreated, chronic reflux may cause esophageal stricture, bleeding ulcers, perforation, and scarring. Continued reflux may lead to Barrett&#39;s esophagus, which involves changes in the cells that make up the esophagus and may lead to cancer. 
   The current mode of treatment is primarily pharmacological starting with antacids and progressing to proton pump inhibitors (PPIs). The progression of the disease is noted by the development of a hiatal hernia caused by the stomach being forced into the thoracic cavity. The pharmacological treatment ends with double and triple dosing of PPIs. At the point that the patient is not responding to the PPIs, surgical intervention is often recommended. 
   The current standard for surgery is the Nissen fundoplication. The fundoplication procedure involves wrapping the fundus of the stomach around the lower end of the esophagus and fastening it in place to make the lower esophageal sphincter (LES) less compliable. Traditionally, this procedure is accomplished via open surgery with the use of sutures to secure the plicated fundus of the stomach around the esophagus without penetrating (incising) the stomach. However, with the advent of laparoscopic surgery came the development of a corresponding laparoscopic Nissen procedure. 
   In an effort to further reduce the invasiveness of treatment for GERD, endoscopic techniques are being explored. Techniques that are currently under trials include the implantation of bulking agents, cautery techniques to produce scarring, and suturing or otherwise fastening internal tissue. 
   For example, U.S. Pat. No. 5,403,326 to Harrison et al. discloses a method of performing endoscopic fundoplication using surgical staples or two-part surgical fasteners. The procedure disclosed by Harrison et al. involves performing two percutaneous endoscopic gastrotomies (incisions through the skin into the stomach) and the installation of two ports through which a stapler, an endoscope, and an esophageal manipulator (invagination device) are inserted. Under view of the endoscope, the esophageal manipulator is used to pull the interior of the esophagus into the stomach. When the esophagus is in position, with the fundus of the stomach plicated, the stapler is moved into position around the lower end of the esophagus and the plicated fundus is stapled to the esophagus. The process is repeated at different axial and rotary positions until the desired fundoplication is achieved. While, the procedure disclosed by Harrison et al. is a vast improvement over open surgery, it is still relatively invasive requiring two incisions through the stomach. 
   U.S. Pat. No. 5,571,116 to Bolanos et al. discloses a non-invasive treatment of gastroesophageal reflux disease which utilizes a remotely operable invagination device and a remotely operable surgical stapler, both of which are inserted transorally through the esophagus. According to the methods disclosed by Bolanos et al., the invagination device is inserted first and is used to clamp the gastroesophageal junction. The device is then moved distally, pulling the clamped gastroesophageal junction into the stomach, thereby invaginating the junction and involuting the surrounding fundic wall. The stapler is then inserted transorally and delivered to the invaginated junction where it is used to staple the fundic wall. 
   Bolanos et al. disclose several different invagination devices and several different staplers. Generally, each of the staplers disclosed by Bolanos et al. has an elongate body and a spring biased anvil which is rotatable approximately 15 degrees away from the body in order to locate the invaginated gastroesophageal junction between the body and the anvil. The body contains a staple cartridge holding a plurality of staples, and a staple firing knife. Each of the invagination devices disclosed by Bolanos et al. has a jaw member which is rotatable by at least 45 degrees and in some cases more than 90 degrees to an open position for grasping the gastroesophageal junction. One of the chief disadvantages of the methods and apparatus disclosed by Bolanos et al. is that the stapler and the invagination device are separately inserted but must both be present in the esophagus at the same time. With some of the embodiments disclosed, the presence of both instruments is significantly challenged by the size of the esophagus. Moreover, the esophagus cannot form a seal about both the instruments and, thus, it is difficult to insufflate the stomach to facilitate the procedure. In addition, the actuating mechanism of the device disclosed by Bolanos et al. is awkward. In particular, the stapler anvil is biased to the open position, and it is not clear whether or not the stapler anvil can be locked in a closed position without continuously holding down a lever. In addition, it appears that the staple firing trigger can be inadvertently operated before the anvil is in the closed position. This would result in inadvertent ejection of staples into the stomach or the esophagus of the patient. 
   U.S. Pat. No. 6,086,600 to Kortenbach discloses an endoscopic surgical instrument adapted to perform fundoplication, between the stomach wall and the esophagus. The instrument includes a flexible tube, a grasping and fastening end effector coupled to the distal end of the tube, and a manual actuator coupled to the proximal end of the tube. The manual actuator is coupled to the end effector by a plurality of flexible cables which extend through the tube. The tube contains a lumen for receiving a manipulable endoscope and the end effector includes a passage for the distal end of the endoscope. The end effector has a store for a plurality of male fastener parts, a store for a plurality of female fastener parts, a rotatable grasper, a rotatable fastener head for aligning a female fastener part and a male fastener part with tissues therebetween, and a firing member for pressing a male fastener part through tissues grasped by the grasper and into a female fastener part. According to a stated preferred embodiment, the overall diameters of the flexible tube and the end effector (when rotated to the open position) do not exceed approximately 20 mm so that the instrument may be delivered transorally to the fundus of the stomach. 
   While transoral fundoplication devices and methods hold promise, it is still difficult to deliver and manipulate the necessary apparatus transorally. One reason for the difficulty is that the overall diameter, or more accurately the cross sectional area, of the equipment is too large. Moreover, even if the Kortenbach device could be reduced to 20 mm in diameter (314 mm 2  cross sectional area), it would still be difficult to manipulate. Those skilled in the art will appreciate that larger instruments are less pliable and the plication and fastening procedure requires that the instruments be retroflexed nearly 180 degrees. Moreover, it will be appreciated that large instruments obscure the endoscopic view of the surgical site. 
   Recently, PCT WO 00/78227 (NDO Surgical Inc.) has disclosed a device sized to receive an endoscope and which is purportedly capable of plicating and damaging portions of the stomach wall to effect serosa-to-serosa contact which results in stomach wall tissue adhesion. As a result, compliance of the tissue about the esophagus would be reduced and a flap (i.e., valve) would be formed about the LES. For this purpose, the plication and adhesion should preferably be created at the horseshoe-shaped tissue in the stomach surrounding the LES. The distance from the Z line (esophageal/stomach borderline) to the horseshoe-shaped target tissue is approximately 1 to 3 cm into the stomach and plication at this location permits the greatest stress to be placed on the tissue about the LES. In order to approach plication at this location the device has a particularly complicated and unwieldy multi-component end effector adapted to grab tissue, plicate the tissue, and fasten the tissue together. That is, while the above referenced device appears to offer a solution, it may not be practical to implement mechanically or operate during the procedure. Further, the above referenced device, while respectfully having a relatively smaller diameter than other prior art (approximately 18 mm in diameter and 254 mm 2  in cross-sectional area) maintains that cross-sectional area over its entire length. In addition to limited flexibility, the size of the device renders it difficult to traverse the tracheopharangeal passage. Moreover, while it is desirable to plicate the stomach wall in a direction parallel to the esophagus in order to satisfactorily reduce compliance of the tissue, it is noted that the end effector of the above referenced device is unable to approach the target tissue from the desired direction. 
   It is also preferable that any fastener used for the apposition of tissue in the stomach cavity be removable in the event of tissue ischemia, vagus nerve irritation, or continued reflux, and be relatively non-injurious to the patient should the fastener inadvertently become loose from the device or dislodged from the tissue. In addition, current fasteners are difficult to locate within the stomach via an endoscope if it becomes necessary to find the fastener for removal. 
   SUMMARY OF THE INVENTION 
   It is therefore an object of the invention to provide methods and apparatus for transoral plication and fastening of tissue of the stomach wall. 
   It is another object of the invention to provide an apparatus for transoral plication and fastening of tissue which is adapted to form a plication at a location substantially adjacent the lower esophageal sphincter (LES). 
   It is also an object of the invention to provide an apparatus for transoral plication and fastening of tissue which is adapted to approach the stomach tissue in a direction substantially parallel to the esophagus. 
   It is an additional object of the invention to provide an apparatus that has a relatively small cross-sectional area and is adapted for transoral plication and fastening of tissue. 
   It is a further object of the invention to provide an endoscopic apparatus for transoral plication and fastening of tissue which can be detached from the endoscope while the endoscope is located within the stomach. 
   It is a further object of the invention to provide methods and apparatus for transoral plication and fastening of tissue which damages tissue such that adhesion occurs during healing. 
   It is still another object of the invention to provide a tissue fastener which will not cause ischemia and which, if necessary, is relatively easily endoscopically removable from the stomach. 
   It is still a further object of the invention to provide a fastener which, if inadvertently released into the stomach, will not cause harm to the gastrointestinal tract. 
   It is yet another object of the invention to provide a fastener which can easily be identified in the stomach with an endoscope. 
   In accord with these objects which will be discussed in detail below, a two-part fastener, and an instrument and system for application of the fastener to the stomach wall in a manner which effectively treats gastroesophageal reflux disease (GERD) are provided. 
   The fastener includes male and female parts which can be adjustably coupled together to define various spaces therebetween such that depending on the amount of tissue between the components a desired amount of force can be applied to the tissue therebetween by the fastener, i.e., such that the tissue does not necrose. The male part includes a plurality of tissue-piercing posts which are spring-biased to collapse into a base of the male part to prevent injury to the patient should the male part inadvertently become separated from its respective jaw prior to coupling with the female part or separated from the female part after coupling therewith. In addition, the female part is provided with a cover which shields the piercing tips of the posts after the male and female parts are coupled together. The fastener when in a fastened configuration may be unfastened by moving portions of the cover relative to each other. This can be performed, e.g., using a snare device to lasso the device and moves portions of the female part relative to each other. 
   The instrument includes a relatively short distal end effector which may be coupled over a portion of the endoscope, a proximal actuation handle, and a relatively small diameter control shaft extending between the handle and the end effector. As only the control shaft extends from the handle of the instrument to the end effector, during use, the cross-sectional area of the system within the esophagus at all locations other than the distal end of the instrument, is substantially small (the sum of the areas of the endoscope and the control shaft); i.e., less than half that of other proposed systems. In addition, at the distal end of the instrument, the system cross-sectional area is also smaller than that of prior art systems. 
   More particularly, the distal end effector may be provided with a sleeve that can be slidably positioned over the end of the endoscope and likewise slidably removed therefrom. The sleeve is preferably proximally and distally tapered to ease insertion into and removal from the esophagus. The distal end effector also includes a clevis about which a pair of rotatable jaws are coupled. The jaws are laterally displaced relative to the control shaft. The jaws are each adapted to each hold one part of the two-part fastener. When the jaws are in a closed position with the parts of the fastener located therebetween, the jaws extend substantially parallel to the longitudinal axis of the control shaft. That is, the jaw assembly is fixed in a retroflexed or “looking back” arrangement, directed 180° from the distal end of the control shaft. In addition, the jaws and fastener parts together define posts adapted to grab the stomach tissue, pierce and damage the serosa of the stomach tissue, and plicate the stomach tissue when the jaws are moved from an open position to a closed position. 
   The instrument includes a first control element that moves the jaws between open and closed positions, and a second control element that couples the fastener parts together and releases the fastener parts from the jaws. 
   One embodiment of using the system includes sliding the sleeve of the instrument over the distal end of the endoscope and moving the sleeve to a central location on the scope. The endoscope is next inserted through the tracheoesophageal passage and into the stomach. The distal end of the instrument, with the jaws in a closed low profile configuration, is then slid over the endoscope, through the tracheoesophageal passage, into the stomach, and off the distal end of the endoscope. The endoscope may be retroflexed during a portion of the insertion of the distal end of the instrument such that the instrument insertion is performed under view of the endoscope. 
   The jaws of the instrument are then opened by actuation of the handle, and the handle and/or control shaft are pulled back to cause the open jaws to forcibly contact the stomach tissue surrounding the lower esophageal sphincter; i.e., the target tissue 1 cm to 3 cm into the stomach. As the jaws contact the tissue, a post on the female jaw and the posts of the male part of the fastener pierce the mucosa, deep muscle and/or serosa of the tissue. An endoscopic grasping instrument extending through the endoscope may be used in conjunction with the end effector to aid in pulling the target tissue between the jaws. The handle is then actuated to cause the jaws to move into a closed position, pulling into apposition two portions of the tissue to form a plication. The posts of the male part of the fastener extend through both layers of tissue at the ends of the plication and enter corresponding openings in the female part as the jaws are closed and the fastener is clamped, but not locked, about the tissue. If desired, the jaws can then be opened to apply a different clamping pressure to the tissue or entirely relocate the fastener. Once the fastener is in a desired location and with a desired pressure on the tissue, the handle is actuated to lock the fastener and release the fastener from the jaws. The instrument may then be recoupled to the endoscope, and the endoscope and the instrument may be withdrawn from the patient. 
   Other instruments and methodologies which provide other couplings between the instrument and the endoscope, and which do not require any coupling of the instrument to the endoscope are also provided. 
   Additional objects and advantages of the invention will become apparent to those skilled in the art upon reference to the detailed description taken in conjunction with the provided figures. 

   
     BRIEF DESCRIPTION OF THE DRAWINGS 
       FIG. 1  is a bottom perspective view of a two-part tissue fastener with male and female parts thereof shown mated but in an unlocked configuration; 
       FIG. 2  is a perspective view of a male part of the two-part fastener of  FIG. 1 , shown with posts of the male part in an upright configuration; 
       FIG. 3  is a perspective view of a male part of the two-part fastener, similar to  FIG. 2 , shown with posts of the male part in a collapsed configuration; 
       FIG. 4  is a top perspective view of the two-part tissue fastener in the same configuration as  FIG. 1 ; 
       FIG. 5  is a bottom perspective view of the two-part tissue fastener in the same configuration as  FIG. 1 , shown with the latch body removed from the female part of the fastener to facilitate viewing the interior structure of the female part of the fastener; 
       FIG. 6  is a bottom perspective view of a two-part tissue fastener with male and female parts thereof shown mated and in a locked configuration; 
       FIG. 7  is a bottom perspective view of the two-part tissue fastener in the same configuration as  FIG. 6 , shown with the latch body removed from the female part of the fastener to facilitate viewing the configuration of the interior structure of the female part of the fastener; 
       FIG. 8  is a perspective view of an alternate post of a male part of the fastener and an alternate sliding assembly of a female part of the fastener; 
       FIG. 9  is a broken side view of an endoluminal tissue plication and fastener applicator instrument according to the invention, shown with a fastener in the end effector; 
       FIG. 10  is a side end perspective view of the distal end of the instrument of  FIG. 9 , shown with a fastener in the end effector; 
       FIG. 11  is a top perspective view of the distal end of the instrument of  FIG. 9 , shown with a fastener in the end effector, but without the female jaw torsion spring; 
       FIG. 12  is a perspective view of the distal end of the instrument, with control shaft removed for clarity, and shown with the jaws in an open configuration and without the fastener; 
       FIG. 13  is a view similar to  FIG. 12 , shown with the fastener. 
       FIG. 14  is a perspective view of the distal end of the instrument, with control shaft removed for clarity, and shown with the jaws in a closed configuration and without the fastener; 
       FIG. 15  is a side elevation view of the distal end of the instrument, with control shaft removed for clarity, and shown with the jaws in a closed configuration and without the fastener; 
       FIG. 16  is a perspective view of the distal end of the instrument, with control shaft removed for clarity, and shown with the jaws in an open configuration and without the fastener; 
       FIG. 17  is a perspective view of the distal end of the instrument, with control shaft removed for clarity, and shown with the jaws in a closed configuration and without the fastener; 
       FIG. 18  is a perspective view of the distal end of the instrument, with the control shaft and the mounting sleeve removed for clarity, and shown with the jaws in an open configuration with a fastener; 
       FIG. 19  is a plan view of the distal end of the instrument, with the control shaft and the mounting sleeve removed for clarity, and shown with the jaws in a closed configuration with a fastener; 
       FIG. 20  is a perspective view of the distal end of the instrument, with the control shaft and the mounting sleeve removed for clarity, and shown with the jaws in a closed configuration without a fastener; 
       FIG. 21  is a partial view of the proximal actuation handle of the instrument of the invention; 
       FIG. 22  illustrates the instrument of the invention coupled to an endoscope during insertion of the two into the stomach; 
       FIG. 23A  is an end view schematic illustration of a cross-sectional area across line  23 A- 23 A in  FIG. 9  across a portion of the distal end effector of the instrument; 
       FIG. 23B  is an end view schematic illustration of a cross-sectional area across line  23 B- 23 B in  FIG. 9  across a portion of the distal end effector of the instrument; 
       FIG. 24  is a schematic illustration of the cross-sectional area of the endoscope and the control shaft; 
       FIG. 25  is a schematic illustration of the cross-sectional area of a prior art device; 
       FIG. 26  illustrates the instrument separated from the endoscope and shown with the jaws in an open position; 
       FIG. 27  is a view similar to  FIG. 26 , and additionally shows a grasping instrument advanced through the endoscope and engaging the target tissue at which a plication is desired to be made; 
       FIG. 28  illustrates the jaws of the instrument plicating the target tissue and the fastener in a locked configuration; 
       FIG. 29  illustrates the jaws of the instrument in an open position and the fastener holding the plicated tissue together; 
       FIG. 30  illustrates an alternate embodiment of the procedure in which the end effector is operated while coupled to an endoscope; 
       FIG. 31  is a side elevation of a second embodiment of the distal end effector adapted to be coupled in the distal opening of a working channel of an endoscope; 
       FIG. 32  is a perspective view of the second embodiment of the distal end effector shown in  FIG. 31 ; 
       FIG. 33  is a side perspective view of a third embodiment of the distal end effector adapted to be advanced over a guidewire; 
       FIG. 34  rear perspective view of the third embodiment of the distal end effector shown in  FIG. 33 ; 
       FIGS. 35 through 45  illustrate a second embodiment of the procedure in which the end effector is advanced over a guidewire into the stomach and operated under view of an endoscope; 
       FIG. 46  is an end view schematic illustration of a cross-sectional area across line  46 - 46  in  FIG. 33 ; and 
       FIG. 47  is an end view schematic illustration of a cross-sectional area across line  46 - 46  in  FIG. 33 . 
   

   DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
   Turning now to  FIG. 1 , a two-part fastener  10  according to the invention is shown. The fastener  10  includes male and female parts  12 ,  14 . Referring to  FIGS. 1 and 2 , the male part  12  includes a base  18  defining two openings  20 ,  22  therethrough and, in one side, two elongate channels  24 ,  26  and two spring shelves  28 ,  30 . Two tissue-piercing posts  32 ,  34  are rotatably coupled to the base  18  in alignment with the channels  24 ,  26 . Each posts includes an enlarged portion  33 ,  35  having a diametric bore (not shown). Axles  36 ,  38  extend across openings  20 ,  22 , through the bores, and are press-fit into the base  18  such that the posts  32 ,  34  are rotatable thereabout. The posts  32 ,  34  have a length of preferably at least 2 mm such that they are adapted to penetrate the serosa of the stomach tissue, and a diameter of preferably less than 1.5 mm inch so that the holes made thereby in the stomach tissue are not prone to leakage. Furthermore, while the posts  32 ,  34  are adapted to pierce tissue, they are also slightly rounded at the tips so as to preferably only displace tissue rather than cut tissue. Torsion springs  40 ,  42  are coupled to the posts  32 ,  34  and are stopped against the base  18  at the shelves  28 ,  30 . Referring to  FIGS. 1 through 3 , the torsion springs  40 ,  42  operate to bias the posts  32 ,  34  toward a collapsed configuration in which the posts lie within the channels  24 ,  26 . The channels  24 ,  26  are oriented at an angle within the base  18  to accommodate posts  32 ,  34  of a maximized length for the size of the base  18 . An upper portion of each post  32 ,  34  is provided with a plurality of slots (notches or grooves)  44  along a medial side thereof, and a lower end  43 ,  45  of each post is provided with a diametric bore  46 ,  48 . 
   Referring to  FIGS. 1 ,  4  and  5 , the female part  14  includes a latch body  50  and a sliding assembly  52  which is slidably movable relative to the latch body. Referring particularly to  FIG. 1 , the latch body  50  includes a base portion  54  and a cover (or shield) portion  56  which are manufactured as a single unit or a fixed assembly of separate elements. The base portion  54  includes two holes  58 ,  60 , each sized to receive a post  32 ,  34  therethrough and preferably having chamfered openings. The cover portion  56  is preferably U-shaped, having an end portion  62  and two sides  64 ,  66  that extend around a portion of the periphery of the base portion  54 . The end portion  62  of the cover portion  56  defines a lower recess  68  and opening  69  at the recess  68 . 
   The sliding assembly  52  includes a latch slide  70 , a latch lock  72 , and a slide cover (or shield)  74 . Referring particularly to  FIG. 5 , the latch slide  70  defines two elongate slots  82 ,  84 , a lower recess  86 , a head portion  76  having a relatively larger width than the remainder of the slide, and cutouts  78  between the head portion  76  and the remainder of the slide. The latch lock  72  resides in recess  86  and the recess is shaped to stably hold a central portion  88  of the lock  72  and to provide space for lateral displacement of elongate portions of the lock  72 . More particularly, the lock  72  includes a generally Z-shaped central portion  88 , and two arms  90 ,  92  extending from a central extension  91  of the central portion  88 . Arm  90  includes a central laterally extending stop  94  and, at its terminus, a beveled catch  96 . Arm  92  includes a central beveled catch  98 , and at its terminus, a laterally extending stop  100 . Each arm  90 ,  92  is biased in the direction of the extension of its stop  94 ,  100 , with the bevel of its catch  96 ,  98  directed toward a respective slot  82 ,  84 . The latch slide  70 , with latch lock  72  positioned therein, is slidably inserted through the opening  69  of the cover portion  56  of the latch body  50 , and the slide cover  74  is then fixed onto the latch slide  70  with pins  104  that are press fit into respective coupling holes  106 ,  108  ( FIGS. 4 and 5 ). It is appreciated that the latch lock  72  is retained in the recess  86  by the base portion  54  of the latch body  50 . The slide cover  74  defines a central space  110 . In addition, referring to  FIG. 5 , the latch slide  70  and slide cover  74  define a setback  112  at which the female part  14  can be engaged with an applicator instrument  200  ( FIG. 9 ), as described further below. 
   By way of example only, preferred dimensions for one exemplar fastener sized for being passed through the esophagus and coupling portions of the stomach tissue together are as follows. The male part  12  has a length of 15 mm, a width of 6.25 mm, and a height of 2 mm (excluding the posts). The female part  14  has a length of 15 mm, a width of 6.25 mm, and a height of 4 mm. The coupled fastener  10  has overall dimensions of a length of 15 mm, a width of 6.25 mm, and a height of 6 mm plus the thickness of the tissue between the male and female parts. 
   The parts  12 ,  14  are preferably constructed of titanium or titanium alloy, and then anodized according to processes known in the art of metallurgy to impart to the parts a color distinct from the natural tissue of the stomach cavity. Preferred colors include purple, blue and black. 
   As discussed in more detail below, when the male and female parts  12 ,  14  of the fastener  10  are brought into apposition on opposite sides of tissue located therebetween by the below described instrument  200  ( FIG. 9 ) (with the posts  32 ,  34  of the male part  12  held upright against the bias of the torsion springs  40 ,  42 , as detailed below), the posts  32 ,  34  of the male part  12  can pierce through tissue and extend into the holes  58 ,  60  of the base portion  54  of the female part  14  ( FIG. 1 ). The chamfered openings of the holes  58 ,  60  facilitate this mating by guiding the posts into the holes  58 ,  60  even if the parts  12 ,  14  are slightly misaligned. The male and female parts  12 ,  14  of the fastener  10  are then clamped about the tissue. The slide cover  74  and cover portion  56  shield the sharp portions of posts  32 ,  34 , respectively, which extend through the base portion  54  of the female part  14 . 
   Referring now to  FIGS. 6 and 7 , once the fastener  10  is clamped about tissue with a desired clamping force (or desired pressure), the sliding assembly  52  is longitudinally slidable relative to the latch body  50  until the head  76  of the latch slide  70  abuts the cover portion  56  within the recess  68  and until the catches  96 ,  98  on the latch lock  72  ride against their bias into respective slots  44  of the posts  32 ,  34 , thereby locking the male and female parts  12 ,  14  together. The plurality of slots  44  and the substantial length of the posts  32 ,  34  permits the base  18  of the male part  12  and base portion  54  of the female part  12 ,  14  to be coupled at several distances relative to each other. In addition, the base  18  and base portion  54  may even be skewed relative to each other to further accommodate various configurations of tissue therebetween, with the catches  96 ,  98  entering, for example, a third notch of post  32  and a fourth notch of post  34 . As a result of this adjustability, a desired amount of force can be applied to tissue between the parts  12 ,  14 , whether or not the tissue therebetween is of uniform thickness, and with such force preferably limited to prevent tissue necrosis. 
   Furthermore, it is noted that when the sliding assembly  52  is moved relative to the latch body  50 , the catches  96 ,  98  will automatically find an appropriate slot  44 , as the latch lock  72  is spring-loaded and compliant. That is, should a catch  96 ,  98  of the latch lock  72  initially contact a post  32 ,  34  at a non-slotted location, the compliance of the latch lock  72  will cause the catch  32 ,  34  to snap into an adjacent slot  44  when subject to small additional movement. 
   It is also noted that the movement of the sliding assembly  52  relative to the latch body  50  causes the slide cover  74  to be spaced apart from the latch body cover  56 . This opens a space  108  between the slide cover  74  and the latch body cover  56 . 
   Even after the male and female parts  12 ,  14  have been locked together, they may be unlocked from each other. Moving the sliding assembly  52  in an opposite direction relative to latch body  54 , such that the slide cover  74  and cover portion  56  are moved relatively closer together, operates to unlock the male and female parts  12 ,  14  such that they may then be separated from each other. That is, this mechanism facilitates decoupling of a fastener and thereby permits atraumatic retrieval of an implanted fastener. One manner of effecting the decoupling can be performed with a standard endoscopic snare device. A loop of the snare device is provided over and about the slide cover  74  and cover portion  56  and the two parts are pulled toward each other by decreasing the size of the snare loop. A portion of the snare loop may be positioned through recess  68  to prevent the loop from slipping off the fastener  10 . Moreover, it is noted that the unnatural color of the fastener  10  relative to the tissue of the stomach cavity facilitates endoscopically locating an implanted fastener for such retrieval. 
   As discussed above, the posts  32 ,  34  are spring-biased to collapse into a base of the male component when not retained against the bias. This operates to prevent injury to the patient should the male part  12  inadvertently become separated from the applicator instrument  200  or from the female part  14  after coupling therewith. Given the size of the parts and the protection of sharps from exposure to the body, the parts may be safely passed through the gastrointestinal system. 
   It is recognized that various other configurations for locking the latch lock  72  of the female part  14  relative to the posts  32 ,  34  of the male part  12  can be used. For example, referring to  FIG. 8 , the posts  32   a  may be provided with circumferential grooves  44   a . And the latch lock  72   a  may have another configuration which effectively provides a catch which can be locked within the grooves  44   a . In  FIG. 8 , the latch lock  72   a  includes, for post  32   a , two resilient, spaced-apart, spring-biased arms  92   a ,  93   a  each with a catch  98   a ,  99   a  adapted to engage within a groove on the post  32   a  and, for the second post (not shown), two resilient, spaced-apart, spring-biased arms  90   a ,  91   a  each with a catch  96   a ,  97   a  adapted to engage within a groove on the post. 
   As further discussed below and clearly shown in the figures relating thereto, the parts  12 ,  14  of the fastener  10  are delivered through the esophagus in a lengthwise orientation. 
   Turning now to  FIG. 9 , an endoluminal tissue plication and fastener applicator instrument  200  is shown. The instrument  200  generally includes a distal end effector  202 , a proximal actuation handle  204 , and a tubular control shaft  206  housing first and second control elements  208 ,  210  (wire, cables, coils, ribbons, etc.) extending between the handle  204  and the end effector  202 . 
   The control shaft  206  is preferably a stainless-steel flat wire wound coil covered in a lubricious sheath, and is substantially smaller in diameter than a conventional endoscope. The flat wire limits elongation of the control shaft when the control shaft is under tension due one or the other of the control elements  208 ,  210  being under compression. Alternatively, a rounded wire coil can be used which permits the control shaft to bent into a tighter radius than the flat wire wound coil. In addition, the control shaft  206  has a relatively small diameter relative to the distal end effector  202 , preferably not exceeding 5 mm and more preferably approximately 4 mm. 
   The distal end effector  202  is adapted to plicate tissue and apply the two-part fastener  10  to opposed sections of the plicated tissue, and according to several embodiments is optionally adapted to be coupled to an endoscope, as described in detail below. The actuation handle  204  operates the control elements  208 ,  210  to effect clamping and opening of the jaw assembly  218  and locking and release of the fastener  10 , as also described in detail below. 
   Referring now to  FIGS. 10 through 12 , the distal end effector  202  includes a jaw assembly  218  having a clevis  224 , first and second arms  220 ,  222  mutually rotatable about the clevis  224 , a housing  290 , and a sleeve (continuous or slit cuff)  320  integral with the housing  290  and adapted to be slidably positioned about (or, if slit, snapped over) an end of an endoscope. 
   Comparing  FIGS. 10 and 12 , it can be seen that the jaws assembly  218  moves the jaws  226 ,  228  in an actuation plane (between closed and open positions, respectively). An axis of the shaft  206  defines a first line of orientation A. A second line B can be said to emerge in between the two jaws  226 ,  228  within the actuation plane. Thus, line B extends from the clevis  224  between the two jaws  226 ,  228 . Lines A and B, together, define an intersecting plane, which can be referred to as a shaft effector plane P. From this, it can be said that the jaws operate in the actuation plane at an angle to the shaft effector plane P. 
   The first arm  220  of the jaw assembly  218  includes a male jaw  226  (adapted to receive the male part  12  of the fastener  10 ), and an opposite tang  230  having a coupling hole  232  adapted to receive a wire-like element. The second arm  222  includes a female jaw  228  (adapted to receive the female part  14  of the fastener  10 ), and an opposite tang  234  having a coupling hole  236 . 
   More particularly, the inside of the male jaw  226  includes a rectangular recess  240  adapted to receive the back of the male part  12  of the fastener  10 , two stepped throughbores  242 ,  244 , and two threaded holes  248 ,  250 . Referring to  FIGS. 3 and 13 , when the male part  12  is loaded into and held within the recess  240  of the male jaw  226 , the lower portions  43 ,  45  as well as portions of the enlarged portions  33 ,  35  of the posts  32 ,  34  are received in the stepped throughbores  242 ,  244 . This retains the posts  32 ,  34  in an upright configuration and consequently prevents their rotation into a collapsed configuration. Referring back  FIGS. 10 and 12 , the outside of the male jaw  226  also includes a recess  246  through which the threaded holes  248 ,  250  are accessed, and an exit opening  252  in communication with a track  258  (which carries a release element, discussed below) through the first arm  220 . The end of the male jaw  226  is also provided with a groove  254 , the function of which is described below. 
   A first release element  259  extends within the track  258  of the first arm  220  from a housing  290  of the clevis  224  and through the exit opening  252 . The first release element  259  includes an actuation end  255  which is split to define two U-shaped portions  261 ,  263  which are respectively inserted into the bores  46 ,  48  ( FIG. 3 ) of the lower end  43 ,  45  of the posts  32 ,  34  of the male part of the fastener. Friction plates  265 ,  267  are held over the U-shaped portions  261 ,  263 , with screws  271 ,  273  inserted into the threaded holes  248 ,  250 , to provide frictional resistance from inadvertently dislodging the U-shaped portions from within the bores  46 ,  48 . 
   Referring to  FIGS. 11 through 13 , the female jaw  228  includes a relatively large generally rectangular opening  260  sized to receive the latch body cover  56  and latch slide cover  74  of the female part  14  of the fastener  10 . The jaw  228  also defines a ledge  275  ( FIG. 16 ), and two catches  262 ,  264  that extend into the opening. The female part  14  is inserted into the jaw  228  in the locked position and then moved into the unlocked position such that the head  76  of the latch slide  70  ( FIG. 5 ) lies over the ledge  275  and the catches  262 ,  264  extend within the setback  112  ( FIG. 5 ) to lock the part  14  in the jaw  228 . A tissue piercing post  256  is provided to the terminus of the female jaw  228 . Referring to  FIGS. 14 and 15 , when the female and male jaws  226 ,  228  are free of the fastener parts  12 ,  14  and closed together (e.g., after the fastener has been released and during retraction of the instrument), the post  256  resides in the groove  254  of the male jaw  226  to provide a more tapered configuration to aid in removal of the instrument from the patient. 
   Referring now to  FIGS. 15 and 16 , a torsion spring  266  is coupled to the female jaw  228  and adapted to force the female part  14  of the fastener  10  toward the terminus of the jaw. This operates to help align the male and female parts  12 ,  14  as the jaws  226 ,  228  are rotated toward each other through an arc. Moreover, the spring  266  permits movement of the female part  14  within the opening  260  to accommodate misalignment due to the amount of the tissue between the fastener parts. Referring to  FIGS. 16 and 17 , the female jaw  228  also includes an exit opening  268  for a wire track  270  extending along a side of arm  222 . A second release element  272  extends within the track  270  from the housing  290  through the exit opening  268 , as described further below. 
   Referring now to  FIG. 18 , the clevis  224  also includes a mount  280  at which the control shaft  206  ( FIG. 9 ) is attached to the distal end effector  202  of the instrument  200 . The mount  280  includes a bracket  282  that is coupled to the clevis  224  at pivot  284 . The clevis  224  also defines a housing  290  for a mechanical assembly  292  which operates to transmit an input force on the control elements  208 ,  210  to the end effector  202  to effect movement of the jaw arms  220 ,  222  and locking and release of the fastener  10  therefrom. 
   More particularly, the mechanical assembly  292  preferably includes a first bell crank  294  rotatably coupled about a pivot  296  that is preferably integrally formed with the housing. A distal end  298  of control element  208  is coupled to the first bell crank  294  at an input side of the bell crank, and a V-shaped wire  300  is attached to the bell crank at an output side of the bell crank. The V-shaped wire  300  extends to and is coupled within the coupling holes  232 ,  236  ( FIG. 12 ) of the tangs  230 ,  234  of both of the two jaw arms  220 ,  222 . Alternatively, two separate wires can be used to extend from the output side of the bell crank to the two tangs. Referring to  FIGS. 18 and 19 , when control element  208  is moved distally relative to the control shaft, the first bell crank  294  is rotated, pulling the V-shaped wire  300  away from the jaws and thereby rotating the jaws  226 ,  228  into a closed position. Still referring to  FIGS. 18 and 19 , it is also noted that when the jaws  226 ,  228  are forced into a completely closed position, additional force on control element  208  causes rotation of the mount  280  about the pivot  284  to cause the jaws to move closer to the control shaft  206 . This reduces the profile of the end effector to aid in removal of the instrument from the stomach and esophagus after a fastener  10  has been released from the instrument  200 . When control element  208  is moved proximally relative to the control shaft  206 , the first bell crank  294  is rotated to cause the V-shaped wire  300  to forcibly rotate the jaws  226 ,  228  into an open position. In addition, referring back to  FIG. 18 , when the jaws  226 ,  228  are in a fully opened position, additional force on control element  208  causes rotation of the mount  280  about the pivot  284  which pushes the jaw assembly  218  away from the control shaft  206 . This provides additional space between the jaw assembly  218  and the control shaft  206  to facilitate grabbing tissue between the jaws  226 ,  228 . 
   Referring still to  FIGS. 18 and 19 , the mechanical assembly  292  also includes a second bell crank  302  that is rotatably coupled about a pivot  304  which is also preferably integrally formed with housing  290 . A distal end  306  of control element  210  is attached to one side of the second bell crank  302 . Another side of the second bell crank  302  defines a push bar  310 . The ends of release elements  259 ,  272  ( FIG. 17 ) terminating within the housing  290  are preferably bent or otherwise formed at an angle such as to define contact portions  312 ,  314  ( FIGS. 18 and 19 ) which, when the jaw arms  220 ,  222  are in a closed position (FIG.  19 ), are oriented substantially perpendicular to the orientation of the push bar  310 . 
   Referring now to  FIGS. 19 and 20 , when the jaws are in a closed position and control element  210  is pushed distally relative to the control shaft  206  to apply a pushing force to the second bell crank  302 , the push bar  310  is forced against the contact portions  312 ,  314  and moves the release elements  259 ,  272  ( FIG. 16 ) into the respective jaws  226 ,  228 . This effects both locking together the male and female parts  12 ,  14  of the fastener  10  and release of fastener  10  from the jaws  226 ,  228 , as follows. First, when the end of release element  272  is pushed against the sliding assembly  52 , the sliding assembly is forced to move relative to the latch body  50 . This locks the catches  96 ,  98  of the latch lock  72  relative to the posts  32 ,  34 , and thereby locks the male and female parts  12 ,  14  of the fastener together. Second, movement of the sliding assembly spaces moves the latch slide cover  74  to free the head  76  of the latch slide from the ledge  275  and free the catches  262 ,  264  of the female jaw  228  from the setback  112  (aligning space  108  ( FIG. 6 ) with the catches  262 ,  264 ), to thereby release the female part  14  from the female jaw  228 . Third, the U-shaped ends  261 ,  263  ( FIG. 10 ) of the bifurcated release element  255  are moved out of the bores  46 ,  48  of the posts  32 ,  34  to release the male part  12  from the male jaw  226 . It is noted that the force on release element  255  is sufficient to overcome the friction created by plates  265 ,  267 . 
   It is noted that the push bar  310  is decoupled from the release elements  259 ,  272  as the contact portions  312 ,  314  of the release elements will be differently located relative to the push bar  310  based upon whether large or small amounts of tissue are located between the closed jaws  226 ,  228  and to what degree the jaws are closed. This decoupled adjustable mechanism operates to effect the appropriate amount of movement to the release elements regardless of the exact closed jaw configuration. 
   Alternatively, rather than use a bell crank system in which control element  208  is placed under tension to close the jaws and control element  210  is placed under compression to operate the lock the fastener parts and release the fastener from the jaws, another system may be used to couple the control elements  208 ,  210  to the jaws  226 ,  228  and release elements  259 ,  272 , respectively. For example, each of the control elements may include an end provided with a U-shape in which the end of the control element defines a return extending non-coaxial but parallel to the remainder of the control element. For example, the U-shaped end of the control element  208  can be coupled to the jaws such that when control element is placed under compression the return portion of the U-shape pulls the jaws closed. Similarly, the U-shaped end of the control element  210  can be configured to act on release elements  259 ,  272  such that control element is placed under tension to the U-shaped portion pushed on the release elements  259 ,  272 . Other mechanisms may likewise be used. 
   Referring back to  FIGS. 10 and 11 , the sleeve  320  of the distal end effector  218  preferably has an opening  321  with a diameter of approximately 9 mm, corresponding to the diameter of a relatively small endoscope. The exterior dimensions of the sleeve  320  are minimized to provide as low a profile as possible to facilitate passage of the distal end effector  218  through the tracheoesophageal passage of a patient. The sleeve  320  may also be provided with a slant nose or other tapered or otherwise streamlined shape that further facilitates introduction and withdrawal of the distal end effector  202  through the tracheoesophageal passage. In addition, the sleeve  320  is preferably constructed of a preferably soft, low friction, lubricious material such as polytetrafluoroethylene (PTFE), nylon, or silicone to aid in movement over the endoscope and prevent injury to the human body. The sleeve  320  is coupled over the housing  290  to enclose the mechanical assembly  292  ( FIG. 18 ). To facilitate the coupling of the sleeve  320  to the end effector  202 , it is preferable that the sleeve  320  be provided with two holes  322 ,  324  and that pivots  296  and  304  ( FIG. 18 ) for the first and second bell cranks  294 ,  302  be provided with an internal thread ( FIG. 18 ). Screws  326 ,  328  are inserted in holes  322 ,  324  and thread into the pivots  296 ,  304  to lock the sleeve over the housing  290 . 
   Referring now to  FIGS. 9 and 21 , the proximal actuation handle  204 , which according to one embodiment is a pistol-grip style handle, includes a stationary handle  340 , and a lever  342  rotatable relative thereto. The stationary handle  340  is integral with a housing  344  which defines a longitudinal slot  346 . A proximal end  356  of the control shaft  206  extends into the housing  344  and is coupled to an upper portion of the lever  342 . The first control element  208 , which is coupled at its distal end  298  to the jaw arms  220 ,  222  via the first bell crank  294 , includes a proximal end  358  that extends out of the proximal end  356  of the control shaft  206  and is fixed at a second mount  360  within the housing  344 . The second control element  210 , which operates to lock and release the fastener  10  via the second bell crank  302 , includes a proximal end  362  that is coupled to a cross bar  364  movable within the longitudinal slot  346 . The cross bar  364  includes a handle portion  365  ( FIG. 9 ) located external the housing  344 . The lever  342  is biased into an open position with a first spring  350  that is coupled between a lever mount  352  on the lever and a first mount  354  within the housing  344 . The lever  342  is also provided with a locking system  366  that operates to lock the position of the lever relative to the handle  340 . The locking system  366  includes a plurality of teeth  368  on the lever, a pawl  370  mounted on a pivot  372  and biased with a second spring  374  toward the teeth  368 , and a cam  376  that can be manually rotated with an external knob  378  ( FIG. 9 ) to contact the pawl  370  and effect disengagement of the pawl from the teeth  368 . 
   In operation, when the handle lever  342  is rotated toward to the stationary handle  340 , the control shaft  206  is moved distally relative to the first control element  208  to effect closing the jaws  226 ,  228 . With the jaws in a closed position, the cross bar  364  can be moved distally relative to the stationary handle  340  in order to operate the second bell crank  302  (via control element  210 ) to cause lock and release of the fastener  10 . After a fastener  10  is released, the cam  376  can be operated to release the handle locking system  366  and permit the handle lever  342  to rotate relative to the stationary handle  340 , thereby allowing the jaws to reopen. 
   While a pistol-grip embodiment of the handle  340  has been shown for operation of the instrument  200 , as such a handle includes significant mechanical advantage, it may be preferred to use an inline-type handle or other handle configured to also provide the desired mechanical advantage. 
   The instrument  200  is highly torqueable with great ability to direct the end effector via manipulation of the handle in gross. That is, the instrument  200  has a torsionally rigid flexible shaft particularly for its length of at least approximately 150 cm, and more likely 190 cm length. This torqueability permits the end effector assembly  212  to be rotated through 180° (for any approach toward the target tissue) via rotation of the handle preferably by no more than approximately 180°. This is facilitated, in part, by control element  208  being rotational fixed to the handle  340 . Control element  208  is relatively large in diameter, and is most preferably an approximately 0.035 inch stainless steel wire. A wire of similar construct having a diameter preferably between approximately 0.020 inch and approximately 0.062 inch should also be suitable. 
   According to one embodiment of the method of the invention, the instrument  200  may be operated as follows with respect to the treatment of GERD. Turning to  FIG. 22 , the sleeve  320  of the distal end effector  202  is slidably coupled over the distal end of an endoscope  400  and the end effector is slid proximally over the endoscope. The distal end of the endoscope  400  is then inserted into the tracheopharangeal passage and moved through-the esophagus and into the stomach, with the end effector  202  of the instrument  200  mounted preferably approximately 20 cm back from the distal end of the endoscope  400 . The handle  204  and/or control shaft  206  are then manipulated in gross to slide the distal end effector  202  over the distal end of the inserted endoscope  400  and into the stomach, with the endoscope  400  functioning as a guidewire for the sleeve  320 . The endoscope  400  may optionally be retroflexed to look back toward to the LES  402  of the esophagus and visualize the advancement of the end effector  202 . 
   Referring to  FIG. 23A , it is particularly noted that during insertion of the end effector over the endoscope and into the patient (and later withdrawal of the end effector from the patient), the maximum cross-sectional area of the system extending within the esophagus occurs with the combined area of the sleeve  320  and the portion of the clevis  224  that extends outside the footprint of the sleeve; i.e., approximately 188 mm 2 , smaller than any of the existing or proposed devices in the prior art. The second largest cross-sectional area of the system within the esophagus is at the location of the jaws  226 ,  228  with the jaws loaded with a fastener  10 . Referring to  FIG. 23B , this area includes the footprint of the jaw assembly  218  loaded with a fastener as well as the control shaft  206  and the endoscope  400 , and is approximately 178 mm 2 . The portions of the system having the cross-sectional areas of  FIGS. 23A and 23B  are located within the esophagus only during insertion and removal of the end effector into the patient. Referring to  FIG. 24 , at all other times and along all other portions of the present system proximal the distal end effector, the cross-sectional area of the system in the esophagus is substantially smaller, limited to the combined cross-sectional areas of the endoscope  400  (approximately 63.6 mm 2  for a 9 mm scope) and the control shaft  206  (approximately 12.6 mm 2  for a 4 mm control shaft); i.e., a total cross-sectional area of approximately 76.2 mm 2  or less. 
   In contrast, prior art  FIG. 25  shows the relative size of a cross-sectional area corresponding to a prior art device  900  having an 18 mm diameter (254 mm 2 ), such as the NDO device described above in the State of the Art section. This relatively larger area obstructs the esophagus throughout the procedure. 
   If the endoscope is retroflexed during insertion of the distal end effector  202 , the passage of the distal end effector into the stomach is performed under view of the endoscope  400 . Once the distal end effector is located in the stomach, the endoscope is preferably straightened if it was retroflexed, and the end effector is moved distally off the endoscope such that the endoscope  400  and instrument  200  are completely separated. Referring to  FIG. 26 , the endoscope  400  is then again retroflexed and the instrument handle  204  is operated to open the jaws  226 ,  228  of the end effector  202 , as described above. 
   Referring to  FIG. 27 , a tissue grasping instrument  406 , e.g., a forceps, helical needle, or tagging device, is preferably then inserted through a working channel  408  of the endoscope  400  and directed at target tissue  410  one to three centimeters into the stomach adjacent the LES where the center of a plication is to be located. The grasping instrument  406  engages the tissue  410  and pulls the tissue back between the jaws  226 ,  228  of the end effector  202  of the instrument  200 . In addition, the handle  204  and/or control shaft  206  of the instrument  200  are pulled back in gross (i.e., in the direction of withdrawing the instrument) such that the jaws approach the tissue  410  in a direction substantially parallel to the esophagus. This is a highly desirable angle of approach that has been previously unattainable with endoscopic GERD treatment instruments. That is, any device that retroflexes must extend through an arc. It is not possible for a retroflexed device to be both parallel to an entry path and also displaced a couple of centimeters away from the entry path. 
   The proximal actuation handle  204  is then operated to cause the jaws  226 ,  228  to close. As a central point of the tissue  410  is held in a fixed location between the jaws by the grasping instrument  406  during movement of the jaws, a tissue plication  412  if formed by the jaws and the male and female parts  12 ,  14  of the fastener  10  are brought together with the plication  412  clamped therebetween. When the jaws  226 ,  228  are closed about the tissue plication  412 , the posts  32 ,  34  of the male part  12  of the fastener  10  preferably pierce the tissue down to the serosa, and the piercing post  256  of the female jaw  228  preferably pierces through the deep muscle of the tissue and sufficiently to damage the tissue to cause serosa to serosa contact. Experimental procedures have shown that this contact results in tissue adhesion after healing, such that the tissue is permanently reconfigured; i.e., even if the fastener  10  is later removed. In this manner, a zone of reduced compliance is created about the LES. 
   The location and size of the plication as well as the relative positions of the fastener parts are observed via the scope. Moreover, more or less clamping pressure can be applied to the plicated tissue by control of the proximal actuation handle  204 . 
   Referring to  FIG. 29 , if the plication  412  appears satisfactory, the proximal actuation handle  204  is then operated, as described above, to lock the male and female parts  12 ,  14  of the fastener  10  and release the coupled fastener from the jaws  226 ,  228 . If the plication or fastener position is not satisfactory, prior to locking and release, the jaws can be opened, reoriented if necessary, and another plication can be formed. 
   After the fastener is applied, the jaws are then closed, the endoscope is straightened, and the end effector is preferably re-docked over the distal end of the endoscope. The instrument and endoscope are preferably together withdrawn through the esophagus and out of the patient. Alternatively, the endoscope may be withdrawn first, followed by the withdrawal of the instrument preferably under visualization. 
   As discussed above, if at any time the fastener or either of the parts thereof become loose during the implantation procedure or any time after the procedure, the sharps on the fastener elements are adapted to assume a safe configuration or are permanently covered. As such, the fastener or its parts may be safely passed through the gastrointestinal system of the patient. 
   While it is preferable to decouple the instrument from the endoscope during the procedure, it is appreciated that the instrument may be operated while coupled to the endoscope. That is, referring to  FIG. 30 , the target tissue is approached by opening the jaws  226 ,  228  and simply retracting the instrument  200  along the endoscope  400  until the tissue about the LES is contacted. The jaws  226 ,  228  are then closed and the fastener  10  applied, as described above. In order to utilize this procedure, the sleeve  320  of the instrument should be offset relative to the jaws  226 ,  228  so that the jaws can clear the endoscope when opening and closing. 
   Turning now to  FIGS. 31 and 32 , a first alternative embodiment of a distal end effector  502  of the instrument  200  according to the invention is shown. The end effector  502  is adapted to couple within the distal end of a working channel of an endoscope, rather than be coupled about the endoscope with a sleeve. To that end, the housing  590  of the end effector  502  is provided with a proximally directed peg  620  preferably located above, but in line with the control shaft  206 , and sized to be received within the distal end of a working channel of an endoscope. In addition, the housing  590  also includes a concave surface  622  permitting the housing  590  and endoscope to be adjacent in a minimized profile. 
   In use, the end effector is docked with the distal end of the endoscope using the peg  620 , and the control shaft  206  is held taught relative to the endoscope to maintain the coupling. The cross-sectional area for the system at the end effector (end effector and endoscope coupled together) is approximately 150 mm 2 . It is noted that the cross-sectional area of the system is smaller than the area defined by a system utilizing a sleeve, as the endoscope is close fitting with the end effector and the sleeve dimensions are eliminated. The endoscope, with end effector  502  attached at its distal end, is then inserted into the patient&#39;s stomach. The proximal handle  204  and/or control shaft  206  is then manipulated in gross to disengage the end effector. Thereafter, the procedure continues, preferably as discussed above, until plication and fastener application is achieved. Then, prior to removal of the instrument and endoscope, the end effector  502  is preferably re-docked with the endoscope, and the instrument and endoscope are withdrawn from the patient. Alternatively, the endoscope and instrument are separately removed. 
   While the instrument has been shown adapted to be coupled to an endoscope, it is recognized that the instrument may be modified for use in a manner in which it is always decoupled from an endoscope. Referring now to  FIGS. 33 and 34 , a second alternate embodiment of the distal end effector  702  of the instrument  200  is shown. The housing  790  of the end effector  702  is provided with a tapered nose piece  820  defining a longitudinal passage  822  sized to receive a guidewire  824 . The guidewire may have a diameter less than one millimeter. The nose piece  820  is preferably formed from a highly flexible material such as silicone. 
   According to a preferred method of use, referring to  FIG. 35 , an endoscope  400  is preferably first inserted through the tracheopharangeal passage  414  and into the stomach  416  in accord with a well-known procedure. Next, referring to  FIG. 36 , a guidewire  924  is advanced through the endoscope into the stomach. Referring to  FIG. 37 , the endoscope  400  is then preferably withdrawn from over the guidewire  824 . Referring to  FIG. 38 , the end effector  702  is then blindly advanced over the guidewire  924  and introduced into the stomach  416 . The tapered nose piece  820  and relatively small head-on cross-sectional area of the system facilitate the introduction. Referring to  FIG. 39 , after the end effector  702  is located in the stomach  716 , the guidewire  824  is preferably withdrawn from the stomach. Referring now to  FIGS. 40 and 41 , the endoscope is then reintroduced alongside the control shaft of the instrument, advanced into the stomach and retroflexed to view the end effector  702 . The jaws  726 ,  728  of the end effector  702  are also opened and brought adjacent the tissue which is to be plicated. Referring to  FIG. 42 , a tissue grabbing device  920  is deployed through a working channel of the endoscope  400  and operated to engage tissue  910  at a location at which the fold of a plication is desired. The tissue grabbing device preferably includes piercers which extend through the mucosa and the muscularis (deep muscle) to thereby hold these layers together and prevent delamination. Turning to  FIG. 43 , the jaws of the end effector  702  are closed, forming a plication  812  about the engaged tissue  910 , the plication  912  being substantially parallel to the esophagus. The plication extends from the location held by the device  920  to the end of the jaws of the instrument. Referring to  FIG. 44 , the fastener  10  is deployed and the jaws of the end effector  702  are opened. Referring to  FIG. 45 , the jaws of the end effector  702  are closed, and the end effector  702  is withdrawn through the esophagus  414  under visualization of the endoscope  400 . That is, the closed jaws of the end effector  702  are preferably positioned directly distal of the endoscope  400  to minimize the cross-sectional area of the endoscope/instrument system as well as to permit constant visualization of the end effector during the retraction of the end effector through the esophagus. 
   It is noted that this embodiment provides the smallest cross-sectional area for the system in the esophagus, as the area is limited to either (1) the end effector, or (2) the endoscope and control shaft, but never both (1) and (2) at the same time. Referring to  FIG. 46 , for (1), the end effector cross-sectional area across the clevis  790  distal of the jaw assembly is approximately 75 mm 2 . Also for (1), the end effector cross-sectional area proximal of the clevis and across the jaw assembly  718  is (with the jaw assembly in a closed position) is approximately 115 mm 2  (calculated as the approximately 102 mm 2  cross-sectional area of the jaw assembly  718  plus the 12.6 mm 2  cross-sectional area of a 4 mm control shaft). For (2), the combined cross-sectional area of the endoscope and control shaft is 76.2 mm 2 , calculated as 63.6 mm 2  for a 9 mm endoscope and 12.6 mm 2  for a 4 mm control shaft. 
   There have been described and illustrated herein several embodiments of fasteners, instruments, systems, and methods for the endoluminal treatment of gastroesophageal reflux disease (GERD). While particular embodiments of the invention have been described, it is not intended that the invention be limited thereto, as it is intended that the invention be as broad in scope as the art will allow and that the specification be read likewise. For example, while particular preferred dimensions have been provided for both elements of the instrument and fastener, as well as cross-sectional areas of the system, it is appreciated that the system and its elements may have different relative sizes. For example, the cross-sectional areas can be decreased further if a pediatric endoscope (4 to 6 mm) is used. Also, while a “looking back” instrument has been disclosed particularly for fastener application designed to treat GERD, it is appreciated that a “forward looking” straight instrument with similar jaw assembly can be used to apply the fastener for treatments of other conditions, e.g., obesity, ulceration, stomach cancer, implantation of pH measurement or monitoring devices, feeding tubes, etc. Moreover, a straight device can be smaller in diameter and be operated through a working channel of an endoscope. It will therefore be appreciated by those skilled in the art that yet other modifications could be made to the provided invention without deviating from its spirit and scope as so claimed.