Post decompression marker introducer system

<u>Field of the Invention</u>

0001This invention relates generally to a medical device for marking a target site within a tissue mass and more specifically to a medical device having a marker for marking a biopsy site in breast tissue that is deployed after the breast tissue has been decompressed.

<u>Description of the Related Art</u>

0002A biopsy is a well-known medical procedure that involves taking a sample of tissue from a person and examining it for diagnostic purposes. This is often done when an abnormality is found in a tissue mass, for example when a lump is found in breast tissue or when an imaging system, such as mammography or ultrasonography detects a suspicious area. Examining a sample of tissue from an abnormal site or lesion is currently the only way to accurately diagnose cancer.

0003A vacuum-assisted biopsy (VAB) uses an imaging system, such as ultrasonography or mammography, to locate a lesion in the breast tissue and to guide a biopsy probe to the site. An example of a known VAB device 200 is shown in <figref idref="f0001">Fig. 1</figref>. Such a VAB device is described in <patcit id="pcit0001" dnum="US6712774B"><text>United States Patent No. 6,712,774</text></patcit>. The details of the VAB device are not germane to the invention and thus will only be briefly described. The probe 70 has a pointed tip 76 to facilitate its insertion through the tissue mass, an opening 78 in the side wall of the probe near the pointed tip, and a vacuum chamber 72. Once the probe 70 is in position at the lesion site, a vacuum pump creates a vacuum in chamber 72 and draws the tissue through the opening 78 and into a sampling chamber where a cutting device is advanced through the probe 70 to cut and remove a tissue sample. Other instruments can be inserted through the probe 70 in addition to the cutting device.

0004The position of the patient during VAB depends on the imaging system used to locate the lesion and position the probe. If ultrasonography is used, the patient will be in a supine position. If mammography is used, the patient typically lies prone on a specialized table such that the breast protrudes through a hole in the table. The breast is compressed between two plates while an image of the lesion is produced on a monitor by a mammography unit. Once the lesion is imaged, the VAB probe, which is mounted to the table or the mammography unit, is inserted into the breast tissue and the tissue sample is gathered as described above.

0005In some cases, it is desirable to mark the location of the lesion site in case a future biopsy or surgery is necessary. This is done with a marker that is made of any suitable material that can be imaged by an imaging system, such as ultrasonography, magnetic resonance, or mammography, or that is palpable through the skin and tissue of the patient. The marker must be accurately placed at the lesion site in the breast tissue and must remain at the site so that the lesion can be located and identified at a later time, if necessary. However, there sometimes is a need for a marker to be repositioned after its initial placement, such as if the marker was not placed at the desired location or if the marker shifts upon decompression of the tissue. Thus, the marker must be able to remain anchored in the breast tissue, yet permit its repositioning.

0006One type of marker is a biocompatible clip that can be placed at the lesion site to facilitate locating the lesion during later procedures. The clip has the advantage of being implanted entirely within the tissue mass, so that there is no possibility of accidental repositioning by pulling or tugging the clip. The clip is placed after the tissue sample has been gathered from the lesion site and while the breast is still compressed. The clip is inserted into the tissue mass through the VAB probe and thus does not require the tissue mass to be repierced. Since the clip is deployed when the breast tissue is compressed, upon decompression the clip may be found to be implanted away from the lesion site, leading to inaccurate marking of the lesion site. An illustrative example of the post-decompression shifting problem is a rubber ball that is normally 5 cm in diameter, but compressed to 2 cm. If a clip is to be placed 1 cm from the edge of the ball, the clip would be placed at the center of the ball. However, if upon decompression of the ball the clip stays at the center of the ball or shifts away from the target site, the clip is misplaced by up to several centimeters. Coopers ligaments in the breast exacerbate the problem of inaccurate marking by acting to pull the clip away from the site of implantation when the breast is uncompressed.

0007<patcit id="pcit0002" dnum="US6234177B"><text>US 6,234,177</text></patcit> describes an apparatus for deploying an expandable biopsy marker. In the apparatus, a deployment catheter having an axial catheter lumen is provided, with the marker being deployed by a plunger axially received in the lumen of the catheter. The preamble of claim 1 is based on this prior art.

SUMMARY OF THE INVENTION

0008According to the present invention, an apparatus for implanting a locatable marker at a target site within a tissue mass comprises a insertion device comprising a lumen having an exit opening, an introducer system comprising a sheath slidably received within the lumen and comprising a first lumen having a distal opening, a locatable marker received within the first lumen and deployable through the distal opening, and an anchor operably coupled to the sheath to fix the location of the sheath in the tissue mass, wherein the insertion device can be located within the tissue mass and the sheath can be inserted into the tissue mass through the exit opening of the insertion device, and the anchor can fix the position of the sheath in the tissue mass for deployment of the locatable marker at the target site.

0009The introducer system can comprise a second lumen having a distal opening, with the anchor received within the second lumen and deployable through the distal opening. The introducer system can comprise a distal terminal end and the distal terminal end can comprise an insertion tip. At least one of the introducer system distal openings can be formed in the terminal end of the introducer system. At least one of the introducer system distal openings can be formed in a side wall of the introducer system. At least one of the sheath distal openings formed in the side wall can comprise a ramp to guide the locatable marker through the at least one of the introducer system distal openings formed in the side wall.

0010The apparatus can further comprise a pushrod slidably received within the first lumen that deploys the locatable marker through the distal opening.

0011The anchor can comprise an anchor wire. The anchor wire can be operable between a straight configuration where the anchor wire is contained within the second lumen and a curved configuration where the anchor wire is extended through a distal opening. The anchor wire can be embedded in the tissue mass in the curved configuration.

0012The apparatus can further comprise a cannula received within the insertion device lumen, the cannula comprising a cannula lumen having a distal opening, with the introducer system received within the cannula lumen. The cannula distal opening can comprise a ramp to guide the introducer system through the cannula distal opening.

0013The insertion device can be a biopsy probe. The probe can be a vacuum-assisted biopsy probe. The exit opening can comprise a ramp. The introducer system can be flexible. The introducer system can comprise distance markings.

0014The apparatus can further comprising a pair of compression plates for compressing the tissue mass prior to location of the insertion device into the tissue mass at the target site and for decompressing the tissue mass prior to implantation of the locatable marker.

0015The apparatus can further comprise a hemostatic agent received within the first lumen and deployable through the distal opening. The locatable marker can be one of an imaging marker and a palpable marker. The locatable marker can be a clip.

BRIEF DESCRIPTION OF THE DRAWINGS

0016In the drawings: <ul id="ul0001" list-style="none" compact="compact"><li><figref idref="f0001">Fig. 1</figref> is a schematic illustration of a prior art VAB device.</li><li><figref idref="f0002">Fig. 2</figref> is a schematic illustration of a VAB probe containing an introducer system according to the first embodiment of the present invention comprising a sheath having a first lumen containing a marker clip and a pushrod and a second lumen containing an anchor wire.</li><li><figref idref="f0002">Fig. 3</figref> is an enlarged view of the first embodiment of the introducer system from <figref idref="f0002">Fig. 2</figref>.</li><li><figref idref="f0003">Fig. 4</figref> is a sectional view of the introducer system taken along line 4-4 from <figref idref="f0002">Fig. 3</figref>.</li><li><figref idref="f0004">Fig. 5</figref> is a drawing similar to <figref idref="f0002">Fig. 3</figref> illustrating the anchor wire extended from the second lumen.</li><li><figref idref="f0004">Fig. 6</figref> is a drawing similar to <figref idref="f0004">Fig. 5</figref> illustrating the pushrod extended from the first lumen to push the marker clip out of the introducer system.</li><li><figref idref="f0005">Fig. 7</figref> is a schematic illustration of the VAB probe from <figref idref="f0002">Fig. 2</figref> inserted into a tissue mass comprising a breast that is compressed between compression plates.</li><li><figref idref="f0006">Fig. 8</figref> is a close-up view of area VIII from <figref idref="f0005">Fig. 7</figref> illustrating the insertion of the introducer system into the VAB probe.</li><li><figref idref="f0007">Fig. 9</figref> is a drawing similar to <figref idref="f0006">Fig. 8</figref> illustrating the introducer system extended from the VAB probe and into the tissue mass.</li><li><figref idref="f0008">Fig. 10</figref> is a drawing similar to <figref idref="f0007">Fig. 9</figref> illustrating the anchor wire extended from the second lumen and anchored in the tissue mass.</li><li><figref idref="f0009">Fig. 11</figref> is a drawing illustrating the tissue mass in an uncompressed state with the introducer system anchored in the tissue mass and the retraction of the VAB probe from the tissue mass.</li><li><figref idref="f0010">Fig. 12</figref> is a close-up view of area XII from <figref idref="f0009">Fig. 11</figref> illustrating the pushrod extended from the first lumen to push the marker clip out of the introducer system and into the tissue mass.</li><li><figref idref="f0011">Fig. 13</figref> is a drawing similar to <figref idref="f0010">Fig. 12</figref> illustrating the marker clip implanted in the tissue mass and the retraction of the introducer system from the tissue mass.</li><li><figref idref="f0012 f0013 f0014">Figs. 14-16</figref> are schematic illustrations showing a method of relocating the introducer system within the tissue mass.</li><li><figref idref="f0015">Fig. 17</figref> is a schematic illustration of an introducer system having distance markings on the first and second lumens.</li><li><figref idref="f0016">Fig. 18</figref> is an enlarged view of a second embodiment of the introducer system.</li><li><figref idref="f0016">Fig. 19</figref> is a sectional view of the introducer system taken along line 19-19 from <figref idref="f0016">Fig. 18</figref>.</li><li><figref idref="f0016">Fig. 20</figref> is an enlarged view of a third embodiment of the introducer system showing the anchor wire extended from the second lumen.</li><li><figref idref="f0017">Fig. 21</figref> is an enlarged view of the introducer system from <figref idref="f0016">Fig. 20</figref> showing the anchor wire in a compressed configuration within the second lumen.</li><li><figref idref="f0017">Fig. 22</figref> is an enlarged view of the introducer system from <figref idref="f0016">Fig. 20</figref> showing the anchor wire in a straight configuration within the second lumen.</li><li><figref idref="f0018">Fig. 23</figref> is an enlarged view of a fourth embodiment of the introducer system.</li><li><figref idref="f0018">Fig. 24</figref> is an enlarged view of a second embodiment of the VAB probe.</li><li><figref idref="f0019">Fig. 25</figref> is a drawing similar to <figref idref="f0002">Fig. 2</figref> illustrating the introducer system contained within an outer cannula that is contained within the VAB probe.</li></ul>

DESCRIPTION OF THE PREFERRED EMBODIMENT

0017Referring now to the drawings and particularly to <figref idref="f0002">Fig. 2</figref>, an embodiment of the marker introducer system 10 is illustrated contained within a VAB probe 70 of a VAB system (<figref idref="f0001">Fig. 1</figref>). The VAB probe 70 comprises a vacuum chamber 72, a lumen 74, a closed insertion tip 76, and a proximal opening (not shown) into which the introducer system 10 can be inserted. An opening 78 in the cannula 72 allows a tissue sample to be taken from a tissue mass as previously described.

0018Referring additionally to <figref idref="f0002">Fig. 3</figref>, the introducer system 10 comprises a first sheath 12 and a second sheath 14 which respectively define a first lumen 16 and a second lumen 18. The first sheath 12 comprises an open distal insertion tip 22 and an open proximal end (not shown). The second sheath 14 comprises an open distal tip 32 and an open proximal end (not shown). An anchor wire 40 is contained within the second lumen 18 and a marker in the form of a clip 50 and a pushrod 60 are contained within the first lumen 16.

0019The sheaths 12, 14 are preferably independently fabricated from a biocompatible plastic that is flexible and bonded together as shown in <figref idref="f0003">Fig. 4</figref>. The gap between the sheaths 12, 14 and the corresponding pushrod 60 and anchor wire 40 is exaggerated in <figref idref="f0002">Fig. 3</figref> to better discern the elements. One or both of the sheaths 12, 14 could also be formed from a coiled wire or any other biocompatible material that is sufficiently flexible such that the introducer system 10 can be inserted through the VAB probe and out of the opening 78.

0020Referring to <figref idref="f0004">Fig. 5</figref>, the anchor wire 40 comprises a hook 42 and a thread 44. When mounted in the sheath 14 prior to implantation in the tissue mass, the hook 42 is contained within the second lumen 18 and a portion of the thread 44 extends exteriorly of from the proximal end of the sheath 14. The thread 44 is of sufficient length such that the proximal end of the thread 44 is exterior to the proximal end of the sheath 14 to manipulate the anchor wire 40 relative to the sheath 14.

0021The hook 42 is fabricated from a resilient, biocompatible material, for example a shape-memory alloy such as Nitinol. This allows the hook to assume a straight first configuration in the lumen as illustrated in <figref idref="f0002">Fig. 3</figref>, and a curved second configuration outside the lumen as illustrated in <figref idref="f0004">Fig. 5</figref>.

0022The hook 42 is preferably formed from the same wire as the thread 44 such that the hook is a continuation of the thread with the end of the hook 42 being connected to the thread 42 to complete hook 42. Alternately, the hook 42 and the thread 44 can be formed from different wires and or different materials. In either case, the hook 42 can be bonded or welded to the thread 44 to form the connection.

0023While the anchor wire 40 is shown having a hook 42 that engages the tissue mass, the anchor wire 40 can be formed with any one of a number of different anchors. For instance, as disclosed in <patcit id="pcit0003" dnum="US20060111629A" dnum-type="L"><text>U.S. Patent Application 2006/0111629</text></patcit>, the anchor wire 40 can be formed with a diamond or square shaped anchor, a triangular shaped anchor, a circular shaped anchor, or any other anchor shape or type that provides a secure implantation of the introducer system 10 in the tissue mass. The shape of the anchor can be selected upon, for example, the density of the tissue into which the wire is to be placed, the size of the lesion, and/or the anchoring force required to implant the introducer system 10 in the tissue mass.

0024While only one anchor wire 40 is illustrated in the embodiments shown herein, it is understood that the introducer system 10 can comprise more than one anchoring device. For example, the introducer system 10 can have multiple anchor wires 40 loaded in the second sheath 14, or the introducer system 10 can have multiple sheaths that each hold one anchor wire 40. In either case, the anchor wires 40 can be configured to engage the tissue mass at different angles to provide for a more secure implantation of the introducer system 10.

0025Referring to <figref idref="f0004">Fig. 6</figref>, the pushrod 60 comprises a distal end 62 and a proximal end (not shown). The distal end 62 is used to force the clip 50 out of the sheath 12 and into the tissue mass. The pushrod 60 is of sufficient length such that the proximal end of the pushrod is exterior to the proximal end of the sheath 12 to manipulate the pushrod 60 relative to the sheath 12. The pushrod 60 can be made of any material that is sufficiently flexible in order to be threaded through the sheath 12, yet stiff enough to push the clip 50 out of the open tip 22 of the sheath 12.

0026The clip 50 can be any suitable type of marker that can be detected and located. The clip 50 can be imaged by an imaging technique or palpable through the skin and tissue. Types of imagable markers include markers that are echogenic, radiopaque, or a combination of these types. The imaging technique used locate the clip 50 can be a standard imaging system such as ultrasonography, mammography or magnetic resonance imaging.

0027Referring to <figref idref="f0005 f0006 f0007 f0008 f0009 f0010 f0011">Figs. 7-13</figref>, the clip 50 is deployed into the tissue mass as follows. The VAB probe 70 is inserted into the tissue mass 80 illustrated as a breast that is compressed between two plates 82 and containing a target site 84. The target site can comprise a lesion or biopsy site. Referring to <figref idref="f0006">Fig. 8</figref>, after a VAB procedure has been performed during which a sample of tissue is taken from the target site 84, the introducer system 10 is inserted through the open proximal end of the VAB probe 70. Referring to <figref idref="f0007">Fig. 9</figref>, the introducer system is threaded through lumen 74 and through opening 78 so that the distal tips 22, 32 of the sheaths 12, 14 protrude into the tissue mass 80.

0028The introducer system 10 is then secured in the tissue mass 80 using the anchor wire 40. Referring to <figref idref="f0008">Fig. 10</figref>, the anchor wire 40 is embedded at the target site 84 by moving the thread 44 through lumen 18 relative to the sheath 14 such that the anchor wire 40 emerges from tip 32. As anchor wire 40 emerges from tip 32, hook 42 expands from the straightened first configuration to the curved second configuration. As it expands into the surrounding tissue, the hook 42 pierces the adjacent tissue to imbed the anchor wire 40 at the target site 84.

0029After anchoring the introducer system 10, the tissue mass 80 is uncompressed by removing the compression plates 82. The VAB probe is next retracted from the tissue mass 80 as illustrated by an arrow in <figref idref="f0009">Fig. 11</figref>. An image is taken of the tissue mass 80 to determine if the introducer system 10 has been correctly positioned at the target site 84. Correct positioning of the introducer system constitutes a placement that allows the clip 50 to be deployed at the target site 84 and thus is determined by the position of tip 22.

0030If the introducer system 10 is correctly positioned, the clip 50 is implanted in the tissue mass 80 to mark the target site 84. Referring to <figref idref="f0010">Fig. 12</figref>, the pushrod 60 is moved through lumen 16 relative to the sheath 12 such that the distal end 62 pushing the clip 50 emerges from tip 22 thus deploying clip 50 at the target site 84. The pushrod 60 and the anchor wire 40 are then retracted back into their respective sheaths 12 and 14, and the introducer system 10 is retracted from the tissue mass 80, leaving the clip 50 implanted at the target site 84 as illustrated in <figref idref="f0011">Fig. 13</figref>.

0031If it is determined by the image taken after the tissue mass 80 is uncompressed that the introducer system 10 has be incorrectly placed, the introducer system 10 can be repositioned within the tissue mass 80 as shown in <figref idref="f0012 f0013 f0014">Figs. 14-16</figref>. Repositioning is normally accomplished with the aid of an ultrasound. In the event of misplacement, it is most often the case that the introducer system 10 is deep to or beyond the target site 84 as illustrated in <figref idref="f0012">Fig. 14</figref>. Referring to <figref idref="f0013">Fig. 15</figref>, to reposition the introducer system, the anchor wire 40 is pulled back into lumen 18 by moving the thread 44 relative to the sheath 14. The introducer system 10 is next retracted back an appropriate distance such that the tips 22, 32 are at the target site 84. The introducer system is then secured in the tissue mass 80 using the anchor wire 40 and another image can be taken to confirm that the introducer system 10 is correctly positioned at the target site 84. The introducer system 10 can be repositioned as many times as necessary until the introducer system 10 is correctly positioned as illustrated in <figref idref="f0014">Fig. 16</figref>. The clip 50 is then implanted in the tissue mass 80 to mark the target site 84 as previously described.

0032Referring to <figref idref="f0015">Fig. 17</figref>, to facilitate the repositioning of the introducer system 10, the sheaths 12, 14 could be provided with distance markings 96, for example centimeter markings that would enable the introducer system to be moved a distance determined from the image taken after the breast is uncompressed. Distance markings on the sheaths 12, 14 allow the introducer system 10 to be repositioned more accurately and reduces the possibility that the introducer system 10 has to be repositioned more than once to achieve correct placement of the introducer system 10.

0033Although a rare occurrence, the introducer system 10 can be misplaced shallow to or before the target site. To reposition the introducer system 10 in this case, a hollow cannula can be inserted over the introducer system 10 and then the cannula and introducer system 10 are advanced an appropriate distance to the target site 84. The cannula is next removed and the clip 50 is deployed.

0034<figref idref="f0015">FIG. 17</figref> also illustrates the optional placement of a hemostatic agent 97 in addition to the placement of the clip 50. The hemostatic agent 97 can comprise a solid hemostatic agent such as a plug of collagen, chitosan, thrombin, Factor Xa, fibrinogen, nonsoluble polysaccharide, cellulose and dried gelatin; or a hemostatic agent in liquid form that is coated or impregnated in a bioabsorbable material. The hemostatic agent 97 can be loaded into the first sheath 12 along with the clip 50 and can be positioned relative to the clip 50 to be expelled prior to or just after the clip 50 as the push rod 60 is advanced. In another contemplated embodiment, the clip 50 can be coated with or encompassed by the hemostatic agent 97. The presence of the hemostatic agent 97 can prevent the clip 50 from being displaced due to bleeding at the target site 84.

0035While the VAB probe 70 is illustrated as the structure for providing a passageway into the tissue mass for the insertion of the introducer system, it should be noted that other insertion devices can be used and the introducer system is not limited to the VAB probe 70. For example, another insertion device can be a cannula with an axial opening or an opening in the side wall.

0036A second embodiment of the introducer system is shown in <figref idref="f0016">Figs. 18 and 19</figref> where like elements are identified with the same reference numerals. In this embodiment, the first sheath 12 has a partition 86 that extends the length of the sheath and divides the sheath 12 into first lumen 16 and second lumen 18. Such a configuration has a smaller cross-sectional size as illustrated in <figref idref="f0016">Fig. 19</figref> and the clip 50 is deployed in the same manner as described for the first embodiment of the introducer system 10.

0037A third embodiment of the introducer system is shown in <figref idref="f0016 f0017">Figs. 20-22</figref> where like elements are identified with the same reference numerals. In this embodiment, the tip 32 of the sheath 14 is closed and an opening 36 is provided in a side wall of the sheath 14, near the distal end of the sheath 14. As the anchor wire 40 is inserted into the sheath 14 it assumes the straight first configuration as shown in previous illustrations. When the hook 42 reaches the opening 36, it will assume the curved second configuration as it protrudes from the lumen 18 into the tissue mass to anchor the introducer system 10. Referring to <figref idref="f0017">Fig. 21</figref>, if it is then necessary to reposition the introducer system 10, the thread 44 is pushed forward, forcing the hook 42 through opening 36 and against the closed tip 32. Because of the forwardly-directed force on the wire 40, the hook 42 remains in the curved second position but is slightly compressed. After repositioning the introducer system 10, the thread 44 is pulled back, and the hook 42 exits the opening 36 to anchor the system into the tissue mass. Referring to <figref idref="f0017">Fig. 22</figref>, when the introducer system 10 is removed, the thread 44 is pulled back farther such that the hook 42 abuts the proximal edge of the opening 36 and assumes the straight first configuration as the hook 42 enter the second lumen 18.

0038A fourth embodiment of the introducer system is shown in <figref idref="f0018">Fig. 23</figref> where like elements are identified with the same reference numerals. In this embodiment, both tips 22, 32 are closed and openings 26, 36 are provided near the proximal end 24, 34 of the sheaths 12, 14, respectively. A ramp 28 is provided on the distal side of the opening 26 that occludes lumen 16 and prevents advancement of the clip 50 and the pushrod 60 beyond opening 26. The ramp 28 is angled to guide the clip 50 and the pushrod 60 upward and through the opening 26.

0039The VAB probe 70 can be altered in a similar fashion to facilitate the movement of the introducer system 10 out of the probe 70. A second embodiment of the probe 70, shown in <figref idref="f0018">FIG. 24</figref> where like elements are identified with the same reference numerals, has a ramp 88 formed on the distal side of the opening 78 such that it occludes lumen 74 and prevents the introducer system 10 from advancing beyond the opening 78. The ramp 80 is angled to guide the introducer system 10 upwards and through opening 78. While the second embodiment of probe 70 is shown in conjunction with the first embodiment of the introducer system 10, it is understood that any embodiment of the introducer system 10 can be used with the second embodiment of the probe 70.

0040Referring to <figref idref="f0019">FIG. 25</figref>, the introducer system 10 can also be inserted through an outer cannula 90 to facilitate the movement of the introducer system 10 out of the probe 70. The cannula 90 defines a lumen 92 and comprises a closed distal end 94 and a proximal end (not shown). An opening 98 near the distal end 94 is provided with a ramp 100. The opening 98 is located on the cannula 90 such that when the cannula 90 is fully inserted, the opening 98 is aligned with opening 78. The cannula 90 is considered to be fully inserted into the probe 70 when the closed end 94 contacts the closed insertion tip 76, thus aligning opening 98 with opening 78. The cannula 90 has an outer diameter sized so that is can easily fit through the lumen 74 of the probe 70 and an inner diameter sized so that the introducer system 10 can easily fit through lumen 92.

0041To deploy the clip 50, the outer cannula 90 is first inserted into the probe 70 and pushed forward until it is fully inserted. Full insertion of the cannula 90 can be determined when resistance is felt against the further forward movement of the cannula 90. Then, the introducer system 10 is inserted into the cannula 90 such that the introducer system 10 is guided up the ramp 100 and out of the opening 98. Next, the introducer system 10 is anchored by the anchor wire 40 and the probe 70 and cannula 90 are simultaneously retracted leaving the introducer system 10 in the tissue mass. The clip 50 is then deployed following the same steps as previously described.

0042While the invention has been specifically described in connection with certain specific embodiments thereof, it is to be understood that this is by way of illustration and not of limitation.