USING REVERSIBLE ELECTROPORATION ON CARDIAC TISSUE

Abstract

In one embodiment, an electroporation method includes inserting a catheter having multiple electrodes into a chamber of a heart, applying an electrical field using at least two of the electrodes to tissue of the chamber of the heart at a given location within the chamber with an amplitude sufficient to cause reversible electroporation, but below a threshold for irreversible electroporation, and measuring an effect of the reversible electroporation on electrical activation signals in the tissue of the chamber of the heart in a vicinity of the location.

Claims

1. An electroporation method, comprising: inserting a catheter having multiple electrodes into a chamber of a heart; applying an electrical field using at least two of the electrodes to tissue of the chamber of the heart at a given location within the chamber with an amplitude sufficient to cause reversible electroporation, but below a threshold for irreversible electroporation; and measuring an effect of the reversible electroporation on electrical activation signals in the tissue of the chamber of the heart in a vicinity of the location.

2. The method according to claim 1, wherein the electrical field is less than 450 Volts per centimeter.

3. The method according to claim 2, further comprising generating a pulsed electrical signal and wherein the applying the electrical field includes applying the electrical field using the at least two electrodes responsively to the generated pulsed electrical signal.

4. The method according to claim 3, wherein the pulsed electrical signal includes a series of biphasic pulses, each biphasic pulse including a positive and a negative phase pulse.

5. The method according to claim 3, wherein the pulsed electrical signal includes a series of bursts, each burst including a series of pulses.

6. The method according to claim 5, wherein: each of the pulses has a pulse length between 1 and 20 microseconds; and the series of bursts includes a gap between bursts of between 100 microseconds to 1000 milliseconds.

7. The method according to claim 6, wherein: each burst includes up to 100 of the pulses; and the series of bursts includes up to 100 bursts.

8. The method according to claim 1, further comprising: rendering to a display an indication of the electrical activation signals in the tissue of the chamber of the heart in the vicinity of the location; and then applying another electrical field using at least two of the electrodes to the tissue of the chamber of the heart at the given location within the chamber with an amplitude sufficient to cause irreversible electroporation.

9. The method according to claim 8, further comprising: generating an electroanatomic map of the chamber of the heart responsively to the electrical activation signals; and rendering the electroanatomic map to the display.

10. The method according to claim 8, wherein the electric field with the amplitude sufficient to cause reversible electroporation but below a threshold for irreversible electroporation is less than 450 Volts per centimeter, and the other electric field with the amplitude sufficient to cause irreversible electroporation is greater than 800 Volts per centimeter.

11. The method according to claim 10, further comprising generating a pulsed electrical signal and wherein the applying the other electrical field includes applying the other electrical field using the at least two electrodes responsively to the generated pulsed electrical signal.

12. The method according to claim 11, wherein the pulsed electrical signal includes a series of biphasic pulses, each biphasic pulse including a positive and a negative phase pulse.

13. The method according to claim 11, wherein the pulsed electrical signal includes a series of bursts, each burst including a series of pulses.

14. The method according to claim 13, wherein: each of the pulses has a pulse length between 1 and 20 microseconds; and the series of bursts includes a gap between bursts of between 100 microseconds to 1000 milliseconds.

15. The method according to claim 14, wherein: each burst includes up to 100 of the pulses; and the series of bursts includes up to 100 bursts.

16. An electroporation system, comprising: a catheter including multiple electrodes, and configured to be inserted into a chamber of a heart; a signal generator coupled to at least two of the electrodes, and configured to generate an electrical signal for supply to the at least two electrodes which responsively to the electrical signal apply an electrical field to tissue of the chamber of the heart at a given location within the chamber, the electrical field having an amplitude sufficient to cause reversible electroporation, but below a threshold for irreversible electroporation; and processing circuitry configured to: receive from the catheter electrical activation signals in the tissue of the chamber of the heart in a vicinity of the location; and measure an effect of the reversible electroporation on the electrical activation signals in the tissue of the chamber of the heart in a vicinity of the location.

17. The system according to claim 16, wherein the electrical field is less than 450 Volts per centimeter.

18. The system according to claim 17, wherein the electrical signal is a pulsed electrical signal.

19. The system according to claim 17, wherein the pulsed electrical signal includes a series of biphasic pulses, each biphasic pulse including a positive and a negative phase pulse.

20. The system according to claim 17, wherein the pulsed electrical signal includes a series of bursts, each burst including a series of pulses.

21. The system according to claim 20, wherein: each of the pulses has a pulse length between 1 and 20 microseconds; and the series of bursts includes a gap between bursts of between 100 microseconds to 1000 milliseconds.

22. The system according to claim 21, wherein: each burst includes up to 100 of the pulses; and the series of bursts includes up to 100 bursts.

23. The system according to claim 16, wherein: the processing circuitry is configured to render to a display an indication of the electrical activation signals in the tissue of the chamber of the heart in the vicinity of the location; and the signal generator is configured to generate another electrical signal for supply to at least two of the electrodes which responsively to the other electrical signal apply another electrical field to tissue of the chamber of the heart at the location within the chamber with an amplitude sufficient to cause irreversible electroporation.

24. The system according to claim 23, wherein the processing circuitry is configured to: generate an electroanatomic map of the chamber of the heart responsively to the electrical activation signals; and render the electroanatomic map to the display.

25. The system according to claim 23, wherein the electric field with the amplitude sufficient to cause reversible electroporation but below a threshold for irreversible electroporation is less than 450 Volts per centimeter, and the other electric field with the amplitude sufficient to cause irreversible electroporation is greater than 800 Volts per centimeter.

26. The system according to claim 25, wherein the other electrical signal is a pulsed electrical signal.

27. The system according to claim 26, wherein the pulsed electrical signal includes a series of biphasic pulses, each biphasic pulse including a positive and a negative phase pulse.

28. The system according to claim 26, wherein the pulsed electrical signal includes a series of bursts, each burst including a series of pulses.

29. The system according to claim 28, wherein: each of the pulses has a pulse length between 1 and 20 microseconds; and the series of bursts includes a gap between bursts of between 100 microseconds to 1000 milliseconds.

30. The system according to claim 29, wherein: each burst includes up to 100 of the pulses; and the series of bursts includes up to 100 bursts.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0044] The present invention will be understood from the following detailed description, taken in conjunction with the drawings in which:

[0045] FIG. 1 is a schematic view of a medical procedure system constructed and operative in accordance with an exemplary embodiment of the present invention;

[0046] FIG. 2 is a schematic view of a catheter for use in the system of FIG. 1;

[0047] FIG. 3 is a flowchart including steps in a method of operation of the medical procedure system of FIG. 1;

[0048] FIG. 4 is a schematic view of intracardiac electrograms generated by the system of FIG. 1; and

[0049] FIG. 5 is a schematic view of an electroanatomic map generated by the system of FIG. 1.

DESCRIPTION OF EXAMPLE EMBODIMENTS

Overview

[0050] Irreversible electroporation (IRE) applies short electrical pulses that generate high enough electrical fields (typically greater than 450 Volts per centimeter) to irreversibly damage the cells. Non-thermal IRE may be used in treating different types of tumors and other unwanted tissue without causing thermal damage to surrounding tissue. Small electrodes are placed in proximity to target tissue to apply short electrical pulses. The pulses increase the resting transmembrane potential, so that nanopores form in the plasma membrane. When the electricity applied to the tissue is above the electric field threshold of the target tissue, the cells become permanently permeable from the formation of nanopores. As a result, the cells are unable to repair the damage and die due to a loss of homeostasis and the cells typically die by apoptosis.

[0051] IRE may be used for cardiac ablation as an alternative to other cardiac ablation techniques, e.g., radio-frequency (RF) cardiac ablation. IRE cardiac ablation is sometimes referred to as Pulse Field Ablation (PFA). As IRE is generally a low thermal technique, IRE may reduce the risk of collateral cell damage that is present with the other techniques. e.g., in RF cardiac ablation. However, similar to other ablation techniques, such as RF cardiac ablation, until after IRE pulses have actually been applied to a target location of the heart, thereby killing the cells in the target location, a physician may not be certain that killing the cells of the target location is the correct procedure to be followed.

[0052] Exemplary embodiments of the invention solve the above problems by applying an electrical field to induce reversible electroporation at a target location. Reversible electroporation applies short electrical pulses, generating high electrical fields (up to around 450 Volts per centimeter), to cells so as to temporarily break down the membranes of cells. Reversible electroporation occurs when the electricity applied with the electrodes is below the electric field threshold of the target tissue allowing cells to repair. Reversible electroporation does not kill the cells, but allows a physician to see the effect of reversible electroporation on electrical activation signals in the vicinity of the target location.

[0053] While the reversible electroporation is being induced, or substantially immediately afterwards, for example, up to about a few seconds afterwards. electrical activation signals from the vicinity of the target location are acquired. The acquired signals may be processed to provide a visual indication or indications of the electrical activation signals. The visual indication(s) may be compared with those prior to the application of the reversible electroporation, to check if an expected change in the electrical activity of the target location has actually occurred. Additionally, or alternatively, the electrical activation signals may be processed to generate an electroanatomic map which may then be compared with an electroanatomic map generated prior to the application of the reversible electroporation.

[0054] After the effect of the reversible electroporation on electrical activation signals in the vicinity of the target location has been evaluated by the physician, the physician may decide whether or not to perform another procedure, such as, IRE or RF cardiac ablation at the target location. For example, if an expected change has in fact occurred, IRE (or another suitable ablation technique) may be applied to the target location to irreversibly kill the cells of the target location. If no expected change is observed, IRE (or another suitable ablation technique) may not be applied to the location.

[0055] Applying reversible electroporation to a target location prior to applying IRE (or another suitable ablation technique) to the location allows the physician to check if ablating the location gives an expected result. The reversibility of reversible electroporation enables the physician to perform the check without there being any permanent damage to the heart tissue.

System Description

[0056] Reference is now made to FIG. 1, which is a schematic view of a medical procedure system 20 constructed and operative in accordance with an embodiment of the present invention. Reference is also made to FIG. 2, which is a schematic view of a catheter 40 for use in the system 20 of FIG. 1.

[0057] The medical procedure system 20 is used to determine the position of the catheter 40, seen in an inset 25 of FIG. 1 and in more detail in FIG. 2. The catheter 40 includes a shaft 22 and a plurality of deflectable arms 54 (only some labeled for the sake of simplicity) for inserting into a body-part of a living subject. The deflectable arms 54 have respective proximal ends connected to the distal end of the shaft 22.

[0058] The catheter 40 includes a position sensor 53 disposed on the shaft 22 in a predefined spatial relation to the proximal ends of the deflectable arms 54. The position sensor 53 may include a magnetic sensor 50 and/or at least one shaft electrode 52. The magnetic sensor 50 may include at least one coil, for example, but not limited to, a dual-axis or a triple axis coil arrangement to provide position data for location and orientation including roll. The catheter 40 includes multiple electrodes 55 (only some are labeled in FIG. 2 for the sake of simplicity) disposed at different, respective locations along each of the deflectable arms 54. Typically, the catheter 40 may be used for mapping electrical activity in a heart of the living subject using the electrodes 55, or for performing any other suitable function in a body-part of a living subject, for example, but not limited to, reversible and/or irreversible electroporation and/or RF ablation.

[0059] The medical procedure system 20 may determine a position and orientation of the shaft 22 of the catheter 40 based on signals provided by the magnetic sensor 50 and/or the shaft electrodes 52 (proximal-electrode 52a and distal-electrode 52b) fitted on the shaft 22, on either side of the magnetic sensor 50. The proximal-electrode 52a, the distal-electrode 52b, the magnetic sensor 50 and at least some of the electrodes 55 are connected by wires running through the shaft 22 via a catheter connector 35 to various driver circuitries in a console 24. In some embodiments, at least two of the electrodes 55 of each of the deflectable arms 54, the shaft electrodes 52, and the magnetic sensor 50 are connected to the driver circuitries in the console 24 via the catheter connector 35. In some embodiments, the distal-electrode 52b and/or the proximal electrode 52a may be omitted.

[0060] The illustration shown in FIG. 2 is chosen purely for the sake of conceptual clarity. Other configurations of shaft electrodes 52 and electrodes 55 are possible. Additional functionalities may be included in the position sensor 53. Elements which are not relevant to the disclosed embodiments of the invention, such as irrigation ports, are omitted for the sake of clarity.

[0061] A physician 30 navigates the catheter 40 to a target location in a body part (e.g., a heart 26) of a patient 28 by manipulating the shaft 22 using a manipulator 32 near the proximal end of the catheter 40 and/or deflection from a sheath 23. The catheter 40 is inserted through the sheath 23, with the deflectable arms 54 gathered together, and only after the catheter 40 is retracted from the sheath 23, the deflectable arms 54 are able to spread and regain their intended functional shape. By containing deflectable arms 54 together, the sheath 23 also serves to minimize vascular trauma on its way to the target location.

[0062] Console 24 comprises processing circuitry 41, typically a general-purpose computer and a suitable front end and interface circuits 44 for generating signals in, and/or receiving signals from, body surface electrodes 49 which are attached by wires running through a cable 39 to the chest and to the back, or any other suitable skin surface, of the patient 28.

[0063] Console 24 further comprises a magnetic-sensing sub-system. The patient 28 is placed in a magnetic field generated by a pad containing at least one magnetic field radiator 42, which is driven by a unit 43 disposed in the console 24. The magnetic field radiator(s) 42 is configured to transmit alternating magnetic fields into a region where the body-part (e.g., the heart 26) is located. The magnetic fields generated by the magnetic field radiator(s) 42 generate direction signals in the magnetic sensor 50. The magnetic sensor 50 is configured to detect at least part of the transmitted alternating magnetic fields and provide the direction signals as corresponding electrical inputs to the processing circuitry 41.

[0064] In some embodiments, the processing circuitry 41 uses the position-signals received from the shaft electrodes 52, the magnetic sensor 50 and the electrodes 55 to estimate a position of the catheter 40 inside an organ, such as inside a cardiac chamber. In some embodiments, the processing circuitry 41 correlates the position signals received from the electrodes 52, 55 with previously acquired magnetic location-calibrated position signals, to estimate the position of the catheter 40 inside a cardiac chamber. The position coordinates of the shaft electrodes 52 and the electrodes 55 may be determined by the processing circuitry 41 based on, among other inputs, measured impedances, or on proportions of currents distribution, between the electrodes 52, 55 and the body surface electrodes 49. The console 24 drives a display 27, which shows the distal end of the catheter 40 inside the heart 26.

[0065] The method of position sensing using current distribution measurements and/or external magnetic fields is implemented in various medical applications, for example, in the Carto® system, produced by Biosense Webster Inc. (Irvine, Calif.), and is described in detail in U.S. Pat. Nos. 5,391,199, 6,690,963, 6,484,118, 6,239,724, 6,618,612, 6,332,089, 7,756,576, 7,869,865, and 7,848,787, in PCT Patent Publication WO 96/05768, and in U.S. Patent Application Publication Nos. 2002/0065455 A1, 2003/0120150 A1 and 2004/0068178 A1.

[0066] The Carto®3 system applies an Active Current Location (ACL) impedance-based position-tracking method. In some embodiments, using the ACL method, the processing circuitry 41 is configured to create a mapping (e.g., current-position matrix (CPM)) between indications of electrical impedance and positions in a magnetic coordinate frame of the magnetic field radiator(s) 42. The processing circuitry 41 estimates the positions of the shaft electrodes 52 and the electrodes 55 by performing a lookup in the CPM.

[0067] Other methods of determining the location of the distal end of the catheter may be used, for example, based on ultrasonic transducers and receivers, using imaging techniques such as ultrasound or MRI or CT scans which may include disposing radiopaque tags on the catheter 40.

[0068] Processing circuitry 41 is typically programmed in software to carry out the functions described herein. The software may be downloaded to the computer in electronic form, over a network, for example, or it may, alternatively or additionally, be provided and/or stored on non-transitory tangible media, such as magnetic, optical, or electronic memory.

[0069] FIG. 1 shows only elements related to the disclosed techniques, for the sake of simplicity and clarity. The system 20 typically comprises additional modules and elements that are not directly related to the disclosed techniques, and thus are intentionally omitted from FIG. 1 and from the corresponding description.

[0070] The catheter 40 described above includes eight deflectable arms 54 with six electrodes per arm 54. Any suitable catheter may be used instead of the catheter 40, for example, a catheter with a different number of flexible arms and/or electrodes per arm, or a different probe shape such as a balloon catheter or a lasso catheter, by way of example only.

[0071] The medical procedure system 20 may also perform electroporation or RF ablation (or other ablation technique) of heart tissue using any suitable catheter, for example using the catheter 40 or a different catheter and any suitable ablation method. The console 24 may include a signal generator 34 configured to generate an electrical signal to be applied by an electrode or electrodes of a catheter connected to the console 24, (and optionally one or more of the body surface electrodes 49), to perform electroporation of RF ablation of a myocardium of the heart 26. The console 24 may include a pump (not shown), which pumps irrigation fluid into an irrigation channel to a distal end of a catheter performing RF ablation. The catheter performing the RF ablation may also include temperature sensors (not shown) which are used to measure a temperature of the myocardium during RF ablation and regulate an ablation power and/or an irrigation rate of the pumping of the irrigation fluid according to the measured temperature.

[0072] Reference is now made to FIG. 3, which is a flowchart 60 including steps in a method of operation of the medical procedure system 20 of FIG. 1.

[0073] The catheter 40 (FIG. 1) is configured to be inserted (block 62) into a chamber of the heart 26 (FIG. 1).

[0074] The signal generator 34 (FIG. 1) is coupled to at least two of the electrodes 55 (FIG. 2) of the catheter 40. The signal generator 34 is configured to generate (block 64) an electrical signal for supply to at least two of the electrodes 55 which responsively to the electrical signal apply an electrical field to tissue of the chamber of the heart 26 at a given location within the chamber. The electrical field has an amplitude sufficient to cause reversible electroporation, but below a threshold for irreversible electroporation. The field may be applied between any two of the electrodes 55, for example, between adjacent electrodes 55, and/or between some of the electrodes 55 and a reference electrode of the electrodes 55. The electrical field applied by the electrodes 55 to the tissue at the given location is generally less than 450 Volts per centimeter. The electrical signal supplied by the signal generator 34 may be a pulsed electrical signal. The pulsed electrical signal may include a series of biphasic pulses, with each biphasic pulse including a positive and a negative phase pulse. For example, the series of biphasic pulses may include a positive phase pulse of 2 microseconds, followed by a delay of 0.5 microseconds, followed by a negative phase pulse of 2 microseconds, and so on. The pulsed electrical signal may include a series of bursts, with each burst including a series of pulses, such as the biphasic pulses or a single-phase pulse. Each of the pulses may have any suitable length, for example, between 1 and 20 microseconds. The series of bursts includes a gap between bursts of any suitable length, for example, between 100 microseconds to 1000 milliseconds. Each burst may include any suitable number of pulses, for example, up to 100 pulses. The series of bursts may include any suitable number of bursts, for example, up to 100 bursts.

[0075] The various parameters of the electrical signals (such as amplitude, pulse length, gap, and number of pulses and bursts) may be suitably adjusted to provide an electrical field which causes reversible electroporation into the tissue to a depth of at least 2-3 mm without substantially heating surrounding tissue. The term “without substantially heating surrounding tissue” as used in the specification and claims, is defined as heating the tissue to a level at which there is no clinical effect. In some applications a three degrees centigrade increase in temperature may be acceptable for the durations used in electroporation.

[0076] During the time period in which the electric field is being applied, or substantially immediately afterwards, the effect of the reversible electroporation on the electrical activation signals in the tissue of the chamber of the heart 26 in the vicinity of the location where the electric field was/is being applied is measured.

[0077] The processing circuitry 41 is configured to receive (block 66) from the catheter 40 electrical activation signals in the tissue of the chamber of the heart 26 in the vicinity of the location.

[0078] The processing circuitry 41 is configured to measure (block 68) an effect of the reversible electroporation on the electrical activation signals in the tissue of the chamber of the heart 26 in the vicinity of the location. Measuring an effect of the reversible electroporation may include measuring an amplitude of signals captured from the vicinity of the location, and/or processing the signals to generate graphs of the signals and/or generating an electroanatomic map based on the electrical activation signals. The “vicinity” of the location may be in and/or around the location at which the reversible electroporation is performed.

[0079] Therefore, in some embodiments, the processing circuitry 41 is configured to generate (block 70) an electroanatomic map of the chamber of the heart responsively to the electrical activation signals. The step of block 70 is described in more detail with reference to FIG. 5 below.

[0080] The processing circuitry 41 is configured to render (block 72) to the display 27 an indication of the electrical activation signals in the tissue of the chamber of the heart in the vicinity of the location. The indication may include an amplitude or amplitudes of the activation signals, a graph or graphs of the activation signals or an electroanatomic map representing the activation signals.

[0081] In some embodiments, before, during or after inducing the reversible electroporation in the tissue, a substance may be applied to the tissue, and the effect of the reversible electroporation and the substance on the electrical activation signals may be examined.

[0082] Reference is now made to FIG. 4, which is a schematic view of intracardiac electrograms 80 generated by the system 20 of FIG. 1. The intracardiac electrograms 80-1, 80-2 are rendered to the display 27 by the processing circuitry 41 (FIG. 1) and represent electrical activation signals captured at a point around the location of the reversible electroporation, prior to the reversible electroporation being applied (shown in intracardiac electrogram 80-1) and during or substantially immediately after the reversible electroporation has been applied (shown in intracardiac electrograms 80-2), respectively. It can be seen that the reversible electroporation has had an effect on reducing electrical activity at the point around the location.

[0083] Reference is now made to FIG. 5, which is a schematic view of an electroanatomic map 82 generated by the system 20 of FIG. 1. Reference is also made to FIG. 3.

[0084] The processing circuitry 41 (FIG. 1) is configured to process the electrical activation signals captured by the catheter 40 (FIG. 1) over time at multiple sample locations over the surface of the chamber(s) of the heart 26 to determine respective activation times at the multiple locations over the surface of the chamber(s) of the heart 26. The processing circuitry 41 is configured to prepare the electroanatomic map 82 including a plurality of velocity vectors 84 (only some labeled for the sake of simplicity) describing the propagation of activation wavefronts associated with the activation times. One method for preparing the electroanatomic map 82 is described in U.S. Pat. No. 6,301,496. Any suitable method for preparing the electroanatomic map 82 may also be used. Other electroanatomic maps may be generated for example, showing activation times using colors.

[0085] The processing circuitry 41 is configured to render (block 74) the electroanatomic map 82 to the display 27. The electroanatomic map 82 may be displayed alongside another electroanatomic map representing electrical activity of the chamber(s) of the heart 26 prior to the reversible electroporation being performed in order to further visualize the effect of the reversible electroporation.

[0086] Reference is again made to FIG. 3. The physician examines the intracardiac electrograms 80 (FIG. 4) and/or the electroanatomic map 82 (FIG. 5) or other data to determine if the location at which reversible electroporation was applied should be permanently ablated using IRE or another ablation technique or not ablated at all. If the physician decides to permanently ablate, the physician operates the system 20 to perform the ablation. The signal generator 34 (FIG. 1) is configured to generate another electrical signal for supply to at least two of the electrodes 55 which responsively to the other electrical signal apply another electrical field to tissue of the chamber of the heart 26 (FIG. 1) at the location within the chamber with an amplitude sufficient to cause irreversible electroporation (block 76). Alternatively, the physician could use another form of ablation, such as RF ablation which kills the cells of the tissue due to its heating effect.

[0087] The field may be applied between any two of the electrodes 55, for example, between adjacent electrodes 55, and/or between some of the electrodes 55 and a reference electrode of the electrodes 55.The electrical field applied by the electrodes 55 to the tissue at the given location is generally more than 800 Volts per centimeter. The electrical signal supplied by the signal generator 34 may be a pulsed electrical signal. The pulsed electrical signal may include a series of biphasic pulses, with each biphasic pulse including a positive and a negative phase pulse. For example, the series of biphasic pulses may include a positive phase pulse of 2 microseconds, followed by a delay of 0.5 microseconds, followed by a negative phase pulse of 2 microseconds, and so on. The pulsed electrical signal may include a series of bursts, with each burst including a series of pulses, such as the biphasic pulses or a single-phase pulse. Each of the pulses may have any suitable length, for example, between 1 and 20 microseconds. The series of bursts includes a gap between bursts of any suitable length, for example, between 100 microseconds to 1000 milliseconds. Each burst may include any suitable number of pulses, for example, up to 100 pulses. The series of bursts may include any suitable number of bursts, for example, up to 100 bursts. The various parameters of the electrical signals (such as amplitude, pulse length, gap, and number of pulses and bursts) may be suitably adjusted to provide an electrical field which causes IRE and a lesion in the tissue to a depth of at least 2-3 mm without substantially heating surrounding tissue.

[0088] As used herein, the terms “about” or “approximately” for any numerical values or ranges indicate a suitable dimensional tolerance that allows the part or collection of components to function for its intended purpose as described herein. More specifically, “about” or “approximately” may refer to the range of values ±20% of the recited value, e.g. “about 90%” may refer to the range of values from 71% to 99%.

[0089] Various features of the invention which are, for clarity, described in the contexts of separate embodiments may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment may also be provided separately or in any suitable sub-combination.

[0090] The embodiments described above are cited by way of example, and the present invention is not limited by what has been particularly shown and described hereinabove. Rather the scope of the invention includes both combinations and subcombinations of the various features described hereinabove, as well as variations and modifications thereof which would occur to persons skilled in the art upon reading the foregoing description and which are not disclosed in the prior art.