- Step 1: Calculate total conductance (G_Total, current divided by voltage, or I/V, where I is the current injected and V is the voltage recorded) for two ends (proximal and distal) of a segment.
- Step 2: Calculate the Coeff ratio (cross-sectional area divided by total conductance, or CSA/G_Total) at the two ends of the segment.
- Step 3: Linearly interpolate along the length of the pull back for the Coeff, so that the two ends of the segment have the same Coeffs calculated fromStep 2 above.
- Step 4: Calculate total conductance (G_Total) for the entire length of the pull back (distance between the two ends of the segment).
- Step 5: At each point calculated in the pull back, multiply the total conductance (G_Total) times its respective Coeff. The product of this calculation is the cross-sectional area (CSA).
- Step 6: Determine the diameter from the cross-sectional area (CSA) along the entire profile.

A mathematical explanation of the concept referenced in the procedure above is as follows. First, the equation governing the physics of electrical conductance has the following form:

\begin{matrix} G_{Total} = \frac{I}{V} = \frac{CSA \cdot σ}{L} + G_{p} & [14] \end{matrix}

where G_Totalis the total conductance, I is the current, V is the voltage, CSA is the cross-sectional area, σ is the conductivity of the fluid, L is the detection electrode spacing on the catheter, and G_pis the parallel conductance at a point.

Experimentation as shown that parallel conductance (G_p) is linearly related to cross-sectional area, with a negative slope. For example, a larger CSA has a smaller G_p. As such, G_pcan be replaced with a linear function of CSA as follows:

\begin{matrix} G_{Total} = \frac{I}{V} = \frac{CSA \cdot σ}{L} + m \cdot CSA + b & [15] \end{matrix}

where G_Totalis the total conductance, I is the current, V is the voltage, CSA is the cross-sectional area, σ is the conductivity of the fluid, L is the detection electrode spacing on the catheter, m is the slops, and b is the intercept as can be determined for a linear least square fit. This may be rearranged as follows:

\begin{matrix} G_{Total} = (\frac{σ}{L} + m) CSA + b & [16] \end{matrix}

It is shown that total conductance (G_Total) is clearly linearly related to cross-sectional area (CSA). If the coefficient b is ignored (wherein b should be equal to zero if CSA is equal to zero), then we have the following:

\begin{matrix} (\frac{CSA}{G_{Total}}) = Coeff & [17] \end{matrix}

The Coeff value at both ends of a segment can be found where the two injections are made, and those values may then be used to linearly interpolate across the profile. Once a Coeff value for every point in the pull back is determined, those Coeff values are multiplied by their respective G_Totalvalues to determine the CSA values along the profile, namely:

CSA=Coeff*G_Total [18]

and

\begin{matrix} Diameter = \sqrt{\frac{4 * CSA}{π}} & [19] \end{matrix}

to determine a diameter.

Exemplary Three-Injection Approach

In at least one method of the disclosure of the present application, a three-injection approach to determine a profile as outlined above with respect to the four-injection approach is also provided. In at least one approach, three injections are provided, with two injections at the distal end of a segment, simultaneous withdrawal of one of the injection sources, and one injection at the proximal end of the segment.

In an exemplary study, the first two injections at the distal end may deliver, for example, a volume of 1.5% NaCl and a volume of 0.5% NaCl, noting that any number of solutions, volumes, and concentrations thereof suitable for such a study could be utilized. In this exemplary study, the first two injections (1.5% NaCl and 0.5% NaCl) may be made at the distal point of the segment, wherein the catheter system is simultaneously withdrawn with the injection of the 0.5% NaCl so that the 0.5% NaCl may also be used for the proximal end. These injections would then be followed by a 1.5% NaCl injection at the proximal end of the segment.

Advantages to this particular approach over the four-injection approach are that (1) the conductivity would be simplified as that of 0.5% rather than blood, and (2) there are only three injections required instead of four. However, the three-injection method also requires that a physician using a catheter system to perform such a procedure would be required to inject and pull back simultaneously. A physician comfortable with simultaneous injection and pull back may prefer the three-injection approach, while a physician not comfortable with simultaneous injection and pull back may prefer the four-injection approach. Either approach is possible using the algorithm provided herein.

Ex-Vivo and In-Vivo Validation of Algorithm

Studies were performed ex-vivo in in-vivo to validate the algorithm provided herein. The former was validated in a carotid artery with an artificial stenosis to compare the algorithm disclosed herein versus cast measurements for both for the two-injection method at several discrete points and the reconstructed profile. The latter validation was done in vivo in a coronary artery (LAD) where a comparison between LR (LumenRecon) and IVUS (intravascular) was made.

Ex-Vivo Validation of Algorithm

To validate the algorithm ex-vivo, a segment of a swine carotid artery was removed and mounted on a bench stand as shown inFIG. 9. A small portion of one end of the vessel was removed and used to create a stenosis around the vessel, which was accomplished by wrapping this piece of tissue around the middle of the vessel and shortening the piece of tissue using suture. A black indicator was used to mark the outside of the vessel at six locations along the length (length=3.23 cm). As shown inFIG. 9, the bottom portion of the vessel is the distal end, and black marks signify where LumenRecon measurements were made using a two-injection method of the present disclosure.

The LumenRecon system was calibrated using the 0.45% and 1.5% saline concentrations. A two-injection method according to the present disclosure was used to make single diameter measurements at the six locations along the length of the vessel. “Pull back” measurements were also made along the length of the vessel to create a continuous profile of the vessel diameter.

After the LumenRecon measurements were taken, a cast mold of the vessel was created. The diameter of the cast mold of the vessel was determined using microscopy. The cast measurements were taken at the six locations marked by the black indicator and at intermediate locations along the vessel.

The diameters from the LumenRecon two injection method and the pull back measurements were plotted against the cast measurements, respectively.FIG. 10 shows the data for the six locations using a two-injection method of the present disclosure, comparing the diameters calculated by the LumenRecon system to those measured from the cast mold of the vessel using microscopy. The least square fit of the data shows y=1.0599x−0.1805, R²=0.9944.FIG. 11 shows a profile of data points (diameters) using a pull back method of the present disclosure, comparing the diameters calculated by the LumenRecon system to those measured from the cast mold of the vessel using microscopy.

In Vivo Validation

The LumenRecon system was used to make measurements in the left anterior descending (LAD) coronary artery in an anesthesized swine. A two-injection method of the present disclosure was used to construct a profile which was compared to IVUS at four different locations along the profile.FIG. 12 shows the LumenRecon measurements plotted against the IVUS measurements, showing the measurements before and after the temperature correction. The temperature correction was incorporated into the calibration of the catheter. It was determined that a NaCl solution injected at room temperature (25° C.) reaches 30° C. when at the body site of measurement (39° C.). Hence, calibrations of fluid were made at 30° C. to account for the heating of the fluid during injection.

Phasic Changes of Vessel Lumen Area

As discussed above and herein, an exemplary two-injection method may provide the mean CSA and G_pat any particular point. Equation [14], as described in detail above, provides the equation governing the physics of electrical conductance as applied to CSA, fluid conductivity, and parallel conductance. At a fixed spatial position in a vessel, the mean conductivity of blood, σ_bcan then be determined from Equation [14] as follows:

\begin{matrix} {\overline{σ}}_{b} = \frac{L}{\overline{CSA}} [G_{Total} (t) - \overline{G_{p}}] & [20] \end{matrix}

whereinσ_b is the mean conductivity of blood, L is the detection electrode spacing on a catheter,CSA is the mean cross-sectional area, G_Total(t) is the total conductance at a given time, andG_p is the mean parallel conductance. In at least one embodiment, and in a situation where only one parallel conductance value is known, the value of the parallel conductance value may be substituted in place of a mean parallel tissue conductance value.

As blood conductivity only varies by approximately ten percent (10%) through the cardiac cycle, blood conductivity, for the purposes described herein, may also be considered as a constant having a mean value. Hence, the phasic change of CSA (at any given location) during the cardiac cycle can be calculated by the following equation:

\begin{matrix} CSA (t) = \frac{L}{{\overline{σ}}_{b}} [G_{Total} (t) - {\overline{G}}_{p}] & [21] \end{matrix}

wherein CSA(t) is the phasic change in cross-sectional area, L is the detection electrode spacing on a catheter,σ_b is the mean conductivity of blood, G_Total(t) is the total conductance at a given time, andG_p is the mean parallel conductance.

The temporal changes of CSA, or diameter derived therefrom as referenced herein, can be determined from the phasic changes of total conductance. For example, conductance data as shown inFIG. 15A, can be converted to CSA or diameter of the artery as outlined above.FIG. 15A shows the phasic changes of total conductance showing cardiac and respiratory changes, with the narrow tall peaks representing detected heart rate, and the sinusoidal wave (approximately three and one half wavelengths shown) represents respiratory changes (inhalation and exhalation).

The phasic changes of diameters of a normal coronary artery (FIG. 15B) or an atherosclerotic coronary artery (FIG. 15C) are shown throughout several cardiac cycles.FIG. 15B shows the phasic changes of a “normal” blood vessel (without any sort of stenosis or lesion) having a similar profile to the profile shown inFIG. 15A. The cardiac as well as respiratory changes of coronary diameter are apparent for the normal animalFIG. 15C shows the same parameters (changes in diameter of a vessel over time) shown inFIG. 15B, but instead of a “normal” vessel, the results are reflective of a diseased (atherosclerotic) vessel. As shown inFIG. 15C, only changes in vessel diameter due to the cardiac cycle are shown, noting that respiration has no visible impact on vessel diameter of this exemplary diseased vessel (noting that the respiratory changes for the conductance data vanish in the atherosclerotic animals).

The phasic changes of blood vessel shown inFIGS. 15A-15C have clinical importance. A healthy vessel, for example, will show significant changes in vessel diameter through the cardiac cycle as shown inFIG. 15B. A calcified vessel, on the other hand, will show no changes in diameter through the cardiac cycle as shown inFIG. 15C. A decrease in compliance (or increase in stiffness) of vessels has been well established with vascular disease.

The compliance of a vessel determined by the change of CSA per change of pressure through the cardiac cycle is described as follows:

C=ΔCSA/ΔP [22]

wherein C is vessel compliance, ΔCSA is the change of cross-sectional area, and ΔP is the change in pressure through the cardiac cycle. Alternatively, since the ΔP is relatively constant for various patients, an index of compliance can be expressed as

%ΔCSA=(CSA_systolic−CSA_diastolic)/CSA_diastolic×100 [23]

wherein % ΔCSA is the index of compliance, CSA_systolicis the cross-sectional area of a vessel during systole, and CSA_diastolicis the cross-sectional area of a vessel during diastole. Similarly, Equations [22] and [23] can be expressed in terms of diameter, wherein values for cross-sectional area are replaced with values for diameter.

Such relations, as described herein, can be used to determine a phasic change or the compliance of the vessel and hence the degree of vascular disease. For example, if a vessel is deemed to have relatively low compliance or have a relatively low calculated phasic change in diameter or cross-sectional area, the extent of vessel disease may be determined to be relatively high. Conversely, and for example, if a vessel is deemed to have relatively high compliance or have a relatively high calculated phasic change in diameter or cross-sectional area, the extent of vessel disease may be determined to be relatively low. Currently, no other imaging method, including, but not limited to, angiography or IVUS, has the temporal resolution to provide the phasic changes throughout the cardiac cycle in real-time as referenced herein. Any number of devices of the present disclosure, including but not limited to device101 (such as, for example,catheter20,catheter20A,catheter20B,catheter21,catheter22,catheter23, catheter29,wire18,device1000, and/or other impedance device embodiments referenced herein that are configured for use with one, two, three, or potentially more electrodes as described herein), may be useful to determine phasic change and vessel compliance if configured with the necessary components and features as referenced herein.

In addition to the foregoing, the disclosure of the present application discloses various devices, systems, and methods for removing contrast from luminal organs. Such devices, systems, and methods provide endovascular detection of contrast medium using impedance sensing to remove contrast during angiography. An aspiration (suction) catheter, for example and referred to below as device1000 (which could also be, for example, any of adevice101,catheter20,catheter20A,catheter20B,catheter21,catheter22,catheter23, catheter29,wire18, and/or other impedance device embodiments referenced herein configured for use as referenced below), is equipped with impedance sensors and can be inserted into the coronary sinus to allow automated detection and withdrawal of contrast to prevent circulation of contrast and CIN. As referenced herein, “contrast” relates to a contrast medium itself, as well as a bodily fluid, such as blood, and/or a non-native fluid, such as saline, which has mixed with the contrast medium.

During contrast injection into the coronary arteries to obtain an angiogram, for example, the blood is diluted with iodine which lowers its electrical conductivity (i.e., contrast is non-conductive relative to blood).FIG. 16 shows an example of an electrical conductance measurement (G=I/V) where I is the electrical current and V is the voltage drop measurement along the detection electrodes, which in the tested subject shows a baseline of bloodconductance sample readings 0 to about 380. A downward spike can be observed at sample 380 due to iodine injection which substantially reduces the blood conductivity, as iodine is much less conductive than blood as shown inFIG. 16. A saline injection is then followed which shows an increased conductance. The signal to noise ratio is sufficient to trigger aspiration of the contrast at the time of detection and to stop aspiration when contrast is removed.

Catheterization of the coronary sinus can be carried out in accordance with standard procedures. As discussed in further detail below, anexemplary device1000 of the present disclosure can be introduced through a venous access (femoral vein or axillary vein) into the right atrium and coronary sinus. A balloon coupled todevice1000 may be inflated just prior to injection of contrast, or can be triggered by sensing of contrast just prior to suction, as referenced below.

An exemplary device for removing contrast from a mammalian luminal organ of the present disclosure is shown inFIG. 17. As shown inFIG. 17,device1000 comprises an elongated body1002 (which may be, for example,elongated body104 or another elongated body of the present disclosure) having at least onelumen1004 extending therethrough, and anaperture1006 defined alongelongated body1002 proximal or distal to afirst detector1010. In the embodiment shown inFIG. 17,aperture1006 is defined along elongated body proximal todetector1010. In at least one embodiment,device1000 comprises a catheter.Detector1010, according to the present disclosure and as shown inFIG. 17, may be positioned at or near distal end1008 (such as distal end19) ofelongated body1002, wherein saidfirst detector1010 is capable of detecting a contrast present within a mammalian luminal organ (such as, for example, an iodine contrast present within blood within the luminal organ). Anexemplary device1000 of the present disclosure may comprise a coronary sinus catheter having the features described herein.

Another exemplary embodiment of adevice1000 of the present disclosure is shown inFIG. 18. As shown inFIG. 18,device1000 comprises anelongated body1002 having at least onelumen1004 extending therethrough, whereinlumen1004 terminates at anaperture1006 defined at or near adistal end1008 ofelongated body1002. The exemplary embodiments ofdevices1000 shown inFIGS. 17 and 18 are shown in two sections, whereby the two sections actually comprise oneoverall device1000 by way of the circled Xs shown in the figures.

Device

1000, as shown inFIGS. 17 and 18, may also comprise aninflatable balloon1012 coupled toelongated body1002. In at least one embodiment,balloon1012 is coupled toelongated body1002 proximal tofirst detector1010, as shown inFIGS. 17 and 18. Asecond detector1014, positioned insideballoon1012 alongelongated body1002, may operate to detectballoon1012 inflation.

In exemplary embodiments ofdevices1000, such as shown inFIGS. 17 and 18,first detector1010 ofdevices1000 comprises a first pair of

excitation electrodes

1016,1018 located onelongated body1002, and a first pair ofdetection electrodes1020,1022 located onelongated body1002 in between the first pair of

excitation electrodes

1016,1018. In at least one embodiment,first detector1010 is capable of obtaining a conductance measurement of a fluid, including contrast for example, present within the mammalian luminal organ at ornear device1000. In at least another embodiment,second detector1014 ofdevice1000 comprises a second pair of

excitation electrodes

1024,1026 located onelongated body1002 and a second pair of

detection electrodes

1028,1030 located onelongated body1002 in between the first pair of

excitation electrodes

1024,1026, wherein each of

electrodes

1024,1026,1028, and1030 are positioned withinballoon1012. In at least one embodiment,second detector1014 is capable of obtaining a conductance measurement of a fluid within the balloon to determine, for example, balloon cross-sectional area.

In an exemplary embodiment of adevice1000 of the present disclosure, at least one excitation electrode of the first pair of

excitation electrodes

1016,1018 and at least one excitation electrode of the second pair of

excitation electrodes

1024,1026 is/are in communication with acurrent source1032 capable of supplying electrical current to said electrodes. In addition, and as shown inFIGS. 17 and 18,exemplary devices1000 of the present disclosure may further comprise a data acquisition andprocessing system1034 capable of receiving conductance data from the first pair ofdetection electrodes1020,1022 and/or from the second pair of

detection electrodes

1028,1030.

In at least one embodiment ofdevice1000, whenfirst detector1010 detects contrast present within a mammalian luminal organ,device1000 is operable to withdraw contrast from the mammalian luminal organ throughaperture1006 theelongated body1002. Said contrast, which may include other fluid within the luminal organ such as blood and/or saline, may be withdrawn from the luminal organ throughaperture1006, throughlumen1004, and potentially out ofdevice1000 altogether. In an exemplary embodiment,device1000 is capable of removing contrast from a luminal organ by introducing suction at or near aproximal end device1000 to facilitate contrast entry intolumen1004 ofelongated body1002 throughaperture1006.

In anexemplary device1000 of the present disclosure,device1000 further comprises asuction apparatus1036 coupled toelongated body1002, and anelectronic module1038 coupled to thesuction apparatus1036 andfirst detector1010, wherein whenfirst detector1010 detects contrast within the luminal organ,electronic module1038 activatessuction apparatus1036 to withdraw contrast from the luminal organ. In such an embodiment, for example, withdrawal of contrast from the luminal organ involves operatingsuction apparatus1036 to withdraw contrast from the luminal organ, throughaperture1006, and throughlumen1004. In at least one embodiment,suction device1036 comprises acollector1040 for collecting contrast.

In at least one embodiment of adevice1000 of the present disclosure,device1000 further comprises aninflation source1042 coupled toballoon1012, and anelectronic module1038 coupled toinflation source1042 andfirst detector1010, wherein whenfirst detector1010 detects contrast within the luminal organ,electronic module1038 activatesinflation source1042 to inflateinflatable balloon1012. In an exemplary embodiment,electronic module1038 connected toinflation source1042 is the sameelectronic module1038 as connected tosuction apparatus1036, as shown inFIGS. 17 and 18, but can comprise separateelectronic modules1038 as well. In addition, various components ofdevice1000, including but not limited tocurrent source1032, data acquisition andprocessing system1034,suction apparatus1036,electronic module1038,collector1040, andinflation source1042, may be coupled and/or connected to various other components including those listed and, for example,

detectors

1010 and1014 andballoon1012, via various electrical connections such as wires and/or tubing/conduits to facilitate fluid suction and/or inflation, as appropriate to accomplish the same as referenced herein.

In various embodiments ofdevice1000, and as referenced generally above, when a fluid is injected throughlumen1004 ofelongated body1002 intoballoon1012,second detector1014 is capable of obtaining a fluid conductance measurement withinballoon1012, wherein the fluid conductance measurement is useful to determine balloon cross-sectional area. In at least one embodiment, and as shown inFIGS. 17 and 18, fluid may enterballoon1012 fromlumen1004 by way of suction/infusion port1044.

Steps of an exemplary method for removing contrast from a mammalian luminal organ of the present disclosure is shown inFIG. 19. As shown inFIG. 19,exemplary method1100 comprises the steps of inserting at least part of adevice1000 for removing contrast into a luminal organ (an exemplary insertion step1102) and detecting contrast present within the luminal organ (an exemplary detection step1104).Insertion step1102 may be performed to, for example,insert device1000 into a coronary sinus of a mammalian heart.

In at least one embodiment,device1000 comprises adetector1010 and aballoon1012 positioned along anelongated body1002 and at least onelumen1004 extending therethrough terminating at anaperture1006 defined at or near a distal end ofdevice100. In at least one embodiment,method1100 further comprises the steps of inflatingballoon1012 to prohibit fluid flow within the luminal organ proximal to balloon1012 (an exemplary inflation step1106), removing contrast throughaperture1006 of device1000 (an exemplary contrast removal step1108), and ceasing removal of contrast from the luminal organ when a threshold amount of contrast is no longer detected within the luminal organ (an exemplary removal cessation step1110).

Balloon inflation step

1106, for example, may be performed by inflatingballoon1012 to a desired size. Such a size may be, for example, identified by way ofdetector1014 present withinballoon1012, so thatballoon1012 is inflated so that contrast is prevent from escapingpast balloon1012 and to optimize trapping/removal of contrast without injury to the luminal organ.

In at least one embodiment of amethod1100 of the present disclosure,detection step1104 is performed usingdetector1010 ofdevice1000. In an exemplary embodiment ofmethod1100,inflation step1106 is performed using aninflation source1042 upon detection of contrast present within the luminal organ. In at least one embodiment,inflation step1106 andcontrast removal step1108 are performed simultaneously.Contrast removal step1108 may be performed quite rapidly (in the order of a few seconds, for example), depending on the configuration oflumen1004 and/oraperture1006, wherein larger corresponds to quicker removal of contrast, and the amount of suction applied thereto by, for example,suction apparatus1036.Contrast removal step1108 may be performed to remove no more than approximately 100 ml of contrast (contrast medium plus blood, for example).

In anexemplary method1100 for removing contrast from a mammalian luminal organ of the present disclosure,detection step1104, as shown inFIG. 19, comprises obtaining one or more initial conductance measurements within the luminalorgan using detector1010, the one or more initial conductance measurements obtained without contrast present therein, and then obtaining one or more subsequent conductance measurements within the luminalorgan using detector1010, wherein at least one of the one or more subsequent conductance measurements is a threshold percentage lower than at least one of the one or more initial conductance measurements, which is indicative of the presence of contrast. In such an embodiment, for example, the threshold percentage is at least approximately 10% lower than at least one of the one or more initial conductance measurements.

In at least oneexemplary method1100 of the present disclosure,method1100 further comprises the step of deflatingballoon1012 to permit fluid flow within the luminal organ proximal to balloon1012 (an exemplary balloon deflation step1112), as shown inFIG. 19. In at least one embodiment ofmethod1000,deflation step1112 is performed in response to at least a partial conductance measurement recovery. In an exemplary embodiment, the partial conductance measurement recovery is approximately within 5% of at least one of the one or more initial conductance measurements.Deflation step1112 may be performed by, for example, operatinginflation source1042 in a way to decrease fluid pressure withinballoon1012 to deflateballoon1012. For example,inflation source1042 may comprise a syringe used to inject fluid into aballoon1012, and removal of fluid fromballoon1012 to deflateballoon1012 could be performed by withdrawing fluid fromballoon1012 using the same syringe.

Exemplary systems

1200 for removing contrast from luminal organs of the present disclosure may compriseexemplary devices1000 with one or more components/features present. For example, anexemplary device1000 may comprise anelongated body1002 with a lumen therethrough1004 terminating at anaperture1006, as well as adetector1010 and aballoon1012 coupled thereto. Anexemplary system1200 may comprise that same embodiment of adevice1000, for example, along with acurrent source1032, a data acquisition andprocessing system1034, asuction apparatus1036, anelectronic module1038, acollector1040, and/or aninflation source1042.Devices1000 andsystems1200 of the present disclosure, depending on configuration, may be one in the same, and any description regarding components and/or features ofdevices1000 of the present disclosure also apply tovarious systems1200 of the present disclosure. By way of example, and as shown in the block diagram ofFIG. 20, an exemplary system of the present disclosure comprises adevice1000 coupled a data acquisition andprocessing system1034, but is not limited to such a configuration. In addition, said components/features may be described using more than one reference number; therefore, corresponding descriptions as to such components/features among various devices, systems, and methods are intended to apply to each component/feature. For example,

excitation electrodes

40 and41 may be one in the same as

excitation electrodes

1016 and1018, and description in connection with one is intended to apply to the other.

An exemplary embodiment of adevice1000/system1200 of the present disclosure positioned within a heart1250 (an exemplary luminal organ) is shown inFIG. 21. As shown inFIG. 21,device1000/system1200 comprises anaperture1006 proximal to adetector1010 capable of obtaining real-time conductance changes as shown inFIG. 16. Theexemplary device1000/system1200 shown inFIG. 21 is shown positioned within acoronary sinus1252, whereby aballoon1012 can be inflated to occludecoronary sinus1252 during suction of contrast.Device1000/system1200, as shown inFIG. 21, is also connected to (or further comprises) asuction apparatus1036 which can be triggered by anelectronic module1038 that senses the level of contrast to permit only removal of blood containing the contrast.

Thevarious devices1000,systems1200, andmethods1100 for removing contrast from a luminal organ of the present disclosure have a number of advantages over other means for removing contrast which may be used prior to this disclosure. For example, thedevices1000 andsystems1200 of the present disclosure provide active monitoring and detection, whereby, in at least one embodiment,such devices1000 andsystems1200 may be activated/triggered when adetector1010 detects contrast.Such devices1000 and/orsystems1200 do not require constant monitoring by a physician, for example, as they can be configured as referenced herein to operate to remove contrast when detected, which can be in the order of a few seconds.Such devices1000,systems1200, andmethods1100 also minimize the amount of blood removed while maximizing the amount of contrast removed as referenced herein, thus reducing or eliminating the risk of contrast-induced nephropathy.

Again, it is noted that the various devices, systems, and methods described herein can be applied to any body lumen or treatment site. For example, the devices, systems, and methods described herein can be applied to any one of the following exemplary bodily hollow organs: the cardiovascular system including the heart, the digestive system, the respiratory system, the reproductive system, and the urogenital tract.

Referring to the embodiment shown inFIG. 6, theangioplasty balloon30 is shown distended within thecoronary artery150 for the treatment of stenosis. As described above with reference toFIG. 1B, a set of

excitation electrodes

40,41 and

detection electrodes

42,43 are located within theangioplasty balloon30. In another embodiment, shown inFIG. 7, theangioplasty balloon30 is used to distend thestent160 withinblood vessel150.

For valve area determination, it is not generally feasible to displace the entire volume of the heart. Hence, the conductivity of blood is changed by injection of hypertonic NaCl solution into the pulmonary artery which will transiently change the conductivity of blood. If the measured total conductance is plotted versus blood conductivity on a graph, the extrapolated conductance at zero conductivity corresponds to the parallel conductance. In order to ensure that the two inner electrodes are positioned in the plane of the valve annulus (2-3 mm), in one preferred embodiment, the twopressure sensors36 are advantageously placed immediately proximal and distal to the detection electrodes (1-2 mm above and below, respectively) or several sets of detection electrodes (see, e.g.,FIGS. 1D and 1F). The pressure readings will then indicate the position of the detection electrode relative to the desired site of measurement (aortic valve: aortic-ventricular pressure; mitral valve: left ventricular-atrial pressure; tricuspid valve: right atrial-ventricular pressure; pulmonary valve: right ventricular-pulmonary pressure). The parallel conductance at the site of annulus is generally expected to be small since the annulus consists primarily of collagen which has low electrical conductivity. In another application, a pull back or push forward through the heart chamber will show different conductance due to the change in geometry and parallel conductance. This can be established for normal patients which can then be used to diagnose valvular stenosis.

In one approach, for the esophagus or the urethra, the procedures can conveniently be done by swallowing fluids of known conductances into the esophagus and infusion of fluids of known conductances into the urinary bladder followed by voiding the volume. In another approach, fluids can be swallowed or urine voided followed by measurement of the fluid conductances from samples of the fluid. The latter method can be applied to the ureter where a catheter can be advanced up into the ureter and fluids can either be injected from a proximal port on the probe (will also be applicable in the intestines) or urine production can be increased and samples taken distal in the ureter during passage of the bolus or from the urinary bladder.

In one approach, concomitant with measuring the cross-sectional area and or pressure gradient at the treatment or measurement site, a mechanical stimulus is introduced by way of inflating the balloon or by releasing a stent from the catheter, thereby facilitating flow through the stenosed part of the organ. In another approach, concomitant with measuring the cross-sectional area and or pressure gradient at the treatment site, one or more pharmaceutical substances for diagnosis or treatment of stenosis is injected into the treatment site. For example, in one approach, the injected substance can be smooth muscle agonist or antagonist. In yet another approach, concomitant with measuring the cross-sectional area and or pressure gradient at the treatment site, an inflating fluid is released into the treatment site for release of any stenosis or materials causing stenosis in the organ or treatment site.

Again, it will be noted that the methods, systems, and devices described herein can be applied to any body lumen or treatment site. For example, the methods, systems, and devices described herein can be applied to any one of the following exemplary bodily hollow systems: the cardiovascular system including the heart; the digestive system; the respiratory system; the reproductive system; and the urogenital tract.

Finite Element Analysis:

In one preferred approach, finite element analysis (FEA) is used to verify the validity of Equations [4] and [5]. There are two major considerations for the model definition: geometry and electrical properties. The general equation governing the electric scalar potential distribution, V, is given by Poisson's equation as:

∇·(C∇V)=−I [13]

where C, I, and ∇ are the conductivity, the driving current density, and the del operator, respectively. Femlab or any standard finite element packages can be used to compute the nodal voltages using equation [13]. Once V has been determined, the electric field can be obtained from as E=−∇V.

The FEA allows the determination of the nature of the field and its alteration in response to different electrode distances, distances between driving electrodes, wall thicknesses and wall conductivities. The percentage of total current in the lumen of the vessel, % I, can be used as an index of both leakage and field homogeneity. Hence, the various geometric and electrical material properties can be varied to obtain the optimum design; i.e., minimize the non-homogeneity of the field. Furthermore, the experimental procedure was simulated by injection of the two solutions of NaCl to verify the accuracy of Equation [4]. Finally, an assessment of the effect of presence of electrodes and catheter in the lumen of vessel may be performed. The error terms representing the changes in measured conductance due to the attraction of the field to the electrodes and the repulsion of the field from the resistive catheter body were quantified.

Poisson's equation for the potential field was solved, taking into account the magnitude of the applied current, the location of the current driving and detection electrodes, and the conductivities and geometrical shapes in the model including the vessel wall and surrounding tissue. This analysis suggest that the following conditions are optimal for the cylindrical model: (1) the placement of detection electrodes equidistant from the excitation electrodes; (2) the distance between the current driving electrodes should be much greater than the distance between the voltage sensing electrodes; and (3) the distance between the detection and excitation electrodes is comparable to the vessel diameter or the diameter of the vessel is small relative to the distance between the driving electrodes. If these conditions are satisfied, the equipotential contours more closely resemble straight lines perpendicular to the axis of the catheter and the voltage drop measured at the wall will be nearly identical to that at the center. Since the curvature of the equipotential contours is inversely related to the homogeneity of the electric field, it is possible to optimize the design to minimize the curvature of the field lines. Consequently, in one preferred approach, one or more of conditions (1)-(3) described above are met to increase the accuracy of the cylindrical model.

Theoretically, it is impossible to ensure a completely homogeneous field given the current leakage through the vessel wall into the surrounding tissue. Research leading to the disclosure of the present application identified that the isopotential line is not constant as one moves out radially along the vessel as stipulated by the cylindrical model. In one embodiment, a catheter with a radius of 0.55 mm is considered whose detected voltage is shown inFIGS. 8A and 8B for two different NaCl solutions (0.5% and 1.5%, respectively). The origin corresponds to the center of the catheter. The firstvertical line220 represents the inner part of the electrode which is wrapped around the catheter and the secondvertical line221 is the outer part of the electrode in contact with the solution (diameter of electrode is approximately 0.25 mm). The six different curves, top to bottom, correspond to six different vessels with radii of 3.1, 2.7, 2.3, 1.9, 1.5, and 0.55 mm, respectively. It can be seen that a “hill” occurs at the

detection electrode

220,221 followed by a fairly uniform plateau in the vessel lumen followed by an exponential decay into the surrounding tissue. Since the potential difference is measured at the

detection electrode

220,221, the simulation generates the “hill” whose value corresponds to the equivalent potential in the vessel as used in Eq. [4]. Hence, for each catheter size, the dimension of the vessel was varied such that equation [4] is exactly satisfied. Consequently, the optimum catheter size for a given vessel diameter was obtained such that the distributive model satisfies the lumped equations (Equation [4] and [5]). In this way, a relationship between vessel diameter and catheter diameter may be generated such that the error in the CSA measurement is less than 5%.

In an exemplary embodiment, different diameter catheters are prepackaged and labeled for optimal use in certain size vessel. For example, for vessel dimension in the range of 4-5 mm, 5-7 mm or 7-10 mm, analysis in accordance with the disclosure of the present application shows that the optimum diameter catheters will be in the range of 0.9-1.4, 1.4-2.0 or 2.0-4.6 mm, respectively. A clinician can select the appropriate diameter catheter based on the estimated vessel diameter of interest. This decision will be made prior to the procedure and will serve to minimize the error in the determination of lumen CSA.

The present disclosure also includes disclosure of impedance devices having one or more electrodes or poles thereon. For device101 (such as, for example,catheter20,catheter20A,catheter20B,catheter21,catheter22,catheter23, catheter29,wire18,device1000, and/or other impedance device embodiments referenced herein that are configured for use with one, two, three, or potentially more electrodes as described herein), embodiments having only one electrode/pole102 thereon, therein, or otherwise coupled thereto (hereinafter referred to a “unipolar” devices101), saiddevices101 are operable to work with at least one external electrode/pole145 to generate an electric field that can be detected by a detection electrode (another exemplary electrode/pole102).Device101 embodiments having more than one electrode/pole102, such as an embodiment having two electrodes/poles102, three electrodes/poles102, or four or more electrodes/poles102, may also be configured and operable to work with at least one external electrode/pole102. For purposes of the present disclosure, the term “electrode/pole” refers to an electrode or another item operable as a pole, such as a metallic clip, button, pad, sheath, lead, wire, or other item, wherein the item can work with another electrode/pole to generate an electric field. Electrodes/poles102 of the present disclosure may also include one or more of

electrodes

25,26,27,28,40,41,42,43,51,52,53,54,55,56,57,1016,1018,1020,1022,1024,1026,1028, and/or1030 as generally referenced herein if configured for use in connection with a particular embodiment.

FIG. 13A shows a distal portion of anexemplary device101 of the present disclosure having one electrode/pole102 thereon, therein, or otherwise coupled thereto. Such adevice101 is referred to herein as a “unipolar device,” as it has one electrode/pole102 thereon, therein, or otherwise coupled thereto. Such adevice101, in various embodiments, is used to perform a unipolar method of detection within a mammalian body.

With aunipolar device101 configuration, and in general, saiddevice101 has a single electrode/pole102 that has both excitation and detection functionality. “Excitation,” as referenced herein, refers to the ability to generate an electric field that a detection electrode/pole102 can detect at least one conductance measurement within in connection with one or more methods of the present disclosure. Phrased differently, an electrode/pole102, in aunipolar device101 embodiment, needs to be able to can excite a field and detect within said field.

Generation of an electric field using aunipolar device101 embodiment requires a second electrode/pole102 positioned somewhere other thandevice101. For example, a second electrode/pole102 may comprise part of apatch130, part of asheath140, aclip145, and/or another item that, when used with the electrode/pole102 ofunipolar device101, can allow for a field to be excited and conductance measurements to be obtained within said field. Should there only be two total electrodes/poles102 (one ondevice101 and one not on device101), both electrodes/poles102 would operate to excite/generate a field and detect within a field. If aunipolar device101 is used in connection with two additional items (electrodes/poles102 and/or items including electrodes/poles102), then the electrode/pole102 ondevice101 would still have excitation and detection functionality, but the other two electrodes/poles102 would not require dual functionality, as long as one electrode/pole102 can work with the electrode/pole102 ondevice101 to excite a field, and as long as another electrode/pole102 can work with the electrode/pole102 on device to detect within the excited field.

Devices

101 of the present disclosure can comprise a number of components/features. For example,devices101 may be wires or catheters, and thus having an elongated body104 (such aselongated body1002 or other elongated bodies present with the various impedance devices referenced herein) with one ormore lumens175 optionally defined therethrough (such as incatheter device101 embodiments).Lumens175, as referenced herein, may include

lumens

60,71, or1004,pressure conduit95A,pressure conduit95B, and/ortunnel96, as generally referenced herein. Additional components, such as one or

more balloons

30 or1012, pressure sensors110 (which may be a sensor or may be configured as a

pressure port

36,90, and/or91 as generally referenced herein),temperature sensors112,ablation contacts114, cuttingportions116, and/or other components/features known in the intravascular device art thereon, therein, or otherwise coupled thereto. Furthermore,devices101 may define one or

more apertures

118 or1006,grooves120, housings122 (such as to house a balloon30), suction ports124 (which may be, for example, an

infusion port

35,36, and/or37, anaperture1006, or a suction/infusion port1044, in various embodiments), and/orvacuum ports126 therein.FIG. 14 shows a block component diagram of anexemplary device101 of the present disclosure, whereindevice101 comprises the various components referenced herein.Other device101 embodiments may have more or less components than as shown therein. For example, an exemplaryunipolar device101 embodiment may comprise anelongated body104 configured as a wire, one electrode/pole102, atemperature sensor112, and anablation contact114.

A combination of anexemplary device101 of the present disclosure plus one other component external to the device, such as another electrode/pole102, apatch130, asheath140, aclip145, or another item, would comprise anexemplary system180 of the present disclosure. The component diagram shown inFIG. 14 also shows that anexemplary system180 of the present disclosure can comprise anexemplary device101 of the present disclosure and one or more other components, such as one or more electrodes/poles102,patches130,sheaths140,clips145, and/or other items. Further, anexemplary system180 of the present disclosure may comprise the use of one or more additional components, such as a second catheter182 (such as, for example, aguide catheter23 as generally referenced herein), astent160, avalve device206, alead208, asecond wire210, aneedle212, adiagnostic device214, and/or atherapeutic device216, for example. In addition, anexemplary system180 of the present disclosure may comprise a data acquisition and

processing system

100 or1034, a processor219 (which may be or comprise part of acomputer160 and/or a data acquisition andprocessing system100, in various embodiments), astorage medium222, apower source224, an injection source226 (such as, for example, a

system

105 or106 as generally referenced herein), and/or a vacuum source228 (such as, for example, asystem106 referenced herein). Various components ofdevices101 and/orsystems180 of the present disclosure may be coupled to one another, or otherwise in communication with one another, so to operate as intended, such as through one or more wires230 (such as, for example,electrical leads70A or70B or other types of wires/leads),tubes232, and/orconnectors234.Various systems180 of the present disclosure may be the same or similar tosystems1200.

FIG. 13B shows a distal portion of anexemplary device101 of the present disclosure having two electrodes/poles102 thereon, therein, or otherwise coupled thereto. Such adevice101 is referred to herein as a “bipolar device,” as it has two electrodes/poles102 thereon, therein, or otherwise coupled thereto. Such adevice101, in various embodiments, is used to perform a bipolar method of detection within a mammalian body.

FIG. 13C shows a distal portion of anexemplary device101 of the present disclosure having three electrodes/poles102 thereon, therein, or otherwise coupled thereto. Such adevice101 is referred to herein as a “tripolar device,” as it has three electrodes/poles102 thereon, therein, or otherwise coupled thereto. Such adevice101, in various embodiments, is used to perform a tripolar method of detection within a mammalian body.

Generation of an electric field using atripolar device100 can be performed using two electrodes/poles102 ofdevice100 by way of an excitation functionality of said electrodes/poles102. If two electrodes/poles102 of device can excite an electric field and two electrodes/poles102 of device can excite and detect within the electric field (where one electrode/pole102 can excite and detect within the field), only three electrodes/poles102 are required. However, if only one electrode/pole102 ofdevice100 can excite an electric field, such an embodiment requires an additional electrode/pole102 positioned somewhere other thandevice100. For example, an additional electrode/pole102 may comprise part of apatch130, part of asheath140, aclip150, and/or another item that, when used with one of the electrodes/poles102 oftripolar device100, can allow for a field to be excited and conductance measurements to be obtained within said field. In such an embodiment, one electrode/pole102 ondevice100 would be used to excite the field, and the other two electrodes/poles102 would be used to detect within the field, while the electrode/pole102 outside of thedevice100 would also be used to excite the field.

Atetrapolar device101 would include four electrodes/poles102 ondevice101, wherein two electrodes/poles102 (also referred to as excitation electrodes) would operate to generate a field, while the other two electrodes/poles102 (also referred to as detection electrodes), would be positioned in between the two excitation electrodes and detect within a field. Such devices are as disclosed within U.S. Pat. No. 7,454,244 to Kassab et al., the entire contents of which are hereby incorporated into the present disclosure by reference. Such devices would be used to perform tetrapolar methods, which could involve, in some embodiments, the use of one or more fluid injections (saline, for example), in connection with the performance of the same, as described within said patent.

Conductance measurements obtained usingdevices101 and/orsystems180 of the present disclosure may use various formulas and/or algorithms, such as Ohm's Law and/or a distance between two electrodes/poles102 used to detect within an electric field, one or more saline injections, etc., as described in one or more of the following references, wherein saiddevices101 and/or systems are configured to perform one or more of the following procedures/tasks:

(a) determining the size (cross-sectional area or diameter, for example) of a mammalian luminal organ, parallel tissue conductance within a mammalian luminal organ, and/or navigation of a device within a luminal organ, such as generally referenced herein and described within U.S. Pat. No. 7,454,244 to Kassab et al., U.S. Pat. No. 8,114,143 to Kassab et al., U.S. Pat. No. 8,082,032 to Kassab et al., U.S. Patent Application Publication No. 2010/0152607 of Kassab, U.S. Patent Application Publication No. 2012/0053441 of Kassab, U.S. Patent Application Publication No. 2012/0089046 of Kassab et al., U.S. Patent Application Publication No. 2012/0143078 of Kassab et al., and U.S. Patent Application Publication No. 2013/0030318 of Kassab, the entire contents of which are hereby incorporated into the present disclosure by reference;

(b) determining the location of one or more body lumen junctions and/or profiles of a luminal organ, such as generally referenced herein and described within U.S. Patent Application Publication No. 2009/0182287 of Kassab, U.S. Patent Application Publication No. 2012/0172746 of Kassab, U.S. Patent Application Publication No. 2010/0010355 of Kassab, and U.S. Pat. No. 8,078,274 to Kassab, the entire contents of which are hereby incorporated into the present disclosure by reference;

(c) ablating a tissue within a mammalian patient and/or removing stenotic lesions from a vessel, such as generally referenced herein and described within U U.S. Patent Application Publication No. 2009/0182287 of Kassab, U.S. Patent Application Publication No. 2009/0204134 of Kassab, and U.S. Patent Application Publication No. 2010/0222786 of Kassab, the entire contents of which are hereby incorporated into the present disclosure by reference;

(d) determining the existence, potential type, and/or vulnerability of a plaque within a luminal organ, such as described within U.S. Patent Application Publication No. 2010/0152607 of Kassab, U.S. Patent Application Publication No. 2011/0034824 of Kassab, and U.S. Pat. No. 7,818,053 to Kassab, the entire contents of which are hereby incorporated into the present disclosure by reference;

(e) determining phasic cardiac cycle measurements and determining vessel compliance, such as generally referenced herein and described within U.S. Pat. No. 8,185,194 to Kassab and U.S. Pat. No. 8,099,161 to Kassab, the entire contents of which are hereby incorporated into the present disclosure by reference;

(f) determining the velocity of a fluid flowing through a mammalian luminal organ, such as described within U.S. Pat. No. 8,078,274 to Kassab, U.S. Patent Application Publication No. 2010/0152607 of Kassab, U.S. Patent Application Publication No. 2012/0053441 of Kassab et al., and U.S. Patent Application Publication No. 2012/0089046 of Kassab et al., the entire contents of which are hereby incorporated into the present disclosure by reference;

(g) sizing of valves using impedance and balloons, such as sizing a valve annulus for percutaneous valves, as described within U.S. Patent Application Publication No. 2010/0168836 of Kassab, the entire contents of which are hereby incorporated into the present disclosure by reference;

(h) detecting and/or removing contrast from mammalian luminal organs, such as described within U.S. Pat. No. 8,388,604 to Kassab, the entire contents of which are hereby incorporated into the present disclosure by reference;

(i) determining fractional flow reserve, such as described within U.S. Patent Application Publication No. 2011/0178417 of Kassab and U.S. Patent Application Publication No. 2011/0178383 of Kassab, the entire contents of which are hereby incorporated into the present disclosure by reference; and/or

(j) to place leads within a mammalian luminal organ, such as by using adevice101 of the present disclosure to navigate through a mammalian luminal organ to a location of interest, and usingdevice101 and/or a second device to place a lead within said luminal organ.

In addition to the foregoing,various devices101 of the present disclosure, and various other impedance devices as described in one or more of the aforementioned patents and/or patent applications (such as tetrapolar devices), may be operable to perform one or more of the following additional procedures/tasks:

Ablate relatively small veins.Various devices101 of the present disclosure, and various other impedance devices as described in one or more of the aforementioned patents and/or patent applications (such as tetrapolar devices), may be used to navigate through mammalian luminal organs for Endovascular Laser Therapy (EVLT) (also known as endovenous laser treatment (ELT)) for treatment of venous insufficiency of varicose veins (cosmetic procedures). One objective is to ablate a smaller vein (such as saphenous vein and/or a popliteal vein) as opposed to a larger vein (such as a femoral vein or a common femoral vein). EVLT procedures are currently performed within a physician's office using ultrasound (US) and not fluoroscopy. In obese patients, the saphenous popliteal junction is difficult to image with US. As such, a laser catheter (an exemplary or other suitable ablation device (such as a device with an ablation contact/portion114 thereon)) is delivered over an impedance wire (anexemplary device101 of the present disclosure or a tetrapolar device as referenced herein), which may be, for example, a 0.035″ guidewire. Use of such a device for navigation (peripherally), one can differentiate (based on a vessel profile) large from small veins, and also can size the luminal organ in connection with one or more saline injections, for example), prior to ablation.

In view of the same, at least one embodiment of a device (device101 or otherwise, such ascatheter20,catheter20A,catheter20B,catheter21,catheter22,catheter23, catheter29,wire18,device1000, and/or other impedance device embodiments referenced herein configured for use as referenced herein) of the present disclosure can be used by introducing at least a portion of the same into a patient's vasculature, navigating the same through the vasculature to obtain a general vasculature profile within the vasculature, identify a vein within the vasculature based upon the profile, and ablate the vein using an ablation device. Ablation can occur to treat venous insufficiency or cosmetically to treat, remove, or eliminate the outer appearance of, varicose veins. The ablation device can be advanced over the originally-navigated device, and can comprise a laser catheter or another ablation device.

Navigation for Urological Uses.Various devices101 of the present disclosure, and various other impedance devices as described in one or more of the aforementioned patents and/or patent applications (such as tetrapolar devices), may be used to measure ureter stenosis at different levels, including at level of ureter emerging from the kidney, as well as to measure the urethra/urinary bladder junction, strictures of abnormal congenital ureter in children, enlargement of ureter in pregnant women due to compression of the uterus against ureter, trauma with pelvic fracture, and other urological conditions. Diagnosis of a urinary obstruction is currently largely established by x-ray studies, noting that the prostate and testis are most vulnerable to x-ray. These studies include kidney x-ray, kidney ultrasound, CAT scan, intravenous pyelogram (IVP) and MRI. Some of these studies may require administration of oral or intravenous contrast (dye) and even diuretics drugs which are painful to the patient and require x-ray exposure. To overcome these problems, said devices could be used to navigate through a ureter and obtain measurements therein to potentially identify a stenosis or other ureter size abnormality.

In view of the same, at least one embodiment of a device (device101 or otherwise, such ascatheter20,catheter20A,catheter20B,catheter21,catheter22,catheter23, catheter29,wire18,device1000, and/or other impedance device embodiments referenced herein configured for use as referenced herein) of the present disclosure can be used by introducing at least a portion of the same into a urological luminal organ of a mammalian patient, such as a ureter, urethra, and bladder, etc., so to ultimately identify a condition, junction, or other feature of interest. For example, a portion of an exemplary device can be introduced into the urethra and optionally advanced to the urethra/urinary bladder junction, into the bladder, into a ureter, and to the kidney. Stenoses at various portions of that pathway can be determined by way of operating the device (such as to obtain one or more conductance values, as generally discussed herein in connection with various device embodiments, and using the same to calculate or otherwise determine one or more diameters or cross-sectional areas along that pathway, and optionally creating a profile, also as generally discussed herein, to visually identify one or more stenoses, junctions, size abnormalities, and the like, as referenced herein.

In at least one experimental study using an exemplary device of the present disclosure, the device was inserted into a mammalian urethra, and conductance values were obtained at various locations from the urethra to the bladder. In the study, it was found that the conductance was much higher in the bladder with or without urine as compared to the urethra, so that even with a bladder that was not full of urine, the conductance was still higher and allowed the user of the device to identify that the detection portion of the device had moved from the urethra to the bladder.

It can be appreciated that any number of devices may be used in accordance within the scope of the present disclosure, including, but not limited to, any number of catheters and/or wires. In exemplary embodiments, catheters, including, but not limited to, impedance and/or guide catheters, and wires, including, but not limited to, impedance wires, guide wires, pressure wires, and flow wires, may be used as appropriate as devices, systems, and/or portions of systems of the present disclosure, and may be used as appropriate to perform one or more methods, or steps thereof, of the present disclosure.

While various embodiments of impedance devices and methods of using the same have been described in considerable detail herein, the embodiments are merely offered as non-limiting examples of the disclosure described herein. It will therefore be understood that various changes and modifications may be made, and equivalents may be substituted for elements thereof, without departing from the scope of the present disclosure. The present disclosure is not intended to be exhaustive or limiting with respect to the content thereof.

Further, in describing representative embodiments, the disclosure may have presented a method and/or process as a particular sequence of steps. However, to the extent that the method or process does not rely on the particular order of steps set forth herein, the method or process should not be limited to the particular sequence of steps described. Other sequences of steps may be possible. Therefore, the particular order of the steps disclosed herein should not be construed as limitations of the present disclosure. In addition, disclosure directed to a method and/or process should not be limited to the performance of their steps in the order written. Such sequences may be varied and still remain within the scope of the present disclosure.