阅读说明：本技术 基于组织的频率响应的触摸检测 (Tissue-based frequency response touch detection ) 是由 A.戈瓦里 于 2019-05-29 设计创作，主要内容包括：本发明题为“基于组织的频率响应的触摸检测”。本发明公开了一种方法,所述方法包括在第一电频率下测量装配在患者器官中的医疗器械的远侧端部处的远侧电极和在外部附接到所述患者的表面电极之间的第一阻抗量值。在第二电频率下测量所述远侧电极和所述表面电极之间的第二阻抗量值。计算第一测量阻抗量值和第二测量阻抗量值之间的差值。基于所计算的差值,判定并且输出所述远侧电极是与组织物理接触还是浸入血液中的指示。(The invention is directed to tissue-based frequency response touch detection. A method includes measuring a first impedance magnitude at a first electrical frequency between a distal electrode at a distal end of a medical instrument fitted in a patient organ and a surface electrode externally attached to the patient. A second impedance magnitude between the distal electrode and the surface electrode is measured at a second electrical frequency. A difference between the first measured impedance magnitude and the second measured impedance magnitude is calculated. Based on the calculated difference, an indication of whether the distal electrode is in physical contact with tissue or immersed in blood is determined and output.)

1. A method, comprising:

Measuring a first impedance magnitude at a first electrical frequency between a distal electrode at a distal end of a medical instrument fitted in a patient organ and a surface electrode externally attached to the patient;

Measuring a second impedance magnitude between the distal electrode and the surface electrode at a second electrical frequency;

Calculating a difference between the first measured impedance magnitude and the second measured impedance magnitude; and

Based on the calculated difference, an indication of whether the distal electrode is in physical contact with tissue or immersed in blood is determined and output.

2. The method of claim 1, wherein determining whether the distal electrode is in physical contact with tissue comprises comparing the calculated difference to a given threshold and determining that the distal electrode is in touch with tissue if the difference is greater than the given threshold.

3. The method of claim 1, wherein measuring the first and second impedance magnitudes comprises measuring a first set of impedance magnitudes at the first electrical frequency and a second set of impedance magnitudes at the second electrical frequency, wherein calculating the difference comprises calculating a plurality of differences between the respective first and second impedance magnitudes, and wherein determining whether the distal electrode is in physical contact with tissue comprises determining based on the plurality of calculated differences.

4. The method of claim 3, and comprising measuring the first and second sets of impedance magnitudes with a plurality of distal electrodes.

5. the method of claim 3, and comprising:

Fitting one or more statistical distributions to the plurality of calculated differences;

Applying one or more statistical tests to the distribution;

Deriving whether the calculated differences between the differences of the respective groups are statistically significant based on the results of the one or more statistical tests; and

Determining whether the distal electrode is in physical contact with tissue or immersed in blood based on whether the calculated difference is statistically significant.

6. The method of claim 1, wherein the first electrical frequency is equal to 1.5KHz or less, and wherein the second electrical frequency is equal to 20KHz or more.

7. The method of claim 1, wherein outputting the indication comprises representing the indication on an electroanatomical map.

8. A system, the system comprising:

an electrical interface for communicating with a distal electrode at a distal end of a medical instrument fitted in a patient organ; and

A processor configured to:

receiving, via the electrical interface: (i) a first impedance magnitude measured between the distal electrode and a surface electrode at a first electrical frequency, and (ii) a second impedance magnitude measured between the distal electrode and the surface electrode at a second electrical frequency;

Calculating a difference between the first measured impedance magnitude and the second measured impedance magnitude; and

Based on the calculated difference, an indication of whether the distal electrode is in physical contact with tissue or immersed in blood is determined and output.

9. the system of claim 8, wherein the processor is configured to determine whether the distal electrode is in physical contact with tissue by comparing the calculated difference to a given threshold and determining that the distal electrode is touching tissue if the difference is greater than the given threshold.

10. The system of claim 8, wherein the processor is configured to measure the first and second impedance magnitudes by measuring a first set of impedance magnitudes at the first electrical frequency and a second set of impedance magnitudes at the second electrical frequency to calculate a plurality of differences between the respective first and second impedance magnitudes, and determine whether the distal electrode is in physical contact with tissue based on the plurality of calculated differences.

11. the system of claim 10, wherein the processor is configured to measure the first set of impedance magnitudes and the second set of impedance magnitudes through a plurality of distal electrodes.

12. The system of claim 10, wherein the processor is configured to:

Fitting one or more statistical distributions to the plurality of calculated differences;

Applying one or more statistical tests to the distribution;

Deriving whether the calculated differences between the differences of the respective groups are statistically significant based on the results of the one or more statistical tests; and

determining whether the distal electrode is in physical contact with tissue or immersed in blood based on whether the calculated difference is statistically significant.

13. The system of claim 8, wherein the first electrical frequency is equal to 1.5KHz or less, and wherein the second electrical frequency is equal to 20KHz or more.

14. The system of claim 8, wherein the processor is configured to output the indication by representing the indication on an electroanatomical map.

Technical Field

The present invention relates generally to intrabody medical procedures and instruments, and in particular to cardiac electroanatomical sensing and ablation.

Background

Various techniques have been proposed for confirming that the catheter is in contact with the heart tissue. For example, U.S. patent application publication 2016/0287137 describes a method and system for assessing electrode-tissue contact prior to delivering ablation energy. The method may generally include: determining a difference between a maximum impedance magnitude for a given electrode at a low frequency and an absolute minimum impedance magnitude for all electrodes at the low frequency; determining a difference between a maximum impedance magnitude for a given electrode at a high frequency and an absolute minimum impedance magnitude for all electrodes at the high frequency; and determining the difference between the maximum impedance phase at high frequency for a given electrode and the absolute minimum impedance phase at high frequency for all electrodes. These differences may be correlated to each other using a linear model whose results determine whether a given electrode is in contact with tissue or not.

U.S. patent application publication 2016/0278841 describes a medical device that includes an elongated body having a proximal end and a distal end and a pair of electrodes or electrode portions (e.g., a split-tip electrode assembly). Systems and methods are described for performing contact sensing and/or ablation confirmation based on electrical measurements obtained when applying energy at different frequencies to the pair of electrodes or portions of electrodes. The touch sensing system and method may calibrate the network parameter measurement to compensate for hardware elements in the network parameter measurement circuit or account for differences in the cables, instrumentation, or hardware used.

disclosure of Invention

Embodiments of the present invention provide a method comprising measuring a first impedance magnitude at a first electrical frequency between a distal electrode at a distal end of a medical instrument fitted in a patient organ and a surface electrode externally attached to the patient. A second impedance magnitude between the distal electrode and the surface electrode is measured at a second electrical frequency. A difference between the first measured impedance magnitude and the second measured impedance magnitude is calculated. Based on the calculated difference, an indication of whether the distal electrode is in physical contact with tissue or immersed in blood is determined and output.

in some embodiments, the method includes comparing the calculated difference to a given threshold and determining that the distal electrode is in contact with tissue if the difference is greater than the given threshold.

In some embodiments, the method includes measuring a first set of impedance magnitudes at a first electrical frequency and measuring a second set of impedance magnitudes at a second electrical frequency, wherein calculating the difference includes calculating a plurality of differences between the respective first and second impedance magnitudes, and wherein determining whether the distal electrode is in physical contact with the tissue includes determining based on the plurality of calculated differences.

In one embodiment, the method further comprises measuring the first set of impedance magnitudes and the second set of impedance magnitudes with a plurality of distal electrodes.

In one embodiment, the method further comprises fitting one or more statistical distributions to the plurality of calculated differences. One or more statistical tests are applied to the distributions. Deriving whether the calculated differences between the differences of the respective groups are statistically significant based on the results of the one or more statistical tests. Based on whether the calculated difference is statistically significant, it is determined whether the distal electrode is in physical contact with tissue or immersed in blood.

In some embodiments, the first electrical frequency is equal to 1.5KHz or less, and wherein the second electrical frequency is equal to 20KHz or more.

In some embodiments, the method includes representing the indication on an electroanatomical map.

There is also provided, in accordance with an embodiment of the present invention, a system including an electrical interface and a processor. The electrical interface is configured for communication with a distal electrode at a distal end of a medical instrument fitted in a patient organ. The processor is configured to receive, via the electrical interface: (i) a first impedance magnitude measured between the distal electrode and the surface electrode at a first electrical frequency, and (ii) a second impedance magnitude measured between the distal electrode and the surface electrode at a second electrical frequency. The processor is further configured to calculate a difference between the first measured impedance magnitude and the second measured impedance magnitude, and based on the calculated difference, determine and output an indication of whether the distal electrode is in physical contact with tissue or immersed in blood.

The invention will be more fully understood from the following detailed description of embodiments of the invention taken together with the accompanying drawings, in which:

Drawings

Fig. 1 is a schematic illustration of a system for electroanatomical mapping according to an embodiment of the present invention;

FIG. 2 is a schematic diagram illustrating the frequency dependence of the impedance magnitude of cardiac tissue versus blood according to an embodiment of the present invention; and is

Fig. 3 is a flow chart that schematically illustrates a method for sensing touch with cardiac tissue, in accordance with an embodiment of the present invention.

Detailed Description

SUMMARY

during a catheterization procedure of a body organ, such as cardiac electro-anatomical mapping and/or ablation, it may be necessary to verify whether an electrode fitted at the distal end of a medical device, such as a catheter, is in physical contact with the tissue. To verify such physical contact, a contact force sensor at the distal end of the catheter may be used. However, the need to use a dedicated sensor can make the catheterization procedure cumbersome and time consuming, and can also increase the size and cost of the catheter.

Embodiments of the invention described herein provide methods and systems for determining whether a distal electrode of a catheter is in physical contact with tissue of an organ (such as cardiac tissue) by using the distal electrode itself without additional hardware. In some cases, physical contact may even be verified using the same electrical signal applied and/or sensed by the electrode. Further, in some cases, the physical contact may be determined when the electrode is used to perform other tasks (such as impedance-based position measurement, electro-anatomical sensing and/or ablation of cardiac tissue).

For clarity and simplicity, the following description refers to a single distal electrode. Alternatively, any suitable number of distal electrodes may be fitted to the catheter, and there may be more than one catheter in parallel in the heart that employs the disclosed methods.

to verify physical contact, embodiments of the present invention utilize a measurement of the magnitude of the electrical bioimpedance between the distal electrode and one or more major surface electrodes. This magnitude is hereinafter referred to as the "impedance magnitude". The dependence of the impedance magnitude on electrical frequency provides an indication of whether the distal electrode is in direct physical contact (i.e., touching) with the cardiac tissue.

Specifically, over a particular range of frequencies (e.g., between about 1kHz and 30 kHz), the impedance magnitude of cardiac tissue drops sharply with frequency. On the other hand, the impedance magnitude of blood is largely independent of frequency. In some embodiments, the processor analyzes the frequency-dependent difference in impedance magnitude to determine whether the distal electrode is touching tissue or in blood. To determine contact, the processor may apply any suitable criterion, such as checking whether the difference in impedance magnitudes exceeds a given threshold.

in some embodiments, the distal electrode is used to inject and/or measure a frequency-dependent electrical signal (e.g., voltage and/or current and/or impedance). One or more surface electrodes are used to measure a frequency-dependent signal when the electrodes inject the signal. In an alternative embodiment, voltages modulated at different frequencies are applied between the surface electrodes, and the distal voltage is used to measure the resulting signal. Either way, the processor analyzes the measured frequency-dependent signal and determines whether the distal electrode is in physical contact with the heart tissue or immersed in blood.

In some embodiments, the processor performs a statistical analysis on a plurality of measured frequency-dependent impedance magnitudes for providing a robust indication that the distal electrode is in physical contact with tissue. The processor may apply any suitable statistical test (e.g., a t-test) and provide a test result. If a given indication for each given distal electrode passes the statistical test as having a statistical significance, the processor compares the indication to a criterion, such as a preset threshold in terms of change in impedance magnitude between a given low frequency or a given high frequency, in order to determine whether the particular distal electrode is touching tissue or immersed in blood.

In some embodiments, the presently disclosed technology is used in a catheter-based electro-anatomical mapping and ablation system that uses a distal electrode to determine locations through which arrhythmias may originate or propagate, for diagnostic purposes and/or to enable a physician to decide whether to ablate selected locations on the inner surface of the heart.

The disclosed technology does not require dedicated sensors and other hardware for detecting physical contact of the electrodes with the tissue. Avoiding the use of additional system resources and eliminating the need to package additional sensors into the limited space of the catheter distal end may simplify the catheter and/or catheter-based system. Thus, the cardiac diagnostic and therapy system may be simplified. The disclosed techniques may also simplify and further improve the clinical outcome of diagnostic and therapeutic procedures.

Description of the System

fig. 1 is a schematic illustration of an electroanatomical mapping system according to an embodiment of the present invention. Fig. 1 shows a physician 27 performing an electro-anatomical mapping of a heart 23 of a patient 25 using an electro-anatomical catheter 29. Catheter 29 includes one or more arms 20 at its distal end, which may be mechanically flexible, with one or more distal electrodes 22 coupled to each of the one or more arms. During the mapping procedure, the electrodes 22 acquire and/or inject signals into tissue of the heart 23. Processor 28 receives these signals via electrical interface 35 and uses the information contained in these signals to construct electro-anatomical map 31. During and/or after the procedure, processor 28 may display an electro-anatomical map 31 on display 26.

During this procedure, a tracking system is used to track the respective positions of the distal electrode 22 so that each of these signals can be correlated with the position at which the signal was acquired. For example, the active current position (ACL) system described in us patent 8,456,182, the disclosure of which is incorporated herein by reference, may be used. In an ACL system, the processor estimates the respective positions of the electrodes based on the impedance measured between each of the distal electrodes 22 and the plurality of surface electrodes 24 coupled to the skin of the patient 25.

For example, three surface electrodes 24 may be coupled to the chest of the patient, and additional three surface electrodes 24 may be coupled to the back of the patient (only one surface electrode is shown in fig. 1 for ease of illustration). While the electrode 22 is located within the patient's heart 23, current is passed between the electrode 22 and the surface electrode 24. Based on the ratio between the resulting current amplitudes measured at the surface electrodes 24 (or between the impedances represented by these amplitudes), and given the known positions of the electrodes 24 on the patient's body, the processor 28 calculates the position of each of the electrodes 22 within the patient's heart. Thus, the processor may correlate any given impedance signal received from the electrode 22 with the location at which the signal was acquired.

in one embodiment, processor 28 is further configured to estimate and verify the quality of physical contact between each of electrodes 22 and the inner surface of the heart chamber during the measurement. This indication is based on modeling the frequency response of the impedance sensed by each of the electrodes 22, which is different for blood versus tissue, and thus may be used as an indication of physical contact, as described in detail below.

The exemplary illustration shown in fig. 1 was chosen purely for the sake of conceptual clarity. Impedance-based measurements may also be accomplished by applying voltage gradients using surface electrodes 24 or other skin-attached electrodes, using electrodes 22 for measuring voltages induced in the heart relative to reference surface electrodes. An example of such a system is the 4 technology invented by Biosense-Webster company (Biosense-Webster, Inc. (Irvine, California)) of gulf city, California, usa. Thus, embodiments of the present invention are applicable to any position sensing method in which electrodes apply and/or measure modulated electrical signals.

Other types of sensing and/or therapy catheters may be equivalently employed, such as and catheters (produced by Biosense-Webster, Inc.). The contact sensor may be mounted at the distal end of the electro-anatomical catheter 29. As described above, other types of electrodes (such as those used for ablation) may be utilized in a similar manner as electrodes 22 for acquiring desired frequency-dependent impedance data. Thus, for the problems in this specification, the ablation electrode used to collect frequency-dependent impedance data is considered the distal electrode.

in general, the processor 28 may be implemented as a single processor or a group of cooperatively networked or clustered processors. Processor 28 is typically a programmed digital computing device that includes a Central Processing Unit (CPU), Random Access Memory (RAM), non-volatile secondary storage (such as a hard disk drive or CD ROM drive), a network interface, and/or peripheral devices. As is well known in the art, program code and/or data, including software programs, is loaded into RAM for execution and processing by the CPU and results are generated for display, output, transmission or storage. For example, the program code and/or data may be downloaded to the computer in electronic form over a network, or alternatively or additionally, it may be provided and/or stored on non-transitory tangible media, such as magnetic, optical, or electronic memory. Such program code and/or data, when provided to a processor, results in a machine or special purpose computer configured to perform the tasks described herein.

Touch detection by different frequency responses of tissue

Fig. 2 is a schematic diagram illustrating the frequency dependence of the impedance magnitude of cardiac tissue versus blood according to an embodiment of the present invention. The magnitude of the impedance of the cardiac tissue as a function of frequency is given by curve 50. The magnitude of the impedance of the blood as a function of frequency is given by curve 51.

The magnitude of the blood impedance, shown by curve 51, which is largely independent of frequency, is about 100 Ω. As shown by curve 50, the cardiac tissue impedance magnitude is typically several times higher (in some cases about 300 Ω) at the lower end of the frequency and becomes similar to blood at the higher end of the frequency. As can be seen, the tissue impedance magnitude is strongly frequency dependent between about 1kHz and 30 kH. Medical devices, authored by Webster, published in 1998 by John Wiley & Sons, new york, usa: another example of the characteristic frequency dependence of blood impedance magnitude versus the characteristic frequency dependence of body tissue impedance magnitude is provided in the third edition of the Application and Design ("Medical Instrumentation: Application and Design," Webster (ed.)3rd Ed., John Wiley & Sons, Inc., New-York, 1998).

Physiologically, because tissue cells allow high frequency channels (while absorbing some of their energy), impedance varies with frequency as current flows through the tissue. In contrast, conduction dominates in plasma (fluid), which is not frequency sensitive. Thus, in the case of good physical contact of the distal electrode 22 with the heart tissue (as opposed to immersion in blood), the resulting difference in the magnitude of the impedance measured using that electrode (as a function of frequency) should be significant. Thus, with an ACL system, from a given low frequency to a given high frequency, the change in frequency of the modulated current injected into the tissue will be manifested in the impedance magnitude difference measurement, but not when the modulated current is injected into the blood.

in one embodiment, using distal electrode 22j (using index j in the case where there are several such electrodes), ACL system 20 measures a set of impedance magnitudes | Zjk (ω l) | and | Zjk ω h) | between distal electrode j and the surface electrode. The impedance values Zjk (ω l) and Zjk (ω h) are complex values having a magnitude and a phase. The impedance magnitudes | Zjk (ω l) | and | Zjk (ω h) | are independent of phase information.

The frequency ω l is a first given low frequency and the frequency ω h is a second given high frequency of the injected modulation current. In one embodiment, the index k counts the number of repeated measurements. In another embodiment, the index k belongs to one of the surface electrodes 24 (k ═ 1,2, … 6).

as described above, the difference in impedance magnitude | Δ Zjk | | | | Zjk (ω l) | - | Zjk (ω h) | | may provide an indication that the distal electrode touches tissue. Curves 50 and 51 of fig. 2 indicate that the corresponding differences in impedance magnitude | Δ zjk (B) | { | | Zjk (ω l) | - | Zjk (ω h) | } B when the distal electrode 22j is immersed in blood are generally smaller than those | Δ zjk (T) | { | Zjk (ω l) | - | Zjk (ω h) | } T when the distal electrode 22j is in physical contact with tissue.

In one embodiment, processor 28 compares the difference between the impedance magnitudes to a criterion (such as a given threshold having a value of R0) such that if the difference in impedance magnitudes exceeds R0, the processor determines that the distal electrode is in contact with the cardiac tissue.

in some cases, the change between the difference | Δ zjk (b) and | Δ zjk (t) | may be interpreted as described in detail above. However, in other cases, e.g., due to other variability of the electrical path in the body, the different electrical paths in the heart may account for only a portion of the total difference in impedance between the distal electrode 22j and the surface electrode. Therefore, it may not be a simple task to distinguish | Δ zjk (t) | from | Δ zjk (b) | in a meaningful way.

In some embodiments, processor 28 performs a statistical analysis on a plurality of differences in impedance magnitudes calculated from the measurements for providing a robust indication that the distal electrode is in physical contact with tissue. For example, for the N distal electrodes 22 and all six surface electrodes of the catheter, one or more statistical distributions (e.g., normal distributions) may be fitted to the difference in calculated impedance magnitudes, such as { | Δ zjk (b) | | j ═ 1,2, … N; k 1,2, … 6} and { | Δ zjk (t) | j ═ 1,2, … N; k is 1,2, … 6 }.

The processor now performs a statistical test (e.g., t-test) on these distributions. In one embodiment, if a given difference | Δ Zjk | passes the statistical test as having a statistical significance, the processor compares the difference to a criterion, such as a threshold difference between impedance magnitudes having a value R0. If the calculated difference in impedance magnitude is below R0, the processor may update the system with information of the particular distal electrode touching the blood, such as by being represented in an electro-anatomical map. If the calculated difference in impedance magnitude is above R0, the processor may update the system with information of the particular distal electrode touch with the tissue, such as by representing it on an electro-anatomical map as the touch location.

The use of statistical methods (such as those specified above) may be particularly beneficial for multi-electrode catheters, which are situations in which additional statistical tools (such as correlations between impedance differences generated by a set of distal electrodes) may be analyzed to provide an indication of physical contact. However, repeated measurements using a single distal electrode may also increase the size of the statistical set in a similarly beneficial manner.

as shown in FIG. 2, the impedance magnitude of tissue as a function of frequency varies primarily between about 1KHz and 30 KHz. In one embodiment, the low frequency ω l is equal to 1.5KHz or less and the high frequency ω h is equal to 20KHz or greater. The selection of low and high frequencies in the method detailed above increases the robustness of the impedance magnitude measurement. Moreover, robust measurements increase the effectiveness of statistical tests for determining whether the calculated difference in impedance magnitude is indicative of tissue contact, blood contact, or negligible insignificant results in a statistically significant manner. The values given above for the high and low frequencies are chosen purely by way of example. In alternative embodiments, any other suitable frequency value may be used.

The example shown in fig. 2 was chosen purely for the sake of conceptual clarity. In another embodiment, each of the one or more distal electrodes 22 senses the modulation voltage applied between the pair of surface electrodes 24 at the first electrical frequency ω l and the second electrical frequency ω h, e.g., using a 4-based system. Thus, the general touch detection principles described herein may be applied to electrodes that apply and/or sense modulated electrical signals.

FIG. 3 is a flow chart that schematically illustrates a method for sensing a physical touch between an electrode and cardiac tissue, in accordance with an embodiment of the present invention. Before the procedure can begin, the physician 27 inserts an electro-anatomical catheter 29 into the heart, deploying and engaging tissue of the heart 23 at a given location.

The process may then begin with processor 28 of system 20 measuring sets of impedance magnitudes between distal electrode 22 and surface electrode 24 at low and high frequencies at a measurement step 62. In one embodiment, the low frequency is selected to be below 1.5KHz and the high frequency is selected to be above 20KHz, as described above with respect to fig. 2. Alternatively, any other suitable low and high frequencies may be used.

Processor 28 calculates, for each distal electrode 22, an associated set of impedance magnitude differences between the measured impedance magnitudes at the low and high frequencies at a calculation step 64. Next, at a statistical test step 66, processor 28 fits one or more statistical distributions to all impedance magnitude differences and applies one or more statistical tests to determine whether the impedance magnitude differences (each associated with a single distal electrode 22) are statistically significant.

If the calculated difference is not statistically significant at check step 68, processor 28 discards the result (i.e., ignores the result) at discard step 70. If the calculated difference is statistically significant, processor 28 applies a suitable criterion, such as comparing the difference to a threshold having a value of R0, at a comparison step 72. If the calculated difference in impedance magnitude is below R0, processor 28 updates the system with information that the particular distal electrode 22 is immersed in blood and not touching the heart tissue at blood decision step 74. If the calculated difference in impedance magnitude is above R0, processor 28 updates the system with information of the particular distal electrode 22 touching the cardiac tissue at tissue decision step 76.

The procedure may be repeated several times for the same location, or moved to another location on the inner surface of the heart 23 by moving the catheter. The method may then return to step 62.

The exemplary flow chart shown in fig. 3 was chosen solely for the sake of conceptual clarity. In alternative embodiments, for example, various additional methods and/or sensors may be applied to assess physical contact with tissue. In alternative embodiments, the statistical test step 66 may be omitted, for example where the measurement results have a sufficiently large signal-to-noise ratio. The process then proceeds directly from step 64 to step 72.

Although the embodiments described herein primarily discuss pulmonary vein isolation, the methods and systems described herein may also be used in other cardiac applications.

It will thus be appreciated that the embodiments described above are cited by way of example, and that the present invention is not limited to what has been particularly shown and described hereinabove. Rather, the scope of the present 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. Documents incorporated by reference into this patent application are considered an integral part of the application, except that definitions in this specification should only be considered if any term defined in these incorporated documents conflicts with a definition explicitly or implicitly set forth in this specification.