Patent ID: 12228546

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Certain exemplary embodiments will now be described to provide an overall understanding of the principles of the structure, function, manufacture, and use of the systems, devices, and methods disclosed herein.

Ions can be separated based on their mobility via ion mobility spectroscopy (IMS). Mobility separation can be achieved, for example, by applying one or more potential waveforms (e.g., traveling potential waveforms, direct current (DC) potential, or both) on a collection of ions. IMS based mobility separation can be achieved by structures of lossless ion manipulation (SLIM) that can systematically apply traveling and/or DC potential waveforms to a collection of ions. This can result in a continuous stream of ions that are temporally/spatially separated based on their mobility. In some implementations, it can be desirable to select ions having a predetermined mobility range from a collection of ions. This can be achieved by mobility based filtering of ions in SLIM devices (“SLIM filters”). SLIM filters (e.g., low pass filters, high pass filters, band pass filters, etc.) can apply a superposition to multiple potential waveforms that are directed (e.g., traveling) in different directions. Properties of the potential waveforms (e.g., amplitude, shape, frequency, etc.) can determine the properties of the SLIM filter (e.g., bandwidth, cut-off mobility values, etc.).

FIG.1is a schematic illustration of an exemplary mobility filter system100. The mobility filter system100includes an ionization source102that can generate ions (e.g., ions having varying mobility and mass-to-charge-ratios) and inject the ions into a SLIM filter104. The SLIM filter104can select ions with one or more predetermined ranges of mobility and direct the select band (or bands) of ions to a detector (or detectors). For example, if two bands of ion mobility are selected, the first band can be directed to detector106aand the second band can be directed to detector106b.

The SLIM filter104can generate potential waveforms (e.g., by application of an RF and/or AC and/or DC voltage on electrodes in the SLIM filter104). For examples, pairs of potential waveforms configured to drive ions in opposite directions (e.g., traveling in opposite directions) can be generated by a first separation region of the SLIM filter. The properties of the pair of waveforms can determine a first threshold mobility around which the ions (“ion packet”) are separated. Ions with mobility higher than the first threshold mobility (first ion sub-packet) are directed in a first direction and ions with mobility smaller than the first threshold mobility (second ion sub-packet) are directed in a second direction. A second separation region of the SLIM filter104can receive the first ion sub-packet. The second separation region can generate a second pair of potential waveforms directed in opposite directions (e.g., traveling in opposite directions). Ions in the first ion sub-packet with mobility higher than a second threshold mobility (third ion sub-packet) are directed in a third direction and ions with mobility smaller than the second threshold mobility (fourth ion sub-packet) are directed in a fourth direction.

In the operation described above, the SLIM filter104can operate as a mobility band pass filter. For example, the fourth ion sub-packet comprises ions having an ion mobility greater than the first threshold mobility and lower than the second threshold mobility. The second/third/fourth ion sub-packet can be directed to the detectors106aand106bfor further detection and analysis.

A controller150can control the operation of an ionization source102, SLIM filter104and detectors106aand106b. For example, the controller150can control the rate of injection of ions into the input SLIM filter104by the ionization source102, threshold mobility of SLIM filter104, and ion detection be the detectors106aand106b. The controller150can also control the characteristics and motion of potential waveforms in the SLIM filter104(e.g., by applying RF/AC/DC potentials to electrodes in the SLIM filter104).

Controller150can control the generation of potential waveforms by applying RF/AC/DC potentials to electrodes in the SLIM filter104. The controller150can control the properties of the potential waveforms (e.g., amplitude, shape, frequency, etc.) by varying the properties of the applied RF/AC/DC potential (or current). In some implementations, the controller150can vary the properties (e.g., iteratively) of the pair of potential waveformS in the separation regions of the SLIM filter to improve the separation of ions (e.g., achieve sharp separation around a threshold mobility). Once the desirable properties are determined, the corresponding values can be stored in a database for future reference. Controller150can also synchronize the arrival time of the ion packet in the SLIM filter104(e.g., arrival at the first/second separation region of the SLIM filter104) with the generation of pairs of traveling/DC potential waveforms directed in opposite directions.

The controller150can include multiple power supply modules (e.g., current/voltage supply circuits) that generate various voltage (or current) signals that drive the electrodes in the SLIM filter104. For example, the controller150can include RF control circuits that generate RF voltage signals, traveling wave control circuits that generate traveling wave voltage signals, DC control circuits that generate DC voltage signals, etc. The RF voltage signals, traveling wave voltage signals, DC voltage signal can be applied to electrodes in the input SLIM filter104. The controller150can include DC control circuits that can generate DC voltage signals which in turn can generate a DC potential waveform in the SLIM filter104. The DC control circuits can vary the amplitudes of the various DC voltage signals which can determine the gradient (or slope) of the DC potential waveform.

In some implementations, the controller150can generate traveling potential waveforms that are traveling in opposite directions in the separation regions of the SLIM filter104. In some implementations, the controller150can generate a traveling potential waveform that is traveling in one direction and a DC potential waveform with a gradient that can drive the ions in the opposite direction. The controller150can also include a master control circuit that can control the operation of the RF/traveling wave/DC control circuits. For example, the master control circuit can control the amplitude and/or phase of voltage (or current) signals generated by the RF/traveling wave/DC control circuits to achieve a desirable operation of the mobility filter system100.

As discussed above, the SLIM filter104can generate DC/traveling potential waveform (e.g., resulting from potentials generated by multiple electrodes in the SLIM filter104). The traveling potential waveform can travel at a predetermined velocity based on, for example, frequency of voltage signals applied to the electrodes. In some implementations, the speed/amplitude/shape of the traveling potential waveform and/or gradient of the DC potential waveform can determine the properties of the SLIM filter104. For example, the type of filter (e.g., low pass, band pass, high pass, etc.), and the cut-off mobility values of the filter can be determined by the properties of the traveling/DC potential waveforms.

In some implementations, the traveling potential waveform can be spatially periodic and the spatial periodicity can depend on the phase differences between the voltage signals applied to adjacent electrode pairs. In some implementations, the phase differences can determine the direction of propagation of the potential waveform. The master control circuit can control the frequency and/or phase of voltage outputs of RF/traveling wave control circuits such that the traveling potential waveform has a desirable (e.g., predetermined) spatial periodicity and/or speed.

In some implementations, the controller150can be communicatively coupled to a computing device160. For example, the computing device160can provide operating parameters of the mobility filter system100via a control signal to the master control circuit. In some implementations, a user can provide the computing device160(e.g., via a user interface) with the operating parameters. Based on the operating parameters received via the control signal, the master control circuit can control the operation of the RF/AC/DC control circuits which in turn can determine the operation of the coupled SLIM-MS100. In some implementations, RF/AC/DC control circuits can be physically distributed over the mobility filter system100. For example, one or more of the RF/AC/DC control circuits can be located in the mobility filter system100. The controller150can receive power from a power source170(e.g., DC power source that provides a DC voltage to the controller150). The various RF/AC/DC control circuits can operate based on the power from the power source170.

FIG.2illustrates an exemplary embodiment of a portion of the SLIM filter104(e.g., first/second separation region, SLIM for transferring ions between/to/from separation regions, etc.). The SLIM filter104can include a first surface103and a second surface105. The first and second surfaces can be arranged (e.g., parallel to one another) to define one or more ion channels between them. The first surface103and second surface105can include electrodes (e.g., arranged as arrays of electrodes on the surfaces facing the ion channel). The electrodes on the first surface103and second surface105can be configured to electrically couple to the controller150and receive voltage (or current) signals or waveforms. In some implementations, the first surface103and second surface105can include a backplane that includes multiple conductive channels that allow for electrical connection between the controller108and the electrodes on the first surface103and second surface105. In some implementations, the number of conductive channels can be fewer than the number of electrodes. In other words, multiple electrodes can be connected to a single electrical channel. As a result, a given voltage (or current) signal can be transmitted to multiple electrodes simultaneously. Based on the received voltage (or current) signals, the electrodes can generate one or more potentials (e.g., a superposition of various potentials) that can confine, drive and/or separate ions along a propagation axis (e.g., z-axis).

The first and the second surfaces103and105can include a plurality of electrodes.FIG.3illustrates an exemplary arrangement of electrodes on the first surface103. Although the electrode arrangement on the first surface103is described below, second surface105can include electrodes with similar electrode arrangement. The first surface103includes a first plurality of electrodes120and125that can receive voltage (or current) signals (or are connected to ground potential) and can generate a pseudopotential that can prevent/inhibit ions from approaching the first surface103. The first plurality of electrodes120and125can be rectangular and the longer edge of the rectangle can be arranged along the direction of propagation of ions undergoing mobility separation (“propagation axis”). For example, inFIG.3, the propagation axis is parallel to the z-axis. The first plurality of electrodes can be separated from each other along a lateral direction (e.g., along the y-axis). For example, the lateral direction can be perpendicular to the propagation axis (e.g. the z axis).

The first surface103can include a second plurality of electrodes130that can be located between the electrodes of the first plurality of electrodes (e.g., in the space between the first plurality of electrodes120and125). The second plurality of electrodes130can include multiple electrodes that are segmented/arranged along (or parallel to) the propagation axis. The second plurality of electrodes130can receive a second voltage signal and generate a drive potential that can drive ions along the propagation axis. The drive potential can lead to separation of ions based on their mobility as they move along the propagation axis.

The first surface can include guard electrodes110that are positioned adjacent to the outer most of the first/second plurality of electrodes. For example, the guard electrodes110can be located at the edges of the first surface103along the lateral direction. The guard electrodes110can receive a voltage signal (e.g., DC voltage signal from a DC control circuit) and generate a guard potential that can confine ions in the ion channels between the guard electrodes along the lateral direction.

The first plurality of electrodes, the second plurality of electrodes, and the guard electrodes can be connected to one or more voltage control circuits (e.g., voltage control circuits in the controller150). In some implementations, the first plurality of electrodes120and125can receive radio frequency (RF) signals that are phase shifted with respect to each other. In some implementations, the master control circuit can control the operation of two RF control circuits to generate two RF voltage signals that are phase shifted from one another.

FIG.4illustrated an exemplary SLIM filter400. The SLIM filter400can be configured to operate in a band pass filtering mode and select (or isolate) ions having mobility between a first threshold mobility M1and a second threshold mobility M2. The SLIM filter400includes an input SLIM402that can receive ion packet410from the ionization source (e.g., ionization source102) and direct the received ions410to the first separation region404. The received ion packet410can be generated by an ionization source (e.g. ionization source102). The ion packet410can include ion sub-packets412,414and416that include ions of various mobility. For example, ion sub-packet414can include ions with mobility ranging between M1an M2.

The input SLIM402can generate a traveling potential waveform422(e.g., based on receipt of a traveling wave voltage signal from the controller108) that can drive the ion packet410to the first separation region404. The first separation region404can extend between a first end430and a second end432. The first separation region404can generate a first potential waveform424aand a second potential waveform424b. The potential waveforms424aand424bcan be traveling in opposite directions (e.g., along +z and −z directions respectively). In some implementations, one of the potential waveforms424aand424bcan be a traveling potential waveform and the other can be a DC potential waveform. The DC potential waveform can be decreasing from one end of the first separation404to another. The direction in which the DC waveform decreases can be opposite to the direction of travel of the traveling potential waveform. For example, if potential waveform424ais a traveling potential waveform traveling along +z axis, potential waveform424bcan be a DC potential waveform (or a gradient) whose amplitude decreases along the −z axis.

Potential waveforms424aand424bcan each apply a force on the ions in the ion packet410(e.g., in the opposite directions). Based on the mobility of a given ion in the ion packet410and properties of the potential waveforms424aand424b(e.g., amplitude, shape, velocity, gradient, etc.) the given ion can travel along a given direction (e.g. +z or −z direction). For example, the properties of the potential waveforms424aand424bcan be set such that ions in the ion packet410with mobility greater than M1(e.g., ion sub-packets414and416) travel along the +z direction and ions with mobility less than M1(e.g. ion sub-packets412) travels along the −z direction. The ion sub-packet412can be ejected out of the separation region404where it can be detected by a detector (e.g., spectrometer, ion counter, etc.) located at the first end430.

The transfer SLIM406can receive the ion sub-packets414and416. The transfer SLIM406can generate a traveling potential waveform426(e.g., based on receipt of a traveling wave voltage signal from the controller108) that can drive the ion sub-packets414and416to the second separation region408. The second separation region408can extend between a third end434and fourth end436, and can generate a third potential waveform428aand a fourth potential waveform428b. The potential waveforms428aand428bcan be traveling in opposite directions (e.g., along +z and −z directions respectively). In some implementations, one of the potential waveforms428aand428bcan be a traveling potential waveform and the other can be a DC potential waveform. As described above, the DC potential waveform can decrease from one end of the second separation408to another. The direction in which the amplitude of the DC waveform decreases can be opposite to the direction of travel of the traveling potential waveform. For example, if potential waveform428ais a traveling potential waveform traveling along +z axis, potential waveform428bcan be a DC potential waveform that decreases along the −z axis (or vice versa).

Based on the mobility of a given ion in the ion sub-packets414and416, and properties of the potential waveforms428aand428b(e.g., amplitude, shape, velocity, gradient, etc.) the given ion can travel along a given direction (e.g. +z or −z direction). For example, ions with mobility greater than M2(e.g., ion sub-packet416) travel along the +z direction and ions with mobility less than M2(e.g. ion sub-packets414) travels along the −z direction. The ion sub-packets414and416can be ejected out of opposite ends of the separation region408(e.g., third end434and436, respectively) where they can be detected by detectors (e.g., spectrometers, ion counter, etc.)

As described above, the SLIM filter400can selectively isolate the ion sub-packet414(having mobility between the first threshold mobility M1and the second threshold mobility M2) that can be ejected out from the third end434of the second separation region408. As a result, the SLIM filter400behaves like a band pass filter. Additionally, the SLIM filter400can behave as a low pass filter by isolating ions having mobility less than M1(ion sub-packet412) and ejecting them from the first end430of the first separation region404. Furthermore, the SLIM filter400can behave as a high pass filter by isolating ions having mobility above M2(ion sub-packet416) and ejecting them from the fourth end436of the second separation region408.

As described above (e.g., inFIG.2), the SLIM filter400can include two surfaces that define one or more channels. The two surfaces can include electrodes (e.g., electrodes110,120,125) that can receive voltage signals from the traveling wave/DC control circuits and generate the potential waveforms422,424a,424b,426,428aand428b. The master control circuit can control the operation of the traveling wave/DC control circuits and can determine the properties (e.g., speed, amplitude, shape, gradient, etc.) of the potential waveforms422,424a,424b,426,428aand428b.

FIG.5illustrates an exemplary cross-section500of a separation region of a SLIM filter (e.g., SLIM filter400). The cross-section500includes electrodes1-8arranged on two planes that define an ion channel. The electrodes1-8can generate (e.g., simultaneously) two traveling potential waveforms502and504. The traveling potential waveforms502and504can travel in opposite direction and each can apply a force on ions512and514. Depending on the mobility of the ions512and514, both the ions512and514can travel to the left, travel to the right, one of the ions512travel to the left and514travel to the right (or vice versa). A person skilled in the art would readily appreciate that potential waveforms502and504represent AC traveling waveforms, however, one or both of the potential waveforms can be DC traveling waveforms without departing from the scope of the present invention.

FIG.6illustrates an exemplary cross-section600of a separation region of a SLIM filter (e.g., SLIM filter400). The cross-section600includes electrodes1-8arranged on two planes that define an ion channel. The electrodes1-8can generate (e.g., simultaneously) a traveling potential waveform (not shown) and a DC potential waveform602.FIG.6also illustrates the superimposed potential waveform604(e.g., superposition of traveling potential waveform and the DC potential waveform602). The superposition potential waveform can drive both the ions612and614to the left or right, one of the ions612and614to the left and the other to the right (or vice versa), etc. A person skilled in the art would readily appreciate that traveling waveform used to create the superposition potential waveform is a AC traveling wave, however, a DC traveling waveform can be utilized without departing from the scope of the present invention.

Properties of the potential waveforms424a,424b,428aand428bcan be varied to achieve desirable separation of ions in the ion packet410. This can be done for example, by the master control circuit and/or by an operator. In one implementation, ion detectors (e.g., ion counters, mass spectrometer) can be located at one or more of the first end430, second end434, and third end436. The ion detectors can detect the ion count and/or mass-to-charge ratio of the exiting ions (e.g., ion sub-packets412,414,416, etc.) and transmit the information to the master control circuit. Based on this information the master control circuit can vary the properties of one or more of the potential waveforms424a,424b,428aand428b.

FIG.7illustrates an exemplary ion current detection at the first end430of the separation region404. The ion current can be varied by changing the speed and/or amplitude of the first potential waveform424aand a second potential waveform424b. Ion current curve702can be obtained by holding the speed and/or amplitude of the potential waveform424bfixed at a first value (or values), and varying the speed and/or amplitude of the potential waveform424a. Similarly, ion current curve704can be obtained by holding the speed and/or amplitude of the potential waveform424bfixed at a second value (or values), and varying the speed and/or amplitude of the potential waveform424a. The ion current curve704varies gradually as a function of speed and/or amplitude of the potential waveform424a. The ion current702, can vary rapidly around a transition value (or values) T1associated with the speed and/or amplitude of the traveling wave424a.

In some implementations, ion separation associated with the curve702can be desirable. Such ion separation can improve the performance of the ion filtering in separation region404(e.g., can provide for a sharp cut-off mobility of the ion separation in the ion separation region404). For example, it can be desirable that a sharp cut-off mobility is achieved at the first threshold mobility M1. In other words, ions with mobility higher than M1are prevented (or suppressed) from heading towards the first end430and ions with mobility lower than M1are prevented (or suppressed) from heading towards the second end432. This can be achieved by varying the speed and/or amplitude of the potential waveform424afor a fixed potential waveform424.

In some implementations, the ion detector at the first end430can be a mass spectrometer that can detect both the ion count and the mobility of the ions ejected at the first end430(e.g., ion sub-packet412). Based on this information, the properties of the potential waveforms424aand424bcan be set to the value of the first threshold mobility M1. As discussed above, the properties of the potential waveforms428aand428bcan be varied to achieve desirable separation in the second separation SLIM408. For example, the properties of the potential waveforms428aand428bcan be varied until a sharp cut-off mobility is achieved at the second threshold mobility M2. For example, ions with mobility higher than M2are prevented (or suppressed) from heading towards the third end434and ions with mobility lower than M1are prevented (or suppressed) from heading towards the fourth end436. A detector placed at the third end434can detect ions (e.g., ion sub-packet414) with mobility below the second threshold mobility M2and above the first threshold mobility M1(“band pass filtering”). A detector placed at the fourth end436can detect ions (e.g., ion sub-packet416) with mobility above the second threshold mobility M2.

The master control circuit can vary the properties of the potential waveforms426a,426b,428aand428bin order to achieve predetermined parameters of the band pass filter (e.g. threshold mobility values M1and M2, drop-off at the threshold mobility values, etc.). In some implementations, the shape of the potential waveforms426a,426b,428aand428bcan be predetermined to improve (e.g., optimize) the mobility based separation of ions.

FIG.8is a plot of average speeds of ions under the influence of traveling potential waveform of various frequencies (which is indicative of the speed of the traveling potential waveforms). As the frequency of the traveling waveform increases from F1to F2, the average ion speed of ion322increases. However, the average ion speed of ion922decreases as the frequency waveform increases from F1to F2. If ion322is placed in the first separation region404, and the potential waveforms424aand424bhave frequencies F1and F2, respectively, ion322will be driven in the direction of potential waveform424b. However, if ion922is placed in the first separation region404, and the potential waveforms424aand424bhave frequencies F1and F2, respectively, ion922will be driven in the direction of potential waveform424a. Therefore, if both the ions322and922are placed in the first separation region404, ion322will be driven in the direction of potential waveform424b, and the ion922will be driven in the direction of potential waveform424a. As a result, the two ions can be separated.

Other embodiments are within the scope and spirit of the disclosed subject matter. One or more examples of these embodiments are illustrated in the accompanying drawings. Those skilled in the art will understand that the systems, devices, and methods specifically described herein and illustrated in the accompanying drawings are non-limiting exemplary embodiments and that the scope of the present disclosure is defined solely by the claims. The features illustrated or described in connection with one exemplary embodiment may be combined with the features of other embodiments. Such modifications and variations are intended to be included within the scope of the present disclosure. Further, in the present disclosure, like-named components of the embodiments generally have similar features, and thus within a particular embodiment each feature of each like-named component is not necessarily fully elaborated upon.

The subject matter described herein can be implemented in digital electronic circuitry, or in computer software, firmware, or hardware, including the structural means disclosed in this specification and structural equivalents thereof, or in combinations of them. The subject matter described herein can be implemented as one or more computer program products, such as one or more computer programs tangibly embodied in an information carrier (e.g., in a machine-readable storage device), or embodied in a propagated signal, for execution by, or to control the operation of, data processing apparatus (e.g., a programmable processor, a computer, or multiple computers). A computer program (also known as a program, software, software application, or code) can be written in any form of programming language, including compiled or interpreted languages, and it can be deployed in any form, including as a stand-alone program or as a module, component, subroutine, or other unit suitable for use in a computing environment. A computer program does not necessarily correspond to a file. A program can be stored in a portion of a file that holds other programs or data, in a single file dedicated to the program in question, or in multiple coordinated files (e.g., files that store one or more modules, sub-programs, or portions of code). A computer program can be deployed to be executed on one computer or on multiple computers at one site or distributed across multiple sites and interconnected by a communication network.

The processes and logic flows described in this specification, including the method steps of the subject matter described herein, can be performed by one or more programmable processors executing one or more computer programs to perform functions of the subject matter described herein by operating on input data and generating output. The processes and logic flows can also be performed by, and apparatus of the subject matter described herein can be implemented as, special purpose logic circuitry, e.g., an FPGA (field programmable gate array) or an ASIC (application-specific integrated circuit).

Processors suitable for the execution of a computer program include, by way of example, both general and special purpose microprocessors, and any one or more processor of any kind of digital computer. Generally, a processor can receive instructions and data from a read-only memory or a random access memory or both. The essential elements of a computer are a processor for executing instructions and one or more memory devices for storing instructions and data. Generally, a computer can also include, or be operatively coupled to receive data from or transfer data to, or both, one or more mass storage devices for storing data, e.g., magnetic, magneto-optical disks, or optical disks. Information carriers suitable for embodying computer program instructions and data include all forms of non-volatile memory, including by way of example semiconductor memory devices, (e.g., EPROM, EEPROM, and flash memory devices); magnetic disks, (e.g., internal hard disks or removable disks); magneto-optical disks; and optical disks (e.g., CD and DVD disks). The processor and the memory can be supplemented by, or incorporated in, special purpose logic circuitry.

To provide for interaction with a user, the subject matter described herein can be implemented on a computer having a display device, e.g., a CRT (cathode ray tube) or LCD (liquid crystal display) monitor, for displaying information to the user and a keyboard and a pointing device, (e.g., a mouse or a trackball), by which the user can provide input to the computer. Other kinds of devices can be used to provide for interaction with a user as well. For example, feedback provided to the user can be any form of sensory feedback, (e.g., visual feedback, auditory feedback, or tactile feedback), and input from the user can be received in any form, including acoustic, speech, or tactile input.

The techniques described herein can be implemented using one or more modules. As used herein, the term “module” refers to computing software, firmware, hardware, and/or various combinations thereof. At a minimum, however, modules are not to be interpreted as software that is not implemented on hardware, firmware, or recorded on a non-transitory processor readable recordable storage medium (i.e., modules are not software per se). Indeed “module” is to be interpreted to always include at least some physical, non-transitory hardware such as a part of a processor or computer. Two different modules can share the same physical hardware (e.g., two different modules can use the same processor and network interface). The modules described herein can be combined, integrated, separated, and/or duplicated to support various applications. Also, a function described herein as being performed at a particular module can be performed at one or more other modules and/or by one or more other devices instead of or in addition to the function performed at the particular module. Further, the modules can be implemented across multiple devices and/or other components local or remote to one another. Additionally, the modules can be moved from one device and added to another device, and/or can be included in both devices.

The subject matter described herein can be implemented in a computing system that includes a back-end component (e.g., a data server), a middleware component (e.g., an application server), or a front-end component (e.g., a client computer having a graphical user interface or a web browser through which a user can interact with an implementation of the subject matter described herein), or any combination of such back-end, middleware, and front-end components. The components of the system can be interconnected by any form or medium of digital data communication, e.g., a communication network. Examples of communication networks include a local area network (“LAN”) and a wide area network (“WAN”), e.g., the Internet.

Approximating language, as used herein throughout the specification and claims, may be applied to modify any quantitative representation that could permissibly vary without resulting in a change in the basic function to which it is related. Accordingly, a value modified by a term or terms, such as “about” and “substantially,” are not to be limited to the precise value specified. In at least some instances, the approximating language may correspond to the precision of an instrument for measuring the value. Here and throughout the specification and claims, range limitations may be combined and/or interchanged, such ranges are identified and include all the sub-ranges contained therein unless context or language indicates otherwise.