Abstract:
Production of perforated two-dimensional materials with holes of a desired size range, a narrow size distribution, and a high and uniform density remains a challenge, at least partially, due to physical and chemical inconsistencies from sheet-to-sheet of the two-dimensional material and surface contamination. This disclosure describes methods for monitoring and adjusting perforation or healing conditions in real-time to address inter- and intra-sheet variability. In situ or substantially simultaneous feedback on defect production or healing may be provided either locally or globally on a graphene or other two-dimensional sheet. The feedback data can be used to adjust perforation or healing parameters, such as the total dose or efficacy of the perforating radiation, to achieve the desired defect state.

Description:
BACKGROUND 
       [0001]    Graphene represents a form of carbon in which the carbon atoms reside within a single atomically thin sheet or a few layered sheets (e.g., about 20 or less) of fused six-membered rings forming an extended planar lattice. In its various forms, graphene has garnered widespread interest for use in a number of applications, primarily due to its favorable combination of high electrical and thermal conductivity values, good in-plane mechanical strength, and unique optical and electronic properties. Of particular interest to industry are large-area graphene films for applications such as, for example, special barrier layers, coatings, large area conductive elements (e.g., RF radiators or antennas), integrated circuits, transparent electrodes, solar cells, gas barriers, flexible electronics and the like. 
         [0002]    Some envisioned applications for graphene and other two-dimensional materials are predicated upon introducing defects, such as forming a plurality of nanometer-scale holes in the planar structure. For example, the hole density of perforated graphene can be used to tune the electrical conductivity of this nanomaterial and in some instances can be used to adjust its electronic band structure. Filtration applications are another area where perforated graphene and other perforated two-dimensional materials have generated considerable interest. Due to the atomic-level thinness of graphene and other two-dimensional materials, it is possible to achieve high fluid throughput fluxes during filtration processes. 
         [0003]    A number of processes are known for perforating and/or defecting graphene and other two-dimensional materials (e.g., ion bombardment, oxidation, nanoparticle bombardment, etc.). Likewise, a number of techniques for healing holes, that are too large for a given application, in graphene and other two-dimensional materials have been disclosed (see, for example, US patent application filed herewith, entitled METHOD FOR MAKING TWO-DIMENSIONAL MATERIALS AND COMPOSITE MEMBRANES THEREOF HAVING SIZE-SELECTIVE PERFORATIONS, Atty Docket No. 111423-1106 incorporated herein in its entirety). However, production of holes with a desired size range, a narrow size distribution, and a high and uniform hole density remains a challenge, at least partially, due to small physical and chemical inconsistencies from sheet-to-sheet of the two-dimensional material (e.g. layers, intrinsic or native defects, strain, electron distribution and crystallinity) and surface contamination. Currently, there is no way to monitor and adjust perforation or healing conditions in real-time. Instead, samples are perforated or healed, then tested by a separate process, and perforation or healing parameters are adjusted and applied to a new sheet of material, which inevitably possesses chemical and physical variations that cause it to respond differently to the new conditions. For example, contamination from sample to sample may vary, and needs to be accounted for. Typically to validate a perforation process, graphene needs to be transferred simultaneously to multiple TEM grids and to a desired support substrate. The TEM grids are then exposed to various different treatments. These must then be individually loaded into an STEM and imaged to determine the perforation results. If one of the conditions turns out to be appropriate, the the graphene on the support substrate is then subjected to the same treatment. 
         [0004]    In view of the foregoing, methods that monitor and adjust for inter- and intra-sheet variability during perforation or healing of graphene and other two-dimensional materials would be of considerable interest in the art. In particular, methods for real-time, in situ monitoring of defect formation or healing would be of considerable interest in the art. For example, monitoring of defect formation or healing for suspended graphene would be of interest. The present disclosure satisfies the foregoing needs and provides related advantages as well. 
       SUMMARY 
       [0005]    This disclosure provides methods for monitoring a variety of perforation and healing procedures via monitoring schemes that provide real-time feedback, while defects are being produced or healed. The invention describes several detection mechanisms that provide in situ or substantially simultaneous feedback on defect production or healing either locally or globally for a graphene or two-dimensional sheet. The feedback data can be used to adjust perforation or healing parameters, such as the total dose or efficacy of the perforating radiation, to achieve the desired defect state. This method advantageously accounts for inter- and intra-sheet chemical and physical variability. Variability may arise from varying substrate/graphene interaction. For example, variability may arise from nanoparticles (NPs) perforating graphene differently in some instances, such as when the area of the substrate pore that the NP spans changes. This method advantageously accounts for this variance in the perforation system, and monitors, for example, defects created by NPs perforating the substrate. 
         [0006]    In an aspect, a method for monitoring defect formation or healing comprises: exposing a surface of a material to incident radiation; detecting scattered, emitted or transmitted radiation from at least a portion of the material exposed to the incident radiation; and generating data indicative of defect formation or healing, wherein the method is performed in situ and the data indicative of defect formation or healing provides a rate of defect formation or healing, a temporal change in the rate of defect formation or healing, a temporal change in the size of the defects, a spatial change in the rate of defect formation or healing, a spatial change in the size of the defects, or combinations thereof. As described herein the incident radiation, and the scattered, emitted or transmitted radiation may be any one or more of electromagnetic radiation, electrons, ions, nanoparticles, or plasma. In an embodiment, incident radiation is processing radiaton, such as perforating or healing radiation or interrogating radiation. The incident radiation may also be both processing radiation and interrogating radiation. As described herein, processing radiation performs a process on the material when incident thereon. 
         [0007]    In an embodiment, the step of generating data indicative of defect formation comprises determining secondary electron yield. 
         [0008]    In an embodiment, the step of exposing the surface of the material to incident radiation produces a plurality of defects in the material. 
         [0009]    In an embodiment, the step of detecting radiation or particles comprises: (i) performing secondary ion mass spectroscopy; (ii) performing Raman spectroscopy; (iii) performing residual gas analysis on particles being removed from the material; (iv) detecting back scattered radiation or particles; (v) detecting Auger electrons; (vi) performing scanning probe microscopy; (vii) performing scanning tunneling microscopy; (viii) performing atomic force microscopy; (ix) performing X-ray photoelectron spectroscopy; (x) performing transmission electron microscopy; (xi) detecting nanoparticles on one or more microbalances or Faraday cups positioned behind the material; (xii) performing small angle electron diffraction; (xiii) detecting nanoparticles on a surface positioned behind the material using surface enhanced Raman scattering (SERS); (xiv) detecting secondary electrons; (xv) detecting transmitted electron or ions; or (xvi) performing a combination of two or more of (i)-(xv). In an embodiment, the back scattered radiation or particles are selected from the group consisting of electrons, protons and helium. In an embodiment, scattered radiation or particles are selected from the group consisting of electrons, protons, helium, gallium, neon, argon, xenon, or ions. 
         [0010]    In an embodiment, the steps of exposing and detecting occur simultaneously. 
         [0011]    In an embodiment, the incident radiation and the scattered, emitted or transmitted radiation are the same type of radiation or different types of radiation. In an embodiment, the scattered, emitted or transmitted radiation results from the incident radiation or an additional source of interrogating radiation. 
         [0012]    In an embodiment, the scattered, emitted or transmitted radiation from the material is collected from a bulk portion of the surface having an area between 1 μm 2  and 1000 cm 2 . In an embodiment, the scattered, emitted or transmitted radiation from the material is collected from a local portion of the surface having an area between 100 nm 2  and 10 mm 2 . 
         [0013]    In an embodiment, the scattered, emitted or transmitted radiation is continuously collected. In an alternate embodiment, the incident radiation is pulsed and the scattered, emitted or transmitted radiation is collected only when the incident radiation is off. As noted above, the incident radiation, and the scattered, emitted or transmitted radiation may be any one or more of electromagnetic radiation, electrons, ions, nanoparticles, or plasma. 
         [0014]    In an embodiment the emitted radiation is secondary electrons. The secondary electrons could be generated by electrons or ions, for example. 
         [0015]    Methods for monitoring defect formation or healing via gas permeation are also contemplated. For example, in an aspect, a method for monitoring defect formation or healing comprises: exposing a surface of a material to incident radiation; detecting movement of an analyte through defects in the material; and generating data indicative of defect formation or healing, wherein the method is performed in situ and the data indicative of defect formation or healing provide a rate of defect formation or healing, a temporal change in the rate of defect formation or healing, a temporal change in the size of the defects, a spatial change in the rate of defect formation or healing, a spatial change in the size of the defects, a maximum size of the defects, a number of pores, or combinations thereof. 
         [0016]    In an embodiment, the step of detecting movement of the analyte through the defects in the material comprises one or more of: (i) determining the presence or absence of the analyte at a detector; (ii) quantifying the analyte; (iii) identifying a composition, mass, average radius, charge or size of the analyte; (iv) determining a rate of movement of the analyte through the defects in the material; or (v) a combination of two or more of (i)-(iv). In an embodiment, the analyte is a gas selected from the group consisting of hydrogen, helium, oxygen, nitrogen, xenon, neon, argon, SF 6 , H 2 O, C x H 2x  where x is 1 to 4, and combinations thereof. In an embodiment, the analyte is a plasma. In an embodiment, the incident radiation is a plasma, potentially capable of perforating or modifying the two-dimensional material, and the analyte is one or more species of the plasma. For example, the one or more species of the plasma may be a charged species. 
         [0017]    Methods for monitoring defect formation or healing via electrical biasing are also contemplated. For example, in an aspect, a method for monitoring defect formation or healing, comprises: exposing a surface of the material to incident radiation; applying an electrical bias to the material; measuring electrical conductivity through a conductive probe in electrical contact with the material; and generating data indicative of defect formation or healing, wherein the method is performed in situ and the data indicative of defect formation or healing provide a rate of defect formation or healing, a temporal change in the rate of defect formation or healing, a temporal change in the size of the defects, a spatial change in the rate of defect formation or healing, a spatial change in the size of the defects, or combinations thereof. In an embodiment, a conductive probe is a conductive grid or a local probe. In an embodiment, defect density and electrical conductivity are inversely related such that an increase in defect density is observed as a decrease in electrical conductivity. In an embodiment the electrical conductivity of the material changes as a result of the defects. Further, defects in graphene other than holes may be beneficial for being detected based on electronic properties in a number of applications. For example, disrupting the graphene lattice and making 5 and 7 member rings, instead of the typical 6 member rings, can beneficially change the electronic properties of graphene. Likewise, doping of the graphene can also be beneficial, for example substituting boron, nitrogen, or silicon atoms in graphene can change the electrical properties sufficiently to be detected. 
         [0018]    Methods for monitoring defect formation or healing via heating are also contemplated. For example, in an aspect, a method for monitoring defect formation or healing, comprises: exposing a surface of a material to incident radiation; heating the material; subsequently measuring temperature of the surface of the material; and generating data indicative of defect formation or healing, wherein the method is performed in situ and the data indicative of defect formation or healing provides a rate of defect formation or healing, a temporal change in the rate of defect formation or healing, a temporal change in the size of the defects, a spatial change in the rate of defect formation or healing, a spatial change in the size of the defects, or combinations thereof. In an embodiment, the step of heating the material comprises applying a potential to the two-dimensional material to induce joule heating. In an embodiment, defect density and thermal conductivity are inversely related such that an increase in defect density is observed as a decrease in thermal conductivity. 
         [0019]    In an embodiment, the incident radiation is a particle beam. In an embodiment for monitoring a bulk portion of a material, the particle beam produces a spot on the surface of the material, the spot having an area between 1 μm 2  and 100 cm 2 , or between 10 μm 2  and 10 cm 2 . In an embodiment for monitoring a local portion of a material, the particle beam is a microbeam that produces a spot on the surface of the material, the spot having an area between 1 nm 2  and 1 mm 2 , or between 10 nm 2  and 10 μm 2 . 
         [0020]    In an embodiment, the particle beam is an ion beam, where the ion beam has an ion energy of at least 20 eV, or at least 50 eV, or at least 100 eV. For example, the ion beam may have an ion energy selected from the range of 20 eV to 10 keV, or 20 eV to 1 keV, or 50 eV to 1 keV, or 100 eV to 1 keV. In an embodiment, the ion beam has a flux selected from the range of 10 pA/mm 2  to 1 μA/mm 2 , or 10 nA/mm 2  to 10 mA/mm 2 , or 50 nA/mm 2  to 5 mA/mm 2 . In an embodiment, the surface of the material is exposed to an ion dose ranging from 1×10 11  ions/cm 2  to 1×10 20  ions/cm 2 , or from 1×10 12  ions/cm 2  to 1×10 18  ions/cm 2 , or from 1×10 12  ions/cm 2  to 1×10 15  ions/cm 2 . In an embodiment, the ion beam comprises ions selected from the group consisting of He + , Xe + , Ne + , Ar + , Cs + , Bi 3+ , Au + , Au 3+  and combinations thereof. In an embodiment, the ion beam comprises organic or organometallic ions having a molecular mass from 90 to 200. In an embodiment, the ion beam comprises ions selected from the group consisting of tropylium ions, ferrocenium ions and combinations thereof. 
         [0021]    In an embodiment, the particle beam is an electron beam. For example, the electron beam has an energy of at least 10 eV, or at least 100 eV, or at least 1 keV. In an embodiment, the electron beam may be interrogating radiation having an energy selected from the range of 10 eV to 40 keV, or 100 eV to 20 keV, or 1 keV to 10 keV. In an embodiment, the electron beam may be perforating radiation having an energy greater than or equal to 84 keV in the case of pristine graphene, or may be lower when the graphene is not pristine, such as when the graphence has carbon atoms without 3 sp 2  bonds. 
         [0022]    In an embodiment, the particle beam is a nanoparticle beam. For example, the nanoparticle beam has an energy of at least 1 keV per nanoparticle, or at least 2 keV per nanoparticle, or at least 10 keV per nanoparticle. In an embodiment, the nanoparticle beam has an energy selected from the range of 2 keV to 500 keV per nanoparticle, or 5 keV to 300 keV per nanoparticle, or 10 keV to 200 keV per nanoparticle. In an embodiment, the nanoparticle beam has a flux selected from the range of 1.6×10 5  nanoparticles/s·cm 2  to 1×10 15  nanoparticles/s·cm 2 , or 1×10 6  nanoparticles/s·cm 2  to 1×10 12  nanoparticles/s·cm 2 , or 1×10 7  nanoparticles/s·cm 2  to 1×10 10  nanoparticles/s·cm 2 . In an embodiment, the surface of the material is exposed to a nanoparticle dose ranging from 1×10 8  nanoparticles/cm 2  to 1×10 12  nanoparticles/cm 2 , or from 1×10 9  nanoparticles/cm 2  to 1×10 11  nanoparticles/cm 2 . In an embodiment, the nanoparticle beam comprises atoms or molecules selected from the group consisting of metal nanoparticles, carbon nanoparticles, gas clusters, core shell nanoparticles and combinations thereof. In an embodiment, the nanoparticle beam comprises atoms or molecules having a molecular mass from 100 to 4,000,000, or from 190 to 2,000,000. 
         [0023]    In an embodiment, the material is a two-dimensional material. For example, the two-dimensional material may be a single atomic layer thick. In an embodiment, the two-dimensional material has a thickness less than or equal to 100 Angstroms. In an embodiment, the two-dimensional material is selected from the group consisting of a graphene or graphene-based film, a transition metal dichalcogenide, α-boron nitride, silicene, germanene, and combinations thereof. In an embodiment, the two-dimensional material is disposed on or supported by a three-dimensional material. In an embodiment, the material comprises a stack of two or more sheets of two-dimensional material, wherein each sheet is a single atomic layer thick. In an embodiment, the size of the holes or defects in the two-dimensional material ranges from 1-50 nm, 1-30 nm, 1-20 nm, 1-10 nm or 3-10 nm. In an embodiment, the two-dimensional material is graphene or a graphene-based material. 
         [0024]    In an embodiment, the defects are pores extending throughout a thickness of the material. For example, the pores may have an average characteristic dimension less than or equal to 1 nm. In an embodiment, the pores have an average characteristic dimension ranging from 0.3 nm to 100 nm, or from 0.5 nm to 10 nm. In an embodiment, in situ or substantially simultaneous feedback on defect production or healing may be provided either locally or globally on a graphene or other two-dimensional sheet. The feedback data can be used to adjust perforation or healing parameters, such as the total dose or efficacy of the perforating radiation, to achieve the desired defect state. 
         [0025]    In an embodiment, a method of monitoring further comprises comparing the data indicative of defect formation or healing to a threshold range for the data; and adjusting an energy or amount of the incident radiation if the data is outside of the threshold range. In this case, the flux, energy, sample temperature, background gas pressure could be changed, as well as the incidence angle. 
         [0026]    In an embodiment, in situ or substantially simultaneous feedback on defect production or healing may be provided either locally or globally on a graphene or other two-dimensional sheet. The feedback data can be used to adjust perforation or healing parameters, such as the total dose or efficacy of the perforating radiation, to achieve the desired defect state. 
         [0027]    In an embodiment, a method of monitoring defect formation or healing further comprises translating the material being defected or healed along a processing stage at a rate dependent upon a rate of defect formation or healing. The rate would depend on flux and energy of the incident radiation. In an embodiment, the fluence delivered to the material may be controlled by the rate at which the material is translated relative to the irradiating beam. In an embodiment, the ions from irradiating beam may be stopped from impinging on the surface of the sample by adjusting the bias on the material up to the ion accelerating voltage to stop the ions. 
         [0028]    The foregoing has outlined rather broadly the features of the present disclosure in order that the detailed description that follows can be better understood. Additional features and advantages of the disclosure will be described hereafter. These and other advantages and features will become more apparent from the following description. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0029]    For a more complete understanding of the present disclosure, and the advantages thereof, reference is now made to the following descriptions to be taken in conjunction with the accompanying drawings describing specific embodiments of the disclosure. 
           [0030]      FIG. 1  is a schematic of graphene, which may be a two-dimensional material monitored by methods herein. 
           [0031]      FIG. 2  shows a flowchart for a method for monitoring defect formation or healing via detection of scattered, emitted or transmitted radiation or particles, according to an embodiment of the present invention. 
           [0032]      FIG. 3  shows a flowchart for a method for monitoring defect formation or healing via detection of movement of an analyte, according to an embodiment of the present invention. 
           [0033]      FIG. 4  shows a flowchart for a method for monitoring defect formation or healing via measurement of electrical conductivity, according to an embodiment of the present invention. 
           [0034]      FIG. 5  shows a flowchart for a method for monitoring defect formation or healing via Joule heating and temperature measurement, according to an embodiment of the present invention. 
           [0035]      FIGS. 6A and 6B  show schematics of exemplary systems for monitoring defect formation or healing, according to the embodiments of the present invention. 
       
    
    
     DETAILED DESCRIPTION 
       [0036]    Graphene has garnered widespread interest for use in a number of applications due to its favorable mechanical and electronic properties, as well as its chemical inertness. Graphene represents an atomically thin two-dimensional layer of carbon in which the carbon atoms reside as closely spaced atoms at regular lattice positions. The regular lattice positions can have a plurality of defects present therein, which can occur natively or be intentionally introduced to the graphene basal plane. Such defects will also be equivalently referred to herein as “apertures,” “perforations” or “holes.” The term “perforated graphene” is used herein to denote a graphene sheet with defects in its basal plane, regardless of whether the defects are natively present or intentionally produced. Aside from such apertures, graphene and other two-dimensional materials can represent an impermeable layer to many substances. Therefore, when sized properly, the apertures in the impermeable layer of such materials can be useful for filtration and sequestration, for example. 
         [0037]    Two-dimensional materials are, most generally, those which are atomically thin, with thickness ranging from single-layer sub-nanometer thickness to a few nanometers, and which generally have a high surface area. Two-dimensional materials include metal chalogenides (e.g., transition metal dichalogenides), transition metal oxides, hexagonal boron nitride, graphene, silicene and germanene (see: Xu et al. (2013) “Graphene-like Two-Dimensional Materials) Chemical Reviews 113:3766-3798). Graphene represents a form of carbon in which the carbon atoms reside within a single atomically thin sheet or few layered sheets (e.g., about 20 or less) of covalently bound carbon atoms forming an extended sp 2 -hybridized planar lattice. In its various forms, graphene has garnered widespread interest for use in a number of applications, primarily due to its favorable combination of high electrical and thermal conductivity values, good in-plane mechanical strength, and unique optical and electronic properties. Other two-dimensional materials having a thickness of a few nanometers or less and an extended substantially planar lattice are also of interest for various applications. In an embodiment, a two dimensional material has a thickness of 0.3 to 1.2 nm. In other embodiments, a two dimensional material has a thickness of 0.3 to 3 nm. 
         [0038]    In various embodiments, the two-dimensional material comprises a sheet of a graphene-based material. In an embodiment, the sheet of graphene-based material is a sheet of single- or multi-layer graphene or a sheet comprising a plurality of interconnected single- or multi-layer graphene domains. In embodiments, the multilayer graphene domains have 2 to 5 layers or 2 to 10 layers. In an embodiment, the layer comprising the sheet of graphene-based material further comprises non-graphenic carbon-based material located on the surface of the sheet of graphene-based material. In an embodiment, the amount of non-graphenic carbon-based material is less than the amount of graphene. In embodiments, the amount of graphene in the graphene-based material is from 60% to 95% or from 75% to 100%. In an embodiment, the amount of graphene in the graphene-based material is measured as an atomic percentage. 
         [0039]    In embodiments, the characteristic size of the perforations of a perforated graphene, graphene-based or two-dimensional material is from 0.3 to 10 nm, from 1 to 10 nm, from 5 to 10 nm, from 5 to 20 nm, from 10 nm to 50 nm, from 50 nm to 100 nm, from 50 nm to 150 nm, from 100 nm to 200 nm, or from 100 nm to 500 nm. In an embodiment, the average pore size of a perforated graphene, graphene-based or two-dimensional material is within the specified range. In embodiments, 70% to 99%, 80% to 99%, 85% to 99% or 90 to 99% of the perforations in a sheet or layer fall within a specified range, but other pores fall outside the specified range. 
         [0040]    The technique used for forming the graphene or graphene-based material in the embodiments described herein is not believed to be particularly limited. For example, in some embodiments CVD graphene or graphene-based material can be used. In various embodiments, the CVD graphene or graphene-based material can be liberated from its growth substrate (e.g., Cu) and transferred to a polymer backing, or may be transferred to a porous substrate. 
         [0041]    Likewise, the techniques for introducing perforations to the graphene or graphene-based material are not believed to be particularly limited, other than being chosen to produce perforations within a desired size range. Perforations are sized as described herein to provide desired selective permeability of a species (atom, molecule, protein, virus, cell, etc.) for a given application. Selective permeability relates to the propensity of a porous material or a perforated two-dimensional material to allow passage (or transport) of one or more species more readily or faster than other species, or to block the other species from passage. Selective permeability allows separation of species which exhibit different passage or transport rates. In two-dimensional materials selective permeability correlates to the dimension or size (e.g., diameter) of apertures and the relative effective size of the species. Selective permeability of the perforations in two-dimensional materials, such as graphene-based materials, can also depend on functionalization of perforations (if any) and the specific species that are to be separated or blocked. Separation of two or more species in a mixture includes a change in the ratio(s) (weight or molar ratio) of the two or more species in the mixture after passage of the mixture through a perforated two-dimensional material. 
         [0042]    Graphene-based materials include, but are not limited to, single layer graphene, multilayer graphene or interconnected single or multilayer graphene domains and combinations thereof. In an embodiment, graphene-based materials also include materials which have been formed by stacking single layer or multilayer graphene sheets. In embodiments, multilayer graphene includes 2 to 20 layers, 2 to 10 layers or 2 to 5 layers. In embodiments, graphene is the dominant material in a graphene-based material. For example, a graphene-based material comprises at least 30% graphene, or at least 40% graphene, or at least 50% graphene, or at least 60% graphene, or at least 70% graphene, or at least 80% graphene, or at least 90% graphene, or at least 95% graphene. In embodiments, a graphene-based material comprises a range of graphene selected from 30% to 95%, from 40% to 80%, from 50% to 70%, from 60% to 95% or from 75% to 100%. In an embodiment, the amount of graphene in the graphene-based material is measured as an atomic percentage. 
         [0043]    Graphene represents a form of carbon in which the carbon atoms reside within a single atomically thin sheet or a few layered sheets (e.g., about 20 or less) of fused six-membered rings forming an extended sp2-hybridized carbon planar lattice. Graphene-based materials include, but are not limited to, single layer graphene, multilayer graphene or interconnected single or multilayer graphene domains and combinations thereof. In embodiments, multilayer graphene includes 2 to 25 layers, 2 to 20 layers, 2 to 10 layers or 2 to 5 layers. In an embodiment, layers of multilayered graphene are stacked, but are less ordered in the z direction (perpendicular to the basal plane) than a thin graphite crystal. 
         [0044]    In an embodiment, graphene-based materials also include materials which have been formed by stacking single or multilayer graphene sheets. Multi-layered graphene as referred to herein includes multiple sheets of graphene formed by layering as-synthesized sheets on a substrate. In an embodiment, layers of as-synthesized sheets of graphene which have been stacked in this fashion are less ordered in the z direction than an as-synthesized multilayer graphene sheet. Suitable as-synthesized sheets include sheets of single layer graphene (SLG), sheets of bi-layer graphene (BLG) or sheets of few layer graphene (FLG graphene, for example up to 5 layers of graphene). For example, a sheet of single layer graphene (SLG) is layered via float-down on top of a substrate. Another sheet of the SLG is then floated down on the already prepared SLG-substrate stack. This would now be 2 layers of “as-synthesized” SLG on top of the substrate. This can be extended to few layer graphene (FLG) or a mixture of SLG and FLG; and can be achieved through transfer methods known to the art. For example, a polymer transfer method can be used to assemble the stack of polymer layers. In some instances a number of layers is intended to refer to that number of separate layers of transferred graphene. In cases where a layer of transferred graphene can have a range of graphene layers (e.g. some regions of the layer are SLG and others are BLG or FLG), the stack has a range of graphene layers. For example, if 5 layers of transferred graphene each have 1 to 5 layers, then regions where the 5 sheets line up with 5 layers, effectively have 25 layers of graphene at that position. Depending on the perforation conditions, the thicker regions of the stack may not perforate. In embodiments, layering of different sheets of graphene results in a desirable membrane for filtration and separation applications. 
         [0045]    In an embodiment, a sheet of graphene-based material is a sheet of single or multilayer graphene or a sheet comprising a plurality of interconnected single or multilayer graphene domains. In embodiments, the multilayer graphene domains have 2 to 5 layers or 2 to 10 layers. As used herein, a “domain” refers to a region of a material where atoms are uniformly ordered into a crystal lattice. A domain is uniform within its boundaries, but different from a neighboring region. For example, a single crystalline material has a single domain of ordered atoms. In an embodiment, at least some of the graphene domains are nanocrystals, having domain size from 1 to 100 nm or 10 to 100 nm. In an embodiment, at least some of the graphene domains have a domain size from 100 nm to 1 micron, or from 200 nm to 800 nm, or from 300 nm to 500 nm. “Grain boundaries” formed by crystallographic defects at edges of each domain differentiate between neighboring crystal lattices. In some embodiments, a first crystal lattice may be rotated relative to a second crystal lattice, by rotation about an axis perpendicular to the plane of a sheet, such that the two lattices differ in “crystal lattice orientation.” 
         [0046]    In an embodiment, the sheet of graphene-based material comprises a sheet of single layer or multilayer graphene or a combination thereof. In an embodiment, the sheet of graphene-based material is a sheet of single layer or multilayer graphene or a combination thereof. In another embodiment, the sheet of graphene-based material is a sheet comprising a plurality of interconnected single or multilayer graphene domains. In an embodiment, the interconnected domains are covalently bonded together to form the sheet. When the domains in a sheet differ in crystal lattice orientation, the sheet is polycrystalline. 
         [0047]    In embodiments, the thickness of the sheet of graphene-based material is from 0.34 to 10 nm, from 0.34 to 5 nm, or from 0.34 to 3 nm. In an embodiment, a sheet of graphene-based material comprises intrinsic or native defects. Intrinsic or native defects are those resulting from preparation of the graphene-based material in contrast to perforations which are selectively or intentionally introduced into a sheet of graphene-based material or a sheet of graphene. Such intrinsic or native defects may include, but are not limited to, lattice anomalies, pores, tears, cracks or wrinkles. Lattice anomalies can include, but are not limited to, carbon rings with other than 6 members (e.g. 5, 7 or 9 membered rings), vacancies, interstitial defects (including incorporation of non-carbon atoms in the lattice), and grain boundaries. 
         [0048]    In an embodiment, the layer comprising the sheet of graphene-based material further comprises non-graphenic carbon-based material located on the surface of the sheet of graphene-based material. In an embodiment, the non-graphenic carbon-based material does not possess long range order and may be classified as amorphous. In embodiments, the non-graphenic carbon-based material further comprises elements other than carbon and/or hydrocarbons. Non-carbon elements which may be incorporated in the non-graphenic carbon include, but are not limited to, hydrogen, oxygen, silicon, copper and iron. In embodiments, the non-graphenic carbon-based material comprises hydrocarbons. In embodiments, carbon is the dominant material in non-graphenic carbon-based material. For example, a non-graphenic carbon-based material comprises at least 30% (weight %) carbon, or at least 40% carbon, or at least 50% carbon, or at least 60% carbon, or at least 70% carbon, or at least 80% carbon, or at least 90% carbon, or at least 95% carbon. In embodiments, a non-graphenic carbon-based material comprises a range of carbon selected from 30% to 95%, or from 40% to 80%, or from 50% to 70%. In an embodiment, the amount of carbon in the non-graphenic carbon-based material is measured as an atomic percentage. 
         [0049]    Such nanomaterials in which pores are intentionally created will be referred to herein as “perforated graphene,” “perforated graphene-based materials” or “perforated two-dimensional materials.” The present disclosure is also directed, in part, to perforated graphene, perforated graphene-based materials and other perforated two-dimensional materials containing a plurality of holes of size (or size range) appropriate for a given application. The size distribution of holes may be narrow, e.g., limited to a 1-10% deviation in size or a 1-20% deviation in size. In an embodiment, the characteristic dimension of the holes is selected for the application. For circular holes, the characteristic dimension is the diameter of the hole. In embodiments relevant to non-circular pores, the characteristic dimension can be taken as the largest distance spanning the hole, the smallest distance spanning the hole, the average of the largest and smallest distance spanning the hole, or an equivalent diameter based on the in-plane area of the pore. As used herein, perforated graphene-based materials include materials in which non-carbon atoms have been incorporated at the edges of the pores. 
         [0050]    In various embodiments, the two-dimensional material comprises graphene, molybdenum disulfide, or hexagonal boron nitride. In more particular embodiments, the two-dimensional material can be graphene. Graphene according to the embodiments of the present disclosure can include single-layer graphene, multi-layer graphene, or any combination thereof. Other nanomaterials having an extended two-dimensional molecular structure can also constitute the two-dimensional material in the various embodiments of the present disclosure. For example, molybdenum disulfide is a representative chalcogenide having a two-dimensional molecular structure, and other various chalcogenides can constitute the two-dimensional material in the embodiments of the present disclosure. Choice of a suitable two-dimensional material for a particular application can be determined by a number of factors, including the chemical and physical environment into which the graphene or other two-dimensional material is to be terminally deployed. 
         [0051]    The process of forming holes in graphene and other two-dimensional materials will be referred to herein as “perforation,” and such nanomaterials will be referred to herein as being “perforated.” In a graphene sheet an interstitial aperture is formed by each six-carbon atom ring structure in the sheet and this interstitial aperture is less than one nanometer across. In particular, this interstitial aperture is believed to be about 0.3 nanometers across its longest dimension (the center to center distance between carbon atoms being about 0.28 nm and the aperture being somewhat smaller than this distance). Perforation of sheets comprising two-dimensional network structures typically refers to formation of holes larger than the interstitial apertures in the network structure. 
         [0052]    Due to the atomic-level thinness of graphene and other two-dimensional materials, it may be possible to achieve high fluid throughput fluxes during separation or filtration processes, even with holes that are in the ranges of 1-200 nm, 1-100 nm, 1-50 nm, or 1-20 nm. 
         [0053]    Chemical techniques can be used to create holes in graphene and other two-dimensional materials. Exposure of graphene or another two-dimensional material to ozone or atmospheric pressure plasma (e.g., an oxygen/argon or nitrogen/argon plasma) can effect perforation. Other techniques, such as ion bombardment, can also be used to remove matter from the planar structure of two-dimensional materials in order to create holes. All such methods can be applied for preparation of perforated two-dimensional materials for use herein dependent upon the hole sizes or range of hole sizes desired for a given application. 
         [0054]    In various embodiments of the present disclosure, the holes produced in the graphene or other two-dimensional material can range from about 0.3 nm to about 50 nm in size. In a more specific embodiment, hole sizes can range from 1 nm to 50 nm. In a more specific embodiment, hole sizes can range from 1 nm to 10 nm. In a more specific embodiment, hole sizes can range from 5 nm to 10 nm. In a more specific embodiment, hole sizes can range from 1 nm to 5 nm. In a more specific embodiment, the holes can range from about 0.5 nm to about 2.5 nm in size. In an additional embodiment, the hole size is from 0.3 to 0.5 nm. In a further embodiment, the hole size is from 0.5 to 10 nm. In an additional embodiment, the hole size is from 5 nm to 20 nm. In a further embodiment, the hole size is from 0.7 nm to 1.2 nm. In an additional embodiment, the hole size is from 10 nm to 50 nm. In embodiments where larger hole sizes are preferred, the hole size is from 50 nm to 100 nm, from 50 nm to 150 nm, or from 100 nm to 200 nm. 
         [0055]    In general, the terms and phrases used herein have their art-recognized meaning, which can be found by reference to standard texts, journal references and contexts known to those skilled in the art. The following definitions are provided to clarify their specific use in the context of the invention. 
         [0056]    As used herein, the term “two-dimensional material” will refer to any extended planar structure of atomic thickness, including both single- and multi-layer variants thereof. Multi-layer two-dimensional materials can include up to about 20 stacked layers. 
         [0057]    A “defect” refers to an opening in a plane of a two-dimensional material. In an embodiment, the defect may be an intrinsic or native defect. Intrinsic or native defects are those resulting from preparation of the two-dimensional material in contrast to perforations which are selectively introduced into a sheet of two-dimensional material. Such intrinsic or native defects include, but are not limited to, lattice anomalies, pores, tears, cracks or wrinkles. Lattice anomalies can include, but are not limited to, carbon rings with other than 6 members (e.g. 5, 7 or 9 membered rings) in graphene or graphene-based materials, vacancies, interstitial defects (including incorporation of non-carbon atoms in the lattice), and grain boundaries. In an embodiment, the defect may be a non-intrinsic defect. Non-intrinsic defects are nanoscale apertures (e.g., pores, holes) formed by a defect formation process, wherein energy (e.g., heat, pressure, electromagnetic radiation and combinations and variations thereof) sufficient to break the chemical bonds of the two-dimensional material is applied to at least one target location of the material. A plurality of non-intrinsic defects may be provided in a uniform or non-uniform (i.e., random) distribution or pattern. Typically, non-intrinsic defects are produced in at a target location of a two-dimensional material with precision of ±50 nm, ±10 nm or ±5 nm. In some embodiments, nanoscale apertures in a two-dimensional material are separated by an average closest edge-to-edge distance less than or equal to 20 nm or less than or equal to 15 nm or less than or equal to 10 nm. 
         [0058]    A defect healing process, as used herein, refers to a process for partially or completely closing one or more openings (defects) in a two-dimensional material. A defect healing process may transform a perforated two-dimensional material into a less perforated or unperforated two-dimensional material using chemical techniques (e.g., bonding), physical techniques (e.g., blocking) or a combination of chemical and physical techniques. Exemplary healing techniques include, but are not limited to, reforming the crystallographic lattice of the two-dimensional material within the defect area, filling the defect with a material other than the two-dimensional material (e.g., epoxy), and covering the defect with a section of the same or different material, which at least partially overlaps the two-dimensional material. In an embodiment, the process of reforming the crystallographic lattice of the two-dimensional material within the defect area utilizes hydrocarbon-based surface contamination that is mobilized by the addition of energy. In an embodiment, the healing may be performed via a reorganization of existing defects without adding any new material. 
         [0059]    “In situ” methods of the present invention are performed on a sample that remains in position throughout the method. For example, a sample that remains “in position” is stationary or does not leave a sample chamber during the in situ method. In situ methods according to the inventive concepts disclosed herein are useful for providing data indicative of a spatial and/or temporal change of a sample that remains in its original position. In some embodiments, an in situ method processes (e.g., perforates or heals) the sample and simultaneously interrogates the sample to provide substantially instantaneous, real-time data. In some embodiments, an in situ method processes (e.g., perforates or heals) the sample and performs nearly simultaneously interrogation of the sample to provide substantially near real-time data. 
         [0060]    As described above, the incident radiation, and the scattered, emitted or transmitted radiation may be any one or more of electromagnetic radiation, electrons, ions, nanoparticles, or plasma. In an embodiment, incident radiation is processing radiaton, such as perforating or healing radiation or interrogating radiation. The incident radiation may also be both processing radiation and interrogating radiation. As described herein, processing radiation performs a process on the material when incident thereon. 
         [0061]    In some embodiments, the incident perforating or healing radiation may also be interrogating radiation, which interacts with the two-dimensional material to produce scattered, emitted or transmitted radiation that is detected by a detector to provide data indicative of defect formation or healing. In an embodiment, the incident perforating or healing radiation is separate from interrogating radiation, which is produced by an alternate source and which interacts with the two-dimensional material to produce scattered, emitted or transmitted radiation that is detected by a detector to provide data indicative of defect formation or healing. 
         [0062]    In an embodiment, the incident radiation does not perforate the two-dimensional material. The incident non-perforating radiation may interrogate the two-dimensional material by interacting with the two-dimensional material to produce scattered, emitted or transmitted radiation that is detected by a detector to provide data indicative of defect formation or healing. 
         [0063]    In some embodiments, especially for methods configured for local sampling, micromechanical shutters disposed between the two-dimensional material and the detector could be opened and closed to allow for targeted sampling. Activation of the micromechanical shutters could be implemented by each shutter being biased to collect current from a respective local portion of the material. In an embodiment, the shutters may be arranged in an array over the two dimensional material, each shutter corresponding to a respective local portion. Thus, the respective local portion of the material may be electronically monitored by actuating its respective shutter to open to allow for appropriate radiation to be incident on the respective portion, and the electrical conductivity data of the local portion may be acquired. The shutters may be electrostatically actuated. When the emitted current divided by the bias current is not equal to 1, the actuator may move because the charge on the shutter moves the shutter by coulombic force. Other ways of moving the actuator once the appropriate signal is received are contemplated. In an embodiment, the shutters may be arranged in a two-dimensional array. In another embodiment, the shutters may be arranged in a one-dimensional array. 
         [0064]    In some embodiments, probes, such as wires, could be contacted with respective local portions of the two-dimensional material to acquire electrical conductivity data. Thus, the electrical conductivity of the respective local portions may be monitored. 
         [0065]    In embodiments, the two-dimensional material is a graphene-based material. In embodiments, the two-dimensional material is graphene. 
         [0066]    In embodiments, at least a portion of the holes in the two-dimensional material are functionalized. 
         [0067]    Additionally, the conductive properties of graphene-based or other two-dimensional membranes can allow for electrification to take place from an external source. In exemplary embodiments, an AC or DC voltage can be applied to conductive two-dimensional materials. 
         [0068]    In some embodiments, the two-dimensional material, such as graphene, can be affixed to a suitable porous substrate. Suitable porous substrates can include, for example, thin film polymers and ceramics. Useful exemplary ceramics include nanoporous silica or SiN. Useful porous polymer substrates include track-etched polymers, expanded polymers or non-woven polymers. The substrate material can be porous or permeable. 
         [0069]      FIG. 1  shows a graphene sheet  10  of carbon atoms defining a repeating pattern of hexagonal ring structures that collectively form a two-dimensional honeycomb lattice. An interstitial aperture  12  of less than 1 nm in diameter is formed by each hexagonal ring structure in the sheet. More particularly, the interstitial aperture in a perfect crystalline graphene lattice is estimated to be about 0.23 nanometers across its longest dimension. Accordingly, graphene materials preclude transport of any molecule across the graphene sheet&#39;s thickness unless there are pores, perforation-induced or intrinsic. The thickness of a theoretically perfect single graphene sheet is approximately 0.3 nm. Further, graphene has a breaking strength about 200 times that of steel, a spring constant in the range 1 N/m to 5 N/m and a Young&#39;s modulus of about 0.5 TPa. 
         [0070]      FIG. 2  shows a flowchart  200  for a method for monitoring defect formation or healing via detection of scattered, emitted or transmitted radiation, according to an embodiment of the inventive concepts disclosed herein. Step  202  involves providing a material having a surface. In step  204 , the surface of the material is exposed to incident radiation. In step  206 , scattered, emitted or transmitted radiation are detected from at least a portion of the material exposed to the incident radiation, and in step  208  data indicative of defect formation or healing is generated. Typically, the method is performed in situ and the data indicative of defect formation or healing provide a rate of defect formation or healing, a temporal change in the rate of defect formation or healing, a temporal change in the size of the defects, a spatial change in the rate of defect formation or healing, a spatial change in the size of the defects, or combinations thereof. 
         [0071]      FIG. 3  shows a flowchart  300  for a method for monitoring defect formation or healing via detection of movement of an analyte, according to an embodiment according to inventive concepts disclosed herein. Step  302  involves providing a material having a surface. In step  304 , the surface of the material is exposed to incident radiation. In step  306 , movement of an analyte through defects in the material is detected, and in step  308  data indicative of defect formation or healing is generated. Typically, the method is performed in situ and the data indicative of defect formation or healing provide a rate of defect formation or healing, a temporal change in the rate of defect formation or healing, a temporal change in the size of the defects, a spatial change in the rate of defect formation or healing, a spatial change in the size of the defects, a maximum size of the defects, or combinations thereof. 
         [0072]      FIG. 4  shows a flowchart  400  for a method for monitoring defect formation or healing via measurement of electrical conductivity, according to an embodiment according to inventive concepts disclosed herein. In step  402 , a material having a surface is provided and in step  404  the surface of the material is exposed to incident radiation. In step  406 , an electrical bias is applied to the material. In step  408 , electrical conductivity is measured with a conductive probe in electrical contact with the material. In step  410 , data indicative of defect formation or healing is generated. Typically, the method is performed in situ and the data indicative of defect formation or healing provide a rate of defect formation or healing, a temporal change in the rate of defect formation or healing, a temporal change in the size of the defects, a spatial change in the rate of defect formation or healing, a spatial change in the size of the defects, or combinations thereof. In an embodiment, a conductive probe is a conductive grid or a local probe. In an embodiment, defect density and electrical conductivity are inversely related such that an increase in defect density is observed as a decrease in electrical conductivity. 
         [0073]      FIG. 5  shows a flowchart  500  for a method for monitoring defect formation or healing via Joule heating and temperature measurement, according to an embodiment according to inventive concepts disclosed herein. In step  502 , a material having a surface is provided and the surface of the material is exposed to incident radiation, in step  504 . In step  506 , the material is heated. Subsequently, temperature of the surface of the material is measured in step  508 . In step  510 , data indicative of defect formation or healing is generated. Typically, the method is performed in situ and the data indicative of defect formation or healing provides a rate of defect formation or healing, a temporal change in the rate of defect formation or healing, a temporal change in the size of the defects, a spatial change in the rate of defect formation or healing, a spatial change in the size of the defects, or combinations thereof. In an embodiment, the step of heating the material comprises applying a potential to the two-dimensional material to induce joule heating. In an embodiment, defect density and thermal conductivity are inversely related such that an increase in defect density is observed as a decrease in thermal conductivity. 
         [0074]    In embodiments, examples of which are schematically illustrated in  FIGS. 6A and 6B , a system  600  for monitoring a two-dimensional material comprises a source  602  for delivering incident radiation  604  to a two-dimensional material  606 , a detector  608  for receiving scattered, emitted or transmitted radiation or particles  610  from the two-dimensional material  606 , and a processor  612  for receiving at least one signal  614  from the detector  608  and transforming the signal  614  into data indicative of defect formation or healing  622 . The data  622  may be stored in a register or memory of the processor. In the embodiment shown in  FIG. 6A , the detector  608  is positioned on the same side of the two-dimensional material  606  as the source  602  to receive scattered or emitted radiation or particles  610 . In the embodiment shown in  FIG. 6B , the detector  608  is positioned on the opposite side of the two-dimensional material  606  relative to the source  602  so that the detector  608  can receive transmitted radiation or particles  610 . In an embodiment (not shown), a system  600  may include two or more detectors  608  positioned on one or both sides of the two-dimensional material  606 . Optionally, the system  600  may also include a controller  616  that receives input  617  from the processor and provides control signals  618  to adjust the incident radiation  604  or a rate of sample translation in response to the data indicative of defect formation or healing  622  and/or a display  620  for visualizing the data. The rate of sample translation may be controlled by translation means, such as rollers  624  and/or a translation stage. Those of skill in the art will appreciate that for some methods disclosed herein the detector may be located on the same side of the two-dimensional material as the incident radiation source. Such configurations typically utilize detectors that are off-axis between about 15° and 75° relative to the trajectory of the incident radiation beam in order to protect the detector from damage. However, other methods disclosed herein may include a detector located on the opposite side of the two-dimensional material from the incident radiation source. Detectors that may be used in the methods disclosed herein include, but are not limited to, electron detectors, mass spectrometers, electromagnetic spectrometers, microbalances, Faraday cups, charge-coupled devices, ion detectors, resistors, capacitors, thermocouples, microchannel plates, phosphor screens, photodiodes and thermistors. 
         [0075]    Inventive concepts disclosed herein will now be described with reference to the following non-limiting example. 
       EXAMPLE 
     In Situ Monitoring of Graphene Defect Formation or Healing 
       [0076]    Suspended graphene on a substrate is loaded into an ion chamber on a platen and pumped down to 10 −6 -10 −7  Torr while being heated to 50° C. Once the pressure is achieved the ion source (Kaufman source), which is a Xe +  beam of approximately 1 mm diameter at 300V and a beam current of 100 nA/mm 2  (6.24×10 13  Xe + /cm 2 ·s), is rastered across the sample. The beam dwells such that the FWHM of the beam profile touches the previous dwell location. The dwell time for each spot is determined by monitoring the secondary electron (SE) emission from the incoming Xe +  using an Everhart-Thornley detector and is compared to known yields (defined as SE emitted for given incident ions in this case) for a given desired pore size, on a particular substrate, with these conditions (i.e. ion voltage, flux, etc.) which were previously acquired empirically. Once the proper SE electron yield is achieved (e.g., actual values match target values on a look-up table), a processor of the control system sends instructions to the instrument to move the beam to the next defect or healing location. The system also accounts for changes in expected yield over time as irradiation progresses. 
       Statements Regarding Incorporation by Reference and Variations 
       [0077]    Although devices and methods have been described with reference to the disclosed embodiments, one having ordinary skill in the art will readily appreciate that these are only illustrative. It should be understood that various modifications can be made without departing from the spirit of the disclosure. The disclosure can be modified to incorporate any number of variations, alterations, substitutions or equivalent arrangements not heretofore described, but which are commensurate with the spirit and scope of the disclosure. Additionally, while various embodiments have been described, it is to be understood that aspects of the disclosure may include only some of the described embodiments. Accordingly, the disclosure is not to be seen as limited by the foregoing description. 
         [0078]    Every formulation or combination of components described or exemplified can be used to practice the invention, unless otherwise stated. Specific names of compounds are intended to be exemplary, as it is known that one of ordinary skill in the art can name the same compounds differently. When a compound is described herein such that a particular isomer or enantiomer of the compound is not specified, for example, in a formula or in a chemical name, that description is intended to include each isomer and enantiomer of the compound described individually or in any combination. One of ordinary skill in the art will appreciate that methods, device elements, starting materials and synthetic methods other than those specifically exemplified can be employed in the practice of the invention without resort to undue experimentation. All art-known functional equivalents, of any such methods, device elements, starting materials and synthetic methods are intended to be included in this invention. Whenever a range is given in the specification, for example, a temperature range, a time range, or a composition range, all intermediate ranges and subranges, as well as all individual values included in the ranges given are intended to be included in the disclosure. When a Markush group or other grouping is used herein, all individual members of the group and all combinations and subcombinations possible of the group are intended to be individually included in the disclosure. 
         [0079]    As used herein, “comprising” is synonymous with “including,” “containing,” or “characterized by,” and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. As used herein, “consisting of” excludes any element, step, or ingredient not specified in the claim element. As used herein, “consisting essentially of” does not exclude materials or steps that do not materially affect the basic and novel characteristics of the claim. Any recitation herein of the term “comprising”, particularly in a description of components of a composition or in a description of elements of a device, is understood to encompass those compositions and methods consisting essentially of and consisting of the recited components or elements. The inventive concepts illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein. 
         [0080]    The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims. 
         [0081]    In general the terms and phrases used herein have their art-recognized meaning, which can be found by reference to standard texts, journal references and contexts known to those skilled in the art. The preceding definitions are provided to clarify their specific use in the context of the invention. 
         [0082]    All references throughout this application, for example patent documents including issued or granted patents or equivalents; patent application publications; and non-patent literature documents or other source material; are hereby incorporated by reference herein in their entireties, as though individually incorporated by reference, to the extent each reference is at least partially not inconsistent with the disclosure in this application (for example, a reference that is partially inconsistent is incorporated by reference except for the partially inconsistent portion of the reference). 
         [0083]    All patents and publications mentioned in the specification are indicative of the levels of skill of those skilled in the art to which the invention pertains. References cited herein are incorporated by reference herein in their entirety to indicate the state of the art, in some cases as of their filing date, and it is intended that this information can be employed herein, if needed, to exclude (for example, to disclaim) specific embodiments that are in the prior art. For example, when a compound is claimed, it should be understood that compounds known in the prior art, including certain compounds disclosed in the references disclosed herein (particularly in referenced patent documents), are not intended to be included in the claims.