AU2013205435B2 - Multifunctional nanoscopy for imaging cells - Google Patents

Abstract

Multifunctional Nanoscopy for Imaging Cells Abstract of the Disclosure: 5 Disclosed herein is an apparatus for sensing characteristics of an object. In a preferred embodiment, the apparatus comprises an array, wherein the array comprises a plurality of nanoscale hybrid semiconductor/metal devices which are in proximity to an object, each hybrid semiconductor/metal device being configured to produce a voltage in response to a perturbation, wherein the produced voltage is indicative of a 10 characteristic of the object. Any of a variety of nanoscale EXX sensors can be selected as the hybrid semiconductor/ metal devices in the array. With such an array, ultra high resolution images of nanoscopic resolution can be generated of objects such as living cells, wherein the images are indicative of a variety of cell biologic processes. - 52 - Interface Metal 106 Semiconductor Figure 1 Acoustic Perturbation Source (200) Semiconductor 1 V2 V3 14 Figure 2

Description

Multifunctional Nanoscopy for Imaging Cells Cross-Reference and Priority Claim to Related Patent Application: This patent application claims priority to U.S. provisional patent application 6o/821,040, filed August 1, 2006, and entitled "Multifunctional Nanoscopy for Imaging Cells", the entire disclosure of which is incorporated herein by reference. 5 Statement Regarding Federally Sponsored Research or Development: This invention was made with government support under NIH grants such as EBoo2168, HLo 4 2 9 5 o, and CO-27o 3 1 awarded by the National Institutes of Health (NIH). The government may have certain rights in the invention 10 Field of the Invention: The field of this invention relates generally to techniques for measuring characteristics of an object (such as the cell function and structure of one or more living cells) on a nanoscale via an array of integrated nanosensors that are responsive 15 to various perturbations such as acoustic waves, light, or electric charge. Background and Summary of the Invention: The rapid acquisition and analysis of high volumes of data in biological samples had its advent in the early days of the human genome sequencing project. Microarray 20 technology has facilitated the interrogation of large numbers of samples for biologically relevant patterns in a variety of physiological, drug-induced or clinically relevant cellular states. A challenge has now presented itself with respect to how these large volumes of information can be integrated into an accurate model of cellular behavior and processes. For example, information relating the effect of a drug to the 25 extent and duration of apoptosis in cancer cells would be invaluable information in a screen for cancer drugs. Similarly, information of cytoskeletal changes leading to invasiveness would greatly streamline the development of an efficient anti-angiogenic drug strategy. The discipline of cytomics has emerged to meet these and other demands in 30 both the academic and industrial research communities. The importance of cytomics derives from the fact that the cell is the minimal functional unit within our physiology.

An attendant technology to the emergence of cytomics is High Content Screening (HCS) which is generally defined as a simultaneous, or near real-time, multiparametric analysis of various aspects of cell state. The complexity of cell function is only part of why cytomics will likely become 5 a major field of study in the near future. Every cell is different, and by studying each cell's unique function, that cell type can be further modeled for subsequent analysis using statistical techniques. Within a short time, the inventors herein forecast that most pharmaceutical companies will not operate without encompassing the essential features of cytomics-drugs-design; a process that will increasingly operate at the level io of modified cellular functions. Future cancer strategies may place greater emphasis on cytome-alignment or cytomic-realignment, which may be viewed as the "cellular form" of tissue engineering. Such an approach will require a better-than-ever understanding of how the cell operates, of how to measure cell function, and of how to characterize a live cell in minute detail. To meet this challenge, there is need in the art for the 15 development of new technologies and new analytical tools for exquisitely sensitive single-cell analysis. A primary goal of cytomics is the discovery of functional relationships between the cell (cytome) and the metabolic pathways (i.e., proteomics, which enables rapid identification of proteins from specific cell populations) resulting from genetic control 20 mechanisms (i.e., genomics; some in the art relate cytomics to functional genomics). With cytomics, the amount of information being collected from the cell is expanded in order to obtain functional data, not just morphological, phenotypic, or genotypic data. Currently, there are two major branches of cytomics: analytical cytology and image cytology. The first, analytical cytology, is comprised of traditional analytical 25 techniques such as: flow cytometry, single cell analysis systems and tissue analysis (after cell separation). The second, image cytology (and analysis) is comprised of techniques such as "quantitative" fluorescence assays, high throughput cell culture assays (96-384-1536 well plates), drug effect assays of cytotoxicity, toxicology assays, apoptosis assays, cell proliferation assays, cell ploidy assays, and DNA array assays. 30 These techniques are typically applied to single cells, tissues and sections, and cell culture systems in both 3 D and 4 D cell culture environments. Laser Scanning Cytometry (LSC) is a well-known example of this type of assay. At the highest level, cytomics links technology to functional biology at the cellular level by relating measurement and detection to structure and function. To -2achieve this end, cytomics integrates tools like flow cytometry, image cytometry, etc. with proteomics and this brings together traditional cytometry and non-traditional cytometry. With the application of so many different measurement technologies to the same problem, informatics now assumes a primary rather than a secondary role in 5 cytomics. For instance, in a typical flow cytometry system, there are 120,ooo events per second per output channel, with measurements being acquired for multiple channels. Another example is offered by very high speed cell culture plate imaging systems applied to detect fluorescent markers in cells. The term HCS is used to differentiate assays that use live cells and to provide io single point readouts (e.g., High Throughput Screening (HTS) assays), which are often based on the biochemistry of ligand binding. HCS combines cell-based arrays with robotics, informatics, and advanced imaging to provide richly detailed information on cell morphology and other responses in large quantities. Many protocols for generating data are already well developed in their 15 respective disciplines, from quantitative Polymerase Chain Reaction (PCR), to flow cytometry, to antibody staining. The methods for acquisition of this data, such as different types of optical microscopy, have already undergone extensive development. Perhaps the most important image acquisition methods for HCS relate to cellular imaging, including drug effect assays for cytotoxicity, apoptosis, cell proliferation, and 20 nucleocytoplasmic transport. Frequently, these approaches utilize cell sensors based on fluorescent proteins and dyes, and thus provide researchers with an ability to screen drugs and to answer more complex biological questions such as target identification and validation and to investigate gene and protein function. In an effort to fill a need in the art for improved cellular imaging techniques, 25 the inventors herein disclose a new, inexpensive, and easy-to-use imaging technology suitable for simultaneous capture of multiple measurements from individual cells that will enable molecular colocalization, metabolic state and motility assessment, and determination of cell cycle, texture, and morphology. This technology will be capable of not only HCS, but also permit selection of single cells for subsequent high 30 resolution imaging based on the outputs of the HCS. By increasing the analytical resolution to assess the sub-cellular state in vivo, the inventors herein hope to increase biological resolution by providing a means to follow the location, timing, and interdependence of biological events within cells in a culture. -3- The present invention builds upon the previous works by one of the inventors herein, wherein the extraordinary magnetoresistance (EMR) and extraordinary piezoconductance (EPC) properties of hybrid semiconductor/metal devices were used to develop improved sensing techniques for a wide variety of applications. For EMR 5 devices, examples include but are not limited to read heads for ultra high density magnetic recording, position and rotation sensors for machine tools, aircraft and automobiles, flip phone switches, elevator control switches, helical launchers for projectiles and spacecraft, and the like. For EPC devices, examples includes but are not limited to a myriad of pressure sensors, blood pressure monitors, and the like. See 10 U.S. patent application publication 2004/0129087 Ai entitled "Extraordinary Piezoconductance in Inhomogeneous Semiconductors", U.S. patents 6,714,374, 6,707,122, 5,965,283, and 5,699,215, Solin et al., Enhanced room-temperature geometric magnetoresistance in inhomogeneous narrow-gap semiconductors, Science, 2000;289, pp. 1530-32; Solin et al., Self-biasing nonmagnetic giant magnetoresistance sensor, 15 Applied Physics Letters, 1996;69, p. 4105-4107; Solin et al., Geometry driven interfacial effects in nanoscopic and macroscopic semiconductor metal hybrid structures: Extraordinary magnetoresistance and extraordinary piezoconductance, Proc. of the International Symposium on Clusters and Nanoassemblies, Richmond, 2003; Rowe et al., Enhanced room-temperature piezoconductance of metal-semiconductor hybrid 20 structures, Applied Physics Letters, 2003; 83, pp. n6o-62; Solin et al., Non-magnetic semiconductors as read-head sensors for ultra-high-density magnetic recording, Applied Physics Letters, 2002; 8o, pp. 4012-14; Zhou et al., Extraordinary magnetoresistance in externally shunted van der Pauw plates, Applied Physics Letters, 2001; 78, p. 667-69; Moussa et al., Finite element modeling of enhanced magnetoresistance in thin film 25 semiconductors with metallic inclusions, Physical Review B (Condensed Matter and Materials Physics) 2oo1; 64, pp. 184410/1-184410/8; Solin et al., Room temperature extraordinary magnetoresistance of non-magnetic narrow-gap semiconductor/metal composites: Application to read-head sensors for ultra high density magnetic recording, IEEE Transactions on Magnetics, 2002; 38, pp. 89-94; Pashkin et al., Room-temperature 3o Al single-electron transistor made by electron-beam lithography, Applied Physics Letters, 2ooo; 76, p. 2256-58; Branford et al., Geometric manipulation of the high field linear magnetoresistance in InSb epilayers on GaAs (ool), Applied Physics Letters, 2005, 86, p. 202n6/1-202n6/3; and Rowe et al, A uni-axial tensile stress apparatusfor temperature-dependent magneto-transport and optical studies of epitaxial layers, -4- Review of Scientific Instruments, 2002; 73, pp. 4270-76, the entire disclosures of each of which being incorporated by reference herein. The inventors herein extend upon the EMR and EPC sensors referenced above to disclose arrays comprised of a plurality of individual hybrid semiconductor/metal 5 devices that can be used to measure voltage responses that are indicative of various characteristics of an object that is in proximity to the hybrid semiconductor/metal devices (such as one or more cells, either in vivo or in vitro) and from which images of the object characteristics can be generated. These hybrid semiconductor/metal devices may comprise a plurality of EXX sensors on a microscale or a nanoscale. 10 Preferably, these EXX sensors comprise nanoscale EXX sensors. As used herein, "nanoscale" refers to dimensions of length, width (or diameter), and thickness for the semiconductor and metal portions of the EXX sensor that are not greater than approximately iooo nanometers in at least one dimension. As used herein, "microscale" refers to dimensions of length, width (or diameter), and thickness for the 15 semiconductor and metal portions of the EXX sensor that are not greater than approximately iooo micrometers in at least one dimension. The term "EXX sensor" refers to a class of hybrid semiconductor/metal devices having a semiconductor/metal interface whose response to a specific type of perturbation produces an extraordinary interfacial effect XX or an extraordinary bulk effect XX. The interfacial or bulk effect 20 XX is said to be "extraordinary" as that would term would be understood in the art to mean a many-fold increase in sensitivity relative to that achieved with a macroscopic device for the same perturbation. Examples of XX interfacial effects include the MR (magnetoresistance) and PC (piezoconductance) effects known from previous work by one of the inventors herein as well as EC (electroconductance) effects. It should be 25 noted that AC (acoustoconductance) effects are effectively the same as the PC effects in that both the EAC and EPC devices can have identical structure. An EAC device can be thought of as a subset of a class of EPC devices, wherein the EAC device is designed to respond to a strain perturbation that is produced by an acoustic wave. An example of an XX bulk effect includes OC (optoconductance) effects. Thus, examples of 30 suitable nanoscale EXX sensors for use in the practice of the present invention include nanoscale EMR sensors, nanoscale EPC sensors, nanoscale EAC sensors, nanoscale EOC sensors, and nanoscale EEC sensors. The inventors herein believe that the use of nanoscale EAC sensors and nanoscale EPC sensors in an imaging array will provide improved imaging resolution, -5improved signal-to-noise ratio (SNR), and higher bandwidth than conventional ultrasonic or other modes of detectors. Accordingly, the use of an array having a plurality of nanoscale EAC sensors and/or a plurality of nanoscale EPC sensors can be used for a myriad of applications, including but not limited to in vitro cell imaging, in 5 vivo invasive catheter-based applications for medical imaging, endoscopic imaging for gastrointestinal, prostate, or urethral/bladder/ureteral applications, transdermal medical imaging for disease characterization, detection of abnormal cells in serum samples, acoustic imaging, pressure sensing in nanofluidics, and blood pressure monitoring inside small vessels. 10 The inventors herein further believe that the use of nanoscale EOC sensors in an imaging array will produce ultra high resolution images of individual cells or tissues that are indicative of the presence of fluorescence in the cells/tissues, a result that can be highly useful in the investigation of cancer and cancer therapeutics, optical microsccopy, photosensors and photodetectors, image intensifiers, position sensitive 15 detectors, and position and speed control systems. The inventors further believe that additional uses for nanoscale EOC sensors in an imaging array include their use in static charge detection, EM radiation sensors, and EKG sensors. The inventors herein further believe that the use of nanoscale EEC sensors in an imaging array will produce ultra high resolution images of electric charge 20 distribution over the surface of one or more living cells, a result that can provide valuable information for monitoring cancer metastasis and targeted drug delivery, particularly so when a series of such images are taken over time to track the progression of the cell's electric charge over time. The inventors herein believe that the nanoscale EEC sensors of the present invention will serve as a significantly more 25 accurate and effective measure of cell electric charge than the conventional electrophoresis technique that is known in the art because electrophoretic measurements suffer from a complicated instrumental dependence and a lack of spatial resolution. The inventors herein further believe that the use of nanoscale EMR sensors in 30 an imaging array will produce ultra high resolution images of magnetoresistance over the surface of one or more living cells, a result that can provide valuable information for studying the magnetic fields produced by nonmagnetic particles embedded in cancer cells, for monitoring magnetically labeled nanoparticles that are trafficking -6inside the cells or for sensing the evolution of imposed magnetic resonance spin orientations. As perhaps the most powerful embodiment of the present invention, the inventors herein envision that a multi-modal array having a plurality of different types 5 of EXX sensors can be used to simultaneously (or nearly simultaneously) generate multiple images that are representative of different characteristics of one or more cells that are imaged by the array. For example, with a multi-modal array having a plurality of EOC sensors and a plurality of EEC sensors, multiple images can be simultaneously generated that are representative of both fluorescent emissions by the cell(s) and the io surface charge of the cell(s). Such images would exhibit a nanoscale resolution. As used herein, the term "type" as used in connection with EXX sensors refers to the type of XX interfacial effect or bulk effect relied upon by the sensor. For example, an EAC sensor is of a different type than an EEC sensor. The inventors further note that the ultra high resolution images produced in 15 the practice of the present invention can not only be two-dimensional images, but optionally can also be three-dimensional images through the use of confocal imaging techniques. These and other features and advantages of the present invention will be described hereinafter to those having ordinary skill in the art. 20 Brief Description of the Drawings: Figure i is a perspective view of an exemplary EMR/EPC/EAC/EOC sensor; Figure 2 is a perspective view of an exemplary EAC sensor that is perturbed by an acoustic perturbation source; 25 Figure 3 is a perspective view of an exemplary EOC sensor that is perturbed by a light perturbation source; Figure 4 depicts graphs that compares the optoconductance of a shunted GaAs/In EOC sensor versus a bare GaAs sensor; Figure 5 is a graph depicting the temperature dependence of the EOC effect 30 observed in a GaAs/In EOC sensor; Figure 6 depicts a top view of an exemplary EOC sensor showing how lead geometry can be adjusted; Figure 7(a) illustrates a voltage response calculation for a uniformly illuminated EOC sensor as determined for different voltage lead geometries; -7- Figure 7 (b) illustrates a voltage response calculation for an EOC sensor that is partially covered to achieve nonuniform illumination as determined for different voltage lead geometries; Figure 7(c) illustrates a plot of a voltage response and an EOC response for a 5 uniformly illuminated EOC sensor and a bare semiconductor device as a function of the ratio Ymax/Xmax; Figures 8(a) and (b) depict a top view and side view for an exemplary EOC sensor having a cover to block light from illuminating a portion of the EOC sensor; Figure 9 is a perspective view of an exemplary EEC sensor; io Figure io depicts an I-V curve measured between the shunt and the semiconductor for an exemplary EEC sensor; Figure n depicts an EEC measurement for an exemplary EEC sensor; Figure 12(a) is a cross-sectional view of an exemplary array of EXX sensors; Figure 12(b) is a perspective view of the array of Figure 12(a); 15 Figure 13 depicts schematic diagrams for exemplary multi-EXX sensor arrays showing various pixel geometries; Figure 14(a) is a top view of an exemplary array whose nanosensors are organized as a plurality of pixels; Figure 1 4 (b) is a top view of a pixel corresponding to a plurality of different 20 types of nanosensors; Figures 15(a) and (b) depict exemplary arrays that show how different nanosensors can be grouped into composite pixels; Figure 16(a) is a cross-sectional view of an exemplary array of EXX sensors having an integral macro-scale PZT transducer; 25 Figure 16(b) is a perspective view of the array of Figure 16(a); Figure 17 is a top view of a cell culture dish having an array of nanoscale EXX sensors incorporated therein; Figure 18 depicts an exemplary pitch-catch linear array of multiple PZT transducers; 30 Figure 19 is a flowchart describing an exemplary method for fabricating a nanoscale EXX sensor; and Figure 20 indicates a synthetic aperture focusing technique applied to a plurality of transmit array elements. -8- Detailed Description of the Preferred Embodiments: Figure i illustrates a preferred architecture for a nanoscale EXX sensor ioo of the types EMR, EPC, EAC, and EOC. As shown in Figure i, nanosensor ioo is a hybrid semiconductor/metal device comprising a semiconductor portion 102 and a metal 5 shunt portion 104. The semiconductor 102 and the metal shunt 104 are disposed on a substrate io6. Together, the semiconductor portion 102 and the metal shunt portion 104 define a semiconductor/metal interface io8. Preferably, the semiconductor portion 102 and the metal shunt portion 104 are substantially co-planar as shown in Figure i. Furthermore, the semiconductor portion 102 and metal shunt portion 104 preferably lie io in a substantially parallel plane as the substrate io6. Also, the plane of the semiconductor/metal interface io8 is preferably substantially perpendicular to the plane of the substrate io6. The architecture of the nanosensor ioo of Figure i is referred to as an externally shunted van der Pauw (vdP) plate. The semiconductor portion 102 is preferably a thin semiconductor film having a 15 thickness of approximately iooo nm. However, it should be understood that other thickness values can be used, for example a thickness in a range between approximately 25 nm and approximately 2ooo nm. Furthermore, the semiconductor film 102 preferably has a length of approximately ioo nm and a width of approximately 50 nm. However, it should be noted that other lengths and widths for the 20 semiconductor film can be used, for example any nanoscale value with a lower limit only bounded by lithography capabilities (currently believed to be around 5 nm, but this lower limit may further decrease with the passage of time and improvements in technology). As used herein, the term "thickness" will refer to the dimension along the z-axis as shown in Figure i, the term "length" will refer to the dimension along the y 25 axis as shown in Figure i, and the term "width" will refer to the dimension along the x axis as shown in Figure i. The dimensions for the metal shunt 104 can be a thickness of approximately 1ooo nm, a length of approximately ioo nm, and a width of approximately ioo nm. However, it should be understood that (i) other thickness values could be used, for 30 example a thickness within a range of approximately 25 nm to approximately 2ooo nm, and (2) other lengths and widths could be used, for example any nanoscale length or width whose minimum value is only restricted by available lithography techniques, as noted above. It should also be noted that the dimensions of the metal shunt 104 relative to the semiconductor film 102 are expected to be continuously variable, and -9this relationship defines the filling factor for the device. Also, relative to the dimensions of the semiconductor film 102, it should be noted that the width of the shunt is typically less than or equal to the width of the semiconductor film. Typically, the thickness of the shunt will be the same as the thickness of the semiconductor film, 5 although the shunt may be thinner than the semiconductor film (normally the shunt would not be thicker than the semiconductor film). Preferably, the dimensions of the substrate io6 are much larger than the semiconductor film and metal shunt. The dimensions for the substrate io6 are preferably a thickness of approximately 400 ptm and a diameter of approximately 2 10 inches. However, it should be understood that these values can vary considerable based upon the design choices of a practitioner of the invention. The nanosensor ioo also preferably includes two current leads no and two voltage leads 112. These leads contact the semiconductor film 102 but not the metal shunt 104. Also, these leads preferably contact the semiconductor film 102 on a surface 15 opposite the semiconductor/metal interface io8, as shown in Figure i. With respect to the geometry of the leads, the two voltage leads 112 are preferably disposed between the two current leads no as shown in Figure i. Furthermore, the spacing between leads is preferably selected in a manner to maximize the extraordinary magnetoresistance/piezoconductance/acoustoconductance/ optoconductance effect of 20 the nanosensor ioo. The use of the architecture of Figure i as an EMR sensor and an EPC sensor is known in the art, as explained in the patents and publications cited above and incorporated by reference herein. However, their principles of operation will be briefly re-iterated. The 4-lead effective resistance of the hybrid semiconductor/metal device 25 ioo of Figure i is Reff = V1 3

/I

4 , wherein I and V represent the current and voltage leads no and 112 respectively. The value of Reff will depend on the relative conductivities of the metal 104 and semiconductor 102 (typically, Umeta/(7semiconductor > iooo), on the resistance of the interface io8, and on the specific placement of the current and voltage leads (the lead geometry). When the hybrid semiconductor/metal device ioo is in a 30 non-perturbed state, the highly conductive metal acts as an effective current shunt, provided that the resistance of interface io8 is sufficiently low, and Reff can be close to that of the metal. However, with a relatively small perturbation such as a change in the magnetic field, pressure/strain or temperature applied to the hybrid semiconductor/metal device ioo, a significant change can be induced in the bulk - 10 resistance of the semiconductor 102 and/or the interface io8 resistance, and concomitantly the current flow across the interface io8 will be significantly altered. These induced changes will manifest themselves as a relatively large change in Reff which can then be easily measured via the output voltage signal from the voltage leads 5 112 when a current flow is provided to the hybrid semiconductor/metal device ioo via current leads no. Figure 2 illustrates a use of the sensor ioo of Figure i as an EAC sensor. With an EAC nanosensor, the perturbation that results in the measurable voltage response is an acoustic wave 202. The acoustic wave 202 from an acoustic perturbation source 200 io generates a strain at the interface io8 that results in a measurable voltage via the extraordinary piezoconductance effect. In this manner, the EAC sensor is highly similar to the EPC sensor. Preferably, the direction of the acoustic wave 202 is generally along the z-axis (or perpendicular to the plane of the semiconductor film 102 and metal shunt 104 or substantially in the same plane as the plane of the interface 15 io8). With an EAC/EPC sensor, the semiconductor/metal interface io8 produces a Schottky barrier to current flow. A tensile (compressive) strain along the direction of the interface io8 increase (decreases) the interatomic spacing, thereby increasing (decreasing) the barrier height. Because the tunneling current through the barrier 20 depends exponentially on the barrier height and any change in that tunneling current is amplified by the EAC geometry, a small strain results in a large voltage change/signal. Experimentation by the inventors has shown that the piezoconductance is largest for an EPC sensor whose geometry is characterized by a filling factor of 9/16. See U.S. patent application publication 2002/0129087 Ai. 25 Examples of acoustic perturbation sources that can be used in the practice of the invention include scanning acoustic microscopes (SAMs), ultrasound emitters using synthetic aperture focusing (SAFT), medical imagers with phased array transducers or single element focused or unfocused ultrasound transducers, shock wave devices, mid-to-high intensity focused ultrasound arrays, or alternative sources 30 that are capable of inducing mechanical waves in cells and tissues. As examples, the characteristics of the acoustic perturbation can be as follows: a frequency across the ultra high frequency (UHF) band (300 MHz to 3 GHz, with corresponding wavelengths between 5 ptm and Soo nm), a frequency in the lower portions of the super high - 11 frequency (SHF) band (3 GHz to 3o GHz, with corresponding wavelengths from 500 nm to 50 nm). Figure 3 illustrates a use of the sensor ioo of Figure i as an EOC sensor. With an EOC nanosensor, the perturbation that results in the measurable voltage response 5 is light 302. The light 302 from a light perturbation source 300 that impacts the light exposed surfaces of the semiconductor film 102 and metal shunt 104 results in a measurable voltage via the extraordinary optoconductance effect. Preferably, the direction of propagation for the light 302 is generally along the z-axis (or perpendicular to the plane of the semiconductor film 102 and metal shunt 104 or substantially in the io same plane as the plane of the interface io8). However, as noted below, as the size of the EOC nanosensor decreases, the light will more uniformly illuminate the EOC nanosensor due to the EOC nanosensor's small size. The light perturbation source 300 can be any source of light emissions, such as a laser emitting device or even a cell with fluorescent emissions (such as would be 15 emitted with the introduction of a fluorine-based contrast agent). Further still, the perturbing light can be electromagnetic radiation, spanning infrared to ultraviolet ranges, with wavelengths measured in the hundreds of nanometers. Figure 4 depicts (i) the photo response of a macroscopic GaAs-In semiconductor-metal hybrid EOC sensor ioo (wherein the semiconductor film 102 20 comprises GaAs and the metal shunt 104 comprises In) (upper panel) when exposed to a focused Ar ion laser beam of wavelength 476 nm, diameter io pim and power 5 mW at 1 5 K, and (2) the photo response of macroscopic bare GaAs (without the In shunt) (lower panel) to the same laser radiation. Figure 4 plots the optoconductance versus a scan position of the laser beam along the x-axis of the EOC sensor ioo for a plurality of 25 discrete scan z positions, wherein the x and z directions are characterized by the insets of Figure 4. The panels of Figure 4 illustrate three noteworthy characteristics of the EOC sensor: (i) the output voltage signal amplitude peaks near the voltage probes 112 (see the peaks in the voltage response at locations on the x-axis corresponding to the locations of the voltage probes 112), (2) the voltage response is much larger (-5oo%) for 30 the shunted EOC sensor than for the bare GaAs (thereby demonstrating the EOC effect), and (3) the output voltage signal amplitude decreases as the focal spot of the laser moves in the z-direction toward the In shunt (which translates to the y-axis direction in the sensor ioo of Figure 3). - 12 - These EOC effects can be understood as follows. The laser perturbation is absorbed by the semiconductor film 102 and creates a very high density of electron hole pairs that is much larger than the ambient "dark" density. Because the electrons have a much higher mobility, and therefore a much large mean free path than the 5 holes, the electrons are effectively shorted to ground by the metal shunt 104, leaving a positively charged region of excess holes that extends radially outward from the center of the impacting laser beam on the surface of the sensor ioo. This excess positive charge creates an additional electric field at the voltage leads 112 which results in an enhanced signal as the laser beam passes the probes 112 along the X-direction. 10 However, as the region of excess positive charge moves closer to the shunt 104 along the Z-direction (or y-axis of Figure 3), more and more of the holes are also shorted to ground and the excess decreases. This results in a decrease in signal with increasing Z direction laser impact. An additional contribution to this decrease comes from the drop off in the excess hole induced electric field at the voltage contact with the Z 15 direction distance of the laser spot from those voltage contacts. When there is no shunt 104 present, the electrons cannot be effectively shorted to ground and the amount of excess positive (hole) charge in the region of the laser spot is significantly reduced. Figure 5 plots the temperature dependence of the EOC effect for the sensors of 20 Figure 4. For the GaAs devices, the EOC effect is most pronounced at low temperatures because it is at these temperatures that the mean free path of the excess electrons is sufficiently long for them to reach and be shorted by the metal shunt 104. The carrier mean free path is proportional to the carrier mobility which is temperature independent and varies inversely with temperature for holes. The plot of Figure 5 also 25 shows a least squares fit to the data with a function that varies as 1/T where T is the sample temperature in degrees K, thereby indicating the temperature dependence of the EOC effect. On the basis of this analysis, we conclude that by using a direct gap but narrow gap semiconductor (such as InSb; the room temperature mobility of which is 70 times that of GaAs) and/or a nanoscopic structure for the EOC sensor, the EOC 30 effect should be realizable at room temperature. Also, to alleviate any thermal drifts of the output voltage, the InSb semiconductor can be doped with Si or Te donors so that an extrinsic carrier concentration in the saturation (e.g., temperature independent) range is achieved. - 13 - Also, the inventors note that as the size of the EOC sensor decreases, a point will be reached where the illumination caused by the light perturbation source becomes effectively uniform over the EOC sensor. This uniformity would operate to effectively integrate the plot of Figure 4 over the X position, which results in a 5 significant decrease in the strength of the voltage response from the EOC sensor. One solution to this problem is to asymmetrically position the leads no and/or 112 along the x-axis. In one embodiment, such asymmetrical positioning can be achieved by asymmetrically positioning only the voltage leads 112 along the x-axis. Figure 6 depicts a top view of an exemplary EOC sensor ioo showing the io semiconductor portion 102, the metal shunt portion 104, and the voltage leads 112, and 1122 (corresponding to the leads V 2 and V 3 from Figure 3 respectively). The positions of the voltage leads 112 along the x-axis are shown in Figure 6, wherein the full distance along the x-axis for the semiconductor 102 is shown by Xmax. Using the leftmost position along the x-axis in Figure 6 as the origin and the rightmost position along the 15 x-axis as the value Xmax, it can be seen that the x-axis position of voltage lead 112, is represented by x 1 , and that the x-axis position of voltage lead 1122 is represented by x 2 . The voltage leads are said to be symmetrical if x, and x 2 exhibit values such that x 2 = Xmax - x 1 . To improve the voltage response of the EOC sensor ioo, it is preferred that the voltage leads 112 be asymmetrically positioned along the x-axis. 20 The voltage potential V23 between voltage leads 112, and 1122 shown in Figures 3 and 6 can be calculated as the integral of the surface charge density over the distance to the charge: V23(X1X2)= 1 1 dxdy 0 0 0 (x-x 1 2 d_2 wherein Ymax is the length along the y-axis for the semiconductor portion 102, wherein 25 a(y) represents the surface charge density, and wherein c, represents the permittivity of free space. The surface charge density a(y) can be modeled in any of a number of ways. For example, in one model, the assumption is made that uniform illumination creates a uniform charge density, which could be represented as: 0-(y)= C'.1 I+-(y-y, 2 30 wherein Ctotai represents the total charge, wherein 0 represents the step (Heaviside) function, wherein the factor 1/2 is derived from the fact that proximity to the shunt 104 - 14increases the net positive charge as the more mobile electrons are taken to ground more effectively, and wherein the parameter ys (see Figure 6) reflects the intrinsic differential mobility of the material of interest. A large value of y, would indicate that all of the mobile carriers have access to ground via the shunt 104, while a small value of 5 ys would indicate that a limited number of the mobile carriers have access to ground via the shunt. In this model, ys can be the distance along the y-axis as shown in Figure 6 over which it is assumed that the electrons are effectively shunted to ground. Another model can be made for the surface charge density by fitting a(y) to experimentally measured V 2 3 (y) data. In an experiment where V 23 was measured for an 10 EOC sensor ioo employing degenerately doped GaAs that is exposed to a focused laser spot for the values of Xmax = 10 mm, x, = 3.4 mm, x 2 = 6.6 mm, and Ymax = 1 mm, the V 2 3 values for different values of x, and x 2 can be calculated using the formula above for V 23 with x and y limits of integration over a 40 ptm square (which approximates lengths corresponding to the diameter of the laser spot). Because the resultant V 2 3 data from 15 such an experiment indicates that V 23 (y) is approximately Gaussian, the integrand in the formula above for V 23 must be of the form: y*exp(-y 2 ). Taking in mind a i/y positional dependence, one can solve for the experimentally fit a(y) as follows: The effective radii of the Gaussian fit, rh, can be 1.5 mm, with an offset yh of -o.88 mm. 20 The plot of Figure 7(a) depicts the calculated voltage output V2 of the EOC sensor ioo assuming a uniform charge density, a fixed ys of o.5 mm, and a Ymax/Xmax ratio of 1/io. The different lead positions x, and x 2 are displayed on the xy plane and the voltage is displayed on the ordinate. In this plot, the symmetry of the voltage response is apparent. In this plot, the optimal lead position can be defined as the 25 (x 1 ,x 2 ) positions of (o mm,5 mm) and (10 mm, 5 mm) where the voltage response is at maximum. These positions, with one lead in the middle of the Xmax distance and the other lead at either end of the Xmax distance, can be understood qualitatively as the middle lead being closest to the most charge compared to the lead on the edge that has access to the least charge. 30 It should also be noted that in another embodiment, asymmetrical lead positioning can be achieved by asymmetrically positioning only the current leads 112 along the x-axis. Further still, it should be noted that asymmetrical lead positioning - 15 can also be achieved by asymmetrically positioning both the current leads no and the voltage leads 112 along the x-axis. Another solution to the uniform illumination problem is to shield a portion of the EOC nanosensor that would be exposed to the light perturbation using a cover 5 8oo, as shown in Figures 8(a) (top view) and 8(b) (side view). In this way, nonuniform illumination can be achieved by blocking some of the light from perturbing the exposed surfaces of the semiconductor 102 and metal shunt 104. For example, cover 8oo can be used to block half of the otherwise exposed surfaces of the semiconductor 102 and metal shunt 104. Cover 8oo can be formed from materials such as a thin film 10 (e.g., 20 nm) layer of an insulator (e.g., SiO 2 ) for a bottom surface of the cover 8oo followed by a thicker layer (e.g., 5o nm or more) of any metal as an exposed surface of the cover 8oo. As another example, cover 8oo can be formed from a single layer (e.g., a 50 nm layer) of any opaque insulator. The plot of Figure 7 (b) depicts the calculated voltage output V 23 of the EOC 15 sensor ioo assuming a uniform charge density, a fixed ys of o.5 mm, and a Ymax/Xmax ratio of 1/io, wherein a cover 8oo is used to block half of the exposed surface of the EOC sensor ioo. The different lead positions x, and x 2 are displayed on the xy plane and the voltage is displayed on the ordinate. As can be seen, symmetrical leads can be used without the degradation that one finds in the plot of Figure 7(a). 20 Another geometric parameter that is result-effective to increase the voltage response of the EOC sensor under uniform illumination is the ratio Ymax/Xmax. This can be seen by way of example in Figure 7(c). Figure 7(c) depicts a plot of a calculated output voltage from a uniformly illuminated EOC sensor as a function of the ratio Ymax/Xmax. Figure 7(c) also depicts a plot of an EOC response, wherein the EOC 25 response is defined as the percent difference in the measured output voltage of the EOC sensor as compared to that of a bare semiconductor sensor. Figure 7(c) also depicts the voltage response for the bare device as a function of the ratio Ymax/Xmax. Figure 9 illustrates a preferred architecture for a nanoscale EEC sensor 900. As shown in Figure 9, nanosensor 900 is a hybrid semiconductor/metal device comprising 30 a semiconductor portion 902 and a metal shunt portion 904. The metal shunt portion 904 is disposed on a surface of the semiconductor portion 902, and the semiconductor portion 902 is disposed on a surface of substrate 906 such that the semiconductor portion 902 is sandwiched between the metal shunt portion 902 and the substrate 906. As shown in Figure 9, the metal shunt portion 904, the semiconductor portion 902, - 16 and the substrate portion 906 preferably lie in substantially parallel planes. Together, the contact between the metal shunt portion 904 and the semiconductor portion 906 define a semiconductor/metal interface 908. Thus, unlike the nanosensor ioo of Figure i, the plane of the semiconductor/metal interface 908 of nanosensor goo is 5 substantially parallel with the plane of the metal shunt/semiconductor/substrate. The semiconductor portion 902 is preferably a thin semiconductor film having a thickness of approximately iooo nm. However, it should be understood that other thickness values can be used, for example a thickness in a range between approximately 25 nm and approximately 2ooo nm, wherein the thickness value is io selected to reduce the input resistance for an improvement in thermal noise reduction and signal-to-noise ratio. Furthermore, the semiconductor film 902 preferably has a length of approximately ioo nm and a width of approximately 5o nm. However, it should be noted other nanoscale length and width values of the semiconductor film 902 can be used, for example nanoscale length and widths whose lower limit is only 15 bounded by lithography capabilities. The dimensions for the metal shunt 904 are preferably a thickness of approximately iooo nm, a length of approximately ioo nm, and a width of approximately 5o nm. For an EEC nanosensor, the width and length of the metal shunt 904 are preferably less than or equal to and do not exceed those of the 20 semiconductor film 902. However, it should once again be understood that other thicknesses can be used (for example, any value within a range of approximately 25 nm to approximately 2ooo nm, wherein the thickness value is selected to reduce the input resistance for an improvement in thermal noise reduction and signal-to-noise ratio). Also, the shunt's nanoscale length and width can also be other values selected so as to 25 not exceed the length and width of the semiconductor film, with the lower limit bounded only by lithography capabilities. Preferably, the dimensions of the substrate 906 are sized appropriately to support the dimensions of the semiconductor film 902, and as such the substrate 906 is typically much larger than the semiconductor film and metal shunt. Exemplary 30 dimensions for the substrate 906 are preferably a thickness of approximately 400 ptm and a diameter of approximately 2 inches. However, it should be understood that other dimensions could be used. The nanosensor 900 also preferably includes two current leads 91o and two voltage leads 912. These leads contact the semiconductor film 902 but not the metal - 17 shunt 904. Also, these leads preferably contact the semiconductor film 902 on a surface along the xz thickness of the semiconductor film 902, as shown in Figure 9. With respect to the geometry of the leads, the two voltage leads 912 are preferably disposed between the two current leads 91o as shown in Figure 9. Furthermore, the 5 spacing between leads is preferably selected in a manner to maximize the extraordinary electroconductance effect of the nanosensor 900. With the EEC nanosensor of Figure 9, in the absence of an external perturbing electric field, bias current entering at current lead I, and exiting a current lead 14 will flow primarily through the metal shunt 904 due to its much higher conductivity than io the semiconductor film 902. However, to access the metal shunt 904, this current must, for the proper choice of materials, tunnel through the Schottky barrier at the interface 908. This tunneling current varies exponentially with the external bias that is applied to the barrier. Thus, if a perturbing electric field impacts the interface 908 (such as the surface charge of a cancer cell that is deposited on the surface of the EEC 15 sensor), then the perturbing electric charge will be normal to the interface 908. This perturbing field will cause a redistribution of the surface charge on the metal shunt 904, which will result in a bias field applied to the Schottky barrier. The resultant exponential change in tunneling current will result in the reapportionment of current flow between the semiconductor 902 and the metal shunt 904, which will result in a 20 large detectable change in the voltage measured between voltage leads 912. The inventors have estimated the magnitude of the electric field that one can expect from a cancer cell as follows. A claim is commonly made that normal cell in vivo have a negative charge, and values between -ioo to -io mV (which does not have the correct units for charge) are cited in the literature. These voltage values are 25 obtained using electrophoresis measurements, which are only indirectly related to the actual cell charge. Frequently, these "charge" measurements are made using a turn key device such as a Zeta-Sizer, which works by using laser light scattering to measure drift velocity of charged particles in an electric field (while suspended in a buffer solution). The directly measured quantity is the velocity v given by: 30 v=pE where E is the applied field (typical value: E - io-' V/m), and where p is the electrophoretic mobility, a derived quantity that depends on the properties of the charge particle. For particles having sizes near those of a cell, one has: - 18 ps /q (Smoluchowski's equation) where s, is the relative permittivity, where q is the viscosity, where so is the permittivity in vacuo, and where ;is the Zeta potential. For a typical measurement, one has - 10-2 to io-' V, 7 ~ 10- 3 Pas, and c, - 8o, which implies p 5 - o.7-7.oXio- 8 ms-'V', which in a typical field of E - 1o-' V/m implies: v = pE = (0.7 x 10- m 2 s- 1

V-

1 to7.0x 10-8m2s-1V-1)x (10-1v /m) = 0.7x 10-9ms- 1 to7.0x 10- 9 ms-1 Assuming that the particles are small, the electric force F that they experience is: F=Exq where q is the total charge on the particle. This is balanced by the viscous drag of the io suspending medium given by: F = 6fcqRv for a small spherical particle, of radius R, moving at velocity v, which is low enough to prevent turbulence. If one assumes a typical cell radius of R - io- m and use the typical values for v and q cited above, one has: 15 F ~6rcRv= 6rcx 10 3 Pasx 10- 5 mx 0.7-7.Ox 10- 9 m/s =1.3-13x10-1 6 N Inserting this value into F=Eq above, and using the typical value of E - 1o-' V/m gives: F : (1.3x10-16 N.to. 1.3x10- 5 N)~ 10-1(V I m)xq which solves as q = 1.3xio' 5 to 13xio' 5 coulombs. If one assumes that this charge resides on the surface of the cell, it will produce a normal electric field on the order of ioo 20 V/cm to iooo V/cm. The inventors estimate that a field in this range will produce an output voltage of 27 to -270 pV in a nanoscale EEC sensor 9oo with a o.5 V forward bias voltage applied between the metal shunt and output current lead. Thus, the surface charge induced bias field at the semiconductor/metal interface 908 should be easily detectable in the voltage response of the EEC sensor. 25 Moreover, in instances where the Schottky barrier of the EEC nanosensor is detrimentally perturbed by chemical impurities at the semiconductor/metal interface 908, the inventors believe that adding a forward bias voltage to the barrier should alleviate this issue. Figure io depicts a measured current-voltage plot of a horizontal configuration 30 for an EEC sensor 9oo having a Schottky barrier interface between GaAs and In as shown in the inset of Figure io. The dimensions of this EEC sensor were 6o Im x 30 - 19 pm x 50 nm, with respect to the x, y, and z axes respectively. From this plot, it can be noted that there is an exponential increase of current with forward bias (positive) voltage in the o - 0.5 V range and that the current is nil in the reverse bias range to about -1.5 V. At higher reverse bias, current leakage results as indicated in Figure io. 5 Figure n depicts a measured EEC characteristic of a circular EEC sensor as shown in the inset of Figure n. These EEC measurements were made as a function of the geometric filling factor, a=r/R (see Figure n inset) and of the direct forward and reverse bias on the Schottky barrier for fields in the range of -1050 V/cm to +450 V/cm, as indicated in Figure n. It can be noted that the estimates of the field at the surface of io a cancer cell due to the known total charge of ~1i*io- Coulomb is in the range io 2 - 1o V/cm. In this regard, as a quantitative measure of the EEC effect, one can define the EEC effect as: EEC = 100%G,,,,,, - G wherein G is the conductance of the EEC sensor, and wherein "with field" means in the 15 presence of the external field that perturbs the EEC sensor (e.g., the field produced by the surface of a cancer cell). As can be seen in Figure n, the EEC depends strongly and increases with filling factor in both the forward and reverse bias directions, reaching values in excess of 50% on saturation in the forward direction. By selectively doping the semiconductor 902 20 with Si to tune the properties of the Schottky barrier, further improvements to the EEC sensor performance can be expected. With respect to these nanoscale EXX sensors, a variety of combinations of semiconductor materials, metal shunt materials, and substrate materials can be chosen. 25 For EMR nanosensors, examples of suitable semiconductor materials include InSb, InAs, and Hg 1 xCdxTe, or any narrow gap semiconductor, and an example of a suitable metal is Au or any good non-magnetic metal. Examples of suitable a substrate material for EMR nanosensors include any highly insulating wide gap semiconductor or insulator, with the preferred material being GaAs both because of its advantageous 30 properties and cost. For EPC and EAC nanosensors, examples of suitable semiconductor materials include GaAs, InAs or other III-V semiconductors, and examples of suitable metals - 20 include Au or any other high conductivity metal. With respect to a substrate material for EPC/EAC nanosensors, the choice of substrate material may vary based on the type of perturbation for the sensor. For example, one can select a "stiff' substrate such as GaAs to detect high frequency, large amplitude acoustic signals, whereas GaSb would 5 be a more desirable choice for low amplitude, low frequency signals. Signal selectivity can also be tuned through judicious design of the substrate's dimensional and geometric properties - for example, a long, thin and narrow substrate would also be linearly responsive to weak acoustic perturbations while a thick substrate would be more linearly responsive to stronger acoustic perturbations. In situations where both io the substrate and semiconductor film are made of GaAs materials, the GaAs used in the semiconductor film should have a different impurity concentration than the GaAs used in the substrate. For EOC nanosensors, examples of suitable semiconductor materials include GaAs, InSb, and other direct gap semiconductors, and examples of suitable metals 15 include In or any high conductivity metal. Examples of a suitable substrate material include GaAs and other high resistance materials. Once again, in situations where both the substrate and semiconductor film are made of GaAs materials, the GaAs used in the semiconductor film should have a different impurity concentration than the GaAs used in the substrate. 20 For EEC nanosensors, examples of suitable semiconductor materials include GaAs, and other doped semiconductors, and examples of suitable metals include Au or any other high conductivity metal. Examples of a suitable substrate material include GaAs or any suitably insulating substrate material. Once again, in situations where both the substrate and semiconductor film are made of GaAs materials, the GaAs used 25 in the semiconductor film should have a different impurity concentration than the GaAs used in the substrate. With respect to providing a current flow to the EXX nanosensors, a suitable biasing current is preferably in a microamp or milliamp range depending upon the application and the actual type of EXX sensor. 30 The nanosensors described above in connection with Figures 1-9 can be combined to create an NxM array 1200 of multiple nanoscale EXX sensors 1202 as shown in Figures 12(a) and 12(b). The values of N and M can be chosen by practitioners of the present invention as a design choice based on their intended use of the nanoscale EXX sensors (e.g., 4x4, 16xi6, 2x20, 64x64, etc. with upper values only - 21 bounded by manufacturing capabilities). For example, the inventors contemplate that nanosensor matrix dimensions judging from current digital display technologies can also be 64ox48o, 8oox6oo, 1024x768, 16oox1200, 2048x1536, and 320ox240o. These nanoscale EXX sensors 1202 can be deposited on an array substrate 1204 such as an 5 SiO 2 substrate. A preferred thickness for substrate 1204 is approximately 400 ptm, although other thicknesses can be used. It should be noted that the voltage and current leads of the individual nanoscale EXX sensors are not shown in Figures 12(a) and (b) for ease of illustration. It should also be noted that a via design for row/column pin-out addressing from the matrix of nanosensors 1202 in the array 1200 io can be used, particularly for arrays having large numbers of nanosensors (see Figure 13). For the array structures shown in Figure 13, each of the 4-leads for the EXX sensors 1202 can be individually addressable, thereby yielding 4n 2 pin-outs for an n x n array. Furthermore, these leads can be selectively combined to yield a reduction to 3n+1 pin outs for an n x n array. 15 It should also be noted that in instances where the individual EXX sensors are designed to have a substrate io6 of the same material as substrate 1204, then the EXX sensor 1202 that is located on array 1200 will not need to include substrate io6 as the material of substrate 1204 can then serve as the appropriate substrate. However, if the substrate materials are dissimilar, then the individual EXX sensors 1202 will preferably 20 include their own substrate io6 (e.g., when the EXX sensor 1202 has a GaAs substrate io6 while the array 12oo has an SiO 2 substrate 1204). Preferably, the array 12oo exhibits tight spacing between EXX sensors 1202. For example, a spacing value that falls within a range of approximately 5o nm to approximately iooo nm can be used. The selection of EXX sensor type(s) and distribution of EXX sensor type(s) over 25 the array 1200 can be highly variable. For example, the array 1200 can include only nanoscale EXX sensors 1202 of a single type (e.g., an array of only EAC sensors, an array of only EOC sensors, an array of only EEC sensors, etc.) Also, the array 1200 can include a plurality of different types of nanoscale EXX sensors, such as any combination of nanoscale EMR/EPC/EAC/EOC/EEC sensors 1202. Integrating 30 multiple different types of EXX nanosensors in an array (such as EAC/EOC/EEC nanosensors) will provide for a screening system capable of performing HCS for prospective interrogation of cells based on the outcome of charge and fluorescent imaging, like LSC. However, the resolution of the acoustic subsystem will be equal to or greater than that obtained from optical microscopy, and moreover will represent - 22 volumetric data (i.e., not be limited to a single focal plane at a time), as the time axis of the digitized ultrasound waveforms contains information that can be mapped to distance into the cell being imaged via the dispersion relationship directly analogous to imaging organ structures with currently available clinical ultrasound systems. This 5 type of instrumentation would offer several advantages not available in current cytometry/microscopy instruments such as simultaneous acquisition of volumetric data based on nanoscale acoustic microscopy, higher resolution than current optical microscopy without necessarily requiring expensive high intensity light sources, high precision and resolution surface charge measurements without the complications and io ambiguities inherent in electrophoretic techniques, and high resolution, low noise fluorescent imaging. It should also be noted that the array 1200 can be thought of as being subdivided into a plurality of pixels 140o, as shown in Figure 14(a). Each pixel 1400 can comprise one or more nanosensors 1202. For example, as shown in Figure 1 4 (b), a pixel 15 1400 can comprise a plurality of different types of nanosensors 1202, such as 4 nanosensors of types "A", "B", "C", and "D" (wherein type "A" could correspond to an EOC nanosensor, wherein type "B" could correspond to an EPC nanosensor, wherein type "C" could correspond to an EEC nanosensor, and wherein type "D" could correspond to an EMR nanosensor). Such groups of different types of nanosensors 20 within a pixel 1400 can be helpful for increasing the sensitivity of the array 12oo by using signal averaging techniques on the voltage responses of the nanosensors. Similarly, it should be noted that pixels 1400 or portions thereof can be grouped with other pixels 1400 or portions thereof to form composite pixels. For example, Figure 15(a) depicts a composite pixel 15oo formed from a grouping of 4 pixels 25 1400 of the arrangement shown in Figure 1 4 (b). Furthermore, the composite pixel 15oo can be formed of only a single type of nanosensors (e.g. only the "A" type nanosensors within those four pixels 140o, as shown by the boldface notation in Figure 15(a)). Once again, such arrangements of composite pixels can be helpful for increasing sensitivity through the use of signal averaging techniques. 30 Figure 1 5 (b) depicts an example of a composite pixel 1502 that is formed from a plurality of nanosensors of the same type that are arranged in a straight line and has a length of a plurality of pixels 1400 (e.g., the "A" type nanosensors shown in boldface within composite pixel 1502). Figure 1 5 (b) also depicts an example of a composite pixel 1504 that is formed from a plurality of nanosensors of the same type that are arranged - 23

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in a straight line orthogonal to composite pixel 1502 and has a length of a plurality of pixels 1400. Composite pixels arranged such as composite pixels 1502 and 1504 can be useful for phase-type imaging of optical signals, polarizing deflected light, or detecting different acoustical modes (e.g., shear, transverse, various plate modes) depending on 5 the type of nanosensor employed. As an object such as one or more cells is placed into contact with the array 1200 on the exposed surfaces of the EXX sensors 1202, and as the EXX sensors 1202 of the array are perturbed, the voltage responses of the various EXX sensors 1202 can be measured, digitized, stored, and processed by receiver electronics including a signal io processor (not shown). The collection of voltage responses can in turn be selectively pixelized based on the spatial relationship among the EXX sensors to generate an image of the object that is indicative of one or more characteristics of the object. Both single-modality images and multi-modal parameterized images can be generated by registering and combining the output from different types of nanosensors. Because of 15 the nanoscale of the array's EXX sensors, the resultant images would also exhibit a resolution that is nanoscale. Furthermore, each nanoscale EXX sensor 1202 can be independently addressable by the receiver electronics to permit an increased data acquisition rate (imaging frames of a given area of an object per unit time). Also, it should be noted that to enhance the ability of cells to grow and adhere to the array 20 surface, the exposed surface of the array on which the one or more cells contact the array can be coated with a protein such as fibronectin, vitronectin, collagen, or a protein-mimetic such as poly-l-lysine or silane. For example, with an array 1200 comprised of multiple EAC and EEC sensors 1202, after a cell is placed on that array, the array can be perturbed with an acoustic 25 wave to obtain voltage responses from the EAC sensors from which an ultrasonic image of the cell having nanoscale resolution can be generated. At the same time, the EEC sensors on the array 1202 can be perturbed with a surface charge from the cell itself to produce voltage responses from the EEC sensors from which an image having nanoscale resolution and representative of the spatial distribution of electric charge 30 over the cell can be generated. Further, still, because the surface charge from the cell is not likely to perturb the EAC sensors and because the acoustic wave is not likely to perturb the EEC sensors, cross-talk between the EEC and EAC sensors can be minimized, and images of multiple characteristics of the cell can be simultaneously generated. - 24- However, it should be noted that in instances where the array 1200 includes both EAC/EPC sensors and EOC sensors, cross-talk can occur where the light perturbation causes an undesired voltage response in the EAC sensor and the acoustic perturbation causes an undesired voltage response in the EOC sensor. To reduce the 5 effects of such cross-talk, one can selectively perturb the EAC sensors at a different time than the EOC sensors with sequentially applied perturbations and selective interrogation of the nanosensors based on which perturbation has been applied. In instances where the cell itself is the source of the light perturbation (presumably not a spontaneous light emission by the cell but rather a light emission following exposure io to an external optical field), cross-talk can be reduced when there is a phosphorescent component present within the cell. In such a case, signal processing techniques (lock in amp, digital lock-in, pulse gating, time correlation, etc.) can be used to distinguish EAC and EOC signals. For EOC in the cases of absorption and reflectance the response of the cell will be essentially instantaneous, e.g. the absorption and reflection signals 15 will have essentially the same profile as the incident light signal with essentially no phase delay on the time scales of relevance here. So temporal separation of either absorption or reflection EOC from EPC should not be problematic. In the case of fluorescence, the EOC signal will depend on the fluoroescence lifetime of the cell. If this is in the sub microsecond range or shorter, the fluorescence signal can be handled 20 in the same way as absorption and transmission EOC. If it is of order a millisecond or longer, then an (essentially DC) EOC baseline shift can be added to the EPC signal but the signal above the base line should still be easily discernable. The corrollary is applicable for detection of an EPC signal in the presence of a long lived fluorescence, but by gating the detection system to coincide with the shorter time acoustic signal the 25 baseline shift can be rejected. There are also hardware methods to accomplish signal selection. By fabricating a substrate with thick and thin regions and depositing the EOC sensors on the thick regions and the EPC sensors on thin ones, the EOC regions can be made impervious to acoustic signals, whatever their temporal properties. Similarly, by depositing a thin but optically opaque surface film on only the EPC 30 sensors, they can be made impervious to any optical signals regardless of their temporal properties. The source of the pertubation(s) for the EXX sensors 1202 can be one or more external perturbation sources as explained above, the object itself (particularly for EOC and EEC nanosensors), or a perturbation source that is integral to the array. For - 25

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example, a laser source such as a near-field scanning optical microscope (NSOM) can use SAFT techniques to spatially localize a photon field to a small size (on the order of i micron or less and less than the spacing between EXX sensors on the array) that can be scanned/driven in X and Y directions across the array by the piezoelectric X and Y 5 motion controls of a scanning tunneling microscope (STM) to which the NSOM has been attached/adapted. The STM could be used to perturb any EAC nanosensors while the NSOM could be used to perturb any EOC nanosensors. The NSOM would guide light from the appropriate laser through a submicron-sized aperture at the end of a tapered and metallized optical fiber. The near field method can provide photon io fields with a lateral localization as small as 5oo nm in the visible region. Further still, a spatially localized field for perturbing EEC nanosensors could be obtained by mounting a tapered metallic tip to the STM scanner and applying a known voltage between the tip and a metallized back surface on the substrate 1204. For both the laser perturbation and the electric field perturbation, the spatial resolution of the applied 15 field would depend on its maintaining close proximity to the surface of the sensor array. Such proximity can be maintained by feedback control of the STM's Z-motion via a signal from the STM (guiding) tip. It is also worth noting each of the array's EXX sensors can receive its own biasing current flow such that not all of the array's EXX sensors will receive the same 20 current flow. For example, EXX sensors i-io of an array may receive current A while EXX sensors 11-20 of that array may receive current B. As a further example, 20 different currents could also be delivered to the array's 20 EXX sensors. Figures 16(a) and (b) illustrate another array embodiment for the present invention wherein a perturbation source is integral to the array 16oo. The array 16oo 25 includes an integral PZT transducer 1604 that serves to generate the acoustic wave for perturbing the array's EAC/EPC nanosensors 1202. As with the array 1200, the voltage and current leads of the individual nanoscale EXX sensors 1202 are not shown in Figures 16(a) and (b) for ease of illustration. However, it should be noted that ground signal-ground (GSG) wiring geometries for electrical traces deposited on substrate 1204 30 to the nanosensor leads can be employed to improve characteristics in the UHF and SHF ranges of signal frequencies. With array 16oo, the EXX sensors 1202 and substrate 1204 can be arranged as explained above in connection with Figures 12(a) and (b). However, due to the presence of the PZT transducer 1604, it is preferred that at least some of the nanoscale EXX sensors 1202 are EPC/EAC sensors. The array 16oo also - 26 preferably includes a transducer backing material 16o8 that lies in a plane substantially parallel to the plane of substrate 1204. A material and thickness for the backing material 16o8 is preferably selected to have an acoustic impedance that is similarly matched to the acoustic impedance of the piezoelectric thin-film transducer 1604 and 5 lossy enough (to attenuate the acoustic wave launched into the backing material) to minimize undesired multiple reverberation resonance effects and to "spoil the Q" of the thin-film 1604 to effectively broaden the useful frequency bandwidth of the device (corresponding to shorter time pulses and greater axial resolution). An example of a backing material 16o8 could be an epoxy-resin with ground Tungsten particles. io However, it should be noted that other backing materials may be used as explained above. Furthermore, as the broadband transducer gets into the GHz range (rather than the MHz range), the inventors herein believe that the choice of backing materials 16o8 may be less impactful on performance. Disposed between the substrate 1204 and the backing material 16o8 is a 15 macroscale piezoelectric transducer 1604 in contact with a ground conductor 1602 and a hot conductor 16o6. The macroscale piezoelectric transducer 1604 also preferably lies in a plane that is substantially parallel to the plane of the substrate 1204. By driving the piezoelectric transducer 1604 with a current flow through conductors 1602 and 16o6, the piezoelectric transducer emits a broadband acoustic plane wave whose 20 plane is substantially parallel to the plane of substrate 1204 and whose direction of propagation is substantially normal to the plane of substrate 1204 (and by derivation in plane with the plane of the semiconductor/metal interfaces io8 of the EPC/EAC nanosensors of the array). This broadband acoustic plane wave serves as the perturbation for the EPC/EAC nanosensors. The piezoelectric transducer 1604 can be 25 formed from a thin-film piezoelectric transducer material, such as thin-film poly crystalline or single crystal of perovskite ceramic materials (e.g., PZT: Lead Zirconate Titanate, and doped-derivatives such as PNZT: Niobium-doped PZT, PLZT: Lanthanum-doped PZT, PMN-ZT: magnesium niobate-doped PZT, etc.), or polymer materials (e.g., PVDF: Polyvinylidene difluoride) and exhibit a thickness between 30 approximately 20 nm and approximately 2ooo nm to tune the frequency response to a desired range. However, it should be noted that other materials and thicknesses can be used. The frequency of the broadband acoustic plane wave can be in the GHz range (e.g., approximately 1-5 GHz), although other frequency values can be used. - 27

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The broadband plane wave produced by the macroscale PZT transducer 1604 serves to improve the quality of images reconstructed from backscattered ultrasound, and the array 16oo permits insonification of an object being imaged at pressure levels that would be difficult to obtain using a nanoscaled acoustic transmitter. Moreover, by 5 separating the transmit and receive elements (transducer 1604 and nanosensors 1202 respectively), the receiving electronics (not shown) can be greatly simplified to permit higher drive levels on transmit and to improve both SNR and bandwidth aspects of signal receipt. Furthermore, by integrating both the transmit and receive elements into a single array, the need for external acoustic perturbation sources such as io expensive SAMs can be avoided. The integrated array 16oo or the array 1200 can be mass produced to provide inexpensive (even disposable) imaging devices that could be incorporated into the bottoms of cell culture dishes 1700 (see Figure 17), thereby providing the ability to acoustically image either large numbers of or single cells and to continuously provide 15 data that facilitates monitoring of the safety and efficacy of therapeutic agents intended for treatment of diseases such as cancer, heart disease, inflammatory conditions, etc. Figure 18 illustrates another embodiment of an imaging array in accordance with the present invention. Figure 18 depicts a multi-element pitch-catch array 18oo. 20 The array 18oo comprises 64 pairs of rectangular piezoelectric (e.g., PZT or other piezoelectric materials such as described above) elements 18io that are spaced evenly in a linear configuration of opposing pairs 1802 that are 20 ptm apart. Base 18o6 and supports 1804 hold the pairs 1802 of PZT elements 18io in opposition to each other. Driving electronics (not shown) for delivering power to the PZT elements will also be 25 included in the array 18oo. Exemplary dimensions for the piezoelectric elements are 6.o ptm high, 30o nm thick, 250 nm wide, and with a 5o nm spacing between elements (for a 30o nm element pitch and an overall azimuth of 19.2 ptm for all 64 elements). However, other dimensions can be used, wherein Sol Gel deposition can be used as a technique to fabricate nanoscale PZT elements. 30 The 64 PZT elements 18io (that are shown in a front view in the bottom portion of Figure 18) are configured to generate ultrasonic pulses that will propagate across the 20 ptm gap to their opposing partners, which will function as receivers. In a pulse/echo mode, the 64 PZT elements on the opposing side of the array will act as reflectors. An - 28 object to be imaged by array 18oo can be placed between the opposing pairs 1802 and ultrasound pulses can be used to generate ultrasound data from which ultrasound images of the object can be reconstructed. Furthermore, an NxM (e.g., 16xi6) array like the one shown in Figures 12(a) and 5 (b) can be made of these PZT elements 18io, fabricated on the nanoscale, for use in the generation of ultrasound images. As with the arrays 12oo and 16oo, such an array can be used to generate ultra high resolution images of a cancer cell that is grown on the array surface. Acoustic images of such a cancer cell can be made with ultrasound at frequencies such as 2.7 GHz or 5.2 GHz using SAFT techniques. To improve such an 10 array's SNR, the pulse-repetition frequency of the ultrasound pulses may be increased, and/or signal averaging techniques can be used. Because the transmit frequency for the preferred ultrasound pulses is high (preferably in the GHz range; thereby implying short pulse lengths) and because the round trip distance would be short, the inventors herein envision that signal averaging for such arrays will not face the usual problems 15 that limit signal averaging's utility to conventional ultrasonics. It should also be noted that the arrays 12oo and 16oo described above could incorporate nanoscale PZT elements 18io in combination with the individual EXX sensors 1202 described above. Figure 19 depicts a methodology for fabricating nanoscale EXX sensors using a multi-step electron beam (e-beam) lithography process At step 19oo, a thin film wafer 20 of semiconductor material 102/902 is provided. Next at step 1902, a 30 nm thick insulating film of Si 3

N

4 (added to prevent shorting between the leads and the shunt) is deposited on the thin film wafer as a cap layer. At step 1904, macroscopic Au strips for wire bonding are deposited on the cap layer in a pattern that radiates outward from the edges of an 8o pm square area that is defined on the substrate 106/906. Next, at 25 step 1906, a 3o nm thick calixarene film is spin coated onto the surface of the thin film wafer. At step 1908, four 3o nm x 3 km Au strips will be delineated in the calixarene in the corners of the 8o pm square area by e-beam lithography. This calixarene pattern and the macroscopic Au strips will serve as a mark for reactive ion etching (RIE) of the Si3N4 layer using conventional methods (step 191o). This RIE process (step 1910) 30 produces a raised mesa of the thin film on its supporting substrate. For InSb films, an appropriate etchant is a CH 4 + H2 mixture. The residual Si3N4 and Au strips serve as an RIE mask. Then, at step 1912, Au leads and an Au shunt will be deposited using a Ge stencil mask and a shadow evaporation technique. The inventors believe that such - 29 fabrication will result in EXX nanosensors with a volumetric resolution of 35 nm (the voltage probe spacing set by the limits of suspended mask e-beam lithography) x 30 nm (the width of the mesa set by RIE etching properties and the resolution of calixarene resist patterns) x 25-250 nm (the thickness of the thin film material, along 5 the x-, y-, and z-axes respectively. See Solin et al., Room temperature extraordinary magnetoresistance of non-magnetic narrow-gap semiconductor/metal composites: Application to read-head sensors for ultra high density magnetic recording, IEEE Trans Mag., 2002;38, pp. 89-94; Pashkin et al., Room-temperature Al single-electron transistor made by electron-beam lithography, Applied Physics Letters, 2ooo; 76, p. 2256; M. 10 Sugawara, Plasma Etching, New York; Oxford, 1998, the entire disclosures of each of which are incorporated by reference herein. As would be understood by a person having ordinary skill in the art, this technique can be applied to the fabrication of not only EPC, EAC, EOC, EMR, and EOC nanosensors but also EEC nanosensors (although the fabrication of the EEC nanosensors may be less demanding because of the 15 architectural difference therebetween). To minimize leakage current through the floor of the mesa, an insulating A1 2 0 3 barrier can be first prepared by depositing and subsequently oxidizing a layer of Al to within 5o nm of the mesa sidewall. An alignment accuracy of about +/- io nm normal to the mesa sidewall is desired. 20 Furthermore, when fabricating an array 1200 or iooo, it is preferred that the EXX nanosensors 1202 be designed and fabricated together as an array rather than individually fabricating each EXX nanosensor 1202 and then aggregating the individual EXX nanosensors 1202 into an array. Also, when fabricating an array of nanoscale EXX sensors, a substrate 1204 25 thinning process can be used to optimize the array's performance, although this thinning is preferably achieved using a feedback-controlled process that thins the substrate at increasingly slower and controllable rates to avoid a punch through of the EXX sensors through the substrate. Further still, when fabricating such arrays of interdigitated nanosensors, several additional mask steps can be used in the suspended 30 mask e-beam lithography process. The SAFTs referenced above can be implemented using conventional SAFTs or several variants thereof, wherein the variants of the conventional SAFT algorithm reduce the number of array elements required and offer improvements in SNR. These variants include multielement-subaperture SAFT (see Gammelmark et al., "Multielement - 30 synthetic transmit aperturn imaging using temporal encoding", IEEE Transactions on Medical Imaging, 2003; 22, pp. 552-63, the entire disclosure of which is incorporated herein by reference), which has been shown to achieve higher electronic signal to noise ratio and better contrast resolution than the conventional synthetic aperture focusing 5 techniques. Another SAFT approach is based on sparse array SAFT which offers the advantage of a reduction in the number of array elements (obtained at the price of lower transmitted and received signal). These drawbacks can be minimized by increasing the power delivered to each transmit element and by using multiple transmit elements for each transmit pulse. Another SAFT option is to use a 10 combination of B-mode and SAFT that has been shown to improve lateral resolution beyond the focus of the transducer and by using apodization to lower the sidelobes, but only at the expense of lateral resolution, as with classical synthetic aperture imaging. Results obtained by this technique show that, for a 15 MHz focused transducer, the 6-dB beamwidths at 3, 5, and 7 mm beyond the focus are 189 tm, 184 15 ptm, and 215 ptm, respectively. For images made by scanning a 0.12 mm wire, SNR is 38,6 dB when the wire is at the focus, and it is 32.8 dB, 35.3 dB and 38.1 dB after synthetic aperture processing when the wire is 3, 5, and 7 mm beyond the focus, respectively. At 1-2 GHz, these beamwidths and SNRs imply resolution would scale down to the nanometer range. 20 Figure 20 shows an approach to synthetic aperture imaging that follows Frazier's description. Figure 20 depicts an array of elements labeled by the index i. In order to simplify the description, only the receive side of the imaging problem where each element is fired simultaneously will be considered. It is desired to process the backscattered signals Si(t) measured at each array element so that those signals are 25 effectively focused at the point P. This may be achieved by appropriately delaying various signals from the array elements and summing them ("delay-and-sum" beam forming). The field from the array will be focused at the point P if all pulses from the array elements arrive there simultaneously. This can be effected in post-processing if one shifts each backscattered pulse by 30 At = 2z /c(1- 1+ id /z) and then summing each of the received waveforms according to: A(t) = w, (P)S,(t - At,) - 31 where the wi(P) terms are weights assigned to each element and are functions of the chosen focal point P and also array element transmit properties that affect the field it transmits. These weights are used to achieve aperture apodization, which is necessary to obtain increased resolution. The inventors have obtained satisfactory results using a 5 unit rectangle function whose width is determined by the transducer used to acquire raw data. See Bracewell, RN, The Fourier Transform and its Applications, New York, McGraw-Hill, 1978, the entire disclosure of which is incorporated by reference herein. For applications where higher resolution is desired such as with the nanosensors described herein, other apodizations such those described by Frazier can be used. 10 While the present invention has been described above in relation to its preferred embodiment, various modifications may be made thereto that still fall within the invention's scope. Such modifications to the invention will be recognizable upon review of the teachings herein. For example, the nanosensor embodiments described herein have been described as having a generally rectangular plate shape. It should be 15 noted that other geometries could be used for the nanosensors. For example, a circular semiconductor material with an embedded concentric metallic shunt. Also, it should be noted that the inventors envision that the nanoscale EXX sensors and/or arrays of such nanoscale EXX sensors can be implanted into a patient's body (such as within a patient's vasculature) for imaging internal bodily conditions of the patient. 20 These sensors or arrays could be implanted in much that same way that subcutaneous pumps, or cardiac pacemakers and defibrillators, or the routes for any prosthetic device are implanted. The inventors contemplate that delivery and deployment via intravascular catheters would be used. Such nanosensors and arrays can be configured with a telemetric output, such as by transmitters incorporated into the arrays that 25 produce signals (e.g. radio signals) that can be monitored remotely with appropriate receivers, as it the case with implanted pacemakers, to provide in vivo ultra high resolution imaging of internal body conditions and processes or they can include on board local memory in which the voltage responses can be stored for subsequent analysis upon retrieval of the array. For biasing currents, the nanosensors or arrays 30 can be configured with their own on board energy sources. Further still, the nanosensors and arrays of the present invention may also be used for other non-medical applications, including but not limited to real-time in process monitoring of any nanoscale events detectable by the sensors and incorporation into field sensors for environmental monitoring. For example, the - 32

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inventors envision that nanoscale EOC sensors can be useful as position sensitive detectors and as photosensors and that nanoscale EEC sensors can be useful for pixel monitoring in flat panel displays. Accordingly, the full scope of the present invention is to be defined solely by 5 the appended claims and their legal equivalents. Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of 10 integers or steps. The reference to any prior art in this specification is not, and should not be taken as, an acknowledgement or any form of suggestion that the prior art forms part of the common general knowledge in Australia. Further, the reference to any prior art in this specification is not, and should not be taken as, an acknowledgement or any 15 form of suggestion that such art would be understood, ascertained or regarded as relevant by the skilled person in Australia. - 33 -

Claims (32)

1. An apparatus for sensing a characteristic of an object, the apparatus comprising: a planar semiconductor material, the semiconductor material comprising a planar surface; and a metal shunt located on the planar surface of the semiconductor material, wherein the metal shunt covers a portion of the planar surface of the semiconductor material, thereby defining a planar semiconductor/metal interface; wherein the semiconductor/metal interface is configured to exhibit a change in resistance thereof in response to the semiconductor/metal interface being perturbed by an electric charge perturbation, the change in resistance being indicative of the characteristic of an object that is in proximity to the apparatus.

2. The apparatus of claim 1 further comprising: at least two current leads in contact with the semiconductor material for delivering a predetermined current flow to the semiconductor material; and at least two voltage leads in contact with the semiconductor material for producing a measurable voltage in response to the perturbation, the voltage being indicative of the characteristic of the object.

3. The apparatus of claim 2 wherein the semiconductor material comprises a semiconductor film having a thickness of in a range of approximately 25 nm to approximately 2000 nm, wherein the metal shunt has a thickness in a range of approximately 25 nm to approximately 2000 nm, and wherein the semiconductor film has a length in a range of approximately 25 nm to approximately 500 nm and a width in a range of approximately 25 nm to approximately 500 nm.

4. A method of generating an image of at least one cell, the method comprising: providing a predetermined current flow to a plurality of EEC sensors that are in proximity with at least one cell, each of the EEC sensors comprising: (1) a planar semiconductor layer, the semiconductor layer having a planar surface, (2) a metal shunt that contacts and partially covers the planar surface of the semiconductor layer, thereby defining a planar semiconductor/metal interface; 35 perturbing the EEC sensors with an electric charge to thereby produce a voltage response by each of the perturbed EEC sensors; for each of the perturbed EEC sensors, measuring the produced voltage response; and generating an image from the voltage responses, wherein the generated image is indicative of at least one characteristic of the at least one cell.

5. The method of claim 4 wherein the EEC sensors comprise nanoscale EEC sensors, and wherein the generated image has a nanoscale spatial resolution.

6. An apparatus comprising: a planar semiconductor layer, the semiconductor layer having a planar surface; and a metal shunt that contacts and partially covers the planar surface of the semiconductor layer, thereby defining a planar semiconductor/metal interface.

7. The apparatus of claim 6 wherein the semiconductor/metal interface is configured to exhibit a change in resistance thereof in response to a perturbation.

8. The apparatus of claim 7 wherein the semiconductor layer and the metal shunt are arranged as a nanoscale sensor, and wherein the sensor, in response to an application of a bias current, is configured to permit a tunneling of a portion of the bias current from the semiconductor layer through the semiconductor/metal interface to the metal shunt.

9. The apparatus of claim 8 wherein the sensor further comprises a plurality of leads that contact the semiconductor layer, the leads configured to provide the bias current to the semiconductor layer.

10. The apparatus of claim 9 wherein the leads do not contact the metal shunt.

11. The apparatus of claim 7 wherein the semiconductor/metal interface is configured as a Schottky barrier.

12. The apparatus of claim 11 wherein the Schottky barrier is configured to respond to the perturbation by reapportioning a flow of tunneling current as between the semiconductor 36 layer and the metal shunt, thereby causing a measurable voltage response indicative of the perturbation.

13. The apparatus of claim 11 wherein the semiconductor layer and the metal shunt are arranged as a nanoscale sensor, the apparatus further comprising a plurality of the nanoscale sensors formed into an array.

14. The apparatus of claim 13 further comprising receiver electronics for receiving a plurality of signals representative of the resistance changes, the receiver electronics configured to generate image data based on the received signals.

15. The apparatus of claim 14 wherein the plurality of the nanoscale sensors correspond to a plurality of pixels such that the generated image data exhibits a nanoscale resolution.

16. The apparatus of any of claims claim 7-15 wherein the perturbation comprises an electric field perturbation.

17. The apparatus of claim 16 wherein the perturbation comprises a plurality of different types of perturbations.

18. The apparatus of any of claims 6-17 wherein the semiconductor layer and the metal shunt are arranged as a nanoscale sensor.

19. The apparatus of any of claims 6-18 wherein the semiconductor/metal interface is substantially perpendicular to a direction of the perturbation.

20. A method comprising: perturbing a sensor with a perturbation, the sensor comprising: (1) a planar semiconductor layer, the semiconductor layer having a planar surface, and (2) a metal shunt that contacts and partially covers the planar surface of the semiconductor layer, thereby defining a planar semiconductor/metal interface; and measuring a signal representative of a resistance change for the semiconductor/metal interface in response to the perturbing step. 37

21. The method of claim 20 wherein the semiconductor/metal interface is configured as a Schottky barrier.

22. The method of claim 21 wherein the sensor comprises a nanoscale sensor, wherein the sensor comprises a plurality of the nanoscale sensors formed into an array, and wherein the measuring step comprises measuring the signals produced by the nanoscale sensors that are representative of the resistance changes in response to the perturbing step.

23. The method of claim 22 further generating an image based on the measured signals.

24. The method of claim 23 wherein the measured signals are indicative of at least one characteristic of an object in proximity to the nanoscale sensors, and wherein the image is representative of the at least one characteristic of the object, the method further comprising repeating the perturbing, measuring, and generating steps over time to generate a real-time sequence of images that are representative of at least one characteristic of the object.

25. The method of claim 23 wherein the plurality of the nanoscale sensors correspond to a plurality of pixels such that the generated image exhibits a nanoscale resolution.

26. The method of claim 23 wherein the image generating step comprises generating an image of a cell based on the measured signals.

27. The method of claim 22 wherein the measured signals are indicative of at least one characteristic of an object in proximity to the nanoscale sensors.

28. The method of claim 27 wherein the object comprises at least one living cell.

29. The method of claim 28 wherein the perturbing step comprises perturbing the sensor with a signal emitted by the at least one living cell itself.

30. The method of claim 22 wherein the perturbing step comprises perturbing the array with light and electric field while an object is in proximity to the array, and wherein the measured 38 signals are indicative of a plurality of different characteristics of the object.

31. The method of any of claims 20-30 wherein the perturbing step comprises perturbing the sensor with an electric field perturbation.

32. The method of claim 31 wherein the perturbation comprises a plurality of different types of perturbations.