Abstract:
The present invention is generally directed to devices and methods for sensing a variety of biologically-related substances. In a device aspect, the present invention is directed to a multilayer device for sensing metal ions, biological molecules, or whole cells. The device comprises: a) one or more cavities that provide for the introduction of a sample to be analyzed and one or more channels that provide for exit of the sample, or one or more channels that provide for the introduction and exit of the sample; b) one or more single-walled carbon nanotubes presented to the one or more cavities or one or more channels; c) a plurality of electrodes electrically connected to the one or more single-walled carbon nanotubes; and, a reference gate electrode presented to the one or more cavities or one or more channels. In a method aspect, the present invention is directed to a method for sensing species such as a metal, biological cells, and one or more biological molecules using the device.

Description:
[0001]    This application claims the benefit of U.S. Provisional Application No. 61/338,214 filed Feb. 16, 2010, which is incorporated-by-reference for all purposes. 
     
    
     FIELD OF THE INVENTION 
       [0002]    The present invention is generally directed to devices and methods for sensing a variety of biologically-related substances. 
       BACKGROUND OF THE INVENTION 
       [0003]    There is a growing need for reliable and low-cost early cancer screening technologies that could enable physicians to detect cancers at early stages when the diseases are most treatable and treatments offer better outcomes for patients. The global market for in-vitro diagnostics (IVD) systems for cancer reached US$ 3.39 billion in 2008 and continues to grow. This increasing demand is the result of the growing costs associated with treating and battling cancer, which in 2008 reached $228 billion in the US alone, where 562,340 people died and 1,479,350 new cancer cases were diagnosed in 2009. (ACS, Facts &amp; Figures 2009). 
         [0004]    In its 2007 report, the National Institute of Health (NIH) provided estimates for the growing costs and expenditures related to battling cancer: direct medical costs and health expenditures ($89.0 billion); indirect morbidity costs due to lost productivity and illness ($18.2 billion); and, indirect mortality costs due to productivity loss and premature death ($112.0 billion). 
         [0005]    One barrier to reducing the staggering number of cancer-related deaths and resulting health care costs is the lack of accurate, reliable and low cost early detection methods. The emerging field of precise molecular diagnostics provides windows of opportunity for the early detection of cancers, among other diseases, because it can enable the detection of molecular biomarkers and biological analytes at very small concentrations. Emerging molecular diagnostic technologies provide opportunities for early cancer detection, as they can enable the detection of minute quantities of biomarker arrays. Current methods, however, are costly and time intensive: they require extensive sample preparation, complex hardware, sophisticated instrumentation and hours to days of analysis. 
       SUMMARY OF THE INVENTION 
       [0006]    The present invention is generally directed to devices and methods for sensing a variety of biologically-related substances. 
         [0007]    The present invention addresses the need for rapid, accurate, reliable and low cost detection methods. It can detect analytes at very low concentrations in gases and fluids, including the sensing of a variety of biologically-related substances, thereby facilitating the detection and screening of diseases. The present invention can also be used in the detection of biological species for national security. Other applications include the detection of metals, pollutants, biologically-related species in ground water, sea water and other water sources (environmental monitoring and remediation). 
         [0008]    In a device aspect, the present invention is directed to a multilayer device for sensing metal ions, biological molecules, or whole cells. The device comprises: a) one or more cavities that provide for the introduction of a sample to be analyzed and one or more channels that provide for exit of the sample, or one or more channels that provide for the introduction and exit of the sample; b) one or more single-walled carbon nanotubes presented to the one or more cavities or one or more channels; c) a plurality of electrodes electrically connected to the one or more single-walled carbon nanotubes; and, a reference gate electrode presented to the one or more cavities or one or more channels. 
         [0009]    In a method aspect, the present invention is directed to a method for sensing species such as a metal, biological cells, and one or more biological molecules. The method comprises the steps of: a) introducing a solution of high affinity and selective binding elements into a device discussed above in the Summary of Invention Section, wherein the high affinity and selective binding elements add functionality to the one or more single-walled carbon nanotubes by binding species of interest to the surface of the nanotubes; b) introducing a buffer-electrolyte solution into one or more cavities, or one or more channels of the device, thereby allowing activation of nanotube-field effect transistors in the device for calibration and for setting a baseline current or voltage reference state; c) introducing a sample in solution with a buffer-electrolyte solution into the one or more cavities, or one or more channels of the device and determining any changes in the current or voltage state of the nanotube-field effect transistors relative to their baseline state. The changes are correlated with the binding of one or more species of interest in the sample. 
     
    
     
       BRIEF DESCRIPTION OF THE FIGURES 
         [0010]      FIG. 1  shows a three-dimensional perspective sketch for the main components of one of the layers of a sensor according to the present invention. 
           [0011]      FIGS. 2-8  show side view cross-sections of multiple different embodiments according to the present invention. 
           [0012]      FIG. 9  shows a three-dimensional perspective sketch for the main components of one of the layers of a sensor according to the present invention. 
           [0013]      FIGS. 10-19  show side view cross-sections of multiple different embodiments according to the present invention. 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     Definitions 
       [0014]    “Cavity” refers to an unfilled space within a mass or substrate. 
         [0015]    “Channel” refers to an enclosed passage between substrates or within a substrate. 
         [0016]    “Microchannel” refers to an enclosed passage with micro-scale dimensions between substrates. 
         [0017]    “Electrode” refers to a conductor used to establish electrical contact with a nonmetallic part of a circuit. 
       DETAILED DESCRIPTION 
       [0018]    The present invention may be used to detect a variety of substances, including clusters of atoms (e.g., Hg, Au, and Pb), specific ions, molecules, biologically-related substances (e.g., molecules and macromolecules, such as proteins, RNA and DNA), and whole biological cells. The sensor comprises carbon nanotubes, which interact with atoms and molecules in their surroundings. The affinity of the nanotubes for specific target analytes and species is enhanced by the binding of high affinity and selective elements such as aptamers, peptides, enzymes, antibodies, antibody fragments (e.g. minibodies, diabodies, cys-diabodies, Fab fragments and F(ab′)2 fragments), or a combination thereof onto the surface of the nanotubes. These high affinity and selective elements serve as links between nanotubes and analytes of interest such that their interaction can be enhanced, detected and quantified at very low analyte concentrations (e.g., nano-, pico-, and femto-molar concentrations). 
         [0019]    The sensor has the capability to separate and decouple microfluidic control and circulation from ionic, electrochemical, and/or electrostatic detection. The microfluidics, for example, may be controlled from one side of the device; and the electronic and electrical input/outputs for detection can be controlled from the opposite side of the device. 
         [0020]    The sensor may be used in a variety of applications. These applications include, but are not limited to, the following: disease detection, including early disease detection and screening; diagnostics; and, monitoring of analytes for therapeutic intervention. Other potential applications include analyte detection for water quality control, environmental monitoring of underground water resources and detection of underground contaminants, environmental monitoring of water reservoirs and sea water, monitoring of potable water for protection against biological and biochemical terrorism, and strategic monitoring of water resources for national security. 
         [0021]    The present invention can be classified onto two main kinds of embodiments: open cavity embodiments and enclosed microchannel embodiments. First, the open cavity embodiments are described starting with the building-block components and elements that are critical to the invention. Next, the enclosed microchannel embodiments are described including the building-block components and elements that are critical to the present invention. Subsequently, utility and functional advantages of the present invention are described. This section ends with a description of the method of detection and analysis that is attainable with the present invention. 
         [0022]    Open-Cavity Embodiments:  FIGS. 1-8   
         [0023]    Elements of the present invention are described in  FIG. 1 , which shows an array of single-walled carbon nanotubes (SWCNT)  103  on the front surface  102   a  of a layer, so-called substrate  102 . The nanotubes  103  are electrically connected in parallel, in series, or a combination thereof at one end by a source electrode  104  and at the second end by a drain electrode  105 . The second component of the present invention is substrate  101 . One embodiment of the present invention is described in reference to  FIG. 2 , where substrate  101  comprises a through-substrate cavity (TSC)  200 .  FIG. 2  shows a lateral cross-section diagram of substrates  101  and  102 . In this embodiment, the biosensor is comprised of two substrates that come together in “face-to-face” fashion. Substrate  101  comprises the TSC  200  and microchannels  107  that allow for the introduction and exit of a sample during analysis. Substrate  102  comprises nanotube  103 , source electrode  104 , and drain electrode  105 . An external gate electrode probe  117  is inserted into the sensing cavity  200 , also referred to as TSC, where the sample is introduced. During detection and analysis, target analytes  116  bind to high affinity species  115  on the surface of the nanotube  103 . 
         [0024]    A slightly different embodiment of the present invention is described in reference to  FIG. 3 , which also shows a lateral cross-section diagram of substrates  101  and  102 . In this embodiment, the biosensor is also comprised of two substrates that come together in “face-to-face” fashion. Substrate  101  comprises the sensing TSC  200  and microchannels  107  that allow for the introduction and exit of a sample during analysis. No external gate electrode probe is used. Instead, a gate electrode  106  runs along the sidewall of the sensing TSC  200  and extends to the top surface of substrate  101 . Substrate  102  comprises nanotube  103 , source electrode  104  and drain electrode  105 . As displayed, target analytes  116  bind to high affinity species  115  on the surface of nanotube  103  during sensing and analysis. 
         [0025]    Another embodiment of the present invention is described in reference to  FIG. 4 , which also shows a lateral cross-section diagram of substrates  101  and  102 . In this embodiment, the biosensor is comprised of two substrates that come together in “face-to-face” fashion. Substrate  101  comprises the sensing TSC  200  and microchannels  107  that allow for the introduction and exit of a sample during analysis. Substrate  102  comprises nanotube  103 , source electrode  104 , drain electrode  105 . and through-substrate vias (TSV)  110  and  112 , which are connected to the source electrode  104  and drain electrode  105 , respectively. Metal traces  118  and  119  on the back surface of substrate  102  are connected to TSVs  110  and  112 , respectively. These metal traces  118  and  119  are points of electrical connection to external power supply systems and/or devices. An external gate electrode probe  117  is inserted into the sensing cavity  200  for analysis and detection when target analytes  116  bind to high affinity species  115  on the surface of nanotube  103 . 
         [0026]    Another embodiment of the present invention is described in reference to  FIG. 5 , which also shows a lateral cross-section diagram. Similarly, the biosensor is comprised of two substrates  101  and  102  that come together in “face-to-face” fashion. Substrate  101  comprises the sensing TSC  200  and microchannels  107  that allow for the introduction and exit of a sample during analysis. Substrate  102  comprises nanotube  103 , source electrode  104 , drain electrode  105 , and through-substrate vias (TSV)  110  and  112 , which are connected to the source  104  and drain electrode  105  respectively. Metal traces  118  and  119  on the back surface of substrate  102  are connected to TSVs  110  and  112 , respectively. In this embodiment there is no external gate probe, but there is a gate electrode  106  on the front surface of substrate  102 . Gate electrode  106  is connected to TSV  108 , which is connected to metal trace  120  on the back surface of substrate  102 . Therefore, metal traces  118 ,  119 , and  120  on the back surface of substrate  102  are electrically connected to electrodes  104 ,  105 , and  106 , respectively. Target analytes  116  bind to high affinity species  115  on the surface of nanotube  103  during sensing and analysis. 
         [0027]    An alternative embodiment of the present invention is described in reference to  FIG. 6 . Instead of utilizing an external gate probe, this embodiment comprises a gate electrode  106  that runs along the sidewall of sensing TSC  200  and extends to the top surface of substrate  101 . Substrate  101  comprises the sensing TSC  200  and microchannels  107  that allow for the introduction and exit of a sample during analysis. Substrate  102  comprises nanotube  103 , source electrode  104  and drain electrode  105 . Source electrode  104  is electrically connected to metal trace  118  via TSV  110 . Similarly, drain electrode  105  is electrically connected to metal trace  119  via TSV  112 . During sensing and analysis, target analytes  116  bind to high affinity species  115  on the surface of nanotube  103 . 
         [0028]      FIG. 7  displays an embodiment of the present invention that is similar to the embodiment described in  FIG. 4 . In addition to comprising all the different elements described in  FIG. 4 , this embodiment further comprises an integrated circuit  202 , which is attached to the back surface of substrate  102 . The connection of the integrated circuit  202  to the metal traces  118 ,  119 , and  120  enables additional miniaturization of the biosensor since electrical inputs and outputs can be programmed, controlled, and recorded by the integrated circuit  202  during sensing and analysis. 
         [0029]      FIG. 8  displays an embodiment of the present invention that is similar to the embodiment described in  FIG. 5 , where a gate electrode  106  is located on the front surface of substrate  102 , and said gate electrode  106  is electrically connected to metal trace  120  via TSV  108 . In addition to comprising all the different elements described in  FIG. 5 , this embodiment further comprises an integrated circuit  202 , which is attached to the back surface of substrate  102 . The connection of the integrated circuit  202  to the metal traces  118 ,  119 , and  120  enables additional miniaturization of the biosensor because electrical inputs and outputs can be programmed, controlled, and recorded by the integrated circuit  202  during sensing and analysis. 
         [0030]    Enclosed Microchannel Embodiments:  FIGS. 10-19   
         [0031]    Elements for this family of embodiments are described in  FIG. 1 , which displays an array of single-walled carbon nanotubes (SWCNT)  103 , a source electrode  104 , and a drain electrode  105  on a layer, so-called substrate  102 . Another critical element is described with reference to  FIG. 9 , which shows a microchannel  107  on the bottom surface  101   a  of a layer, so-called substrate  101 . In reference to  FIG. 1 , the nanotubes  103  are electrically connected in parallel, in series, or a combination thereof at one end by a source electrode  104  and at the second end by a drain electrode  105 . In reference to  FIG. 9 , substrate  101  comprises one or a plurality of horizontal microchannels  107 , which are connected to a plurality of vertical channels. The embodiments described in this section have at least two substrates  101  and  102 , which come together in “face-to-face” fashion. Substrate  101  has a front surface  101   a  and a back surface  101   b  ( FIG. 9 ), and substrate  102  has a front surface  102   a  and a back surface  102   b  ( FIG. 1 ). The enclosed channel embodiments are subdivided into two groups: Embodiments that have nanotubes  103  on surface  101   a  and microchannels  107  on surface  102   a , and embodiments that have nanotubes on surface  102   a  and microchannels  107  on surface  101   a  are also envisioned. 
         [0032]    One embodiment of the present invention is described in reference to  FIG. 10 , which shows a side view cross-section diagram of substrates  101  and  102 . Substrate  101  comprises vertical channels  114 , nanotubes  103  connected to source electrode  104  and drain electrode  105 . Vertical channels  114  allow for the introduction and exit of a sample to microchannel  107  on substrate  102  during sample analysis. Substrate  102  comprises microchannel  107 , gate electrode  106 , TSV  108 , and metal trace  120 . Source electrode  104  is connected to metal trace  118  via TSV  110 . Similarly, drain electrode  105  is connected to metal trace  119  via TSV  112 . Target analytes  116  bind to high affinity species  115  on the surface of nanotube  103  during sample sensing and analysis. A different side view cross-section of this embodiment is displayed in  FIG. 11 . 
         [0033]    In reference to  FIG. 11 , an array of nanotubes  103  are present on the front surface of substrate  101 ; microchannels  107  are etched or mechanically formed on the front surface of substrate  102 . Electrically conductive through-layer means, which are also referred to as through-substrate vias (TSVs), are included in substrate  102 . These through-layer conductive vias are the shortest path of electrical connection between the front side and the back side of substrate  102 . Gate electrode  106  runs along microchannel  107  on the front surface of substrate  102 . This integrates source electrode  104 , nanotubes  103 , gate electrode  106 , and drain electrode  105  into one or a plurality of functional nanotube field effect transistors (NT-FETs), which can be operated and controlled from the back surface of substrate  102  when using an external power supply and an integrated circuit/system. 
         [0034]    Vertical channels  114  connect both sides of substrate  101  such that a fluid or gas sample can flow from back side  101   b  into sensing microchannel  107 , then through a second set of vertical channels  114  back to surface  101   b  to exit the device. In this embodiment, microfluidic control is conducted from surface  101   b . The electronic current/voltage (“I/V”) characteristics are controlled from back side  102   b  using an external integrated circuit and power supply. 
         [0035]      FIG. 12  displays an embodiment of the present invention that is similar to the embodiment described in  FIG. 11 . In addition to comprising all the different elements described for the previous embodiment in  FIG. 11 , this embodiment comprises an integrated circuit  202 , which is attached to the back surface of substrate  102 . The integrated circuit  202  is connected to the metal traces  118 ,  119 , and  120 . This enables additional miniaturization of the biosensor since electrical inputs and outputs can be programmed, controlled, and recorded by the integrated circuit  202 . 
         [0036]    Having the nanotubes on surface  102   a  ( FIG. 1 ) and microchannel  107  on surface  101   a  ( FIG. 9 ) gives rise to multiple embodiments. One embodiment of the present invention with this characteristic is described in reference to  FIG. 13 , which shows a lateral cross-section diagram. Similarly, the biosensor is comprised of two substrates  101  and  102  that come together in “face-to-face” fashion. Substrate  102  comprises nanotubes  103 , source electrode  104 , drain electrode  105 , and gate electrode  106  on surface  102   a . The electrodes  104 ,  105 , and  106 , are connected to metal traces  118 ,  119 , and  120  via TSVs  110 ,  112 , and  108 , respectively. Substrate  101  comprises microchannels  107  and vertical channels  114  for the introduction and exit of a sample during detection and analysis. Target analytes  116  bind to high affinity species  115  onto the surface of nanotube  103  during sensing and analysis. This embodiment is also displayed in  FIG. 14 , but the view corresponds to an orthogonal side view cross-section where an array of nanotubes  103  are visible on surface  102   a . All the elements described in  FIG. 13  are also present in this figure. 
         [0037]    A similar embodiment is displayed with reference to  FIG. 15 . In addition to all the elements described in  FIG. 13  and  FIG. 14 , this embodiment further comprises an integrated circuit  202  connected to the back surface of substrate  102 . The integrated circuit  202  is connected to the metal traces  118 ,  119 , and  120 , which enables additional miniaturization of the biosensor since electrical inputs and outputs can be programmed, controlled, and recorded by the integrated circuit  202 . This embodiment is displayed in  FIG. 16  from a different perspective. An orthogonal side view is displayed to show how target analytes  116  bind to high affinity species  115  on the surface of nanotube  103  during sensing and sample analysis. 
         [0038]    A slightly different embodiment is described with reference to  FIG. 17 . In this embodiment, an array of nanotubes  103  are horizontally grown or deposited on surface  102   a , and microchannels  107  are etched or mechanically formed on the front surface of substrate  101 . Gate electrode  106  runs along microchannel  107  and is connected to metal trace  120  via TSVs  108 . Source electrode  104  on surface  102   a  is connected to TSV  110 , which is connected to metal trace  118 . Similarly, drain electrode  105  is connected to TSV  112 , which is connected to metal trace  119 . This integrates source electrode  104 , nanotubes  103 , gate electrode  106 , and drain electrode  105  into one or a plurality of functional NT-FETs. Substrate  101  comprises microchannels  107 , which are connected to vertical channels  114  to enable the introduction and exit of samples for sensing and analysis. 
         [0039]    A different embodiment is described with reference to  FIG. 18 . In this embodiment, one or multiple nanotubes  103  are deposited or grown on substrate  102  and these are connected to source electrode  104  at one end and to drain electrode  105  at the second end. Source electrode  104  is electrically connected to metal trace  118  via TSV  110 . Drain electrode  105  is electrically connected to metal trace  119  via TSV  112 . Gate electrode  106  is located on the front surface of substrate  102 , and it is electrically connected to metal trace  120  via TSV  108 . Microchannel  107  is formed on the front surface of substrate  101 , and said microchannel  107  runs along the width of the device as described in  FIG. 18 . Microchannel  107  provides for the introduction and exit of a sample during analysis. 
         [0040]    A slightly different embodiment is described with reference to  FIG. 19 . In addition to including all the elements described in  FIG. 18 , this embodiment comprises an integrated circuit  202  attached to the back surface of substrate  102 . Said integrated circuit  202  is electrically connected to metal traces  118 ,  119 , and  120 , and can consequently control the electrical inputs and record electrical outputs of the NT-FET formed by the electrodes  104 ,  105 ,  106 , and nanotubes  103 . 
         [0041]    Utility and Functional Advantages 
         [0042]    Since the microfluidic and the electronic controls are decoupled to the opposite sides of the device as described in  FIG. 4-8  and  FIG. 10-19 , other complementary operations can be added to the device. For instance, if substrates  101  and  102  are transparent, or translucent to light, and a light source (e.g., laser, UV, infrared, or visible) is illuminated from one side of the device, then fluorescence light and/or optical output can be collected and measured from the opposite side of the device for the case of the embodiments described in  FIG. 4-6 ,  FIG. 10-11 ,  FIG. 13-14 , and  FIG. 17-18 , which are embodiments that do not comprise an integrated circuit  202 . If only one substrate is transparent or translucent, substrate  101  or  102 , and the other substrate reflects light (e.g., laser, UV, IR or visible), then a light source and an output detector can be placed on the same side of the present invention. Consequently, fluorescence light and/or optical output can be collected and measured. These utility advantages are particularly relevant with respect to the embodiments described in  FIG. 4-8  and  FIG. 10-19 . Using an external light source (e.g., laser, UV, IR or visible), the light is used to trigger photo-interactions between the high affinity species (e.g., nucleic acids, aptamers, antibodies, or antibody fragments) on the nanotubes with the analyte species of interest contained in the sample. These photo-interactions facilitate complementary forms of molecular characterization using optical means (e.g., laser, optical fluorescence, fluorescence resonance energy transfer (FRET), or other). 
         [0043]    Molecular Detection, Sensing, and Analysis Method 
         [0044]    A method according to the present invention is described in relation to  FIG. 2-8 ,  FIG. 10 ,  FIG. 13 , and  FIG. 17 . A solution of known concentration containing nucleic acids, antibodies, antibody fragments, enzymes, or engineered antibody fragments, or a combination thereof is introduced into sensing cavity  200  or microchannels  107  to coat, functionalize, and add target affinity to nanotubes  103 . Nucleic acid molecules (e.g. aptamers), antibody molecules, antibody fragments, or engineered antibody fragments  115  bind to nanotubes  103 . 
         [0045]    A buffer electrolyte solution is introduced into the sensing cavity  200  or microchannels  107 . The electrolyte solution permits the activation of the NT-FETs at their baseline current/voltage (I/V), which defines a reference state and it is equivalent to zero concentration of the measured targeted specie or analyte (e.g., protein biomarkers). This step is executed as part of the calibration procedure of the present invention. Subsequently, in order to complete the calibration, a solution containing high affinity and selectivity species (e.g., nucleic acids, aptamers, enzymes, antibodies, antibody fragments, engineered antibody fragments, or a combination thereof) and a reagent of known concentration are mixed with the buffer solution and introduced into the device to functionalize the surface of the nanotubes  103  with the high affinity and selectivity species  115 . 
         [0046]    Finally, the sample (e.g., known quantity of blood, plasma serum, or biological fluid) is mixed with known quantities of an electrolyte solution and/or reagents in order to be introduced into the sensing cavity  200  or the sensing microchannel  107 . The arrays of NT-FETs at the bottom of the sensing cavity  200  or inside each sensing microchannel  107  serve as signal amplifiers and enable the recording of changes in I/V characteristics caused by the binding between the high affinity ligands  115  and the targeted analytes  116  (e.g., protein biomarkers) on the surface of the nanotubes  103 . For example, in a blood serum analysis, the recorded I/V characteristics for a specific ligand-analyte pair  115 - 116  on the nanotubes  103  will be directly correlated to the concentration of said analyte  116  in the sample. The compilation of measurements of multiple types of analyte proteins  116  defines a signature-analyte-profile or signature-protein-profile (SAP), which is unique to each individual sample (e.g., blood serum sample). 
         [0047]    Sensing cavity  200  or microchannels  107  may be cleaned and reused. This is done by flushing the sensing cavity  200  or microchannels  107  with a cleaning solution and re-functionalizing the nanotubes  103  with a new set of high affinity and selective species  115 . A subsequent analysis with the same or different set of target analytes  116  (e.g., proteins) is performed to gather more information for the signature-analyte-profile (SAP). 
       LIST OF ELEMENTS 
       [0048]    The following is a list of elements comprised in the present invention. 
         [0000]    
       
         
               
               
             
           
               
                   
               
               
                 Number 
                 Element 
               
               
                   
               
             
             
               
                 101 
                 First layer or substrate 
               
               
                 101a 
                 front surface of substrate 101 
               
               
                 101b 
                 back surface of substrate 101 
               
               
                 102 
                 Second layer or substrate 
               
               
                 102a 
                 front surface of substrate 102 
               
               
                 102b 
                 back surface of substrate 102 
               
               
                 103 
                 Single-walled carbon nanotubes (SWCNT), also referred to as 
               
               
                   
                 nanotube or nanotubes 
               
               
                 104 
                 source electrode 
               
               
                 105 
                 drain electrode 
               
               
                 106 
                 gate electrode 
               
               
                 107 
                 microchannel or microchannels, also referred to as sensing 
               
               
                   
                 microchannel 
               
               
                 108 
                 gate TSV, where through-substrate via (TSV) 
               
               
                 110 
                 source TSV 
               
               
                 112 
                 drain TSV 
               
               
                 114 
                 vertical channel or channels 
               
               
                 115 
                 high affinity and selectivity species 
               
               
                 116 
                 target analytes 
               
               
                 117 
                 external gate electrode probe 
               
               
                 118 
                 source metal trace 
               
               
                 119 
                 drain metal trace 
               
               
                 120 
                 gate metal trace 
               
               
                 200 
                 through-substrate cavity (TSC), also referred to as sensing TSC 
               
               
                   
                 cavity 
               
               
                 202 
                 integrated circuit