Abstract:
A detection apparatus for detecting the presence of a sample, the detection apparatus comprising a chamber, ports for introducing a sample within the chamber, an actuation unit for establishing a controllable electromagnetic field in the chamber; and a sensing unit for sensing changes in the electromagnetic field due to the presence of the sample within the chamber. The sensing unit comprises a sensor device comprising a source and a drain embedded in a FET a gate for the FET, in which the gate is formed of a material whose conductivity is related to the electromagnetic field established in a nonconductive medium in contact with the gate.

Description:
BACKGROUND OF THE INVENTION  
       [0001]     The behavior of matter in electrical or magnetic field, especially nonuniform fields, is of interest to scientists of various branches: Physics, chemistry, engineering, or life sciences. To chemists and physicists, it&#39;s a science of many and varied phenomena. To engineers, it&#39;s a source of new and useful techniques for separating, levitating, and rotating materials or improving material behavior.  
         [0002]     In recent decades, Dielectrophoresis has become a fairly well known phenomenon in which a spatially nonuniform electric field exerts a net force on the field-induced dipole of a particle. Particles with higher polarizability than the surrounding medium experience positive dielectrophoresis and they move toward regions of highest electric field concentration. Particles less polarizable than the surrounding medium experience negative dielectrophoresis, and move towards regions of low electric field concentration. The force depends on the induced dipole and the electric field gradient, not on the particle&#39;s charge. Thus, dielectrophoresis has been used to precipitate DNA and proteins, to manipulate viruses (100 nm diameter), and to manipulate and separate cells and subcellular components such as microtubules.  
         [0003]     Dielectrophoretic levitation fulfills a somewhat specialized need among the scientific and technical applications for dielectrophoresis. Two types of levitation, passive and feedback-controlled may be used to levitate particles exhibiting, respectively, negative and positive DEP behavior.  
         [0004]     DEP is technologically important in its own right, as evidenced by the number of applications in such scientific and technical fields as biophysics, bioengineering, and mineral separation. As an example, which is important in cancer treatment, is cell fusion, as discussed by P. T. Gaynor, and P. S. Bodger in “Electrofusion processes: theoretical evaluation of high electric field effects on cellular transmembrane potentials”,  IEE Proceedings - Science, Measurement and Technology,  vol. 142, no. 2, pp. 176-182, 1995. In this process, the nonuniform electric field collects some fraction of these cells on electrode surfaces where cells of the two types inevitably encounter each other and form chains. A serious of short DC pulse is then applied to the electrodes. The strong DC field disturbs the membranes in the region of contact between cells and initiates their merge or fusion. A potential application of this technique is the production of antibodies useful in cancer research and treatment.  
         [0005]     Lab-on-a-chip based on DEP phenomenon has become one of the hottest areas of research recently. It has many applications in the biological, pharmaceutical, medical, and environmental fields. These applications are characterized by complex experimental protocols, which need both microorganism detection and manipulation. Hence, lab-on-a-chip technology needs to integrate functions such as: actuation, sensing, and processing to increase their effectiveness. On the other hand, lab-on-a-chip technology holds the promise of cheaper, better and faster biological analysis. However, to date there is still an unmet need for lab-on-a-chip technology to effectively deal with the biological systems at the cell level.  
         [0006]     Recently, two different lab-on-a-chip approaches have been proposed by G. Medoro, N. Manaresi, M. Tartagni, and R. Guerrieri, in “CMOS-only Sensors and Manipulation for microorganisms”, Proc. IEDM, pp. 415-418, 2000 and by N. Manaresi, A. Romani, G. Medoro, L. Altomare, A. Leonardi, M. Tartagni, and R. Guerrieri in “A CMOC Chip for Individual Manipulation and Detection”,  IEEE International Solid - State Circuits Conference,  ISSCC 03, pp. 486-488. 2003. The first, which was proposed in 2002, is the first lab-on-a-chip approach for electronic manipulation and detection of microorganisms. The proposed approach combines dielectrophoresis with impedance measurements to trap and move particles while monitoring their location and quantity in the device. The prototype has been realized using standard printed circuit board (PCB) technology. The sensing part in this approach can be performed by any electrode by switching from the electrical stimulus to a transimpedance amplifier, while all the other electrodes are connected to ground. The second lab-on-a-chip, which was proposed in 2003, is a microsystem for cell manipulation and detection based on standard 0.35 μm CMOS technology. This lab-on-a-chip microsystem comprises two main units: the actuation unit, and the sensing unit. The chip surface implements a 2D array of microsites, each comprising superficial electrodes and embedded photodiode sensors and logic. The actuation part is based on the DEP technique. The sensing part depends on the fact that particles in the sample can be detected by the changes in optical radiation impinging on the photodiode associated with each micro-site. During the sensing, the actuation voltages are halted, to avoid coupling with the pixel readout. However, due to inertia, the cells keep their position in the liquid.  
         [0007]     The disadvantage of these lab-on-a-chip microsystems, can be summarized as follows: 
        Based on these two systems, we can detect the position of the levitated cells. However, we cannot sense the actual intensity of the nonuniform electric field that produces the DEP force.     The measurements here are indirect. In other words, there is no “real-time” detection of the cell response under the effect of the nonuniform electric field, as the actuation part is halted while the sensing part is activated.     The sensing part in these two Microsystems depends on the inertia of the levitated cells. In other words, this sensing approach depends on an external factor, which is the inertia of the levitated cells. Thus, only cells with higher inertia can be sensed and detected by using these two Microsystems.        
 
         [0011]     What is needed is a lab-on-a-chip that can be used for direct measurements, where the variations in the electric field can be sensed and the cell can be characterized while the actuation part is still active.  
       SUMMARY OF THE INVENTION  
       [0012]     There is therefore provided, according to an aspect of the invention, a sensor device, comprising a source and a drain embedded in a FET; and a gate for the FET, in which the gate is formed of a material whose conductivity is sensitive to an electric, magnetic or electromagnetic field established in a nonconductive medium in contact with the gate. The field may be non-uniform. The FET may comprise two spatially separated gates and two spatially separated drains, with a common source. Two sensor devices may be connected, where wherein the FET of the first sensor device is a p-type FET and the FET of the second sensor device is a n-type FET. The sensor device may be connected in an array of sensor devices.  
         [0013]     According to a further aspect of the invention, there is provided a detection apparatus, the detection apparatus comprising a chamber; a port or ports for introducing a sample into the chamber; an actuation unit for establishing a controllable electromagnetic field in the chamber; and a FET sensing unit for sensing changes in the electromagnetic field due to the presence of the sample within the chamber. The FET sensing unit may be comprised of sensor devices described above. The changes in the electromagnetic field sensed by the sensing unit may be used to determine the impedance of the sample, or a characterization unit may use the changes sensed by the sensor unit to make a 2D image of the electromagnetic field. The actuation unit may be responsive to feedback from the sensor device. The actuation unit may comprise an array of electrodes, for example in a quadrupole arrangement, and the sensing unit may comprise an array of sensors interspersed with the array of electrodes. At least one of the electrodes and sensors may receive power from an electromagnetic source, wherein the electromagnetic energy is directed by mirrors controlled by the actuation unit, or from a power source controlled by the actuation unit. The electrodes may be elongate members, the elongate members receiving power at one end and generating the electromagnetic field at the other end in response to the power.  
         [0014]     According to a further aspect of the invention, there is provided a method of detecting a sample using dielectrophoresis, using the sensor device and detection apparatus described, where the electromagnetic field is generated and the changes in the electromagnetic field are sensed simultaneously. The particle may be organic matter or a cell.  
         [0015]     A Other aspects of the invention will be found in the detailed description and claims that follow. 
     
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0016]     There will now be given a detailed description of preferred embodiments of the invention, with reference to the drawings, by way of illustration only and not limiting the scope of the invention, in which like numerals refer to like elements, and in which:  
         [0017]      FIG. 1   a  is a block diagram of an apparatus constructed in accordance with the teachings of the present invention;  
         [0018]      FIG. 1   b  is a schematic view of actuation and sensing units used in an embodiment of the invention;  
         [0019]      FIG. 2  shows light-based electrodes used in the actuation unit;  
         [0020]      FIG. 3  shows light beam controlled driving circuits for the electrodes in the actuation unit;  
         [0021]      FIG. 3   a  shows light beam controlled driving circuits for an array of electrodes in the actuation unit;  
         [0022]      FIG. 4  shows various shapes of the tip of the electrode;  
         [0023]      FIG. 5  is a perspective view of the physical structure of an eFET;  
         [0024]      FIG. 6  is the circuit equivalent of an eFET;  
         [0025]      FIG. 7  is the circuit symbol for an eFET;  
         [0026]      FIG. 8  is the circuit symbol of a DeFET;  
         [0027]      FIG. 9  is the circuit equivalent of a DeFET;  
         [0028]      FIG. 10  is the Current-Mode Instrumentation Amplifier (CMIA) circuit used as a readout circuit;  
         [0029]      FIG. 11   a  is a perspective view of a representation of the quadrupole and DeFET;  
         [0030]      FIG. 11   b  is a point charge representation of the quadrupole arrangement;  
         [0031]      FIG. 11   c  shows a large quadrupole configuration of electrodes;  
         [0032]      FIG. 11   d  is a schematic of a single large quadrupole electrode using metal2 stips;  
         [0033]      FIG. 11   e  shows a centric configuration for light beam controlled driving poles with the sensor;  
         [0034]      FIG. 12  is a graph displaying simulation results using Coulomb Software;  
         [0035]      FIG. 13  is a schematic representation of a DeFET according to the invention;  
         [0036]      FIG. 14  is a graph showing simulation results using Cadence Simulator;  
         [0037]      FIG. 15  is a graph showing the frequency response of the CMIA used in the simulation;  
         [0038]      FIG. 16  is a graph showing the different common mode rejection ratio (CMRR) for different CMIA circuits; and  
         [0039]      FIG. 17  is a schematic of a DeFET acting as an impedance sensor. 
     
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS  
       [0040]     The electric field imager disclosed herein is based on conventional TSMC 0.18 μm CMOS technology. Some simulation and experimental results are presented at the end of the disclosure. Referring now to  FIG. 1   a,  the proposed microsystem  10  comprises (a) an actuation unit  12 , which is in a quadruple electrode configuration as shown in  FIG. 1   b  to produce the required DEP force to levitate the sample, for example, a cell, that we want to characterize; (b) a sensing unit  14 , which is a Differential Electric Field Sensitive Field Effect Transistor (DeFET), where, to obtain an image of the electric field, and characterize the levitated cell, the DeFET is used in an array form, and the read out circuit [i.e. the electric field-to-voltage converter (E-to-V converter) circuit] is on a chip; (c) a characterization unit  16  to analyze the images and determine characteristics of the sample; (d) a chamber  18  to hold the sample with ports for inserting the sample; and (e) a controller  20  for controlling the actuation unit  12 . The controller  20  may be programmed to create a specific non-uniform field, and may operate based upon feedback from the sensing unit  14  or the characterization unit  16 . Each component may be located in any convenient location, such as under, inside or outside the chamber. Also, while the actuation unit  12  and sensing unit  14  are shown as separate bodies, it will be understood that they may occupy the same space as shown in  FIG. 1   b.  The chamber  18  has ports  22  for introducing a sample. As described, the apparatus  10  is capable of simultaneously actuating, sensing, and manipulating the sample in the chamber  18 , and can be used to process samples such as cells, particles, liquids, powder, organic matter, bio-live or dead species, or other types of samples. In this document, processing a sample includes, but is not limited to, actuating, sensing, testing, levitating, separating, manipulating, isolating, trapping, analyzing, or identifying the sample as a whole or a part thereof, performed individually, or in combination. It will also be understood that when an electric field is referred to, the discussion may equally apply to magnetic fields, or electromagnetic field, since a time varying electric field will have a magnetic field component. Each of the components presented above will now be discussed in more detail.  
         [0000]     The Actuation Unit  
         [0041]     The actuation unit  12  comprises poles  24 , or electrodes, that generate the electric field in the chamber  18 . The poles  24  are spatially distributed as shown in  FIG. 1   b  and produce the required force to process a sample (not shown). Sensors  28  are also spatially distributed. Each pole  24  and sensor  28  is connected to a corresponding terminal  25  to allow them to be individually addressed. Referring to  FIG. 11   a,  the sample  26  is shown in the center of four poles  24  with sensors  28  below. Referring again to  FIG. 1   b,  each pole  24  can be individually addressed and actuated using electrical signals, a light beam such as a laser, or other sources of energy, such as a magnetic source connected to terminals  25  to produce the desired field and therefore operate on the sample  26 . In the case of the laser, the light beam will use a set of mirrors and lenses to focus the beam on the ele2ctrode to be actuated.  FIG. 2  shows the light-based electrodes  24  and  FIG. 3  shows the driving circuits  34  where the light beam  36  controls a switch  38  that adjusts the voltage at the top of the pole  24 , which in turn affects the electric field and corresponding DEP force that is generated between the pole  24  and the grounded plate  78  on the other side. Mirror  80  and lenses  82  are shown directing the beam  36 . The arrangement used may be a much more complex system, where the position of mirrors  80  and lenses  82  are controlled to address individual poles  24 . The cross-section of the tip of pole  24 , where the force is generated, can be hexagonal, square, rectangular, or other shapes, with examples shown in  FIG. 4 . Each pole  24  may be programmed to adjust its value based on the readout of the sensing unit  14  to create a feedback loop that can verify the exact value of the generated force.  
         [0042]      FIG. 3   a  shows the spatial distributed poles to generate an arbitrary electric field by controlling the values of the volt at the individual electrodes. The poles  52 ,  54 ,  56 , and  58  are similar to the configuration in  FIG. 3  but with different height to enable single addressable poles. The pole  52  that is closer to the light source is shorter than the far poles ( 54  and  56 ) in the other raw. The poles in the same row  56  have the same height to simplify the addressing mechanism. A light or energy source  30  is used to control the volt at the pole. The energy will be modulated using a modulator  35 . A micro-mirror array  40  is used to direct the energy to a switch  38  in  FIG. 3 . Each micro-mirror is separately controlled or programmable to reflect the light or the energy to a specific pole. The energy beams  45  reflected from the mirror and falling on the switch at each pole will control the voltage (driven from the voltage source  38 ) at the electrode tip. The actuation pole can be various shapes and concentric as shown in  FIG. 11   e.  Each electrode should have a metallic tip.  
         [0043]     Referring now to  FIG. 11   b,  the actuation poles  24  in the quadrupole configuration shown in  FIG. 11   a  are approximated by a system of four point charges  39  (±Q) located in the x-y plane and arranged symmetrically about the z-axis. Due to symmetry, the radial component of the force is zero (i.e. F p =0), and the z-component of the DEP force is defined by the following equation:  
             F   z       a   5       ≅       -       3   ⁢     Q   2         πɛ   1         ⁢     Re   ⁡     [     K   2     ]       ⁢       (     z   /   b     )           b   7     ⁡     (     1   +       (     z   /   b     )     2       )       6           =       -       3   ⁢     Q   2         πɛ   1         ⁢     Re   ⁡     [     K   2     ]       ⁢       G   QUAD     ⁡     (   z   )             
 
 where G QUAD (z) collects the geometric dependencies and  
         K   2     =       10   ⁢     (       ɛ   p   *     -     ɛ   m   *       )           2   ⁢     ɛ   p   *       +     3   ⁢     ɛ   m   *               
 
 where ε* p  is the complex permittivity of the cell with radius α immersed in a media with complex permittivity ε* m . From the first equation, we can observe that the force F z  is proportional to α 5  (radius) 5 , so we can levitate the small particles using this configuration. On the other hand, the quadrupole levitator comprises an azimuthally symmetric electrode arrangement capable of sustaining passive stable particle levitation. Also, as a diagnostic tool, quadrupole levitation offers researchers insight into the detailed electrical composition of materials. For these reasons, we selected the quadrupole electrode configuration as an actuation part in our design. It will be apparent to those skilled in the art that other designs may also be used. 
 
         [0044]     To implement a large (100 μm) quadrupole system in the 0.18 CMOS technology, we are using four identical octagons using metal2 layer. These octagons are in the x-y plane and arranged symmetrically about the z-axis (see  FIG. 11   a ), with a distance 100 μm between each other, as shown in  FIG. 11   c.    FIG. 11   d  shows a schematic diagram of a single electrode. The dimension of the electrode is 100 μmx 100 μm from edge to edge. This dimension violates the direct rule check (DRC) of the standard 0.18 μm technology, for which the maximum metal area should be &lt;35 μm×35 μm. Thus, we used a grid or mesh arrangement of metal2 that leaves a 1 μm space between each metal2 rectangle, as shown in  FIG. 11   d.  Individual strips  27  of metal2 overlap each other and are spaced with gaps between them to form a mesh electrode.  FIG. 11   e  shows a concentric continuous pole  50  with embedded sensors  60 . The poles have different heights. The inner pole has light sensitive switch  42 , the outside pole has switch  48  and the in-between two poles have the switches  44  and  46 . The poles are connected to a voltage source  38 . The shape in  FIG. 11   e  is octagonal because it is easier to fabricate in 0.18 μm standard TSMC technology, but any other shape can be used. It is worth noted that the continuity of the electrodes generate a better and more accurate planar electric field.  
         [0000]     The Sensing Unit  
         [0045]     The sensing unit  14  is composed of an array of the Differential Electric Field Sensitive MOSFET (DeFET)  40  shown in  FIG. 8  acting as sensor elements  28  in  FIG. 1   b.  DeFETs  40  allow us to record accurate information about the in-situ intensity of the applied nonuniform electric field. Referring to  FIG. 1   b,  the sensor elements  28  are individually addressable through terminals  25  to read individual sensor values. As discussed above for the actuation unit  12 , each sensor  28  may be actuated using electrical signals or a light beam, such as a laser. The sensors  28  are located in convenient locations around where the sample  26  will be processed by the actuation unit  12 , such as in the space between the actuation electrodes  24  so that measurements around the characteristics of the sample  26  are recorded, and the intensity of the applied non-uniform electric field and force. More detail will now be given on the construction and operation of the DeFET  40 .  
         [0046]     The Electric Field Sensitive Field Effect Transistor (eFET)  
         [0047]     In the DEP levitation process, the manipulating electric field is a nonuniform electric field (i.e. the electric field is a function of the distance). Thus, we can detect the electric field by using the Electric Field Sensitive MOSFET (eFET)  42  shown in  FIG. 5  as a novel electric field sensor.  FIG. 5  shows the physical structure of the eFET  42 . It has two adjacent drains  44 , two adjacent floating gates  46  on silicon oxide (SiO 2 ) layers  47 , and one source  48 . For the eFET  42 , it is equivalent to two identical enhancement MOSFET devices, as shown in  FIG. 6 . Thus, the two drain currents are equal if no electric field applied. Under the influence of a nonuniform electric field, a current imbalance between the two drain currents occur. Due to the drain current dependence on the gate voltage, the eFET device  42  that has two adjacent gates  46 , and two adjacent drains  44 , but isolated and spatially separated from each other, can sense the difference between the two gate voltages, which reflects the intensity of the applied nonuniform electric field between the two locations of the gates  46 .  FIG. 7  shows the circuit symbol of the eFET  42 . To increase the dynamic range of the eFET  42 , the CMOS concept is used to implement the DeFET  40  sensor, and this sensor may be used as the basic sensing block in the electric field imager. If only one side of the eFET were present (i.e. one gate  46 , one drain,  44 , and the source  48 ), the drain current would still be related to the electric field that is present, however, there would be nothing to compare the value with. This would be useful if a proper calibration technique was used. More accurate and meaningful results are therefore obtained using the eFET  42  as described, with a fixed distance between gates  46 .  
         [0048]     The Differential Electric Field Sensitive MOSFET (DeFET)  
         [0049]     Referring to  FIG. 8 , the DeFET  40  is formed of two complementary eFETs  42 , one of them is a p-type eFET  42  and the other is an n-type eFET  42 . The equivalent circuit of the DeFET  40  is shown in  FIG. 9 . Referring to  FIG. 9 , the two gates  46  of the p-type eFET  42  and n-type eFET  42  are connected with each other, and there is a cross coupling between the two drains  44  of the p-type eFET  42  and the n-type eFET  42 . The output current I O  is equal to the difference between the two drain currents I D2 -I D3  (i.e. I O =I D2 -I D3 , see  FIG. 9 ). On the other hand, I D2  and I D3  are functions of the two applied gate voltages V in1  and V in2 , respectively, so, I O  is directly related to the difference between the two applied gate voltages (V in1 -V in2 ), and V in1 -V in2  is equal to the applied electric field above the two gates  46  multiplied by the distance between them (V in1 -V in2 /d=E), where d is the distance between the two split gates  46 , which is constant. So, I O  is related directly to the intensity of the applied nonuniform electric field. Thus by measuring I O  we can detect the intensity of the nonuniform electric field.  
         [0000]     The Read-Out Circuit  
         [0050]     For the read-out circuit  50 , a higher differential gain is needed to amplify the small current signal at the output; also, it has to have a high common mode rejection ratio (CMRR) to reject any common mode signal. Referring to  FIG. 10 , a suitable read-out circuit  50  is the Current-Mode Instrumentation Amplifier (CMIA) proposed by Yehya H. Ghallab, Wael Badawy, Karan V.I.S. Kaler and Brent J. Maundy in “A Novel Current-Mode Instrumentation Amplifier Based on Operational Floating Current Conveyor”, submitted to  IEEE Transaction in instrumentation and measurement,  (33 pages), January 2003. It is formed of two operational floating current conveyors (OFCC)  52 , two feedback resistors (R W1  and R W2 )  54 , a gain determined resistor (R G )  56  and a ground load (R L )  58 .  
         [0000]     The Characterization Unit  
         [0051]     The characterization unit  16  reads the output of the sensors  28  and develops a 2D image for the values and compares it with the actuated value. The difference between the actuation values and the sensed values are used to detect and characterize the levitated sample  26  and the characteristics of the contents and liquid inside the micro-channel which may be used as the chamber  18 . The characterization unit  16  can also use a sequence of images and process them using image and video processing algorithms to identify the contents of the sample, algorithms such as edge detection, motion tracking, or DSP techniques.  
         [0000]     The Controller  
         [0052]     The controller  20  adjusts the value of the actuation unit  12  so it generates the required force. The controller  20  may adjust the actuation values using preprogrammed values, or it can read values from the sensing unit  14  or the characterization unit  16  to adjust the actuation unit  12  if needed.  
         [0000]     Sensor-Actuation Integration  
         [0053]     The integrated quadruple poles  24  with the sensing unit  14  is shown in  FIG. 11   a.  It shows the quadrupole configuration to levitate the sample with the proposed electric field sensors  28  (DeFET  40 ) implanted in the middle.  FIG. 12  shows the simulation results with the electric field sensors, represented by line  74  and without the electric field sensors, represented by line  76 . From  FIG. 12 , we can observe that:  
         [0054]     a) The Electric field sensors didn&#39;t disturb the profile of the electric field; alternatively, it improves the profile as we under a very small levitation height (Z=3 μm) the levitated particle is on the stable range of operation. In other words, the insertion of the DeFETs reduces the appearance of the unstable regime of operation, thus, we can easily levitate the cells can passively.  
         [0055]     b) The z component of the dielectrophoertic force is increased, so we can levitate the heavy cells without any need of any other external forces, also, we can levitate the cell far from the electrodes, so many processes can be done (e.g. cell fusion, . . . etc . . . ).  
         [0056]     The sensing part (i.e. DeFET) is analyzed, designed, simulated, and implemented using Cadence analog design tool. The schematic representation of a single DeFET  40  is shown in  FIG. 13 , and the simulation results which confirm the functionality of the DeFET is shown in  FIG. 14 , where the different lines show different variations between the gates ranging from 3V (top line) to −3V (bottom line). From this figure, we can observe the linear relationship between the output current and the variation of the two gate voltages, which can reflect the variation with the applied electric field above the gates.  
         [0000]     DeFET as an Impedance Sensor  
         [0057]     We can also use a DeFET  40  as an impedance sensor by using the technique shown in  FIG. 17 . In this figure, an excitation electrode  60  is used to trap the sample  26 , in this case, a biocell, between it and the DeFET. The output current of the DeFET  40  is connected to a transimpedance amplifier  62  to convert the output current into voltage. In this technique, by measuring the output voltage, we can determine the impedance of the trapped biocell  26 . The mathematical derivation is shown below.  
         [0058]     Here we have a biocell  26  above the DeFET  40 , so the output voltage (V owcell ) is related to V in  by the equation:  
         V   owcell     =         V     i   ⁢           ⁢   n           R   sen     +     (       R   cell     //     C   cell       )         ⁢     (       R   F     //     C   F       )           
 
 where R F  is the feedback resistance, C F  is the feedback capacitance, R sen  is the output resistance of the DeFET  40 , R cell  is the biocell  26  resistance, and C cell  is the biocell  26  capacitance. To get R sen , we will determine the output voltage without the biocell  26 , and the above equation will be:  
         V   o     =         V     i   ⁢           ⁢   n         R   sen       ⁢     (       R   F     //     C   F       )           
 
         [0059]     From the above equation, we can get R sen , so we can simply use this value in the first equation to get the impedance of the biocell (i.e. R cell //C cell ).  
         [0000]     Simulation  
         [0060]     To verify the operational characteristics of the proposed read out circuit  50 , a simulation was developed using PSPICE version 7.1. Then, the proposed CMIA was prototyped and the simulation results were verified. The proposed current-mode instrumentation amplifier (CMIA) is shown in  FIG. 10 . It uses two OFCC  52 . Each OFCC is constructed using a current feedback op amp  64  (such as serial no. AD846AQ,) and current-mirrors composed of transistor arrays  66  (such as a device from Harris, serial no. CA3096CE,). From  FIG. 15 , we can observe that the experimental results validate the simulated results, and by using external resistors, simply, we can control the gain. To measure the common-mode rejection ratio (CMRR) of the circuit in  FIG. 10 , we connected both v in1  and v in2  together to the same input voltage source. CMRR was measured experimentally as a function of frequency for a differential voltage gain of 20. The result obtained is plotted in  FIG. 16 . From  FIG. 16 , we can see that the proposed topology shows CMRR magnitude and bandwidth is ≈76 dB @185 KHz. In  FIG. 16 , a comparison between the proposed and the currently used CMIA is done. We can observe that the proposed CMIA circuit has higher CMRR as well a higher bandwidth associated with this CMRR as shown by line  68  than other topologies, where line  70  is from A. A. Khan, M. A. Al-Turaigi and M. Abou El-Ela, in “An Improved Current-mode Instrumentation Amplifier with Bandwidth Independent of gain,”  IEEE Trans. Instr. Meas.,  vol. 44, no. 4, 1995, and line  72  is from B. Wilson in “Universal Conveyor Instrumentation Amplifier,”  Elect. Let.,  vol. 25, no. 7, pp. 470-471, 1989 and S. J. G. Gift, in “An Enhanced Current-Mode Instrumentation Amplifier,”  IEEE Trans. Instr. Meas.,  vol. 50, no. 1, pp. 85-88, 2001. So this CMIA is the best choice for our design.  
         [0061]     Immaterial modifications may be made to the invention described here without departing from the invention. In the claims, the word “comprising” preceding a listing of claim elements does not exclude other elements being present in the method or apparatus referred to. In the claims, the use of the indefinite article preceding an element does not exclude more than one of the element being present.