WO2009017854A2 - Système de sonde et procédé utilisant celui-ci - Google Patents

Système de sonde et procédé utilisant celui-ci Download PDF

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Publication number
WO2009017854A2
WO2009017854A2 PCT/US2008/061351 US2008061351W WO2009017854A2 WO 2009017854 A2 WO2009017854 A2 WO 2009017854A2 US 2008061351 W US2008061351 W US 2008061351W WO 2009017854 A2 WO2009017854 A2 WO 2009017854A2
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Prior art keywords
sensor
field effect
effect transistor
target
gate area
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PCT/US2008/061351
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English (en)
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WO2009017854A3 (fr
Inventor
Vladislav A. Oleynik
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Biowarn, Llc.
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Publication of WO2009017854A2 publication Critical patent/WO2009017854A2/fr
Publication of WO2009017854A3 publication Critical patent/WO2009017854A3/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/403—Cells and electrode assemblies
    • G01N27/414—Ion-sensitive or chemical field-effect transistors, i.e. ISFETS or CHEMFETS
    • G01N27/4145—Ion-sensitive or chemical field-effect transistors, i.e. ISFETS or CHEMFETS specially adapted for biomolecules, e.g. gate electrode with immobilised receptors

Definitions

  • the present invention relates generally to sensors for detecting the presence of biological and biochemical target substances, and more particularly to sensors that rely on reactions between biological and biochemical target substances and target recognition element types disbursed over a sensing surface to produce an electrical charge detectable by electronic means. It relies on a combination of semiconductor integrated circuitry in combination with digital signal processing techniques to optimize the detection process and negate the undesirable effects of environmental and electrical noise and other perturbations that produce errors and decrease sensitivity.
  • Sensors, particularly biochemical sensors have application in fields such as medical diagnostics, industrial safety, environmental monitoring and bioterror prevention for detection, identification and quantification of diseases, infectious agents, and toxic elements. They are also useful for detection, identification and quantification of biochemical elements that are beneficial to the human population and the environment.
  • Biochemical sensors may generally be used for detection of various biochemical substances such as viruses, bacteria, spores, allergens and other toxins.
  • Biochemical sensors may also be useful for medical diagnostics for detecting diseases such as avian influenza and Human Immunodeficiency Virus (HIV-I)) infection. Whether found in medical laboratories or in industrial complexes for monitoring ambient air quality, sensors must be capable of rapid detection and identification of biochemical substances as well as notification to those responsible for such activities.
  • the present invention provides a means for detecting the presence of one or more biochemical target substances, such as toxins, pathogens, nucleic acids, proteins, viruses, bacteria, spores, allergens, toxins and enzymes. It is capable of providing a high level of detection sensitivity through the use of an integrated differential pair of field effect transistors having a common substrate and common source, collocated in close proximity on a common silicon substrate.
  • the common substrate also includes a temperature sensor and heating element.
  • the common substrate, common source, temperature sensor and heating element are controlled by a digital signal processor for optimizing performance, including detection sensitivity.
  • the use of a differential pair of field effect transistors reduces the effects of common mode perturbations to the differential pair.
  • An embodiment of the of the invention is a sensor system for detecting one or more target substances, comprising one or more target recognition element types disbursed over a sensor gate area of a differential pair of field effect transistors for sensing an electrical charge created when the one or more target recognition element types react with the one or more target types.
  • the sensed electrical charge modulates a sensor channel of the differential pair field effect transistors to provide a differential output signal signature in which the differential pair of field effect transistors comprises a sensor field effect transistor and a reference field effect transistor having a common substrate connection and a common source connection controlled by a digital signal processor.
  • a reference gate area of the reference field effect transistor is isolated from the effects of the sensed electrical charge created on the sensor gate area, the digital signal processor for monitoring parameters of the differential pair, executing optimization algorithms, and controlling the operating characteristics to provide a differential output signal signature of the differential pair based on the optimization algorithms.
  • the digital signal processor measures, processes, identifies and stores a differential output signal signature from the differential pair of field effect transistor when a reaction of the one or more target recognition element types with the one or more target types is sensed by the sensor gate area. There is a means for notifying a user of the detection. Detection can be continuous, instantaneous and occur in real-time.
  • the invention comprises a sensor system for detecting one or more target substances, comprising: one or more target recognition element types disbursed over a sensor gate area of a differential pair of field effect transistors.
  • a digital signal processor monitors parameters of the differential pair of field effect transistors and controls operating characteristics of the differential pair of field effect transistors to an optimum operating range for signal sensing.
  • the differential pair of field effect transistors senses an electrical charge created by a reaction between the one or more target recognition element types and the one or more target substances in proximity of the sensor gate area, and provides a responsive output signal.
  • the digital signal processor measures, processes, identifies and stores the responsive output signal signature, and notifies a user of an identifying result.
  • a specific target recognition element of the sensor system may react with one or more specific target types, that is, a first target recognition element type may react with a first target type.
  • the sensor system may further comprise an operating structure of the differential pair of field effect transistors selected from the group consisting of p-channel enhancement mode, p-channel depletion mode, n-channel enhancement mode, and n-channel depletion mode.
  • the differential pair of field effect transistors may be fabricated on a common silicon substrate in close proximity to one another for minimizing differences in environmental and electrical influences between both field effect transistors in the differential pair.
  • the digital signal processor may control the operating characteristics of the differential pair by controlling a common substrate voltage, a common source current, and a quiescent drain voltage of the reference field effect transistor based on the optimization algorithms.
  • the sensor system may further comprise a temperature sensor and a heating means fabricated on a single silicon substrate with the differential pair of field effect transistors.
  • the digital signal processor of the sensor system may read the temperature sensor signal and control the temperature of the single silicon substrate by controlling a signal to the heating means.
  • the temperature sensor and heating means of the sensor system controlled by the digital signal processor may be used for self-cleaning the sensor gate area, for preparing the sensor gate area for disbursement of one or more target recognition element types, and for maintaining a stable temperature during normal sensing operations.
  • a single target recognition element type of the sensor system disbursed over the sensor gate area may react with only a single target type for producing a unique time- varying, signature output signal from the sensor field effect transistor and reference field effect transistor of the differential pair.
  • the time- varying signature output signal comprises an amplitude and a plurality of frequencies.
  • the digital signal processor of the sensor system may include a memory having a plurality of stored signature output signals for comparing with the measured signature output signal and identifying the single target type.
  • a first target recognition element type of the sensor system disbursed over the sensor gate area may react with only a first target type and a second target recognition element type disbursed over the sensor gate area may react with only a second target type for producing a unique time- varying, superimposed first and second signature output signal from the sensor field effect transistor and reference field effect transistor of the differential pair.
  • the digital signal processor of the sensor system may include a memory having a plurality of stored signature output signals for comparing the stored signature signals with the measured superimposed first and second signature output signal and identifying the first and second target type.
  • the recognition element may be a protein, nucleic acid, inorganic molecule or and organic molecule.
  • the recognition element may also be an antibody, antibody fragment, oligonucleotide, DNA, RNA, aptamer, enzyme, cell fragment, receptor, bacteria, bacterial fragment, virus or viral fragment.
  • the target substance may be a molecule, compound, complex, nucleic acid, protein, virus, bacteria, bacterial fragment, cell or cell fragment.
  • the target substance may be a protein, nucleic acid, inorganic molecule or and organic molecule.
  • the present invention includes sensor array comprising two or more sensor systems described above.
  • the sensor array may comprise two or more sensor systems for detecting the presence of two or more target types.
  • the sensor array may comprise a first sensor system for detecting the presence of a first target type and a second sensor system for detecting the presence of a second target type.
  • Yet another embodiment of the present invention is a sensor method for detecting the presence of one or more target types, comprising the steps of disbursing one or more target recognition element types over a sensor gate area of a differential pair of field effect transistors for sensing an electrical charge created when the one or more target recognition element types react with the one or more target types, the sensed electrical charge modulating a sensor channel of the differential pair field effect transistors, controlling a common substrate connection and a common source connection of the differential pair of field effect transistors comprising a sensor field effect transistor and a reference field effect transistor by a digital signal processor, wherein a reference gate area of the reference field effect transistor is isolated from the effects of the sensed electrical charge created on the sensor gate area, determining characteristics of the differential pair, executing optimization algorithms, and controlling the operating characteristics of the differential pair based on the optimization algorithms by the digital signal processor, measuring, processing, identifying and storing a differential output signal signature from a sensor field effect transistor and a reference field effect transistor of the differential pair by the digital signal processor when a reaction of the one
  • the disbursing step may comprise disbursing a specific target recognition element over a sensor gate area of a differential pair of field effect transistors for sensing an electrical charge created when the one or more target recognition element types react with the one or more target types, the sensed electrical charge modulating a sensor channel of the differential pair field effect transistors.
  • the sensor method may further comprise selecting an operating structure of the differential pair of field effect transistors from the group consisting of p-channel enhancement mode, p-channel depletion mode, n-channel enhancement mode, and n- channel depletion mode.
  • the sensor method may further comprise fabricating the differential pair of field effect transistors on a common silicon substrate in close proximity to one another for minimizing differences in environmental and electrical influences between both field effect transistors in the differential pair.
  • the controlling step may further comprise controlling the operating characteristics of the differential pair by controlling a common substrate voltage, a common source current, and a quiescent drain voltage of the reference field effect transistor based on the optimization algorithms.
  • the sensor method may further comprise fabricating a temperature sensor and a heating means on a single silicon substrate with the differential pair of field effect transistors controlled by the digital signal processor.
  • the sensor method may further comprise reading the temperature sensor signal and controlling the temperature of the single silicon substrate by controlling a signal to the heating means by the digital signal processor.
  • the sensor method may further comprise self-cleaning the sensor gate area, preparing the sensor gate area for disbursement of one or more target recognition element types, and maintaining a stable temperature during normal sensing operations by controlling the temperature sensor and heating means by the digital signal processor.
  • the disbursing step may comprise disbursing a single target recognition element over a sensor gate area of a differential pair of field effect transistors for sensing an electrical charge created when the target recognition element reacts with the one or more target types, the sensed electrical charge modulating a sensor channel of the differential pair field effect transistors producing a unique time- varying signature output signal from the sensor field effect transistor and reference field effect transistor of the differential pair.
  • the sensor method may further comprise storing a plurality of signature output signals in a digital signal processor memory for comparing with the measured signature output signal and identifying the single target type.
  • the disbursing step may include disbursing a first target recognition element type over the sensor gate area that reacts with only a first target type and disbursing a second target recognition element type over the sensor gate area that reacts with only a second target type for producing a unique time-varying, superimposed first and second signature output signal from the sensor field effect transistor and reference field effect transistor of the differential pair.
  • the time-varying signature output signal comprises an amplitude and a plurality of frequencies.
  • the digital signal processor used in the sensor method may include a memory having a plurality of stored signature output signals for comparing with the measured superimposed first and second signature output signal and identifying the first and second target type.
  • the sensor system further comprises using the heating means to heat the sensor gate area to a temperature of between about 35° Celsius and about 80° Celsius to self-clean the sensor gate to allow for reuse of the sensor system.
  • the digital signal processor automatically controls the parameters of the heating means for the self- cleaning of the sensor gate and sensor surface process.
  • a sensor method for forming an array comprises assembling an array of two or more sensors according to the method described above.
  • the sensor method may comprise assembling an array of two or more sensors for detecting the presence of two or more target types.
  • the sensor method may comprise assembling a first sensor system for detecting the presence of a first target type and a second sensor system for detecting the presence of a second target type.
  • Figure IA depicts a diagram of a single target recognition element disbursed over a sensor gate area and a multitude of targets and target types;
  • Figure IB depicts a diagram of a single target recognition element disbursed over a gate area binding with a target substance in the presence of a multitude of target types
  • Figure 1C depicts a diagram of a plurality of target recognition element types disbursed over a gate area binding with a plurality of target substances in the presence of a multitude of target types
  • Figures 2A - 2J depict side views of processing steps for fabricating a differential pair of field effect transistors on a silicon substrate;
  • Figure 3 depicts a top view of a dual fabricated differential pair of field effect transistors on a silicon substrate;
  • Figure 4 depicts an electrical equivalent circuit of a packaged dual fabricated differential pair of field effect transistors on a silicon substrate
  • Figure 5A depicts a conceptual relationship between analog differential pair sensor circuits and a digital signal processor
  • Figure 5B depicts a simplified diagram of a sensor system including a differential pair of field effect transistors, two current sources, a digital signal processor and associated circuitry;
  • Figure 5C depicts a detailed diagram of a sensor system including a differential pair of field effect transistors, two current sources, a digital signal processor and associated circuitry;
  • Figures 6A - 6C depict the steps of a sensor optimization algorithm executing in a digital signal processor for automatically controlling the operating characteristics of the differential pair of field effect transistors as shown in Figures 5 A and 5B;
  • Figure 7A depicts typical plotted parametric data obtained from a differential pair of p-channel depletion mode field effect transistors by a digital signal processor where Fig. 7A represents data collected in step 656 and stored in step 658 of Fig. 6B;
  • Figure 7B depicts typical plotted parametric data obtained from a differential pair of n-channel depletion mode field effect transistors by a digital signal processor
  • Fig. 7B represents data collected in step 656 and stored in step 658 of Fig. 6B;
  • Figure 7C depicts an optimization method using the plotted parametric data of Figure 7A, shown as a reference transistor;
  • Figure 7D depicts an optimization method using the plotted data of Figure 7C, shown without chemistry applied, after chemistry and biology are applied, and after an environmental change in acidity (Ph);
  • Figure 8 depicts process steps for implementing an operational embodiment of the present invention.
  • Figures 9A - 9D show typical responses from a differential pair of field effect transistors with binding and without binding of a target recognition element and a target substance.
  • Figure 1OA illustrates a two-by-two sensor array in a system configuration where the recognition elements in the array may be selected from one of the embodiments shown herein;
  • Figure 1OB illustrates a four-by-four sensor array in a system configuration where the recognition elements in the array may be selected from one of the embodiments shown herein.
  • the differential pair field effect sensor and reference elements described below may comprise either p-channel devices or n-channel devices, and may be either depletion mode or enhancement mode devices. Where it is necessary to show a particular device, an arbitrary choice of a p-channel depletion mode is illustrated.
  • the terms "target”, “target substance” or “target type” mean any material, the presence or absence of which is to be detected and that is capable of interacting with a recognition element.
  • the targets that may be detected include, without limitation, molecules, compounds, complexes, nucleic acids, proteins, such as enzymes and receptors, viruses, bacteria, cells and tissues and components or fragments thereof.
  • targets include, without limitation, biochemical weapons such as anthrax, botulinum toxin, and ricin, environmental toxins, insecticides, aerosol agents, proteins such as enzymes, peptides, and glycoproteins, nucleic acids such as DNA, RNA and oligonucleotides, pathogens such as viruses and bacteria and their components, blood components, drugs, organic and inorganic molecules, sugars, and the like.
  • biochemical weapons such as anthrax, botulinum toxin, and ricin
  • environmental toxins such as enzymes, peptides, and glycoproteins
  • nucleic acids such as DNA, RNA and oligonucleotides
  • pathogens such as viruses and bacteria and their components
  • blood components drugs, organic and inorganic molecules, sugars, and the like.
  • the target may be naturally occurring or synthetic, organic or inorganic.
  • recognition element refers to any chemical, molecule or chemical system that is capable of interacting with a target or target type.
  • Recognition elements can be, for example and without limitation, antibodies, antibody fragments, peptides, proteins, glycoproteins, enzymes, nucleic acids such as oligonucleotides, aptamers, DNA, RNA, organic and inorganic molecules, sugars, polypeptides and other chemicals.
  • a recognition element can also be a thin film that is reactive with a target of interest.
  • Figure IA depicts a diagram 100 of a single target recognition element type 140 disbursed over a sensor gate area 117 of a differential pair field effect sensor element and a multitude of target types 130, 132, 134, 136.
  • the target recognition elements 140 may or may not be encased in a gel 148, which allows target typesl30, 132, 134, 136 to pass through and bind with the target recognition elements 140.
  • the field effect sensor element includes a sensor gate area 117 positioned between a source 120 and a drain 122 doped into a silicon base substrate 150.
  • a silicon oxide layer 115 is grown over the substrate 150, drain 120 and source 122.
  • An insulating layer may or may not be deposited over the sensor gate area 117.
  • Metal interconnections 125, 127 connect the drain 120 and source 122 to external terminals of the device.
  • a passivating layer 110 may be applied over the entire device except for the sensor gate area 117.
  • Figure IB depicts a diagram 160 of a single target recognition element 140 disbursed over a sensor gate area 117 binding with a target substance 130 in the presence of a multitude of target types 130, 132, 134, 136.
  • Figure IB is the same as Figure IA except it shows a single target type 140 that binds with a single target recognition element type 130 to produce a unique signature signal that distinguishes the reaction and differentiates the bound target from other targets.
  • Figure 1C depicts a diagram 170 of a plurality of target recognition element types 140, 142, 146 disbursed over a gate area 117 binding with a plurality of target types 130, 132, 136 in the presence of a multitude of target types 130, 132, 134, 136.
  • multiple target recognition types 140, 142, 146 multiple target types 130, 132, 134, 136 may be sensed.
  • the sensor gate element having a coating of H5 and Nl target recognition element types would be capable of sensing the H5N1 avian flu virus.
  • the resultant signature signal output from such a sensor element upon sensing the H5N1 virus would be a superposition of the H5 signature signal shown in Figure 9B and the Nl signature signal shown in Figure 9D, which could be easily stored in the pre-stored signature signal library within a digital signal processor or personal computer.
  • Figures 2A - 2J depict side views 200 of processing steps for fabricating a differential pair of field effect transistors on a silicon substrate base 215.
  • Figure 2A depicts a p-type or an n-type substrate base 215 where a layer of silicon oxide 210 has been grown on the surface of the substrate base 215.
  • Figure 2B depicts contact openings 212 created in the oxide layer 210 by a common photolithographic/photoresist process used in the semiconductor industry.
  • Figure 2C depicts an addition of p++ or n++ wells 220, 225 doped into the substrate base 215 to form drain regions 220 and source regions 225.
  • Figure 2D further depicts removal of certain oxide areas for the creation of channel areas 230 in the substrate base.
  • the channel areas 230 may or may not require additional doping.
  • Figure 2E depicts recreation of an oxide covering 210 over the channel area 230, if the channel area creation required removal of an original oxide covering 210.
  • Figure 2F depicts the addition of a metal interconnection 240 to the drain 220 and a metal interconnection 245 to the source 225 of sensor transistor (this may be the sensor drain) 280 and reference field effect transistor (this may be the reference drain) 290 that comprise the differential pair.
  • Figure 2G depicts the opening of a gate area 250 by removal of the oxide layer 210 of the sensor from the sensor field effect transistor 280. The oxide layer 210 from the gate area 255 of the reference field effect transistor 290 is left intact.
  • Figure 2H depicts an option of covering the gate area 250 of the sensor field effect transistor 280 with a protective insulating layer 260.
  • Figure 2J depicts completion of the differential pair of a sensor field effect transistor 280 and a reference field effect transistor 290 with a covering the completed structure with a passivating layer 265, except for the gate area 250 of the sensor field effect transistor 280, which is not covered with a passivating layer 265.
  • Figure 3 depicts a top view 300 of a first differential pair of field effect transistors 360, 365 and a second pair of field effect transistors 385, 390, all fabricated on a silicon substrate 395.
  • a drain of a sensor field effect transistor 360 of the first differential pair of field effect transistors 360, 365 is interconnected to a wire bonding area 310 by a metallic interconnect 312.
  • the sources of the sensor field effect transistor 360 and reference field effect transistor 365 of the first differential pair of field effect transistors 360, 365 are connected together and interconnected to a common wire bonding area 315 by a metallic interconnect 317.
  • a drain of the reference field effect transistor 365 of the first differential pair of field effect transistors 360, 365 is interconnected to a wire bonding area 320 by a metallic interconnect 322.
  • a drain of a sensor field effect transistor 385 of the second differential pair of field effect transistors 385, 390 is interconnected to a wire bonding area 345 by a metallic interconnect 347.
  • the sources of the sensor field effect transistor 385 and reference field effect transistor 390 of the second differential pair of field effect transistors 385, 390 are connected together and interconnected to a common wire bonding area 350 by a metallic interconnect 352.
  • a drain of the reference field effect transistor 390 of the second differential pair of field effect transistors 385, 390 is interconnected to a wire bonding area 355 by a metallic interconnect 357.
  • a heating element 380 embedded in the substrate 395 is connected to wire bonding areas 325, 340 by metallic interconnects 327, 342, respectively.
  • a temperature sensing element 375 embedded in the substrate 395 is connected to wire bonding areas 330, 335 by metallic interconnects 332, 334, respectively.
  • a metallic film deposition 370 is positioned within the boundaries of the heating element 380 and overlays the field effect transistors 360, 365, 385, 390 and the temperature sensing element 375 to provide uniform heat distribution.
  • each differential pair of field effect transistor 360, 365 and 385, 390 are located in close proximity to each other in order to be under the influence of the same common mode environmental conditions, such as temperature, electromagnetic radiation, noise, and other factors such as light, cosmic rays, and the like. Common mode electrical signal effects from such common mode environmental conditions will be canceled out by the common mode rejection capabilities of the field effect differential pair.
  • Figure 4 depicts an electrical equivalent circuit 400 of a packaged dual fabricated differential pair of field effect transistors 460, 465, 485, 490, heating element 480 and temperature sensing element 475 on a connecting point of the silicon substrate 455.
  • a drain of a reference field effect transistor of a first pair of field effect transistors is connected to a connecting point 410, and a drain of a sensor field effect transistor of a first pair of field effect transistors is connected to a connecting point 420.
  • a common source of the sensor and reference field effect transistors of the first field effect transistor pair is connected to a connecting point 415.
  • a drain of a reference field effect transistor of a second pair of field effect transistors is connected to a connecting point 445, and a drain of a sensor field effect transistor of a second pair of field effect transistors is connected to a connecting point 455.
  • a common source of the sensor and reference field effect transistors of the second field effect transistor pair is connected to a connecting point 450.
  • a base substrate common to the four field effect transistors is connected to a connecting point 495.
  • a heating element is connected to connecting points 425, 440, and a temperature sensing element is connected to connecting points 430, 435.
  • the analog differential pair sensor circuits 503 include analog adjusting circuitry that surrounds the differential pair and comprises current sources and balancing circuitry.
  • the digital signal processor 504 senses the analog parameters of the analog differential pair sensor circuits 503 through the analog to digital converters 549 and determines optimized values for setting the analog values of the current sources and balancing circuitry through the digital to analog converters 547.
  • Other analog to digital converters 549 are used to detect the optimized output signal from the analog differential pair sensor circuits 503 when a reaction between a target recognition element and a target is sensed. These signals are processed by the digital signal processor 504 for identifying the sensed target, which is provided as an output.
  • This configuration represents a unique configuration whereby a digital signal processor is in a feedback loop of an analog circuit for balancing and optimizing the analog circuitry.
  • Figure 5B depicts a simplified diagram of a sensor system
  • the differential pair of field effect transistors 514 comprising a sensor field effect transistor 516 and reference field effect transistor 520, detects reactions at the sensor gate surface 518 between target recognition elements and target substances while providing a means for rejection common mode signals affecting both field effect transistors in the differential pair 514. Detected reactions provide a normal mode signal at the sensor gate surface 518 which is amplified by the differential pair 516, 520, to provide an amplified differential signal at the drains 517, 521 of the differential pair 516, 520.
  • a differential amplifier 512 amplifies and converts the differential drain signals to a normal mode signal, which is sent to the digital signal processor 504 for processing as described below.
  • the output signal at the drain 517 of the sensor field effect transistor 516 is also sent to the digital signal processor 504.
  • Resistors 508, 510 are connected to the drains 571, 521 of the field effect differential pair 516, 520 for providing a source of drain current to the differential pair 516, 520.
  • a common source resistor 524 connected to the common sources 513 of the differential pair 516, 520 enable the differential operation of the differential pair 516, 520.
  • the digital signal processor 504 optimization algorithms also keep the differential pair 516, 520 in balance by controlling and monitoring the current source 502 connected to the reference field effect transistor drain 521.
  • a personal computer 506 provides a user interface for control of the digital signal processor 504.
  • the digital signal processor 504 is connected to a memory 505 that includes a plurality of stored signature outputs signals for comparing with the signature output signal generated from a target interaction to identify a target type.
  • Figure 5C depicts a detailed diagram of a sensor system 530, including a differential pair of field effect transistors 514, two current sources 532, 590, a digital signal processor 504, a personal computer 506 and associated circuitry.
  • the differential pair of field effect transistors 514 comprising a sensor field effect transistor 516 and reference field effect transistor 520, detects reactions at the sensor gate surface 518 between target recognition elements and target substances while providing a means for rejection common mode signals affecting both field effect transistors in the differential pair 514.
  • Detected reactions provide a normal mode signal at the sensor gate surface 518 which is amplified by the differential pair 516, 520, to provide an amplified differential signal at the drains 517, 521 of the differential pair 516, 520.
  • a differential amplifier 556 amplifies and converts the differential drain signals to a normal mode signal, which is sent to the digital signal processor 504 via level shifting circuits for processing as described below.
  • Level shifting circuits are controlled by the digital signal processor 504 and are used to maintain a signal with the dynamic range of the analog-to-digital converters within the digital signal processor 504.
  • Level shifting circuits comprising a differential amplifier 550 and a digital-to-analog converter 552 maintain the sensor field effect transistor signal from a buffer amplifier 554 within dynamic range of an analog-to- digital converter within the digital signal processor 504.
  • Level shifting circuits comprising a differential amplifier 560 and a digital-to-analog converter 562 maintain the normal mode drain signal from a differential amplifier 556 within dynamic range of an analog-to-digital converter within the digital signal processor 504.
  • Level shifting circuits comprising a differential amplifier 580 and a digital-to-analog converter 582 maintain the differential pair 564 common source voltage at the output of a buffer amplifier 578 within dynamic range of an analog-to-digital converter within the digital signal processor 504.
  • the output signal at the drain 517 of the sensor field effect transistor 516 is sent to the digital signal processor 504 via a buffer amplifier 554 and level shifting circuitry 550, 552.
  • Resistors 508, 510 are connected to the drains 517, 521 of the field effect differential pair 516, 520 for providing a source of drain current to the differential pair 516, 520.
  • a common source resistor 524 connected to the common sources 513 of the differential pair 516, 520 enable the differential operation of the differential pair 516, 520.
  • the optimization algorithms in the digital signal processor 504 control a current source 590, 588 connected to the common source resistor 524 via a digital-to-analog converter 594 and amplifier 592, and control a voltage at the common base substrate 515 of the differential pair 516, 520 via a digital-to-analog converter 574, amplifier 572 and resistor 570.
  • the algorithms also monitor the common base substrate voltage via a buffer amplifier 576 and the voltage at the output of the current source 590, 588 via an amplifier 586.
  • the optimization algorithms in the digital signal processor 504 also keep the differential pair 516, 520 in balance by controlling a current source 532, 538 via a digital-to-analog converter 546 and amplifier 544, and by monitoring, via an amplifier 548, the current source 532, 538 connected to the reference field effect transistor drain 521.
  • a personal computer 506 provides a user interface for control of the digital signal processor 544.
  • the digital signal processor 504 is connected to a memory 505 that includes a plurality of stored signature outputs signals for comparing with the signature output signal generated from a target interaction to identify a target type.
  • the detailed sensor system 530 shown in Figure 5C enables the digital signal processor 504 using optimization algorithms to compensate the field effect differential pair 514 for continuously changing environmental factors by altering the operating point on the voltage-current characteristics of the differential pair 514.
  • the control of the differential pair 514 is achieved by two current sources 532, 590 and the base substrate voltage that performs the role of a common gate for all devices on the substrate.
  • the control scheme requires that a change in any one parameter of channel resistance, differential pair balance or average drain voltage requires an adjustment of the other two.
  • the detailed diagram of Figure 5C also includes controlling the temperature operating characteristic using a heating element 564 embedded in the substrate containing the differential pair 514 via a digital-to-analog converter 540 and amplifier 542. Also included in the substrate is a temperature sensing element 566 connected to the digital signal processor 504 for controlling the substrate temperature.
  • a conventional proportional control algorithm may be used in the digital signal processor 504 for maintaining the substrate at a desired temperature.
  • the temperature of the substrate may be used to maintain a temperature most favorable for reactions between target recognition elements and targets. This temperature may be different for different target recognition elements and different targets, but is generally between 28° and 35° Celsius in order to obtain reactions within a reasonably short sampling time of several minutes.
  • the temperature may also be controlled for sensor self- cleaning and for target recognition element deposition on the sensor gate area 518.
  • the heating element is used to heat the sensor surface from between about 35° Celsius and about 80° Celsius.
  • Figures 6A depicts the steps of a sensor optimization algorithm 600 executing in a digital signal processor for controlling the differential pair of field effect transistors as shown in Figures 5A, 5B, and 5C above.
  • the sensor optimization algorithm is started 610 manually by the operator.
  • An initialization routine 612 described in more detail below in Figure 6B below, results in the storing of parametric data 614, illustrated in Fig. 7A and Fig. 7B, for the sensor field effect transistor Sl and the reference field effect transistor Rl derived from measurements performed on the differential pair by the algorithms in the digital signal processor using DAC4, DAC5, DAC6, B3, B4 and A9 (582, 574, 594, 578, 576, 586) shown in Figure 5C.
  • optimized parameter values for the sensor field effect transistor Sl are determined 616, and the optimal operating point of the sensor field effect transistor Sl is identified.
  • the output voltage of DAC5 and DAC6 (574, 594 in Figure 5C) are adjusted 618 to provide source current for the sensor field effect transistor Sl and the reference field effect transistor Rl, and voltage to the common substrate base of the differential pair that conforms to optimized parameter values.
  • the differential pair is then balanced 622, as described in further detail in figure 6C described below.
  • the actual position of the sensor field effect transistor Sl operating point is determined 626 and compared to the computed optimal operating point 628.
  • the processing of recognition element reactions with targets is conducted 630, and any reaction data is stored 632. This reaction data are used for analyzing and final decision-making about chemical and biochemical processes on the surface of the Sl sensor. If a STOP command is not received from an operator 636, and Sl is optimal 642, the target recognition process continues 630. If Sl is found to be not optimal the initialization step is repeated 612. Returning to step 628, if the determined operating point is significantly different from the computed operating point 628, the optimization process of the differential pair of field effect transistors is conducted. If the Sl operating point is not optimal 628, it is determined if the source current source is optimal 634.
  • the source current is not optimal 634
  • the current is adjusted via DAC6 640 (594 in Figure 5C), the differential pair is balanced according to Figure 6C below 644, and it is then determined if the drain voltage is optimal 624. If, in step 634, it was determined that the current source current is optimal, it is also then determined if the drain voltage is optimal 624. If the Sl drain voltage is not optimal 624, DAC5 (574 in Figure 5C) is adjusted 620 and the differential pair is balanced 622 according to Figure 6C below. If the Sl drain voltage is optimal 624, the differential pair is also balanced 622
  • Figure 6B depicts the steps required 650 for the initialization step in Figure 6A above.
  • the initialization process is to control and confirm the functionality of differential pair of field effect transistors.
  • transistor curve data and work point of differential pair Sl and Rl are collected 656 and stored 658.
  • the drain-to- source voltage data of the differential pair (514 in Fig. 5B) is determined by varying the source current via DAC6 (594 in Fig. 5B) for incremental values of base substrate voltage 656 via DAC5 (574 in Fig. 5B).
  • the base voltage, source voltage and current source output voltage are simultaneously measured (576, 578, 586 in Fig.
  • Sampled data values of the drain-to-source voltage and source current for the sensor field effect transistor Sl and reference field effect transistor Rl are stored 658. These sampled data values are represented by the data points plotted in Fig. 7A and Fig. 7B. From this data, it is determined if Rl is operational 660. If either Rl is not operational 660 or Sl is not operational 662, the sensor is not functional 664 and further processing is stopped. 668. If both Rl is operational 660 and Sl is operational 662, control is returned to step 616 in Figure 6A.
  • Figure 6C depicts the steps required to balance the differential pair of field effect transistors Sl and Rl 680.
  • the difference between the drain voltages of Sl and Rl are measured 686 via Bl and B2 (554, 558) in Figure 5C. If the difference is zero 688, control is returned to the requesting step 692 in Figure 6A. If the difference is not zero 688, DACl (546 in Figure 5C) is adjusted so that the difference in drain voltages of Rl and Sl is zero 690, and control is returned to the requesting step 692 in Figure 6A.
  • Figure 7A depicts typical plotted parametric data 700 obtained in step 656 of Figure 6B above from a differential pair of p-channel depletion mode field effect transistors by a digital signal processor.
  • the data points represent values of source current 702 as the drain to source voltage 704 is varied while holding constant incremental values of base-source voltage 706, 708, 710, 712, 714 for the sensor field effect transistor and the reference field effect transistors.
  • Each data point on the graph represents a value of source current for a given value of drain- source voltage and a given value of base- source voltage.
  • Figure 7B depicts typical plotted parametric data 750 obtained in step 656 of Figure 6B above from a differential pair of n-channel depletion mode field effect transistors by a digital signal processor.
  • the data points represent values of source current 722 as the drain to source voltage 724 is varied while holding constant incremental values of base-source voltage 7726, 728, 730, 732 for the sensor field effect transistor and the reference field effect transistors.
  • Each data point on the graph represents a value of source current for a given value of drain- source voltage and a given value of base-source voltage.
  • Figure 7C depicts an optimization method using the plotted static parametric data of Figure 7A, shown as a reference transistor.
  • An optimum operating point 746 of the sensor field effect transistor of a differential pair of field effect transistors is determined by choosing a line 742 that is tangent to a maximum response curve 714 at between a 40° and 45° angle 740 to the horizontal 744.
  • the 40° to 45° angle 740 is chosen to give a maximum gain and dynamic range of the differential pair analog circuitry without saturating the analog circuitry, while maintaining an acceptably low noise level from the analog circuitry.
  • an optimized operating point 746 gives a source current of Iso 748 and a drain-to- source voltage of VDSO 750.
  • Figure 7D depicts an optimization method using the static plotted data and method of Figure 7C, shown as a family of curves A1-A4 786 without chemistry applied, a family of curves B1-B4 776 after chemistry and biology are applied, and a family of response curves C1-C4 766 after an environmental change in acidity (Ph).
  • the optimized operating points 782, 772, 762 are determined by finding a point where a line 784, 774, 764 at an angle between 40° and 45° to the horizontal is tangent to a maximum response curve in a family of response curves 786, 776, 766, respectively.
  • Figure 8 depicts process steps for implementing an operational embodiment of the present invention 800.
  • the process 800 is started 810 by cleaning and activating the surface of the sensor 815. This may be accomplished by mechanical chiseling, laser cleaning, chemically cleaning or thermally cleaning, so as not to affect the effectiveness of the sensor elements.
  • Thermally cleaning the sensor elements comprises raising the temperature of the sensor surface using the sensor heating element (564 in Figure 5C) to a cleaning temperature in excess of the normal operating temperature, typically between 35° Celsius and 80° Celsius.
  • the sensor surface is then treated with a silane solution, washed and cured 820.
  • the surface of the sensor element is then treated with cross-linkers 825 to provide an appropriate orientation to the target recognition elements.
  • the surface of the sensor element is then coated with selected target recognition elements 830 capable of uniquely sensing specific target types, such as an H5 antibody and an Nl antibody and may be suspended in a gel.
  • the sensor optimization algorithm described above in Figure 6A is executed 835 and the system is then deployed to expose the sensor element to targets 840.
  • the system looks for an output signature signal from the sensor element 845. If an output signature signal is detected, it is measured 850 and converted to a digital representation 855.
  • the output signal may be a measurement of conductance, voltage, current, capacitance and resistance that is converted to a digital representation.
  • the digital representation may be a time-varying signal having an amplitude and a plurality of frequencies.
  • the output signature signal is then compared to a library of pre-stored signature signals 860 to determine if there exists a match to a known target or target type 860. If no match exists 865, the system returns to sensing an output signal from the sensor element 845. If a match is found between the output signature signal and one or more pre-stored signature signals in the library 865, an event log and notification is generated and sent to appropriate authorities 870. Based on either pre-selected automatic criteria or user selected criteria, an alert may be sent 870.
  • recognition elements attaching to a sensor and the binding or interaction that occurs when a recognition element combines with a target type are well-known in the art.
  • the recognition elements are attached to the sensor surface, usually by a covalent attachment method (although in other embodiments non- covalent attachment methods may be used).
  • the interaction involves numerous dipole-dipole interactions resulting from the specific amino-acids mostly within a region of the antibody known as the hypervariable region and with specific features or amino-acids within the antigen (epitope-region).
  • the antibody and antigen may each be considered as complex dipoles with their own electric fields, which result from negative and positive charged regions.
  • the interaction or binding process involves forming multiple non-covalent bonds and involves various electrostatic attractive and repulsive forces such as hydrogen-bonds, electrostatic forces, Van der Waals and hydrophobic forces between the individual dipole-regions. Though some individual bonds may be weak, the cumulative effect may be very strong. This overall strength of the interaction is known as its affinity. The strength of bonding is a function of the number, separation and nature of these individual bonds. Since these bonds are non-covalent, binding is reversible.
  • the first steps of interaction involve long-distance attraction of oppositely charged dipoles which serve to bring potential binding partners into relatively close proximity. If it is assumed the antibody is covalently attached to the surface, this will mainly involve attraction of the antigen towards the antibody. However, it is recognized that protein molecules (and antigens) are inherently flexible, and that a certain degree of distortion of both the antibody and antigen molecule will occur, and this may alter the distribution of charge on these molecules.
  • Figures 9A - 9D show typical responses 900 from a differential pair of field effect transistors with binding and without binding of a target recognition element and a target. If the sensor gate area shown in Figure IA was coated with H5 target recognition elements and exposed to an Hl target type, a typical response 910 from the sensor differential pair, normalized by differential amplifier A6 556 in Figure 5B, shown in Figure 9A may result.
  • Figure 9A shows a negative signature response characteristic 910 indicating that an H5 target type was not detected.
  • Figure 9B shows a positive signature response characteristic 920 indicating that an H5 target type was detected. If the sensor element shown in Figure IA was coated with Nl target recognition elements and exposed to an N5 target type, a typical response 930 from the sensor differential pair, normalized by differential amplifier A6 556 in Figure 5B, shown in Figure 9C may result.
  • Figure 9C shows a negative signature response characteristic 930 indicating that an Nl target type was not detected.
  • Figure 9D shows a positive signature response characteristic 940 indicating that an Nl target type was detected.
  • Figure 1OA illustrates a two by two sensor array 1010 in a typical system configuration 1000, where the elements 1020, 1022, 1030, 1032 in the array may be selected from one of the embodiments of the sensor elements shown in Figure 2 through Figure 9 above or may be some other type of sensor element such as a single electron transistor.
  • a sample of the output of the sensor elements 1020, 1022, 1030, 1032 is sent a digital signal processor 1040 for conversion to a digital equivalent signal sample.
  • a plurality of digital equivalent signal samples from each sensor element in the sensor array 1010 are combined to form a digital signature signal for each element in the array 1010. This process of digitizing outputs from the sensors and reconstructing a digital signature signal is well-known to those skilled in the relevant art of digital signal processing.
  • the embodiment in Figure 1OA shows one digital signal processor 1040 connected to each individual sensor element 1020, 1022, 1030, 1032. Multiple embodiments with varying combinations of sensor elements and number of digital signal processor are possible. Other embodiments may include more than one digital signal processor, for example, one digital signal processor may be present and connected to one sensor element, a second digital signal processor may be present and connected to a second sensor element, and so forth. Likewise, alternative embodiments of the sensor array may include any combinations of rows and columns of sensor elements.
  • the one or more digital signal processors then may compare each digitized sensor output signature signal with a library of pre-stored signature signals representing known targets that may bind with a recognition element (see Figure 8). In this manner, any target that binds with a recognition element and whose signal matches any one of the stored signals is sensed and processed in real-time.
  • the digital signal processor 1040 may process the signals using several alternate process embodiments.
  • One embodiment is a process to sequentially compare each of a time domain digitized sensor signature signal with each of the pre-stored time domain signature signal in a signal library using cross-correlation techniques to determine a match.
  • Another process embodiment is to sequentially convert each received digitized sensor signature signal to a frequency spectrum and then sequentially compare each of the frequency domain digitized sensor signature signals with each of the pre-stored frequency domain signature signals in the signal library using cross-correlation techniques to determine a match.
  • An example of how recognition elements rows 1070, 1072, 1074, 1076 and columnsl080, 1084, 1086 may be distributed on a four by four sensor array 1050 is shown in Figure 1OB.
  • an array according to the present invention may take on numerous elements and array configurations.
  • an array may be a square array, a rectangular array, a three dimensional array, a circular array and the like.
  • the array may also include any number of array elements.
  • the examples used are illustrative only and not limited to the specific detections described.
  • the detections illustrated in Figures 9 A through 9D and in Figures 1OA and 1OB may encompass detecting the presence or absence of any type of target that is capable of interacting with a recognition element and is not limited to the examples cited herein.

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Abstract

L'invention concerne un système de sonde servant à détecter la présence d'une ou plusieurs substances cibles réagissant avec un ou plusieurs types d'éléments de reconnaissance cibles pour produire une charge électrique détectable par une paire différentielle de transistors à effet de champ, lequel a une sensibilité accrue par minimisation des effets de mode commun sur la paire différentielle. La paire différentielle est contrôlée par des algorithmes d'optimisation dans un processeur de signal numérique qui lit et stocke les caractéristiques électriques de la paire différentielle et maintient la paire différentielle à des points de fonctionnement optimaux sur la base du suivi en continu de la paire différentielle. Un ou plusieurs types d'éléments de reconnaissance cibles sont répartis sur une zone de grille de sonde de la paire différentielle qui détecte un ou plusieurs signaux de signature créés par la liaison d'une ou plusieurs substances cibles avec les types d'éléments de reconnaissance cibles. Les signaux de signature détectés sont comparés à une banque de signaux de signature stockés pour déterminer l'identité des substances cibles.
PCT/US2008/061351 2007-04-23 2008-04-23 Système de sonde et procédé utilisant celui-ci WO2009017854A2 (fr)

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US4608865A (en) * 1984-12-05 1986-09-02 The Regents Of The University Of California Integrated pyroelectric sensor and method
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