Patent Grant
11662325
Embodiments herein relate to systems and methods for kinetic response sensing of gaseous mixtures using a chemical sensor element.
The accurate detection of diseases can allow clinicians to provide appropriate therapeutic interventions. The early detection of diseases can lead to better treatment outcomes. Diseases can be detected using many different techniques including analyzing tissue samples, analyzing various bodily fluids, diagnostic scans, genetic sequencing, and the like.
Some disease states result in the production of specific chemical compounds. In some cases, volatile organic compounds (VOCs) released into a gaseous sample of a patient can be hallmarks of certain diseases. The detection of these compounds or differential sensing of the same can allow for the early detection of particular disease states. However, mixtures of complex gases can be difficult to distinguish from one another with current detection methods.
In a first aspect, a kinetic response system for measuring analyte presence on a chemical sensor element is included. The chemical sensor element can include one or more discrete binding detectors, where each discrete binding detector can include a graphene varactor. The kinetic response system can include a measurement circuit including an excitation voltage generator configured to generate a series of excitation cycles over a time period, where each excitation cycle includes delivering a DC bias voltage to the discrete binding detectors at multiple discrete DC bias voltage values across a range of DC bias voltages. The kinetic response system can include a capacitance sensor configured to measure capacitance of the discrete binding detectors resulting from the excitation cycles. The kinetic response system can include a controller circuit configured to determine the kinetics of change in at least one of a measured capacitance value and a calculated value based on the measured capacitance over the time period.
In a second aspect, in addition to one or more of the preceding or following aspects, or in the alternative to some aspects, the controller circuit is configured to calculate a rate of change of a measured capacitance or a calculated value based on measured capacitance over the time period at multiple discrete DC bias voltages.
In a third aspect, in addition to one or more of the preceding or following aspects, or in the alternative to some aspects, the controller circuit is configured to calculate an average rate of change of measured capacitance over the time period at multiple discrete DC bias voltages.
In a fourth aspect, in addition to one or more of the preceding or following aspects, or in the alternative to some aspects, the controller circuit is configured to determine the start of a steady-state response phase from each of the discrete binding detectors by assessing a rate of change of measured capacitance over the time period.
In a fifth aspect, in addition to one or more of the preceding or following aspects, or in the alternative to some aspects, the controller circuit is configured to determine the start of a non-steady state response phase from each of the discrete binding detectors by assessing a rate of change of measured capacitance over the time period.
In a sixth aspect, in addition to one or more of the preceding or following aspects, or in the alternative to some aspects, the controller circuit is configured to determine the end of the non-steady state response phase from each of the discrete binding detectors by assessing a rate of change of measured capacitance over the time period. The profile of the measured capacitance during the non-steady state response phase for each discrete binding detector can define a unique kinetic response profile for a unique gaseous mixture.
In a seventh aspect, in addition to one or more of the preceding or following aspects, or in the alternative to some aspects, the controller circuit is configured to calculate the rate of change in the Dirac point for the discrete binding detectors over the time period.
In an eighth aspect, in addition to one or more of the preceding or following aspects, or in the alternative to some aspects, the controller circuit is configured to determine a maximum rate of change for capacitance for the discrete binding detectors over the time period.
In a ninth aspect, in addition to one or more of the preceding or following aspects, or in the alternative to some aspects, the kinetic response system can include a nonvolatile memory configured to store measured capacitance values for the discrete binding detectors across the range of DC bias voltages.
In a tenth aspect, in addition to one or more of the preceding or following aspects, or in the alternative to some aspects, the kinetic response system can include a nonvolatile memory configured to store a baseline capacitance for the discrete binding detectors across the range of DC bias voltages.
In an eleventh aspect, in addition to one or more of the preceding or following aspects, or in the alternative to some aspects, each of the plurality of discrete binding detectors has a different surface chemistry.
In a twelfth aspect, in addition to one or more of the preceding or following aspects, or in the alternative to some aspects, each of the plurality of discrete binding detectors has the same surface chemistry.
In a thirteenth aspect, in addition to one or more of the preceding or following aspects, or in the alternative to some aspects, the kinetic response system can include a flow control valve in fluid communication with an upstream flow path relative the chemical sensor element.
In a fourteenth aspect, a method for measuring analyte presence on a chemical sensor element using a kinetic response system is included. The method can include contacting a chemical sensor element including one or more discrete binding detectors with a gaseous mixture, each discrete binding detector including a graphene varactor. The method can include generating a series of excitation cycles over a time period, wherein each excitation cycle includes delivering a DC bias voltage to the graphene varactor at multiple discrete DC bias voltage values across a range of DC bias voltages. The method can include measuring capacitance of each of the discrete binding detectors resulting from the excitation cycles. The method can include determining the kinetics of change in at least one of a measured capacitance value and a calculated value based on the measured capacitance over the time period.
In a fifteenth aspect, in addition to one or more of the preceding or following aspects, or in the alternative to some aspects, the method can include calculating a rate of change of a measured capacitance or a calculated value based on measured capacitance over the time period.
In a sixteenth aspect, in addition to one or more of the preceding or following aspects, or in the alternative to some aspects, the method can include calculating an average rate of change of measured capacitance over the time period at multiple discrete DC bias voltages.
In a seventeenth aspect, in addition to one or more of the preceding or following aspects, or in the alternative to some aspects, the method can include determining the start of a steady-state response phase from each of the discrete binding detectors by assessing a rate of change of measured capacitance over the time period.
In an eighteenth aspect, in addition to one or more of the preceding or following aspects, or in the alternative to some aspects, the method can include determining the start of a non-steady state response phase from each of the discrete binding detectors by assessing a rate of change of measured capacitance over the time period.
In a nineteenth aspect, in addition to one or more of the preceding or following aspects, or in the alternative to some aspects, the method can include determining the end of the non-steady state response phase from each of the discrete binding detectors by assessing a rate of change of measured capacitance over the time period, where the start of the non-steady state response phase and the end of the non-steady state response phase for the discrete binding detectors defines a unique kinetic response profile for a unique gaseous mixture.
In a twentieth aspect, in addition to one or more of the preceding or following aspects, or in the alternative to some aspects, the method can include distinguishing one unique gaseous mixture from another unique gaseous mixture based on the unique kinetic response profile of the unique gaseous mixtures.
In a twenty-first aspect, in addition to one or more of the preceding or following aspects, or in the alternative to some aspects, the method can include calculating the rate of change in the Dirac point for the discrete binding detectors over the time period.
In a twenty-second aspect, in addition to one or more of the preceding or following aspects, or in the alternative to some aspects, the method can include contacting the chemical sensor element with a gas other than a sample gas and detecting a return of each of the discrete binding detectors back toward a baseline capacitance valve.
In a twenty-third aspect, in addition to one or more of the preceding or following aspects, or in the alternative to some aspects, delivering a DC bias voltage across a range of DC bias voltages is conducted from −3 V to 3 V.
In a twenty-fourth aspect, in addition to one or more of the preceding or following aspects, or in the alternative to some aspects, delivering a DC bias voltage to the graphene varactor at multiple discrete DC bias voltage values across a range of DC bias voltages includes stepping through the range of DC bias voltages in 50 mV increments.
In a twenty-fifth aspect, in addition to one or more of the preceding or following aspects, or in the alternative to some aspects, delivering a DC bias voltage to the graphene varactor at multiple discrete DC bias voltage values across a range of DC bias voltages includes stepping through the range of DC bias voltages in 10 mV increments.
In a twenty-sixth aspect, in addition to one or more of the preceding or following aspects, or in the alternative to some aspects, at least 100 measured capacitance values are stored into memory for each discrete binding detector across the range of DC bias voltages.
In a twenty-seventh aspect, in addition to one or more of the preceding or following aspects, or in the alternative to some aspects, the time period for generating a series of excitation cycles comprises from 30 seconds to 1200 seconds.
In a twenty-eighth aspect, in addition to one or more of the preceding or following aspects, or in the alternative to some aspects, the time period for each excitation cycle comprises from 1 second to 30 seconds.
This summary is an overview of some of the teachings of the present application and is not intended to be an exclusive or exhaustive treatment of the present subject matter. Further details are found in the detailed description and appended claims. Other aspects will be apparent to persons skilled in the art upon reading and understanding the following detailed description and viewing the drawings that form a part thereof, each of which is not to be taken in a limiting sense. The scope herein is defined by the appended claims and their legal equivalents.
Aspects may be more completely understood in connection with the following drawings, in which:
While embodiments are susceptible to various modifications and alternative forms, specifics thereof have been shown by way of example and drawings, and will be described in detail. It should be understood, however, that the scope herein is not limited to the particular embodiments described. On the contrary, the intention is to cover modifications, equivalents, and alternatives falling within the spirit and scope herein.
Chemical sensor elements having one or more discrete binding detectors can be configured to bind one or more analytes, such as volatile organic compounds (VOCs), in a complex gaseous mixture. The discrete binding detectors can include graphene quantum capacitance varactors (“graphene varactors”) that can exhibit a change in capacitance in response to an applied bias voltage as a result of the presence of one or more analytes, such as volatile organic compounds (VOCs) on a surface of the graphene varactor. In this way, gas samples can be analyzed by contacting them with a graphene varactor-based sensor element, providing a bias voltage, and measuring capacitance. In many cases, the graphene varactor-based sensor elements can be exposed to a range of bias voltages in order to discern features such as the Dirac point (or the bias voltage at which the varactor exhibits the lowest capacitance). The response signal generated by the discrete binding detectors in the presence or absence of one or more analytes can be used to characterize the content of the gaseous mixture. As such, each gaseous mixture will have a unique set of response signals, or “fingerprint,” for any given array.
Frequently, measurements of capacitance can be thought of as being performed at “steady-state” points in time where values for capacitance are not changing substantially. Exemplary steady-state points in time herein can include a starting state (such as before the graphene varactor is exposed to a gas sample) and an ending state (such as when the graphene varactor has been exposed to a gas sample sufficiently long to exhibit steady values or “plateaued values” for capacitance in response to bias voltages).
However, it has been discovered that measuring capacitance values at times falling between steady-state points in time (such as while capacitance values are changing after initial exposure to a gas sample and before it starts to exhibit steady values for capacitance) can provide substantial additional data for enhanced resolution of gas samples. This is because in some scenarios the capacitance values at a starting state and an ending state for two different gas samples may be extremely similar or the same. Thus, using only data reflecting the steady-state points in time may not be sufficient to distinguish between such gas samples. But the way in which the capacitance values change between steady-state points in time (e.g., the kinetics of the change between a starting state and an ending state) may be quite different. As such, in accordance with various embodiments herein, the kinetics of capacitance value change are measured and recorded to aid in the analysis of gaseous samples.
Referring now to
The sensing device 160 can include a housing 178 and an air intake port 162. In some embodiments, air intake port 162 can be in fluid communication with one or more gas sampling devices 102. In other embodiments, air intake port 162 can be configured as a mouthpiece into which a subject 104 to be evaluated can blow a breath sample. In yet other embodiments, the air intake port 162 can itself act as a gas sampling device. The sensing device 160 can be configured to actively draw a gas into housing 178 or it can be configured to receive a gas passively from a subject 104 or a gas sampling device 102. In some embodiments, the sensing device 160 can include a flow control valve in fluid communication with an upstream flow path relative the chemical sensor element.
The sensing device 160 can also include a display screen 174 and a user input device 176, such as a keyboard. The sensing device 160 can also include a gas outflow port 172. Aspects of sensing systems and devices are described in U.S. Patent Application Publication No. 2016/0109440A1, the content of which is herein incorporated by reference. While
In some embodiments, the kinetic response system 100 can include a local computing device 182 that can include a microprocessor, input and output circuits, input devices, a visual display, a user interface, and the like. In some embodiments, the sensing device 160 can communicate with the local computing device 182 in order to exchange data between the sensing device 160 and the local computing device 182. The local computing device 182 can be configured to perform various processing steps with the data received from the sensing device 160, including, but not limited to, calculating various parameters of the graphene varactors described herein. However, it should be appreciated that in some embodiments the features associated with the local computing device 182 can be integrated into the sensing device 160. In some embodiments, the local computing device 182 can be a laptop computer, a desktop computer, a server (real or virtual), a purpose dedicated computer device, or a portable computing device (including, but not limited to, a mobile phone, tablet, wearable device, etc.).
The local computing device 182 and/or the sensing device 160 can communicate with computing devices in remote locations through a data network 184, such as the Internet or another network for the exchange of data as packets, frames, or otherwise.
In some embodiments, the kinetic response system 100 can also include a computing device such as a server 186 (real or virtual). In some embodiments, the server 186 can be located remotely from the sensing device 160. The server 186 can be in data communication with a database 188. The database 188 can be used to store various subject information, such as that described herein. In some embodiments, the database can specifically include an electronic medical database containing data regarding the health status of a subject, patterns of data associated with various conditions (such as that generated from machine learning analysis of large sets of subject data), demographic data and the like. In some embodiments, the database 188 and/or server 186, or a combination thereof, can store the data generated by the chemical sensor elements(s) as well as data output generated by machine learning analysis.
Each chemical sensor element within the kinetic response system can include one or more discrete binding detectors in an array. The terms “discrete binding detector” and “graphene varactor” can be used interchangeably herein unless otherwise specified or the context dictates otherwise. Each discrete binding detector can include a graphene varactor that can produce a response signal before exposure to a gaseous mixture and a response signal after exposure to a gaseous mixture. To generate a response signal, an excitation current at a particular voltage and/or over a range of voltages is delivered to the graphene varactor(s) over a given time period. Measuring the response signal, such as the measuring the capacitance, provides data that reflects the binding status of analytes to the graphene varactor(s) or the baseline response of a graphene varactor with no bound analytes.
When a graphene varactor is exposed to a gaseous mixture the response signal can change when compared to the baseline response signal in the absence of a gaseous mixture. Referring now to
As analytes within the gaseous mixture are sensed by the graphene varactors upon binding, several different parameters of the graphene varactor response signal can change from a baseline value to a higher or a lower value, and the shape of the response signal can change. Referring now to
In
In some embodiments, a ratio of the maximum capacitance to minimum capacitance can be used to characterize the content of a gaseous mixture. In some embodiments, a ratio of the maximum capacitance to the shift in the Dirac point can be used to characterize the content of a gaseous mixture. In other embodiments, a ratio of the minimum capacitance to the shift in the slope of the response signal can be used to characterize the content of a gaseous mixture. In some embodiments, a ratio of any of the parameters including a shift in the Dirac point, a change in the minimum capacitance, a change in the slope of the response signal, or the change in the maximum capacitance can be used to characterize the content of a gaseous mixture.
The two plots in
However, in accordance with various embodiments, a series of response signals or response curves can be generated by a series of excitation cycles over a given time period while capacitance values are changing (such as in between steady-state time points like following exposure of the graphene varactor(s) to a gaseous mixture and before capacitance stops changing in response to analytes within the gaseous mixture). Thus, in accordance with various embodiment herein, the kinetics of capacitance change can be captured (kinetic data) reflecting how capacitance changes during the binding of analytes to the surface of the graphene varactors within an array. This kinetic data (or non-steady-state data) can be used in addition to or instead of the steady-state data to provide enhanced resolution of gaseous samples.
During the non-steady state response phase (or kinetic phase), the measured parameter increases or decreases over time with respect to a baseline value for each measured parameter. The increase or decrease in the measured parameter can be reflected in a plot of change in the measured parameter over time as a positive or negative increase from the baseline value. The kinetics of the change in at least one of the parameters of the graphene varactor response signal can provide a unique kinetic response profile for each unique gaseous mixture. Thus, in some embodiments, the profile of a measured parameter during the non-steady state response phase for each discrete binding detector defines a unique kinetic response profile for each unique gaseous mixture. In contrast, during a steady-state response phase, the measured parameter of the graphene varactor becomes largely consistent over time and the plot of change in measured parameter over time plateaus.
Referring now to
The same graphene varactors in the presence of different gaseous mixtures can produce unique response signals that can be used to discriminate one gaseous mixture from another. By way of example, the graph 400 shown in
The first and second gaseous mixtures of
The non-steady state phase for plot 502 of
It will be appreciated that if only considering steady-state values (in this case the starting points and the ending points), the two sets of response signals shown in
It will be appreciated that in some embodiments, the response signal in the presence of a gaseous mixture can change in a direction negative to the response signal in the absence of a gaseous mixture (e.g., change of a given capacitance related parameter is not always positive, it can also be negative). Referring now to
The graph 600 shown in
In some embodiments, the graphene sensor response signals can include kinetic phases associated with both the binding (or association) and unbinding (disassociation) of analytes to the receptor surfaces. Referring now to
Referring now to
In some embodiments, the graphene varactors can be heterogeneous in that they are different (in groups or as individual graphene varactors) from one another in terms of their binding behavior or specificity with regard a particular analyte. In some embodiments, some graphene varactors can be duplicated, triplicated, or more, for validation purposes but are otherwise heterogeneous from other graphene varactors. Yet in other embodiments, the graphene varactors can be homogeneous. While the graphene varactors 802 of
In some embodiments, the order of specific graphene varactors 802 across the length 812 and width 814 of the measurement zone can be substantially random. In other embodiments, the order can be specific. For example, in some embodiments, a measurement zone can be ordered so that the specific graphene varactors 802 configured to bind to analytes having a lower molecular weight are located farther away from the incoming gas flow relative to specific graphene varactors 802 configured to bind to analytes having a higher molecular weight which are located closer to the incoming gas flow. As such, chromatographic effects which may serve to provide separation between chemical compounds of different molecular weight can be taken advantage of to provide for optimal binding of chemical compounds to corresponding graphene varactors.
The number of graphene varactors can be from about 1 to about 100,000. In some embodiments, the number of graphene varactors can be from about 1 to about 10,000. In some embodiments, the number of graphene varactors can be from about 1 to about 1,000. In some embodiments, the number of graphene varactors can be from about 2 to about 500. In some embodiments, the number of graphene varactors can be from about 10 to about 500. In some embodiments, the number of graphene varactors can be from about 50 to about 500. In some embodiments, the number of graphene varactors can be from about 1 to about 250. In some embodiments, the number of graphene varactors can be from about 1 to about 50.
In some embodiments, each of the graphene varactors suitable for use herein can include at least a portion of one or more electrical circuits. By way of example, in some embodiments, each of the graphene varactors can include all or a portion of one or more passive electrical circuits. In some embodiments, the graphene varactors can be formed such that they are integrated directly on an electronic circuit. In some embodiments, the graphene varactors can be formed such that they are wafer bonded to the circuit. In some embodiments, the graphene varactors can include integrated readout electronics, such as a readout integrated circuit (ROIC). The electrical properties of the electrical circuit, including resistance or capacitance, can change upon binding, such as specific and/or non-specific binding, with a component from a biological sample. Many different types of circuits can be used to gather data from chemical sensor elements and will be discussed below in reference to
In some embodiments, the graphene varactors embodied herein can include graphene-based variable capacitors (or graphene varactors). Referring now to
Graphene varactor 802 can include an insulator layer 902, a gate electrode 904 (or “gate contact”), a dielectric layer (not shown in
Graphene varactor 802 includes eight gate electrode fingers 906a-906h. It will be appreciated that while graphene varactor 802 shows eight gate electrode fingers 906a-906h, any number of gate electrode finger configurations can be contemplated. In some embodiments, an individual graphene varactor can include fewer than eight gate electrode fingers. In some embodiments, an individual graphene varactor can include more than eight gate electrode fingers. In other embodiments, an individual graphene varactor can include two gate electrode fingers. In some embodiments, an individual graphene varactor can include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more gate electrode fingers.
Graphene varactor 802 can include one or more contact electrodes 910 disposed on portions of the graphene layers 908a and 908b. Contact electrode 910 can be formed from an electrically conductive material such as chromium, copper, gold, silver, tungsten, aluminum, titanium, palladium, platinum, iridium, and any combinations or alloys thereof. Further aspects of exemplary graphene varactors can be found in U.S. Pat. No. 9,513,244, the content of which is herein incorporated by reference in its entirety.
The capacitance of the graphene varactors can be measured by delivering an excitation current at a particular voltage and/or over a range of voltages. Measuring the capacitance provides data that reflects the binding status of analytes to the graphene varactor(s). Various measurement circuitry can be used to measure the capacitance of the graphene varactor(s), as is discussed in reference to
The measurement circuit can also include a capacitance sensor configured to measure capacitance of the discrete binding detectors resulting from the excitation cycles. The measurement circuit can also include a controller circuit configured to determine the kinetics of change in at least one of a measured capacitance value and a calculated value based on the measured capacitance over the time period.
Referring now to
In this case, the excitation signal from the CDC controls the switch between the output voltages of the two programmable Digital to Analog Converters (DACs). The programmed voltage difference between the DACs determines the excitation amplitude, providing an additional programmable scale factor to the measurement and allowing measurement of a wider range of capacitances than specified by the CDC. The bias voltage at which the capacitance is measured is equal to the difference between the bias voltage at the CDC input (via the multiplexor, usually equal to VCC/2, where VCC is the supply voltage) and the average voltage of the excitation signal, which is programmable. In some embodiments, buffer amplifiers and/or bypass capacitance can be used at the DAC outputs to maintain stable voltages during switching.
The above calculated aspects can be used for various diagnostic purposes. In some cases, the above calculated aspects can be indicative of the identity and/or concentrations of specific volatile organic components of a gas sample. As such, each of the calculated values above can serve as a distinct piece of data that forms part of a pattern for a given subject and/or given gas sample. As also described elsewhere herein, the pattern can then be matched against preexisting patterns, or patterns identified in real-time, derived from large stored data sets through techniques such as machine learning or other techniques, wherein such patterns are determined to be characteristic of various conditions or disease states. The above calculated aspects can also be put to other purposes, diagnostic and otherwise.
In some embodiments, calculations such as those described above can be performed by a controller circuit. The controller circuit can be configured to receive an electrical signal reflecting the capacitance of the graphene varactors. In some embodiments, the controller circuit can include a microcontroller to perform these calculations. In some embodiments, the controller circuit can include a microprocessor in electrical communication with the measurement circuit. The microprocessor system can include components such as an address bus, a data bus, a control bus, a clock, a CPU, a processing device, an address decoder, RAM, ROM and the like. In some embodiments, the controller circuit can include a calculation circuit (such as an application specific integrated circuit—ASIC) in electrical communication with the measurement circuit.
The controller circuit can be configured to calculate a rate of change of a measured capacitance or a calculated value based on measured capacitance over the time period at multiple discrete DC bias voltages. In some embodiments, the controller circuit can be configured to calculate an average rate of change of measured capacitance over the time period at multiple discrete DC bias voltages. In other embodiments, the controller circuit can be configured to determine the start of a steady-state response phase from each of the discrete binding detectors by assessing a rate of change of measured capacitance over the time period.
In some embodiments the controller circuit can be configured to determine the start of a non-steady state response phase from each of the discrete binding detectors by assessing a rate of change of measured capacitance over the time period. In some embodiments, when the rate of change exceeds a threshold value, the start of a non-steady state response phase can be recognized. In some embodiments, the controller circuit can be configured to determine the end of the non-steady state response phase from each of the discrete binding detectors by assessing a rate of change of measured capacitance over the time period. In some embodiments, the end of a non-steady state response phase (and the beginning of a steady state response phase) can be recognized based on the rate of change exceeding a threshold value. The controller circuit can be configured to calculate the rate of change in the Dirac point for the discrete binding detectors over the time period. The controller circuit can be configured to determine a maximum rate of change for capacitance for the discrete binding detectors over the time period. The profile of measured capacitance during the non-steady state response phase for each discrete binding detector defines a unique kinetic response profile for a unique gaseous mixture.
In addition, in some embodiments, the system can include a nonvolatile memory. In some embodiments, the non-volatile memory can be configured to store measured capacitance values for the discrete binding detectors across a range of DC bias voltages. In other embodiments, the nonvolatile memory can be configured to store a baseline capacitance for the discrete binding detectors across a range of DC bias voltages. In some embodiments, the nonvolatile memory can be where sensitivity calibration information for the graphene varactors is stored.
By way of example, the graphene varactors could be tested in a production facility, where sensitivity to various analytes such as VOC's can be determined and then stored on an EPROM or similar component. In addition, or alternatively, sensitivity calibration information can be stored in a central database and referenced with a chemical sensor element serial number when subject data is sent to a central location for analysis and diagnosis. These components can be included with any of the pieces of hardware described herein.
In some embodiments herein, components can be configured to communicate over a network, such as the internet or a similar network. In various embodiments, a central storage and data processing facility can be included. In some embodiments, data gathered from sensors in the presence of the subject (local) can be sent to the central processing facility (remote) via the internet or a similar network, and the pattern from the particular subject being evaluated can be compared to those of thousands or millions of other subjects, many of whom have been previously diagnosed with various conditions and wherein such condition data has been stored. Pattern matching algorithms can be used to find other subjects or classes of subjects (for example disease or condition specific classes) to which the current subject's pattern is most similar. Each class of subjects can include a predetermined likelihood of having a given condition or disease state. In this manner, after pattern matching a likelihood of having a given condition or disease state can be provided back across the data network to the facility where the subject is currently located.
In some embodiments, measurement circuits suitable for use herein can include active and passive sensing circuits. Such circuitry can implement wired (direct electrical contact) or wireless sensing techniques. Referring now to
Bias Voltages/Excitation Cycles
Response signals herein can be gathered by measuring capacitance over a range of DC bias voltages. In order to determine a particular capacitance parameter, such as the Dirac point, a current is applied to the graphene varactor at a plurality of bias voltages (an example of an excitation cycle). This can result in data such as that shown in one of the curves in
Many different ranges of DC bias voltages can be used for each excitation cycle. In some embodiments, the DC bias voltages used in the methods herein can include from −3 V, −2.5 V, −2.0 V, −1.5 V, −1.0 V, −0.5 V, 0.5 V, 1.0 V, 1.5 V, 2.0 V, 2.5 V, 3.0 V. It will be appreciated that the DC bias voltages used in the methods herein can include delivering a DC bias voltage within a range, wherein any of the forgoing voltages can serve as the lower or upper bound of the range, provided that the lower bound of the range is a value less than the upper bound of the range.
In various embodiments, a “sweep” across a voltage range can include a number discrete measurements being made during the sweep at a number of discrete bias voltages across the voltage range. In some embodiments, an excitation cycle herein can include a forward sweep (from low bias voltages to high bias voltages). In some embodiments, an excitation cycle herein can include a backward sweep (from high bias voltages to low bias voltages). In some embodiments, an excitation cycle herein can include both a forward and backward sweep, or any combination thereof. In some embodiments, a bias voltage of 0 V or 0.5 V (or other “reset” voltage) can be applied at the end of an excitation cycle and before the next excitation cycle or at the end of all testing.
The length of time for each excitation cycle can depend on various factors including the total number of measurements made of capacitance during the cycle, the total bias voltage range being covered, the voltage step size for each measurement, the time for each measurement, etc. In some embodiments, the time period for each excitation cycle can be about 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 20, 30, 45, 60, 120 seconds or more. It will be appreciated that the time period for each excitation cycle can include a range, wherein any of the forgoing time points can serve as the lower or upper bound of the range, provided that the lower bound of the range is a value less than the upper bound of the range.
In some embodiments, the total time for all excitation cycles can be configured to match the total amount of time for testing of a gaseous sample. In some embodiments, the total time for all excitation cycles can be configured to be equal to a predetermined time that covers a period of interest. In some embodiments, the total time for all excitation cycles can be configured to be equal or greater than the total amount of time for a non-steady state phase (or kinetic phase). In some embodiments, the controller circuit can be configured to determine the start of a non-steady state response phase from each of the discrete binding detectors by assessing a rate of change of measured capacitance over time and initiate excitation cycles at that point. In some embodiments, the controller circuit can be configured to initiate excitation cycles when a signal is received indicating the start of a particular test of gaseous sample, such as receiving a sign from a flow sensor that a sample gas is starting to flow to the discrete binding detectors. In some embodiments, the controller circuit can be configured to determine the end of a non-steady state phase by assessing a rate of change of measured capacitance over time and terminating excitation cycles at that point or reducing the frequency of excitation cycles at that point.
In various embodiments, the total time period for generating a series of excitation cycles (the total time for all excitation cycles) can include from 10 seconds to 1200 seconds. In some embodiments, the time period for generating a series of excitation cycles can include from 30 seconds to 180 seconds. In some embodiments, the time period for generating a series of excitation cycles can include from 10, 15, 20, 25, 30, 40, 45, 60, 90, 120, 150, 180, 360, 540, 720, 1080, 1200 seconds or more. It will be appreciated that the time period for generating a series of excitation cycles can include a range, wherein any of the forgoing time points can serve as the lower or upper bound of the range, provided that the lower bound of the range is a value less than the upper bound of the range.
In some embodiments, stepping through the range of DC bias voltages can include stepping through the range of DC bias voltages in predetermined increments, such as 50 mV increments. In some embodiments, stepping through the range of DC bias voltages can include stepping through the range of DC bias voltages in 10 mV increments. Stepping through the range of DC bias voltages can be performed at voltage increments of 1 mV, 5 mV, 10 mV, 25 mV, 50 mV, 75 mV, 100 mV, 125 mV, 150 mV, 200 mV, 300 mV, 400 mV, or 500 mV, or by a stepped amount falling within a range between any of the foregoing.
Capacitance Parameters
Many different capacitance related parameters can be calculated based on the capacitance data. For example, parameters that can be calculated include maximum slope of capacitance to voltage, change in maximum slope of capacitance to voltage over a baseline value, minimum slope of capacitance to voltage, change in minimum slope of capacitance to voltage over a baseline value, minimum capacitance, change in minimum capacitance over a baseline value, voltage at minimum capacitance (Dirac point), change in voltage at minimum capacitance, maximum capacitance, change in maximum capacitance, ratio of maximum capacitance to minimum capacitance, response time constants, and ratios of any of the foregoing between different graphene sensors and particularly between different graphene sensors having specificity for different analytes.
Kinetics Analysis
Many different parameters can be calculated using the controller circuit or another device and the non-steady state phase (or kinetic phase) data. For example, in some embodiments, parameters calculated can include maximum rate of change during the kinetic phase, time to reach a relative degree of change (such as time to hit a magnitude of 80% of the total change), the function providing the best fit curve (e.g., first, second, third or fourth degree polynomial; exponential functions, sums of exponential functions, etc.), coefficients of a best fit curve, characteristic time constant(s), total time of the kinetic phase, and the like. However, it will be appreciated that in some embodiments none of these values need to be explicitly calculated and the kinetic phase data (with or without corresponding steady-state phase date) can be used in machine learning analysis such as that described herein.
By way of example, as a chemical sensor is exposed to new concentrations of analyte(s), the equilibrium of analyte binding to the surface of the chemical sensor will adjust according to the concentration of analyte above the sensor(s). The binding kinetics of an analyte or mixture of analytes can be analyzed using real-time data based on the rate of association of analyte and the rate of dissociation of analyte. The rate of association of analyte (i.e., analyte binding) can be represented by equation [1] and the rate of disassociation of analyte (i.e., analyte unbinding) can be represented by equation [2]:
where kon is the association rate of analyte binding to the sensor in (mol/L)−1 s−1, koff is the dissociation rate of analyte from the sensor in s−1, CA is the concentration of analyte, CS is the concentration of binding sites on the sensor, and CAS is the concentration of analyte bound to the sensor.
The binding of analyte to the sensor at any given time, t, and any given concentration, c, can be represented by an integration of the rate equations [1] and [2], as shown in equation [3]:
f(t, c)=feq(c)·[1−exp{−konobs·t}] [3]
where konobs is the observable association rate and feq is a terminal value that the chemical sensor signal approaches during analyte binding with the sensor. The observable association rate konobs can be defined by equation [4]:
konobs=c·kon+koff [4]
The terminal value feq depends on analyte concentration and is governed by a characteristic time constant τonobs, where the characteristic time constant is represented by equation [5]:
τonobs=1/konobs [5]
Thus, as analyte concentration changes, so does the chemical sensor signal.
The rate of dissociation of analyte from the chemical sensor can be observed by removing the analyte(s) from the environment of the chemical sensor. This can be accomplished by flushing the chemical sensor with ambient air, an inert gas, and the like. The dissociation of analyte from the sensor can be represented by equation [6]:
f(t)=α·exp{−koff·t} [6]
where koff is the dissociation rate constant of analyte unbinding from the sensor in s−1 and α, or amplitude, represents the fraction of analyte bound to the chemical sensor just before removal of analyte from the chemical sensor. Dissociation of analyte from the chemical sensor is governed by the dissociation rate constant, koff, and the dissociation time constant τoff in sec (s); the dissociation time constant is represented by equation [7]:
τoff=1/koff [7]
Classification and Pattern Matching
Classifying the data sets obtained (including one or both of kinetic phase data and steady-state phase data) into one or more preestablished classifications (such as disease state or health condition classifications) can be performed according to many different machine learning techniques, such as pattern recognition. Classification can include comparing the sample data set against one or more previously determined patterns using a pattern matching or pattern recognition algorithm to determine the pattern that is the best match, wherein the specific previously determined pattern that is the best match indicates the disease state of the subject.
By way of example, patterns amongst large sets of subject data may be originally identified through machine learning analysis or another similar algorithmic technique. Patterns associated with specific disease state classifications can be derived from labeled “training” data (supervised learning) or in the absence of labeled data (unsupervised learning).
Algorithms for pattern matching used herein can include, but are not limited to, classification algorithms (supervised algorithms predicting categorical labels), clustering algorithms (unsupervised algorithms predicting categorical labels), ensemble learning algorithms (supervised meta-algorithms for combining multiple learning algorithms together), general algorithms for predicting arbitrarily-structured sets of labels, multilinear subspace learning algorithms (predicting labels of multidimensional data using tensor representations), real-valued sequence labeling algorithms (predicting sequences of real-valued labels), regression algorithms (predicting real-valued labels), and sequence labeling algorithms (predicting sequences of categorical labels).
Classification algorithms can include parametric algorithms (such as linear discriminant analysis, quadratic discriminant analysis, and maximum entropy classifier) and nonparametric algorithms (such as decision trees, kernel estimation, naïve Bayes classifier, neural networks, perceptrons, and support vector machines). Clustering algorithms can include categorical mixture models, deep learning methods, hierarchical clustering, K-means clustering, correlation clustering, and kernel principal component analysis. Ensemble learning algorithms can include boosting, bootstrap aggregating, ensemble averaging, and mixture of experts. General algorithms for predicting arbitrarily-structured sets of labels can include Bayesian networks and Markov random fields. Multilinear subspace learning algorithms can include multilinear principal component analysis (MPCA). Real-valued sequence labeling algorithms can include Kalman filters and particle filters. Regression algorithms can include both supervised (such as Gaussian process regression, linear regression, neural networks and deep learning methods) and unsupervised (such as independent component analysis and principal components analysis) approaches. Sequence labeling algorithms can include both supervised (such as conditional random fields, hidden Markov models, maximum entropy Markov models, and recurrent neural networks) and unsupervised (hidden Markov models and dynamic time warping) approaches.
Methods
Embodiments herein can include methods for measuring analyte presence on a chemical sensor element using a kinetic response system. Referring now to
In various embodiments, calculating the rate of change of a measured parameter can be included in the methods herein. In some embodiments, the method can include calculating a rate of change of a measured capacitance or a calculated value based on measured capacitance over the time period. In some embodiments, the method can include calculating an average rate of change of measured capacitance over the time period at multiple discrete DC bias voltages. In some embodiments the measured capacitance can include a maximum capacitance or a minimum capacitance. In some embodiments, the method can include calculating the rate of change in the Dirac point for the discrete binding detectors over the time period. In some embodiments, the method can include calculating a rate of change of a shift in the Dirac point or a calculated value based on a shift in the Dirac point over the time period. In other embodiments, the method can include calculating a rate of change in the slope of the response signal or a calculated value based on a change in the response signal over the time period.
The methods herein can include determining a non-steady state response phase and/or a steady-state response phase for the graphene varactor response signal. In some embodiments, the method can include determining the start of a steady-state response phase from each of the discrete binding detectors by assessing a rate of change of measured capacitance over the time period. In some embodiments, the method can include determining the start of a non-steady state response phase from each of the discrete binding detectors by assessing a rate of change of measured capacitance over the time period. In other embodiments, the method can include determining the end of the non-steady state response phase from each of the discrete binding detectors by assessing a rate of change of a measured parameter over the time period, where the start of the non-steady state response phase and the end of the non-steady state response phase for the discrete binding detectors defines a unique non-steady state response profile for a unique gaseous mixture.
In some embodiments, determining the start of the non-steady state response phase comprises determining the start of a kinetic response phase. In some embodiments, the method can include determining the start or end of the kinetic response phase from each of the discrete binding detectors by assessing a rate of change of measured parameter over the time period, and where the start of the kinetic response phase and the end of the kinetic response phase for the discrete binding detectors defines a unique kinetic response profile for a unique gaseous mixture.
The method can also include distinguishing one unique gaseous mixture from another unique gaseous mixture based on the unique kinetic response profile of the unique gaseous mixtures. The methods herein can include contacting the chemical sensor element with an inert gas and detecting unbinding of analytes from each of the discrete binding detectors. The methods herein can include contacting the chemical sensor element with a gas other than a sample gas (such as an inert gas or ambient air) and detecting a full return of each of the discrete binding detectors back toward a baseline capacitance value (appreciating that even in the absence of the sample gas the capacitance may not return all the way back to the original baseline value). In some embodiments, returning the response signal to a baseline capacitance value can include heating the chemical sensor element while under a vacuum to fully return the response signal to a baseline value.
In some embodiments, the methods herein can include contacting and/or storing the chemical sensor element with an inert gas prior to use to maintain a baseline capacitance value before contacting the chemical sensor element with a gaseous mixture. In other embodiments, the methods herein can include contacting the chemical sensor element with an inert gas in combination with a gaseous mixture. In some embodiments, the methods can include contacting the sensor with ambient air or filtered ambient air.
In some embodiments, a graphene varactor can be exposed to ambient air, filtered ambient air, or an inert gas and a response signal can be measured. The graphene varactor can then be exposed to a gaseous mixture, such as an exhaled breath mixture, and a response signal can be measured. The graphene varactor can then be exposed again to ambient air, filtered ambient air, or an inert gas and a response signal can be measured a final time.
Delivering a DC bias voltage to the graphene varactor at multiple discrete DC bias voltage values across a range of DC bias voltages can include stepping through the range of DC bias voltages. Methods herein can also utilize memory for storing measured capacitance values for each of the discrete binding detectors across the range of DC bias voltages delivered to each detector. The methods can include storing at least 100 measured capacitance values are into memory for each discrete binding detector across the range of DC bias voltages.
It should be noted that, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise.
It should also be noted that, as used in this specification and the appended claims, the phrase “configured” describes a system, apparatus, or other structure that is constructed or configured to perform a particular task or adopt a particular configuration. The phrase “configured” can be used interchangeably with other similar phrases such as arranged and configured, constructed and arranged, constructed, manufactured and arranged, and the like.
All publications and patent applications in this specification are indicative of the level of ordinary skill in the art to which this invention pertains. All publications and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated by reference.
The embodiments described herein are not intended to be exhaustive or to limit the invention to the precise forms disclosed in the following detailed description. Rather, the embodiments are chosen and described so that others skilled in the art can appreciate and understand the principles and practices. As such, aspects have been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope herein.
This application claims the benefit of U.S. Provisional Application No. 62/781,254, filed Dec. 18, 2018, the content of which is herein incorporated by reference in its entirety.
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| 2013189502 | Dec 2013 | WO |
| 2014064740 | May 2014 | WO |
| 2015179623 | Nov 2015 | WO |
| 2015191558 | Dec 2015 | WO |
| 2016064740 | Apr 2016 | WO |
| 2016105464 | Jun 2016 | WO |
| 2016145300 | Sep 2016 | WO |
| 2017066583 | Apr 2017 | WO |
| 2017095922 | Jun 2017 | WO |
| 2017218464 | Dec 2017 | WO |
| 2018075731 | Apr 2018 | WO |
| 2018213564 | Nov 2018 | WO |
| 2020102880 | May 2020 | WO |
| 2020112825 | Jun 2020 | WO |
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| Number | Date | Country | |
|---|---|---|---|
| 20200191737 A1 | Jun 2020 | US |
| Number | Date | Country | |
|---|---|---|---|
| 62781254 | Dec 2018 | US |
