Abstract:
Reliable, fast and inexpensive breath gas detector systems for medical diagnostics, including personal, handheld monitoring devices for a variety of diseases and conditions, including, for example, asthma, diabetes, blood cholesterol, and lung cancer. A sensor device ( 100 ) for detecting gases includes a sensing element ( 109 ) having an electrical resistance that changes in the presence of a target gas; a readout circuit, electrically coupled to the sensing element due to the presence of the target gas and converts the measurement to a digital signal; and a feedback loop ( 203 ) from a digital unit ( 205 ) to the readout circuit to compensate for variations in a baseline resistance of the sensing element.

Description:
CROSS REFERENCE TO RELATED APPLICATION 
       [0001]    This application claims the benefit of U.S. Provisional Application No. 61/265,979, filed Dec. 2, 2009, the entire contents of which are incorporated herein by reference. 
     
    
     STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT 
       [0002]    This invention was made with government support under grant number DMR0304169 awarded by the National Science Foundation. The government has certain rights in the invention. 
     
    
     BACKGROUND 
       [0003]    Medical studies reported recently have associated certain gaseous constituents of the human breath with specific types of diseases, and have addressed the importance of diet, dental pathology, smoking, etc, on determining the physiological levels of the marker concentrations in exhaled breath. Inflammation and oxidative stress in the lungs can be monitored by measuring the changes in the concentration of the following gases: NO (which has been widely studied as a bio-marker), and related products NO2-(nitrite); NO3-(nitrite); exhaled CO (also a marker for cardiovascular diseases, diabetes, nephritis, bilirubin production); exhaled hydrocarbons of low molecular mass, such as ethane, n-pentane; ethylene, isoprene (hydrocarbon affected by diet with is a marker for blood cholesterol levels); acetone, formaldehyde; ethanol; hydrogen sulfide, carbonyl sulfides, and ammonia/amines. For example, measurements of exhaled ammonia may differentiate between viral and bacterial infections in lung diseases to justify use of antibiotics. 
         [0004]    Various sensors have been developed measuring these metabolites. Examples are described in, for example, U.S. Pat. No. 7,017,389, the entire contents of which are incorporated herein by reference. There is a continuing need for improvements in diagnostic tool breath analyzers that can provide, for example, a first detection device for fast and early diagnosis of medical conditions. 
       SUMMARY 
       [0005]    The present invention is directed to reliable, fast and inexpensive breath gas detector systems for medical diagnostics, including, in some embodiments, personal monitoring devices for a variety of diseases and conditions, including, for example, asthma, diabetes, blood cholesterol, and lung cancer. The design of integrated microsystems and system-on-a-chip solutions combined with advances in sensor technologies allow for significant miniaturization of sensor devices for gas concentration sensing and integration into handheld devices. 
         [0006]    In one embodiment, a sensor for detecting gases comprises a sensing element having an electrical resistance that changes in the presence of a target gas; a readout circuit, electrically coupled to the sensing element, that measures a change in the resistance of the sensing element due to the presence of the target gas and converts the measurement to a digital signal; and a feedback loop from a digital unit to the readout circuit to compensate for variations in a baseline resistance of the sensing element. 
         [0007]    In certain embodiments, the gas sensor is incorporated in a handheld unit, having a suitable power source, such as a battery, and a display device, such as an LED indicator, included in the unit. One or more heating elements and temperature sensors can be provided to enable precise temperature control within the gas sensor. The sensor device can comprise an array of sensing elements, with a multi-channel integrated readout circuit. 
         [0008]    According to one embodiment, the readout circuit comprises an A/D converter that converts the measurement of the change in the resistance of the sensing element to a digital signal. The A/D converter can comprise, for example, a first-order single-bit delta-sigma modulator device with a digitally configurable oversampling ratio for controlling the conversion scale. In certain embodiments, the resistance recording system has a resolution of 16-bits and a bandwidth of up to 1 kHz. 
         [0009]    In some embodiments, the gas sensor is configured to maintain a constant current through the sensing element and measures a change in voltage due to the change in resistance. Alternatively, the sensor maintains the sensing element biased at a constant voltage and measures a change in current due the change in resistance. 
         [0010]    The feedback loop can, in some embodiments, utilize an independent component analysis (ICA) based signal processing apparatus for compensating for variations in the baseline resistance of the sensing element. A current D/A converter converts a digital signal from the digital unit to a bias current that is provided to the sensing element. The current D/A converter can comprise, for example, a multi-bit (e.g. 10 bit) segmented D/A converter having at least one binary weighted bit and at least one unary weighted bit. The least significant bit(s) can be binary weighted and the most significant bit(s) can be unary weighted to provide a suitable compromise between complexity and monotonicity. 
         [0011]    The present invention further relates to methods of detecting gases using a gas sensor as described above, including methods of detecting breath gases for medical diagnostics. Additional details can be found in “An Acetone Nanosensor For Non-invasive Diabetes detection,” by Wang et al. in the Proceedings of the 13 th  International Symposium of the American Institute for Physics of May 23, 2009, Vol. 113 (Issue 1), pages 206-208, the entire contents of which is incorporated herein by reference. 
         [0012]    In some embodiments, the present invention is a personal breath analyzer for fast and early diagnosis. The diagnostic tool breath analyzer provides a first detection device which can direct more complex diagnostic tools where to focus attention. The personal breath analyzer can also be of great significance in the case of emergency diagnostic, where due to chemical or biological threat, the time of detection and priority of possible victims can be of essence in response to such threat. The present breath analyzer tool is also very useful in low-resource settings, for health monitoring of underprivileged populations, etc. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0013]    Other features and advantages of the present invention will be apparent from the following detailed description of the invention, taken in conjunction with the accompanying drawings of which: 
           [0014]      FIG. 1  is a schematic illustration of a handheld diagnostic breath analyzer according to one embodiment; 
           [0015]      FIG. 2  is a block diagram schematically illustrating the system electronics of the diagnostic breath analyzer; and 
           [0016]      FIG. 3  is a flow diagram illustrating a gas detection method of the invention. 
       
    
    
     DETAILED DESCRIPTION 
       [0017]    This application claims the benefit of U.S. Provisional Application No. 61/265,979, filed Dec. 2, 2009, the entire contents of which are incorporated herein by reference. 
         [0018]    The present invention includes in a preferred embodiment a low-complexity low-power solution for the measurement of gas concentrations from a handheld gas measurement unit. The sensor behaves electronically as a resistance, and therefore a specialized multi-channel instrumentation is required to obtain readouts. VLSI technology offers several advantages for implementation of a highly integrated readout circuitry, including high sensitivity, small feature size, low noise, low power and modularity. The resistance is first converted to a voltage measurement, and the voltage signal is digitized. The input voltage is digitized using an A/D converter design that employs the first-order single-bit delta-sigma modulator architecture with a digitally configurable oversampling ratio for controlling the conversion scale. 
         [0019]    A handheld diagnostic breath analyzer device  100  according to one embodiment is illustrated schematically in  FIG. 1 . The device  100  includes a housing  101  having an opening  103  for receiving a gas  105  to be analyzed. In a diagnostic application, a patient exhales breath gas  105  into the opening  103 . The breath gas  105  enters a chamber  107  where the gas  105  interacts with one or more sensor elements  109 . The sensor elements  109  have a property that changes based on the chemical composition of the gas  105  with which it interacts. In one embodiment, the electrical resistance of the sensor elements  109  changes in response to the presence or absence of particular constituents of the gas  105 . Examples of suitable sensor elements  109  are described in, for example, U.S. Pat. No. 7,017,389, which has been incorporated herein by reference. An integrated circuit device  111  is electrically coupled to the sensor element  109 . The integrated circuit device  111  is configured to read out the change in resistance in the sensor element  109  and convert this change to a suitable electronic signal, such as a digital signal. In some embodiments, the device  100  includes an array of sensor elements  109 , and the integrated circuit device  111  enables multi-channel read-out and signal processing. The sensor elements  109  can be integrated on the circuit device  111 . 
         [0020]    The analyzer device  100  of  FIG. 1  further includes a power source  113 , such as a battery, and a display device  115 . The display device  115  can include, for example, one or more LED indicators that can be configured to indicate the presence or absence of a particular target substance in the breath gas  105 . The display device  115  can be configured to indicate when a threshold amount of one or more substances are detected in the breath gas  105 , for example. The display can be configured to display a diagnosis of a particular medical condition associated with the detected chemical constituent(s) of the breath gas. Other display devices, such as a panel display, can be utilized. Various controls/input devices  121  are provided for controlling the operation of the device  100 . 
         [0021]    The electrical resistance of each of the sensors  109  in the array is composed of a combination of two series resistances. First, a baseline resistance R b  is present that varies across sensor design and even across sensors with the same design. This parameter depends on technology and can be considered constant regardless of the presence of gas. However, due to fabrication and aging of the device, this baseline resistance does record a variation, AR b . Second, another series resistance can be considered that reacts with the amount of gas it is constructed to sense, ΔR gas . Thus, the total resistance of a gas sensor in the array is given by Equation 1: 
         [0000]        R   sens   =R   b   +ΔR   gas   (1)
 
         [0022]    For the sensing elements, the sensor resistance, R sen , ranges from 100 Ω to 20 MΩ and the baseline resistance, R b , ranges from 10 kΩ to 20 MΩ. Since the system has to react to a change in resistance caused by the gas, R gas , two different approaches are possible: keeping the current constant through the sensor and determining the voltage change due to the change in resistance, or keeping the sensor biased at a constant voltage and reading the change in current caused by the change in resistance. 
         [0023]    In one embodiment, in order to keep the measurement as precise as possible in the given range, measures are taken to make the system insensitive to the baseline resistance, R b . This is achieved according to one embodiment by incorporating a feedback loop from the digital unit to the read-out circuit to compensate for this error. Compensation of the variation of baseline resistance (ΔR b ) is achieved through a signal processing independent component analysis (ICA) algorithm. 
         [0024]    A system block diagram is shown in  FIG. 2 . A current D/A converter  201  is used for calibration and cancellation of the effect of inherent baseline resistance of the sensor  109 . In order to calibrate for the large baseline resistance range, a feedback mechanism  203  from the digital unit  205  to the current D/A converter  201  is provided to compensate for the change in baseline resistance. Most current D/A converter topologies are either binary weighted or unary weighted. Unary current D/A converters have the advantage of inherent monotonicity, while increasing the system complexity making it unacceptable for high resolution. The binary D/A converter reduces system complexity but has the issue of monotonicity. A compromise on complexity and monotonicity is achieved and a 10 bit segmented current D/A converter topology is used with six least significant bits binary weighted and four most significant bits unary weighted. 
         [0025]    An A/D converter  207  is then used to track the change in sensor  109  resistance with a change in gas concentration. In one embodiment, the resistance recording system requires a resolution of 16-bit and a bandwidth of up to 1 kHz. The choice of voltage-measuring first-order single-bit delta-sigma modulator matches the low-frequency content of the signal of interest, which allows high oversampling ratios and trade-off between bandwidth and resolution, and offers additional noise reduction. 
         [0026]    In one embodiment, a temperature control system is integrated on the same mixed-signal VLSI chip, since accurate temperature control is necessary due to the strong sensor response dependence on the temperature. One or more heaters  117 , such as polysilicon heaters, and temperature sensors  119  (thermometers) are included, as shown in  FIG. 1 , to obtain a flexible control and setting of the operating temperature gradient. 
         [0027]      FIG. 3  is a flow diagram  250  illustrating a gas detection method of the invention. The method of the invention can be used to measure the concentration of a variety of substances in exhaled breath gas, including without limitation NO, NO2-, NO3-, CO, hydrocarbons, ethane, n-pentane, ethylene, isoprene, acetone, formaldehyde, ethanol, hydrogen sulfide, carbonyl sulfides, and ammonia/amines, and can further be used to diagnose a variety of diseases and medical conditions, such as inflammation and oxidative stress in the lungs, cardiovascular disease, diabetes, nephritis, bilirubin production, blood cholesterol levels, viral and bacterial infections, asthma and lung cancer. A temperature control system can be used to adjust  252  the temperature of the sensor. The method can include the steps of monitoring the baseline resistance  254 , removing the effect of baseline resistance using feedback control  256 , and measuring the change of resistance  258  to detect a gas parameter which is then displayed on a display  260 . 
         [0028]    While the invention has been described in connection with specific methods and apparatus, those skilled in the art will recognize other equivalents to the specific embodiments herein. It is to be understood that the description is by way of example and not as a limitation to the scope of the invention and these equivalents are intended to be encompassed by the claims set forth below.