The ability to measure the concentration of a chemical in a test specimen or sample, and particularly the ability to measure a single chemical in a test specimen containing a complex mixture of chemicals, has numerous applications. Obviously, standard chemical analysis techniques are capable of such determinations, but they tend to have many disadvantages. In recent years, therefore, considerable effort has been directed toward the determination of various properties of materials using sound and electromagnetic waves or one-shot pulses as the basis for analysis. Such wave and pulse based techniques often have an inherent advantage over conventional chemical analysis, namely, the ability to effect a non-invasive in vivo analysis.
Two typical examples of chemical analyses in the health area alone which are of considerable interest today are: the analysis of the sodium content of food and the analysis of glucose content in blood. In both instances the material being analyzed is relatively complex in nature and presents substantial problems in connection with discriminating between the chemical being tested for and similar chemicals present in the sample, which similar chemicals may mask or alter the results of the analysis. Moreover, in connection with any blood glucose analysis, it is highly desirable to accomplish the analysis using a non-invasive technique.
There are a number of alternatives to traditional chemical processes which currently are available and are capable of measuring the concentration of a chemical substance, such as sodium, in a specimen, such as a food specimen. These apparatus include mass spectrophotometry apparatus, nuclear resonance devices, flame photometry apparatus, specific electrodes, conductivity testers, and refractometry devices. Unfortunately, the accuracy of these currently available apparatus is strongly dependent upon their cost. At the low end of the cost scale is the direct current conductivity tester, which measures the conductivity of a test sample to determine sodium content. Unfortunately, a continuity tester will yield inaccurately high test results when the test sample contains other conductive substances, such as vinegar. What is needed is an inexpensive and easy to use, but accurate, sodium measurement apparatus.
Similarly, blood-sugar analysis apparatus and methods are known which are reasonably accurate and can be used by patients themselves to determine their glucose levels. Such apparatus, however, heretofore have required invasive sampling by the patient, and produce results which will vary with the experience of the patient in using the apparatus. Thus, measurements by such patients are primarily valuable in determining relative changes in glucose levels, rather than the absolute value of the glucose level.
The use of sonic and electromagnetic waves and pulses as analytical tools has progressed considerably during the last twenty years. Sonic-based systems generally have depended upon the rate of propagation and/or the attenuation of sound in the test specimen. Electroacoustic transducers are used to transmit sound waves or pulses into the specimen and to receive the waves or pulses after transmission through the specimen. Various methods are employed to determine the rate of propagation of sound through the test specimen or to determine the change in amplitude (attenuation) of the sound transmitted through the specimen. Speed and/or attenuation are then compared to values for calibration specimens having a known amount of the chemical to be studied. Typical of such acoustic-based chemical analysis systems are the apparatus and methods set forth in U.S. Pat. Nos. 4,327,587, 3,654,072 and 3,648,513. An acoustic impedance apparatus also is disclosed in U.S. Pat. No. 4,094,304. The system employs acoustic energy pulses and detection of the echo pulses.
Acoustic-based chemical analysis systems, however, have generally been found to have a limited scope in terms of the compounds which may be studied. Moreover, they lack the ability to discriminate between chemicals as the test specimens become more complex in their make up. Such acoustic apparatus and methods, therefore, lack the precision and specificity which otherwise would be desirable in a chemical analysis system.
The use of electromagnetic waves and pulses in connection with the measurement and analysis of various chemical properties has been found to have various advantages. Such chemical analysis systems are often referred to as microwave spectroscopy techniques, although they may include frequency ranges which are considered by some as being in the radio frequency range.
The method and apparatus of the present invention employ a periodic shaped wave having a frequency which is preferably in about the one megahertz to about one gigahertz range. It is believed that the present method and apparatus may be found to be useful in frequency ranges which are generally accepted to be in the microwave range, i.e., above five hundred megahertz. Moreover, the present system also may be useful at frequencies below one megahertz. Accordingly, references to present invention in this application as being a "radio frequency" spectroscopy method and apparatus are for the sake of convenience only, not by way of limitation.
Microwave and radio frequency spectroscopy has been used extensively to measure the dielectric properties of materials and particularly permittivity. Among the techniques employed in connection with permittivity studies have been reflection, transmission and resonant methods. Guided and free-space systems and pulsed, single frequency and swept frequency range systems all have been studied and reported in the technical literature.
Perhaps the greatest amount of effort has been directed in the area of studying the reflection characteristics of electromagnetic pulses. A single electromagnetic pulse is transmitted down a waveguide to impinge against a target specimen, and the reflection of the pulse off the front and/or back surfaces of the specimen is studied. It is inherent, of course, that multiple reflection techniques using thin samples also have some effect of transmission present in the measurements. In connection with all of these studies, the resulting time delay, phase change and/or pulse attenuation are determined and correlated to permittivity.
The apparatus and method of the present invention are based upon the use of a periodic electromagnetic signal, while most of the time domain spectroscopy techniques reported in the technical literature employ an electromagnetic pulse. Pulse technology is based upon a one-shot or transient event (a voltage increase or decrease) in which one must wait for the system to respond to the event and collect data as to the response before initiating a second event. As used in this application, therefore, the expression "periodic" excludes transient event or one-shot systems (even one-shot systems in which a plurality of events are sequentially used to collect data) and includes waveforms which repeatedly return to a reference level at a frequency substantially faster than the minimum system response time associated with single pulse measurements.
Representative of one-shot or pulse permittivity studies are the following articles: Afsar, et al., "The Measurement of the Properties of Materials," Proceedings of the IEEE, Vol. 74, No. 1, pp. 183-199 (January, 1986); Gestblom, et al., "The Single Reflection Method in Dielectric Time Domain Spectroscopy," The Journal of Physical Chemistry, Vol. 88, No. 4, pp. 664-666 (1984); Gabriel, et al., "Comparison of the Single Reflection and Total Reflection TDS Techniques," J. Phys. E: Sci. Instrum., Vol. 17, pp. 513-516 (1984); Mopsik, "Precision Time-Domain Dielectric Spectrometer," Rev. Sci. Instrum., Vol. 55, No. 1, pp. 79-87 (January, 1984); Chahine, et al., "Drift Reduction of the Incident Signal in Time Domain Reflectometry," Rev. Sci. Instrum., Vol. 54 (9), pp. 1243-46 (September, 1983); Boned, et al., "Automatic Measurements of Complex Permittivity (from 2MH.sub.z to 8GH.sub.z) Using Time Domain Spectroscopy," J. Phys. E.: Sci. Instrum., Vol. 15, pp. 534-538 (1982); Gestblom, et al., "A Computer Controlled Dielectric Time Domain Spectrometer," J. Phys. E: Sci. Instrum., Vol. 13, pp. 1067-1070 (1980); Parisien, et al., "A Microprocessor-Controlled Time-Domain Spectrometer," IEEE Trans. on Inst. and Meas., Vol. IM-28, No. 4, pp. 269-272 (December, 1979); Dawkins, et al., "An On-line Computer-Based System for Performing Time Domain Spectroscopy I. Main Features of the Basic System," J. Phys. E.: Sci. Instrum., Vol. 12, pp. 1091-1099 (1979); Gestblom, et al., "Transmission Methods in Dielectric Time Domain Spectroscopy," The Journal of Physical Chemistry, Vol. 81, No. 8, pp. 782-788 (1977); Gestblom, et al., "A New Transmission Method in Dielectric Time Domain Spectroscopy," Chemical Physics Letters, Vol. 47, No. 2, pp. 349-351 (April, 1977); Bottreau, et al., "On a Multiple Reflection Time Domain Method in Dielectric Spectroscopy: Application to the Study of Some Normal Primary Alcohols," The Journal of Chemical Physics, Vol. 66, No. 8, pp. 3331-3336 (April, 1977); Cole, "Time-Domain Spectroscopy of Dielectric Materials," IEEE Trans. on Inst. and Meas., Vol. IM-25, No. 4, pp. 371-375 (December, 1976); Chahine, et al., "Measurements of Dielectric Properties by Time Domain Spectroscopy," The Journal of Chemical Physics, Vol. 65, No. 6, 2211-2215 (Sept., 1976); Claasen, et al., "Approximate Solutions in Multiple Reflection Time Domain Spectroscopy," The Journal of Chemical Physics, Vol. 63, No. 1, pp. 68-73; van Gemert, "Multiple Reflection Time Domain Spectroscopy. II. A Lumped Element Approach Leading to an Analytical Solution for the Complex Permittivity," The Journal of Chemical Physics, Vol. 62, No. 7, pp. 2720-2726 (April, 1975); Cole, "Evaluation of Dielectric Behavior by Time Domain Spectroscopy. I. Dielectric Response by Real Time Analysis," The Journal of Physical Chemistry, Vol. 79, No. 14, pp. 1459-1469 (1975); Cole, "Evaluation of Dielectric Behavior by Time Domain Spectroscopy. II. Complex Permittivity," The Journal of Physical Chemistry, Vol. 79, No. 14, pp. 1469-1474 (1975); Clark, et al., "Multiple Reflection Time Domain Spectroscopy," Journal of Chemical Society, Vol. 70, pp. 1847-1862 (1974); Rzepecka, et al., "A Lumped Capacitance Method for the Measurement of the Permittivity and Conductivity in the Frequency and Time Domain--A Further Analysis," IEEE Trans. on Inst. and Meas., Vol. IM-24 No. 1, pp. 27-32 (March, 1975); Suggett, "Microwave Dielectric Measurements Using Time Domain Spectroscopy: Note on Recent Technique Advances," J. Phys. E: Sci. Inst., Vol. 8, pp. 327-330 (1975); Springett, et al., "Thin Sample Time Domain Reflectometry for Nonideal Dielectrics," Can. J. Phys., Vol. 52, pp. 2463-2468 (1974); van Gemert, "Evaluation of Dielectric Permittivity and Conductivity by Time Domain Spectroscopy. Mathematical Analysis of Fellner-Feldegg's Thin Cell Method," J. Chem. Phys., Vol. 60, No. 10, pp. 3963-3974 (1974); Hines, et al., "Time-Domain Oscillographic Microwave Network Analysis Using Frequency-Domain Data," IEEE Trans. on Microwave Theory and Techniques, Vol. MTT-22, No. 3, pp. 276-282 (March, 1974); van Gemert, "High-Frequency Time-Domain Methods in Dielectric Spectroscopy," Philips Res. Repts., Vol. 28, pp. 530-572 (1973); Bucci, et al., "Time-Domain Techniques for Measuring the Conductivity and Permittivity Spectrum of Materials," IEEE Trans. on Inst. and Meas., Vol. IM-21, No. 3, pp. 237-243 (August, 1972); Nicholson, et al., Measurement of the Intrinsic Properties of Materials by Time-Domain Techniques," IEEE Trans. on Inst. and Meas., Vol. IM-19, No. 4, pp. 377-382 (November, 1970); Hyde, "Wide-Frequency-Range Dielectric Spectrometer," Proc. Inst. Elect. Eng., Vol. 117, pp. 1891-1901 (1970); Fellner-Feldegg, "The Measurement of Dielectrics in the Time Domain," J. of Phys, Chem., Vol. 75, No. 3, pp. 616-623 (March, 1969); Hill, et al., Dielectric Properties and Molecular Behavior, pp. 108-190, Van Nostrand Reinhold Co. (1969); and Ebert, "Radio Wave Spectra of Sorbed Dipole Molecules," XII. Collogue Ampere, pp. 480-484 (1963).
The use of microwave and radio frequency spectroscopy, and particularly reflectivity studies of the dielectric properties of biological materials, either using invasive sampling or in vivo studies, is described in the following articles: Hill, "Human Whole-Body Radio Frequency Absorption Studies Using a TEM-Cell Exposure System," IEEE Trans. on Microwave Theory and Techniques, Vol. 30, No. 11, pp. 1847-1853 (November, 1982); Athey, et al., "Measurement of Radio Frequency Permittivity of Biological Tissues with an Open-Ended Coaxial Line: Part I," IEEE Transactions on Microwave Theory and Techniques, Vol. MTT-30, No. 1, pp. 82-86 (January, 1982); Stuchly, et al., "Measurement of Radio Frequency Permittivity of Biological Tissues with an Open-Ended Coaxial Line: Part II--Experimental Results," IEEE Transactions on Microwave Theory and Techniques, Vol. MTT-30, No. 1, 87-92 (January, 1982); Stuchly, et al., "Coaxial Line Reflection Methods for Measuring Dielectric Properties of Biological Substances at Radio and Microwave Frequencies--A Review," IEEE Transactions on Instrumentation and Measurement, Vol. IM-29, No. 3, pp. 176-183 (September, 1980); Burdette, et al., "In Vivo Probe Measurement Technique for Determining Dielectric Properties at VHF Through Microwave Frequencies," IEEE Transactions on Microwave Theory and Techniques, Vol. MTT-28, No. 4, pp. 414-427 (April, 1980); and Bianco, et al., "Measurements of Complex Dielectric Constants of Human Sera and Erythrocytes," IEEE Transactions on Instrumentation and Measurement, Vol. IM-28, No. 4, pp. 290-295 (December, 1979).
An impedance measurement study is described in Stibitz, et al., "A computer-Aided Bridge for Impedance Measurements in Biological Tissues," Med. and Bio. Engr., pp. 100-104 (Jan., 1974).
Time domain reflectivity studies are somewhat peripheral to the method and apparatus of the present invention since they employ pulses, not a periodic waveform. They are based upon reflection measurements, not directly upon transmission through the target, and they measure permittivity of the target, not the concentration of a selected chemical in the target. The Clark, et al., article entitled "Multiple Reflection Time Domain Spectroscopy" is somewhat more pertinent in that it discloses the use of a subtraction technique in which the reflection signal from a dielectric filled cell is subtracted from the reflection signal of an air-filled cell to minimize the effects of unwanted reflections.
The article by Gestblom, et al. entitled "Transmission Methods in Dielectric Time Domain Spectroscopy" also is pertinent peripherally to the present invention because it is based upon the transmission of an electromagnetic signal through the test sample. Gestblom, et al. use a step pulse generator and compare the transmission of the pulse through the test specimen and through an air-filled coaxial line. Phase shift data are generated, and the dispersion in the test sample is used to measure permittivity. This is again a permittivity study and does not employ a periodic waveform.
The Gestblom, et al., article entitled "A New Transmission Method in Dielectric Time Domain Spectroscopy" discloses both transmission and reflectivity systems in which several one-shot or transient pulses ar employed to enable averaging. The pulses are separated by sufficient time to allow their effects to die out before the next pulse. Empty and filled cells are used and compared.
The Suggett article similarly examines one-shot systems in what is not a real-time technique. FIG. 3 in Suggett includes an amplitude versus frequency plot in the gigahertz range. The experimental error due to a relatively slow rise time, however, make amplitude variations at high frequency essentially insignificant. No attempt to determine concentrations is made using the techniques discussed.
In addition to the pulse studies, transmission studies have been conducted with a single frequency, continuous, periodic, electromagnetic wave in the microwave region. The phase shift and attenuation of the wave during propagation through the test sample have been used to determine various properties of the sample, for example, thickness.
Such single frequency transmission studies, however, have been found to have numerous disadvantages. Accordingly, one approach which has been employed to overcome such disadvantages and to produce more accurate transmission-based microwave spectroscopy data has been to sweep through a range of discrete frequencies in order to generate a time delay spectrum for the frequency or phase-shifts occurring as a result of transmission of microwaves through the target. This approach is disclosed in U.S. Pat. No. 4,135,131 to Larsen, et al.
Larsen, et al. discloses a system in which a sweep generator is employed to sequentially generate a plurality of periodic microwave signals of differing frequency over a range of frequencies. The swept frequencies are in the gigahertz range to maintain the short wavelengths required for the process. The generator output signal is divided and travels in two channels, a reference channel and a test channel. The signal in the test channel is transmitted by an antenna through a target, usually a biological target. A receiving antenna receives the signal after passing through the target, and the received signal is mixed with the reference signal from the reference channel. A detector sums and subtracts the mixed signals, with a low pass filter removing the sums. The differences in amplitude and phase for each of the plurality of sequentially generated signals is passed to a Fourier analyzer, which produces an amplitude versus frequency time delay spectrum for the instantaneous differences of the range of swept frequencies.
The Larsen et al. patent teaches that use of a sequentially swept range of discrete frequencies to produce a time delay spectrum enables a more accurate correlation of time delay to certain characteristics of a test sample than is possible by using previous microwave spectroscopy techniques which employ a single frequency, continuous wave. By generating a time delay spectrum for a series of different frequencies, shifts in the spectrum or pattern of wave attenuation can be calibrated to selected target characteristics, such as thickness, more accurately than a change in phase and amplitude of a wave having single frequency. The Larsen et al. system, for example, is capable of discriminating as to the thickness of brain tissue down to 6 millimeters (about one-quarter inch).
An analyzer somewhat similar to Larsen, et al. is disclosed in the patent to Ghosh et al., U.S. Pat. No. 3,866,118. The Ghosh et al. invention includes a variable frequency microwave generator which is sequentially swept through a plurality of frequencies. Variations in microwave absorption during propagation through known and unknown samples is detected for the various frequencies. These variations are then correlated to the quantity of the chemical being studied. As in Larsen et al., Ghosh et al. employs a sweep generator and produces an absorption spectrum which it correlates to the tested compound.
Microwave resonance also has been employed as a chemical analysis tool. U.S. Pat. Nos. 4,364,008; 4,110,686 and 4,104,585 are based upon the use of microwave resonant cavities. These apparatus measure the shift in frequency of a standing wave. The need to use resonant cavities, however, inherently limits this approach.
U.S. Pat. No. 4,344,440, discloses a continuous wave microwave monitoring apparatus in which a shaped beam is modulated by the electrical activity of a patient's heart or brain. Backscatter radiation is used to monitor the activity of these human organs. U.S. Pat. No. 4,257,001 discloses a microwave-based analyzer which measures the difference in amplitude, frequency, phase or polarization of a polarized microwave field with and without the object to be tested. U.S. Pat. No. 3,265,967, discloses a microwave measuring system for determining the density of a plasma of ions and electrons. The invention employs microwaves in the gigahertz range as a carrier signal and a lower frequency modulation signal. A phase detector is used to measure phase changes produced by the plasma.
Somewhat more peripheral patent art includes U.S. Pat. No. 4,531,526 in which a tuned circuit provides a ring signal in response to microwave irradiation; U.S. Pat. No. 3,051,896 also employing a resonant circuit; and U.S. Pat. No. 4,488,559 directed to a microwave radiometer which measures microwaves emitted from a patient to determine fluid content within various regions of the body.
In an even more general sense, the patent art contains such alternative chemical analysis techniques as nuclear magnetic resonance spectroscopy, U.S. Pat. No. 3,048,772; impedance variation measurements, U.S. Pat. No. 3,287,638; radio frequency alternating magnetic fields, 3,489,522; and conductivity variation measurements, U.S. Pat. No. 3,765,841.