Patent Description:
The present application relates generally to the non-invasive measurement of various substances in a body, such as the measurement of the concentration of glucose in the human body and, more specifically, to a method employing an electro-optical system to non-invasively analyze the concentration of a substance in a body.

Spectroscopic techniques using infrared ("IR") radiation are known in the prior art and have been widely used for non-invasive measurement of the concentration of substances of interest in a body. One area of particular interest is the use of these techniques for the non-invasive measurement of the concentration of glucose and other constituents of the human bloodstream.

The infrared spectra includes the near infrared (approximately <NUM> to <NUM> microns), the middle infrared (approximately <NUM> to <NUM> microns), the far infrared (approximately <NUM> to <NUM> microns), and the extreme infrared (approximately <NUM> to <NUM> microns). Typical prior art glucose and other non-invasive blood constituent measuring devices operate in the near infrared regions where the absorption of infrared energy by glucose and other blood constituents is relatively low. However, it is known that glucose and other blood constituents have strong and distinguishable absorption spectra in both the middle and far infrared regions.

Several patents disclose methods to non-invasively measure the concentration of a substance, such as glucose, for example, in the bloodstream using infrared detection systems and methods. However, none of the disclosed methods consider a method of analysis of the concentration of a substance in a body wherein infrared emissions from a surface of the body are measured in a plurality of time intervals while the temperature of the surface changes from a first temperature to a second temperature.

The present application discloses a method to analyze and determine, non-invasively, the concentration of a substance in a body. In accordance with one embodiment of the present disclosure, the method comprises the steps of changing the temperature of the surface of a body from a first temperature to a second temperature, then changing the temperature of the surface of the body from the second temperature back to the first temperature. Measuring the infrared radiation absorbed or emitted from the body in a first wavelength band at predetermined time intervals during the change of the temperature of the surface of the body from the second temperature back to the first temperature. Measuring the infrared radiation absorbed or emitted from the body in a second wavelength band at predetermined time intervals during the change of the temperature of the surface of the body from the second temperature to the first temperature. The method further comprises measuring the temperature at the surface of the body, and measuring the ambient temperature. The method further comprises the steps of calculating a normalized ratio parameter based on the IR radiation measured for the first wavelength band, the IR radiation measured for the second wavelength band, the body surface temperature and the ambient temperature, and determining the concentration of the substance in the body by correlating the normalized ratio parameter with the body surface temperature and the ambient temperature. An empirically deprived lookup table may be used to correlate the normalized ratio parameter with the concentration of the substance in the body.

The following figures, in which like numerals indicate like elements, form part of the present specification and are included to further demonstrate certain aspects of the present disclosure. These embodiments depict the novel and non-obvious aspects of the disclosure shown in the accompanying drawings, which are for illustrative purpose only. The disclosure may be better understood by reference to one or more of these figures in combination with the detailed written description of specific embodiments presented herein.

These and other embodiments of the present application will be discussed more fully in the description. The features, functions, and advantages can be achieved independently in various embodiments of the present disclosure, or may be combined in yet other embodiments.

Embodiments of the present disclosure provide methods to non-invasively analyze and measure the concentration of a substance in a body. In certain embodiments, the analyzed substance may be glucose in the human bloodstream. However, those of ordinary skill in the art will appreciate that the present methods may be used to analyze and measure concentrations of other substances as well, such as cholesterol, for example.

All bodies and all substances absorb and emit infrared ("IR") radiation. The magnitude of IR radiation absorbed or emitted at a given wavelength varies as a function of the body's temperature and the ambient temperature. <FIG> illustrates a sample plot of the IR radiation emission spectrum for a hypothetical body, where the ambient temperature TA is equal to x and the body temperature TB is equal to y. As shown, for a given ambient temperature and body temperature, a body more readily emits and absorbs IR radiation at certain wavelengths, represented by the peaks <NUM> in the spectrum shown by curve <NUM>.

The IR spectra includes the near infrared (approximately <NUM> to <NUM> microns), the middle infrared (approximately <NUM> to <NUM> microns), the far infrared (approximately <NUM> to <NUM> microns), and the extreme infrared (approximately <NUM> to <NUM> microns). In certain substances IR absorption/emission is particularly distinctive in the far infrared ("FIR") spectrum. For example, it is known that glucose and other blood constituents have strong and distinguishable absorption spectra in both the middle and far infrared regions. Thus, to measure the concentration of substances such as glucose, for example, in a body, it is advantageous to measure the FIR radiation emitted by the body.

Embodiments of the present methods measure the FIR radiation absorbed or emitted by a body at different wavelength bandwidths or bands. The first wavelength band (or bands) is selected to be in a band (or bands) where the substance of interest is known to have significant absorption/emission characteristics. The second wavelength band (or bands) is selected to be in a band (or bands) where the substance is known to have no or negligible absorption/emission. In an alternate embodiment, the second wavelength band (or bands) is selected to be the entire FIR absorption/emission spectrum of the body.

In some embodiments, the FIR measurements are normalized against a blackbody. A blackbody, as those of ordinary skill in the art will appreciate, is one that absorbs and emits radiation with a theoretical emissivity of one. <FIG> illustrates a sample plot of the FIR absorption/emission spectrum for a hypothetical body (solid curve <NUM>) and for a blackbody (dashed curve <NUM>). For both the body and the blackbody the ambient temperature TA is the same. Similarly, for both the body and the blackbody the body temperature TB is the same for each set of measurements. The dashed vertical lines define a first wavelength band <NUM> in which the substance whose concentration is to be measured is known to have an FIR absorption/emission peak <NUM>. For example, for glucose, the selected band <NUM> may be between about <NUM> microns and about <NUM> microns.

In one embodiment of the present disclosure, to analyze and measure a substance concentration, the temperature of an area of the surface of a body, an area of skin on a human body, for example, is changed from a first temperature to a second temperature for a period of time (i.e., as by heating or cooling), and then allowed to recover or revert from the second temperature to the first temperature over a period of time. During the recovery of the surface temperature of the body, the IR radiation from the surface of the body is measured both in the wavelength bandwidth for the substance of interest and in the wavelength bandwidth not including the wavelength of the substance of interest at each of a plurality of predetermined time intervals. The results of the measurements are plotted as a function of elapsed time versus temperature of the surface in two curves, one for the wavelength bandwidth of interest and one for the wavelength bandwidth not including the wavelength of interest.

The difference between the two curves or functions due to the contribution of the IR wavelength emission/absorption of the substance of interest in the body can be analyzed by calculating the value of the functions for the two curves at each of the measurement times or by determining the difference between the constants for each of the two curves. The average ratio of the two radiation measurements after normalization for a black body reading is correlated to the concentration of the desired substance in the body, such as the concentration of glucose in the bloodstream of a human body, for example.

Referring now also to <FIG>, a block diagram of a system <NUM> for the non-invasive measurement of the concentration of a substance in a body is shown. Broadly, the illustrated embodiment of the present system <NUM> comprises an infrared ("IR") radiation detector <NUM>, an IR filter assembly <NUM>, heating and/or cooling apparatus <NUM>, and apparatus <NUM> for measuring the ambient temperature. In some embodiments, the IR detector <NUM> measures the body surface temperature.

In one embodiment, the IR detector <NUM> may comprise a thermopile with collimating optics. However, those of ordinary skill in the art will appreciate that the IR detector <NUM> may comprise a different type of detector, such as a bolometer, for example. The system <NUM> shown in <FIG> further comprises a display <NUM> for presenting information such as the substance concentration, the measured parameters and other information of interest. In certain embodiments, the display <NUM> may comprise a liquid crystal display ("LCD").

With continued reference to <FIG>, the IR filter assembly <NUM> is positioned between the body and the IR detector <NUM>. In the illustrated embodiment, the IR filter assembly <NUM> comprises two filters <NUM>, <NUM>, although those of ordinary skill in the art will appreciate that the IR filter assembly <NUM> may include any number of filters. A first filter, filter <NUM>, for example, will preferably be a narrow band filter passing the wavelengths of the spectral characteristic of the substance being measured. A second filter, filter <NUM>, for example, will preferably be a narrow band filter passing those wavelengths of a spectral characteristic not sensitive to the substance being measured. For example, in some embodiments, filter <NUM> will limit the bandwidth to that region of the spectrum where there is no emission for the substance being measured (for glucose, for example, the bandwidth may be <NUM>. 5µ-15µ), while filter <NUM> would have a bandwidth characteristic of the emission of the substance being measured (for glucose, for example, the bandwidth may be <NUM>. In some embodiments, the second filter <NUM> may transmit, for example, all of the IR radiation between approximately <NUM> microns and approximately <NUM> microns.

In the illustrated embodiment, the system <NUM> includes a drive motor <NUM>. In certain embodiments, the drive motor <NUM> may comprise a solenoid. The drive motor <NUM> is configured to provide a motive force for changing a position of the filter assembly <NUM> with respect to the IR detector <NUM>. Activation of the drive motor <NUM> enables the filters <NUM>, <NUM> to be sequentially positioned between the body and the IR detector <NUM> as each IR radiation measurement is taken.

Referring now also now also to <FIG>, a schematic perspective view is shown of the configuration of an optical subsystem <NUM> and IR detector <NUM> components of the system <NUM> shown in <FIG>, illustrating the path of travel for IR radiation rays between a body <NUM> and the detector <NUM>. The detector <NUM> includes a detector element <NUM>, detector base <NUM> and detector leads <NUM>. The configuration of the optical and detector components is designed such that an image <NUM> of the sensitive or active area <NUM> of the detector <NUM> is created at the body <NUM> on the focal plane of mirror <NUM>.

In some embodiments, the area of image <NUM> at the surface of body <NUM> preferably has a diameter of approximately <NUM>. IR radiation emitted from or reflected by the body <NUM> at image <NUM> in beam <NUM> is collected and collimated by mirror <NUM>. The IR radiation is reflected by mirror <NUM> and propagated to mirror <NUM> in a collimated beam <NUM> of parallel rays via filter <NUM> or filter <NUM>. The focal plane of mirror <NUM> is located at the surface of a sensitive area of the IR detector <NUM>. The beam <NUM> reaching mirror <NUM> is reflected and propagated as beam <NUM> and focused at the focal plane of mirror <NUM> incident on the IR detector <NUM> sensitive area.

Thus, the optical subsystem <NUM> is aligned such that the image <NUM> is positioned at the surface of body <NUM> and the beam <NUM> of IR radiation is incident on the sensitive area of IR detector <NUM> via mirror <NUM>, filter <NUM> or filter <NUM> and mirror <NUM>.

In one embodiment, mirrors <NUM> and <NUM> are preferably ninety-degree (<NUM>°) off-axis parabolic mirrors coated with gold or other suitable reflective material. Preferably mirror <NUM> will have a focal length of about one (<NUM>) inch and mirror <NUM> will have a focal length of about three (<NUM>) inches. Other suitably designed reflective mirrors may be used for the optical subsystem <NUM> such as ellipsoid mirrors or a combination of ellipsoid and hyperbolic mirrors, for example.

Filter <NUM> and filter <NUM> are mounted in frame <NUM>, frame <NUM> being positioned between mirror <NUM> and mirror <NUM>. The filters <NUM>, <NUM> are switched between positions intercepting the beam <NUM> using a suitable driving mechanism, such as a motor or pneumatic pressure, for example, coupled to frame <NUM>. In one embodiment, motor <NUM> is coupled to the frame <NUM> and positions the frame <NUM> between the mirror <NUM> and mirror <NUM> such that the desired filter <NUM>, <NUM> intercepts the beam <NUM>.

Referring now also to <FIG>, a block diagram of an alternative embodiment of the present system <NUM> is shown. In the system <NUM>, the drive motor <NUM> and the filter assembly <NUM> are replaced with a plurality of fixed position IR detectors. In the illustrated embodiment, two IR detectors <NUM>, <NUM> are shown. However, those of ordinary skill in the art will appreciate that any number of IR detectors may be provided. In the embodiment of <FIG>, each IR detector <NUM>, <NUM> includes its own IR filter <NUM>, <NUM>, respectively. The filters <NUM>, <NUM> may, for example, be substantially similar to the two filters <NUM>, <NUM> provided in the embodiment of <FIG> with respect to the wavelengths of IR radiation each filter transmits. In the embodiment of <FIG>, there are advantageously no moving parts in the detector/filter assembly, and all measurements may be taken simultaneously.

With continuing reference to <FIG> and <FIG>, the illustrated embodiments of the present system, <NUM>, <NUM> include apparatus <NUM> for measuring the ambient temperature. In certain embodiments, the ambient temperature measuring apparatus <NUM> may comprise a thermistor, such as a negative temperature coefficient thermistor. For simplicity, the ambient temperature measuring apparatus <NUM> will be referred to as thermistor <NUM>. However, those of ordinary skill in the art will appreciate that the ambient temperature measuring apparatus <NUM> may be any apparatus that is suitable for measuring the ambient temperature, such as a thermocouple, for example. While in the illustrated embodiments, the thermistor <NUM> is shown attached to the IR detectors <NUM> and <NUM>, <NUM>, those of ordinary skill in the art will appreciate that it need not be. In certain embodiments, the thermistor <NUM> measures the temperature of a housing (not shown) of the IR detectors <NUM> and <NUM>, <NUM> which is typically equal to the ambient temperature.

Referring now also to <FIG>, a block diagram illustrating the control electronics for the systems illustrated in <FIG> and <FIG> is shown. Outputs <NUM> and <NUM>, <NUM> of the IR detector(s) <NUM> and <NUM>, <NUM>, the thermistor <NUM> output <NUM>, and control inputs <NUM>, <NUM> of the drive motor <NUM> and the heating/cooling apparatus <NUM>, respectively, are connected to control electronics <NUM>. <FIG> illustrates further details of the control electronics <NUM>, which include a processing unit <NUM> and memory <NUM>. The memory <NUM> may include one or more lookup tables for calculating and determining results of the measurements taken by the present system <NUM>, <NUM>. For example, the memory <NUM> may include an empirically derived lookup table that correlates a normalized ration parameter with the concentration of the substance of interest in the body. One example of an empirically derived lookup table is described in pending <CIT>, incorporated by reference in its entirety herein. The processing unit <NUM> may comprise a central processing unit ("CPU") running software and/or firmware. Alternatively, the processing unit <NUM> may comprise one or more application-specific integrated circuits ("ASIC"). The processing unit <NUM> also drives the display <NUM> to display results that may include the substance concentration, the measurements taken by the IR detectors <NUM> and <NUM>, <NUM> and/or the thermistor <NUM>, and other information of interest. In the embodiment of <FIG>, the processing unit <NUM> also controls a motor drive <NUM>, which in turn controls the drive motor <NUM> to change the position of the filter assembly <NUM> with respect to the IR detector <NUM>.

With continuing reference to <FIG>, the illustrated control electronics <NUM> include one or more switches <NUM> for switching between measurement channels. For example, the switches <NUM> might change between a first channel that carries a signal from the IR detector <NUM> or IR detectors <NUM>, <NUM> and a second channel that carries a signal from the thermistor <NUM>. The processing unit <NUM> controls the switches <NUM>.

The illustrated control electronics <NUM> further include an integrating amplifier <NUM>. The integrating amplifier <NUM> amplifies a voltage generated by the IR detector <NUM> or IR detectors <NUM>, <NUM> to a measurable value. The voltage generated by the IR detector <NUM> or IR detectors <NUM>, <NUM> is proportional to the detected body IR radiation, and may be very small. The illustrated control electronics <NUM> further includes a comparator <NUM>. The comparator <NUM>, together with the integrating amplifier <NUM>, converts the voltage from the IR detector <NUM> or IR detectors <NUM>, <NUM> into a time interval that is inversely proportional to the input voltage and is measured by the processing unit <NUM>.

With continuing reference to <FIG> and <FIG>, in certain embodiments the heating/cooling apparatus <NUM> comprises a Peltier element <NUM> configured to provide a desired amount of heat or cold, a fan <NUM> to drive the heated or cooled air, and a funnel <NUM> to direct the heated or cooled air onto the body surface. However, those of ordinary skill in the art will appreciate that the heat/cooling apparatus <NUM> may be any apparatus that is suitable for this purpose.

Applying heat or cold to the body (skin) surface stimulates the absorption or emission of IR radiation by the substance whose concentration is to be measured. In the case of glucose, for example, cooling the skin stimulates the absorption of IR radiation while heating the skin stimulates the emission of IR radiation. The heating/cooling apparatus <NUM> heats or cools the surface area of the body from a first temperature to a second temperature and maintains the surface area at the second temperature for a predetermined amount of time. The heating/cooling apparatus <NUM> may also be utilized to heat or cool the surface area to change the temperature of the surface from the second temperature to the first temperature, or an intermediate temperature, at a controlled rate.

Referring now also to <FIG>, a graph illustrating the temperature recovery function of the surface of a body as measured with the optical and detector system of <FIG> and <FIG> is shown. The graph <NUM> shown in <FIG> illustrates the temperature recovery function of the human skin as measured with an electro-optical system employing two IR filters. The upper curve <NUM> describes the function of the recovery of the skin's temperature from a second temperature to a first temperature as measured with a filter for a first wavelength band where the substance of interest has a strong absorption/emission characteristic. The lower curve <NUM> describes the function of the recovery of the skin's temperature from a second temperature to a first temperature as measured with a filter for a second wavelength band where the substance of interest has no or a negligible absorption/emission characteristic.

Alternatively, the lower curve <NUM> could describe the function of the recovery of the skin's temperature from a second temperature to a first temperature as measured with a filter for the entire FIR wavelength band including both a wavelength band where the substance of interest has a strong absorption/emission characteristic as well as the remaining wavelength band where the substance of interest has no or a negligible absorption/emission characteristic. The IR radiation measurements taken by the IR detector <NUM> or the detectors <NUM>, <NUM> are plotted as a function of the temperature of the surface of the body versus the elapsed time when the temperature of the surface begins to change back to a first temperature from a second temperature.

Referring now also to <FIG>, the process flowchart <NUM> illustrates one embodiment of a method for measuring the concentration of a substance within a body. At step <NUM>, the IR radiation detector(s) <NUM> or <NUM>, <NUM> and the heating/cooling apparatus <NUM> are positioned with respect to the body surface. At step <NUM>, the heating/cooling apparatus <NUM> is activated to heat (or cool) the temperature of the body surface area, such as image area <NUM> (as shown in <FIG>), for example, to change the surface area from a first temperature to a second temperature. The temperature of the body surface area is then held at the second temperature for a predetermined period of time. At step <NUM>, the heating/cooling apparatus <NUM> is activated to cool (or heat) the body surface area to change the surface area from the second temperature back to the first temperature at a predetermined rate. Alternatively, air at an ambient temperature may be used to cool (or heat) the body surface area to change the temperature of the body surface area from the second temperature back to the first temperature.

At step <NUM>, the absorption/emission of IR radiation over each of the first and second wavelength bands, the ambient temperature and the body surface temperature are measured at predetermined time intervals as the temperature of the body surface area changes back to the first temperature from the second temperature. In the embodiment of the present system illustrated in <FIG>, measurement of the IR radiation in both the first and second wavelengths is accomplished by switching between the two filters <NUM>, <NUM> at each of the predetermined time intervals. In the embodiment of the present system illustrated in <FIG>, all of the measured parameters including the IR radiation in both the first and second wavelength bands can be measured simultaneously. At step <NUM>, the normalized ratio parameter is calculated from the IR radiation measurements. At step <NUM>, the normalized ratio parameter is correlated with the ambient temperature and the body surface temperature using a lookup table. At step <NUM>, the substance concentration is displayed.

Claim 1:
A method (<NUM>) for measuring a concentration of a substance within a body (<NUM>), the method comprising the steps of:
positioning (<NUM>) the body (<NUM>) with respect to an infrared detector (<NUM>, <NUM>, <NUM>), an optical system (<NUM>, <NUM>), and a heating/cooling apparatus (<NUM>);
activating (<NUM>) the heating/cooling apparatus (<NUM>) to change a body surface temperature from a first temperature to a second temperature;
activating (<NUM>) the heating/cooling apparatus (<NUM>) to change the body surface temperature from the second temperature back to the first temperature at a predetermined rate or using air at an ambient temperature to change the body surface temperature from the second temperature back to the first temperature;
measuring (<NUM>) absorption/emission of infrared radiation over each of a first (<NUM>) and a second wavelength band, an ambient temperature, and the body surface temperature at a plurality of predetermined time intervals during the change of the body surface temperature from the second temperature to the first temperature, the first wavelength band (<NUM>) being a wavelength band or bands in which the substance emits and absorbs infrared radiation, and the second wavelength band is a wavelength band or bands in which the substance has no or negligible emission and absorption of infrared radiation;
calculating (<NUM>) a normalized ratio parameter as the average ratio or the average logarithm of the ratio of the two radiation measurements normalized against a black body at each time interval;
correlating (<NUM>) the normalized ratio parameter with the ambient temperature and the body surface temperature and using an empirically-derived lookup table correlating the normalized ratio parameter with the concentration of the substance in the body to calculate substance concentration; and
displaying (<NUM>) the substance concentration.