Patent Application
20130267799
The present disclosure generally relates to the field of biomedical testing. More specifically, the present disclosure relates to methods and apparatus for noninvasive measurement of concentration of analytes in body tissues.
Noninvasive diagnosis and measurement of blood glucose concentration has attracted tremendous attention in the past two decades because of the emergence of diabetes as an epidemic, particularly when associated with an increased overall obesity of the population. Noninvasive measurement of glucose offers the potential for increased frequency of testing, and thus, enable tighter control of blood glucose concentrations through concomitant adjustment of insulin doses. Noninvasive detection techniques also offer the potential for a portable, closed-loop system for monitoring and regulating insulin dosage. These prospective advantages have led to considerable interest in the commercialization of noninvasive glucose monitoring devices.
Currently, all available portable end-user devices for measuring blood glucose require puncturing the fingertip to obtain a blood sample. The blood sample is then placed on a test strip that indicates the glucose concentration. These devices are very compact and reasonably accurate, but puncturing the fingertip to obtain a blood sample is inconvenient, painful, and poses a risk of infection. Noninvasive devices for measuring blood glucose are not commercially available at present.
A number of attempts have been made to measure blood glucose concentration noninvasively by measuring tissue absorption of light radiation in the near infrared energy spectrum-approximately 650 nm to 2700 nm. U.S. Pat. No. 5,099,123 to Harjunmaa et al., which is incorporated herein in its entirety by reference, discloses a balanced differential (or Optical Bridge™) method for measurement of analyte concentration in turbid matrices, i.e. body fluids and tissue. The method utilizes two wavelengths—a principle wavelength which is highly absorbed in the target analyte, and a reference wavelength, selected using a balancing process, which is not (or much less) absorbed in the target analyte. The two wavelengths are selected to have substantially identical extinction coefficients in the background matrix. When a radiation beam comprising the two wavelengths in alternate succession is applied to the sample tissue matrix, an alternating signal synchronous with the wavelength alternation is registered in a signal detector measuring the radiation transmitted or backscattered by the matrix. The amplitude of the alternating signal is proportional to the concentration of the target analyte in the sample matrix. During the measurement, the Optical Bridge balancing process is used to vary the two alternating wavelengths and their relative intensities such that in the absence of analyte, the detector signal is essentially zero. That is, the Optical Bridge uses the two near infra-red wavelengths to “null out” the background absorption so that the analyte concentration becomes much more visible.
Subsequently, in U.S. Pat. No. 5,178,142, which is incorporated herein by reference, Harjunmaa et al. disclosed a method of changing the extracellular to intracellular fluid ratio of the tissue matrix by varying the mechanical pressure on the tissue, and zeroing the transmitted/reflected signal (balancing) when there is a minimum level of analyte present in the sample.
In U.S. Pat. No. 7,003,337, which is incorporated herein by reference, Harjunmaa et al. disclosed continuous estimation of the amount of fluid containing the target analyte within the sample using another radiation (such as green light which is absorbed by hemoglobin), and combining the output of the sample detector with the fluid volume estimate to calculate the analyte concentration. Further, in U.S. application Ser. No. 11/526,564, which is also incorporated herein by reference, Harjunmaa et al. disclosed a method of producing a radiation beam using three fixed-wavelength laser diodes instead of tuning the laser wavelengths during use.
Other related patents include U.S. Pat. Nos. 5,112,124; 5,137,023; 5,183,042; 5,277,181 and 5,372,135, each of which is incorporated by reference herein in its entirety.
The present disclosure describes a method and apparatus for noninvasively measuring the concentration of a target analyte in a sample using a fiberless transflectance probe. A first aspect of the present disclosure is an illustrative apparatus for noninvasively interrogating a target region for measuring an amount of a target analyte, wherein the apparatus comprises a source for generating a combined beam of electromagnetic radiation including at least two repetitive periods of radiation having different wavelengths, at least two of the wavelengths having different absorption coefficients for the target analyte. The apparatus further comprises a detector arranged to detect a portion of the radiation backscattered by the target region, the detector generating an output signal proportional to the detected intensity of the combined beam at each of the two repetitive periods of radiation, and a fiberless transflectance probe for directing the beam of electromagnetic radiation to the target region and conducting the backscattered light to the detector, wherein the fiberless transflectance probe comprises a tapered tubular housing with an inner reflective surface, a cylindrical optical rod with an outer reflective surface and a detection window through which the radiation beam is transmitted to the target region.
Another aspect of the present disclosure is an illustrative transflectance probe for measuring a property of a sample, which includes a detection window through which the sample is irradiated, an optical rod with an outer reflective surface positioned perpendicular to the detection window, a tapered tubular housing with an inner reflective surface positioned around the optical rod, at least one light source for irradiating the sample, and a detector positioned at the proximal end of the optical rod for detecting the light backscattered by the sample.
Yet another aspect of the present disclosure is an illustrative method of noninvasively interrogating a target region for measuring an amount of a target analyte, comprising the steps of providing a fiberless transflectance probe comprising a tapered tubular housing with an inner reflective surface, a detection window and an optical rod with an outer reflective surface positioned perpendicular to the optical rod. The method further includes providing at least two light sources operating at two different wavelengths for generating a radiation beam consisting of at least two time multiplexed components, transmitting the radiation beam to the target region by reflecting on the inner surface of the tubular housing and the outer surface of the optical rod, conducting the backscattered beam from the target region to the detector by reflecting on the inner surface of the optical rod, and providing a detector that detects the backscattered beam and produces an output signal indicative of the differential absorption of the two wavelengths by the target region.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description, serve to explain the principles of the various aspects of the invention.
Reference will now be made in detail to embodiments consistent with the present disclosure, examples of which are illustrated in the accompanying drawings. Wherever possible, the same reference numbers will be used throughout the drawings to refer to the same or like parts.
In an exemplary embodiment, an optical system comprising a fiberless transflectance probe is used to measure the concentration of a target analyte in a fluid within a sample matrix. The analyte concentration is measured and analyzed using a portable device developed using Optical Bridge™ technology. In accordance with an embodiment of the present disclosure and the Optical Bridge™ technology, noninvasive optical measurements of the analyte concentration are performed using a beam of electromagnetic radiation which alternates at a particular frequency between a “principal” wavelength (λ0), a “reference” wavelength (λ1) and an auxiliary wavelength λ2. λ0 is selected to achieve high analyte absorption, and λ1 is selected to have minimal analyte absorption. During the Optical Bridge™ balancing step, λ1 is adjusted to have the same absorption in blood-less tissue as λ0. The auxiliary wavelength λ2 is selected to have high absorption in a component of the fluid, and is used to provide an estimate of the fluid content of the sample matrix. In an exemplary embodiment of the present disclosure, the fiberless transflectance probe is used to measure the concentration of glucose (i.e. the target analyte) in blood (i.e. the fluid). In such as embodiment, λ0 is selected to be about 1620 nm and λ1 is selected to be about 1380 nm, which are in the near infrared energy spectrum. The auxiliary wavelength λ2 is selected to be about 525 nm, which is an isosbestic wavelength for hemoglobin, and provides an excellent sensitivity to blood. In one such embodiment, the three wavelengths, λ0, λ1, and λ2, are 1620+/−20 nm, 1380+/−20 nm, and 525+/−20 nm, respectively. The beam of electromagnetic radiation consists of time multiplexed component of the three different wavelengths (λ0, λ1 and λ2) alternating at a frequency of 100 Hz. In another embodiment, some or all wavelengths are on at all times, i.e., they are not alternating. In certain embodiments, the separation of the signal into its wavelength components is performed by the detector or processor.
In an exemplary embodiment, the extracellular-to-intracellular fluid ratio of the measurement site 22 is changed during the measurement by exerting varying mechanical pressure on the measurement site. In such an embodiment, the amount of fluid in the measurement site 22 is modulated by means of a linear actuator 26, as illustrated in
The Optical Bridge™ technology exploits the principle that compressed tissue has a relatively lower proportion of fluid with the target analyte than uncompressed tissue, although some residual amount of analyte remains in the measurement site 22 during the compression. In another embodiment, the extracellular-to-intracellular fluid ratio is allowed to change as a result of natural pulsation due to heartbeat, and the measurement cycle is synchronized with such pulsation. When the extracellular fluid volume in the measurement site is reduced either due to mechanical compression or natural pulsation, the optical path of the radiation beam contains minimal fluid and the target analyte. The Optical Bridge™ balancing is performed at this position at the beginning of each measurement to achieve the maximum background rejection. The balancing is performed by adjusting the light intensities at the two wavelengths λ0, λ1, and also by modifying the reference wavelength λ1. The variations in the background matrix structure are compensated for in the balancing process. As indicated in
In an exemplary embodiment which utilizes the compression mechanism, the pressure on the measurement site 22 is relaxed after the Optical Bridge is balanced, allowing fluid to return to the site. The attenuation of the two wavelengths λ0 and λ1 is different at the uncompressed position, as indicated by the larger variation in the Detector Output Voltage 30 in
In one embodiment, an auxiliary radiation source 34, as illustrated in
In one exemplary embodiment, optical probe 20 is configured for transflectance measurements, wherein the radiation beam is inserted into the measurement site 22 and the backscattered beam is detected by the signal detector 18. The detector then generates a signal indicative of the differential absorption of the target analyte. An important consideration for such an embodiment is that the light reflected from the surface of the measurement site 22 should not reach the detector as it would overwhelm the backscattered light.
In one such embodiment, transflectance measurement is performed using a bifurcated bundle of optical fibers, a first portion of which is adapted to receive light from the laser diodes operating at wavelengths λ0 and λ1, and a second portion of which is adapted to conduct the backscattered light to the signal detector. The fiber bundle passes through the optical probe 20, and the common end of the fiber bundle is pressed against the measurement site 22 for the transflectance measurements.
In another embodiment, transflectance measurement is performed using a fiberless transflectance probe 20, as illustrated in
The electromagnetic radiation beam is transmitted to the measurement site 22 through the detection window 46 during a measurement. Thus, the detection window 46 acts as an interface between the sample matrix and device hardware. The detection window 46 is also used to apply mechanical pressure on the measurement site 22 during a compression/decompression procedure, as described earlier. In one embodiment consistent with the present disclosure, the detection window 46 is comprised of glass or quartz. In another embodiment, the detection window 46 is comprised of a thermoplastic polymer that has high transmittance in the wavelength range consisting of λ0, λ1, and λ2, has low moisture absorbility and is suitable for injection molding. Example of such thermoplastic polymers include, but is not limited to, cyclic polyolefins (COP), polymethylmethacrylate (PMMA), and polystyrene (PS).
The optical rod 40 is further surrounded by a tapered tubular housing 50 having an inner reflective surface. In one embodiment, the inner surface 52 is aluminized to increase the reflectivity of the surface. The distal end 54 of the tapered tubular housing 50 is coupled with the detection window 46, as shown in
The tapered tubular housing 50 also facilitates shaping of the radiation beam emitted by the laser diodes and the LEDs. The shape of the inner surface 52 and taper angle of the tubular housing guides the distribution of the emitted beam on the measurement site 22. In one preferred embodiment consistent with the present disclosure, the tubular housing 50 is configured as a truncated conical shell having a cone angle (angle between the longitudinal angle and wall) of 7.5°. In another embodiment, the inner surface of tapered tubular housing 50 is faceted in order to distribute the incident light evenly on the measurement site 22. The number of facets in the tubular housing corresponds to the number of laser diodes and LEDs used in the optical probe 20. In one embodiment, the optical probe 20 includes four laser diodes (two each for the wavelengths λ0 and λ1), and two LEDs operating at wavelength λ2. In such an embodiment, the inner surface 52 of the tapered tubular housing 50 has a faceted hexagonal shape, as shown in
The laser diodes 12, 14 are mounted on a heat sink 60 at the proximal end 56 of tapered tubular housing 50 for temperature stability. In one embodiment, the LEDs 16 are also mounted on the heat sink adjacent to the laser diodes. In another embodiment, the LEDs are mounted on a positioning plate 62 below the heat sink 60, as shown in
The radiation beam comprising the wavelengths λ0, λ1, and λ2, is transmitted to the measurement site 22 by reflecting on the outer surface 45 of the optical rod 40 and the inner surface 52 of the tapered tubular housing 50.
In one exemplary embodiment consistent with the present disclosure and the Optical Bridge™ technology, the analyte testing device 10 is a handheld unit. Referring again to
The analyte testing device 10 can be a standalone system or can operate in conjunction with a mobile or stationary device to facilitate display or storage of data, and to signal healthcare personnel when therapeutic action is needed, if the device is used for continuous monitoring of a diagnostic parameter associated with a disease state. Mobile devices can include, but are not limited to, handheld devices and wireless devices distant from, and in communication with, the analyte testing device 10. Stationary devices can include, but are not limited to, desktop computers, printers and other peripherals that display or store the results of the test. In an exemplary embodiment, the analyte testing device 10 stores each patient file, which includes a summary of the session and test results, on a removable memory card 21, such as compact flash (CF) card. The user can then use the memory card 21 to transfer patient information and procedural data to a computer, or to produce a printout of the data and session summary. In another embodiment, results from the processor 23 are transferred directly to an external mobile or stationary device to facilitate display or storage of data. For example, the results from the processor 23 may be displayed or stored on a PC 29 using a PC interface, such as an USB port, IRDA port, BLUETOOTH® or other wireless link. In yet another embodiment, the results can be transmitted wirelessly or via a cable to a printer 31 that prints the results to be used by attending medical personnel. Further, the analyte testing device 10 can transmit data to another mobile or stationary device to facilitate more complex data processing or analysis. For example, the device, operating in conjunction with PC 29, can send data to be further processed by the computer.
Although the Optical Bridge™ method and the analyte testing device 10 are described here with a focus towards measuring the concentration of glucose in blood, the method and device presented in this disclosure may also be employed to detect the concentration of other analytes, such as urea, cholesterol, nicotine, drugs, etc., in blood or other fluids. Additionally, the fiberless transflectance probe 20 and its method of use may be utilized in any optical detection system operating in the infrared, visible, or ultraviolet wavelength range.
Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.
