System for non-invasive measurement of analytes in vehicle drivers

Abstract

A system for non-invasively measuring an analyte in a vehicle driver and controlling a vehicle based on the analyte measurement. At least one solid-state light source is configured to emit light of different wavelengths. A sampling device is configured to introduce light emitted by the at least one solid-state light source into the tissue of the vehicle driver. One or more optical detectors are configured to detect a portion of the light that is not absorbed by the vehicle driver's tissue. A controller is configured to calculate a measurement of the analyte in the vehicle driver's tissue based on the light detected by the one or more optical detectors, determine whether the measurement of the analyte in the vehicle driver's tissue exceeds a predetermined value, and provide a signal to a device configured to control the vehicle.

Description

[0001] applicant

[0002] Automobile Traffic Safety Association

[0003] Inventor

[0004] Johannes Koeth

[0005] Nicolas Koslowski

[0006] Citations to pending prior patent applications

[0007] This patent application claims the benefit of pending prior U.S. provisional patent application serial number 62 / 860,413, filed on June 12, 2019, by the Auto Traffic Safety Alliance and Johannes Koeth et al., for a system for non-invasive measurement of an analyte in a vehicle driver (Attorney Docket No. ACTS-4 PROV), which is hereby incorporated by reference into this application. Background Art

[0008] The present application generally relates to a system and method for non-invasively measuring analytes in vehicle drivers. More specifically, the present application relates to a measurement quantitative spectroscopic system for measuring the presence or concentration of analytes such as alcohol, alcohol byproducts, alcohol adducts, or substances of abuse using non-invasive techniques combined with multivariate analysis.

[0009] Current practice for alcohol measurement is based on blood measurement or breath testing. Blood measurement defines the gold standard for determining alcohol intoxication levels. However, blood measurement requires a venous or capillary sample and involves significant handling precautions to minimize health risks. Once the blood sample is extracted, it must be properly labeled and transported to a clinical laboratory or other suitable location, where a clinical gas chromatograph is typically used to measure blood alcohol levels. Due to the invasiveness of the procedure and the amount of sample handling involved, blood alcohol measurement is typically limited to critical situations, such as traffic accidents, violations where the suspect requires this type of test, and accidents involving injury.

[0010] Breathalyzers are more commonly encountered in the field due to their less invasive nature. During a breathalyzer test, the subject must breathe air into the instrument for a sufficient time and volume to achieve a steady breath flow originating from the alveoli deep in the lungs. The device then measures the alcohol content in the air, which is related to blood alcohol via the breath-to-blood partition coefficient. The blood-to-breath partition coefficient used in the United States is 2100 (mg EtOH / dL of blood per mg EtOH / dL of air), while other countries vary between 1900 and 2400. This variability in the partition coefficient is due to its high subject-dependence. In other words, each subject will have a partition coefficient ranging from 1900 to 2400, depending on their physiological condition. Because knowledge of the partition coefficient for each subject is unavailable in field applications, each country assumes a single partition coefficient value that applies globally to all measurements. In the United States, defendants in DUI cases often use this globally applicable partition coefficient as an excuse to hinder prosecution.

[0011] Breath measurements have additional limitations. First, the presence of "mouth alcohol" can falsely elevate breath alcohol measurements. This necessitates a 15-minute waiting period before taking a measurement to ensure the absence of mouth alcohol. For similar reasons, individuals observed burping or vomiting require a 15-minute delay. A delay of 10 minutes or more is often required between breath measurements to allow the instrument to return to equilibrium with ambient air and zero alcohol levels.

[0012] Furthermore, the accuracy of breath alcohol measurements is sensitive to many physiological and environmental factors.

[0013] Several government agencies and society at large seek non-invasive alternatives to blood and breath alcohol measurement.

[0014] Quantitative spectroscopy offers the potential for completely non-invasive alcohol measurement that is insensitive to the limitations of current measurement methods. While non-invasive determination of biological properties via quantitative spectroscopy has been found to be highly desirable, it has been extremely difficult to achieve. Examples of properties of interest include analyte presence, analyte concentration (e.g., alcohol concentration), the direction of change in analyte concentration, the rate of change in analyte concentration, the presence of a disease (e.g., alcohol intoxication), disease states, and combinations and subsets thereof. Non-invasive measurements via quantitative spectroscopy are desirable because they are painless, do not require the extraction of fluids from the body, pose little risk of contamination or infection, do not generate any hazardous waste, and can have short measurement times.

[0015] Several systems have been proposed for the non-invasive determination of biological tissue properties. These include techniques that combine polarimetry, mid-infrared spectroscopy, Raman spectroscopy, Chromosomes, fluorescence spectroscopy, nuclear magnetic resonance spectroscopy, radiofrequency spectroscopy, ultrasound, transdermal measurement, photoacoustic spectroscopy, and near-infrared spectroscopy. However, these systems do not replace direct, invasive measurements.

[0016] As an example, Robinson et al., in U.S. Patent No. 4,975,581, disclose a method and apparatus for measuring a characteristic of unknown value in a biological sample using infrared spectroscopy in conjunction with a multivariate model empirically derived from a collection of spectra of biological samples with known characteristic values. The characteristic is typically the concentration of an analyte such as alcohol, but can be any chemical or physical property of the sample. Robinson et al.'s method involves a two-step process that includes both calibration and prediction steps.

[0017] In the calibration step, infrared light is coupled to a calibration sample of known characteristic values ​​such that at least several wavelengths of the infrared radiation are attenuated at known characteristic values ​​as a function of the various components and analytes comprising the sample. The infrared light is coupled to the sample by either passing the light through the sample or reflecting the light off the sample. Absorption of the infrared light by the sample results in a change in the intensity of the light that is a function of the wavelength of the light. For the set of calibration samples of known characteristic values, the resulting intensity changes are measured at the minimum values ​​of several wavelengths. The raw or transformed intensity changes are then empirically correlated with the known characteristics of the calibration sample using a multivariate algorithm to obtain a multivariate calibration model. The model preferably accounts for subject variability, instrument variability, and environmental variability.

[0018] In the prediction step, infrared light is coupled to a sample of unknown characteristic value, and the multivariate calibration model is applied to the raw or transformed intensity variations of the appropriate wavelength of light measured from the unknown sample. The result of the prediction step is an estimate of the characteristic of the unknown sample. The disclosure of Robinson et al. is incorporated herein by reference.

[0019] Additional methods of building calibration models and using such models to predict analytes and / or properties of tissue are disclosed in U.S. Patent No. 6,157,041 to Thomas et al., entitled “Method and Apparatus for Tailoring Spectrographic Calibration Models,” the disclosure of which is incorporated herein by reference.

[0020] In U.S. Patent No. 5,830,112, Robinson describes a general method for robust tissue sampling for non-invasive analyte measurement. The sampling method utilizes a tissue sampling accessory that optimizes the optical path length for measuring analytes such as alcohol across spectral regions. The patent discloses several types of spectrometers for measuring tissue spectra from 400 to 2500 nm, including acousto-optic tunable filters, discrete wavelength spectrometers, optical filters, grating spectrometers, and FTIR spectrometers. Robinson's disclosure is incorporated herein by reference.

[0021] Despite extensive work attempting to produce commercially viable systems for determining biological properties based on noninvasive near-infrared spectroscopy, no such devices are currently available. It is believed that, for one or more reasons, the prior art systems discussed above fail to fully meet the challenges posed by tissue spectral characterization, making the design of noninvasive measurement systems a challenging task. Consequently, there is a significant need for commercially viable systems that incorporate subsystems and methods with sufficient accuracy and precision to make clinically relevant determinations of biological properties in human tissue. Summary of the Invention

[0022] One embodiment of the present invention relates to a system for non-invasively measuring an analyte in a vehicle driver and controlling a vehicle based on the measurement of the analyte. The system includes at least one solid-state light source, a sample device, one or more optical detectors (sometimes also referred to herein as photodetectors), and a controller. The at least one solid-state light source is configured to emit light of different wavelengths. The sample device is configured to introduce light emitted by the at least one solid-state light source into the tissue of the vehicle driver. The one or more optical detectors are configured to detect a portion of the light that is not absorbed by the tissue of the vehicle driver. The controller is configured to calculate a measurement of the analyte in the vehicle driver's tissue based on the light detected by the one or more optical detectors, determine whether the measurement of the analyte in the vehicle driver's tissue exceeds a predetermined value, and provide a signal to a device configured to control the vehicle.

[0023] In one configuration, a novel tissue interface device is provided, wherein the novel tissue interface device combines the functions of sampling and data acquisition in a single unit disposed adjacent to a tissue surface.

[0024] Another embodiment of the present invention relates to a method for non-invasively measuring an analyte in a vehicle driver and controlling a vehicle based on the measurement of the analyte. A sampling device introduces light of different wavelengths emitted by at least one solid-state light source into the tissue of the vehicle driver. One or more optical detectors detect a portion of the light that is not absorbed by the vehicle driver's tissue. A controller calculates a measurement of the analyte in the vehicle driver's tissue based on the light detected by the one or more optical detectors. The controller determines whether the measurement of the analyte in the vehicle driver's tissue exceeds a predetermined value and controls the vehicle based on the measurement of the analyte in the vehicle driver's tissue.

[0025] In one approach, a novel tissue interface device is used that combines the functions of sampling and data acquisition in a single unit disposed adjacent to a tissue surface. Additional features, advantages, and embodiments of the present disclosure may be elucidated by consideration of the following detailed description, accompanying drawings, and claims. Furthermore, it should be understood that both the foregoing summary and the following detailed description of the present disclosure are exemplary and intended to provide further explanation without further limiting the scope of the claimed disclosure.

[0026] In one preferred form of the invention, there is provided a sample interface device for use in identifying the presence of an analyte in a sample, wherein the sample interface device transmits a plurality of monochromatic light beams to the sample and receives backscattered light from the sample, the sample interface device comprising:

[0027] substrate;

[0028] a low absorption injection region carried by the substrate for receiving the plurality of monochromatic light beams and delivering the plurality of monochromatic light beams to the sample; and

[0029] A plurality of concentrically positioned annular photosensors are carried by a substrate, wherein the plurality of concentrically positioned annular photosensors are progressively arranged radially outside a low-absorption injection region, and further wherein each concentrically positioned annular photosensor generates an electrical signal corresponding to an amount of light received by the concentrically positioned annular photosensor.

[0030] In another preferred form of the invention, there is provided a method for delivering a plurality of monochromatic light beams to a sample and detecting scattered light returned from the sample, the method comprising:

[0031] A sample interface device is provided, comprising:

[0032] substrate;

[0033] a low absorption injection region carried by the substrate for receiving the plurality of monochromatic light beams and delivering the plurality of monochromatic light beams to the sample; and

[0034] a plurality of concentrically positioned annular photosensors carried by the substrate, wherein the plurality of concentrically positioned annular photosensors are progressively arranged radially outwardly of the low-absorption injection region, and further wherein each concentrically positioned annular photosensor generates an electrical signal corresponding to an amount of light received by the concentrically positioned annular photosensor;

[0035] directing the plurality of monochromatic light beams into a low-absorption injection region of the sample interface device such that the plurality of monochromatic light beams are delivered to the sample; and

[0036] The scattered light returning from the sample is detected using multiple concentrically positioned annular photosensors on the sample interface device.

[0037] In another preferred form of the invention, there is provided a system for non-invasive measurement of an analyte in a sample, wherein the system comprises:

[0038] an illumination unit for generating a plurality of monochromatic light beams, wherein the plurality of monochromatic light beams constitute a plurality of different wavelengths; and

[0039] A sampling unit is configured to receive the multiple monochromatic light beams from the illumination unit, transmit those monochromatic light beams to the sample, receive scattered light returned from the sample, and convert the scattered light into corresponding electrical signals for subsequent processing and analyte evaluation, wherein the sampling unit comprises:

[0040] A sample interface device, the sample interface device comprising:

[0041] substrate;

[0042] a low absorption injection region carried by the substrate for receiving the plurality of monochromatic light beams and delivering the plurality of monochromatic light beams to the sample; and

[0043] A plurality of concentrically positioned annular photosensors are carried by a substrate, wherein the plurality of concentrically positioned annular photosensors are progressively arranged radially outside a low-absorption injection region, and further wherein each concentrically positioned annular photosensor generates an electrical signal corresponding to an amount of light received by the concentrically positioned annular photosensor.

[0044] In another preferred form of the present invention, there is provided a method for detecting an analyte in a sample, the method comprising:

[0045] A system is provided, wherein the system comprises:

[0046] an illumination unit for generating a plurality of monochromatic light beams, wherein the plurality of monochromatic light beams constitute a plurality of different wavelengths; and

[0047] A sampling unit is configured to receive the multiple monochromatic light beams from the illumination unit, transmit those monochromatic light beams to the sample, receive scattered light returned from the sample, and convert the scattered light into corresponding electrical signals for subsequent processing and analyte evaluation, wherein the sampling unit comprises:

[0048] A sample interface device, the sample interface device comprising:

[0049] an illumination unit for generating a plurality of monochromatic light beams, wherein the plurality of monochromatic light beams constitute a plurality of different wavelengths; and

[0050] A sampling unit is configured to receive the multiple monochromatic light beams from the illumination unit, transmit those monochromatic light beams to the sample, receive scattered light returned from the sample, and convert the scattered light into corresponding electrical signals for subsequent processing and analyte evaluation, wherein the sampling unit comprises:

[0051] A sample interface device, the sample interface device comprising:

[0052] substrate;

[0053] a low absorption injection region carried by the substrate for receiving the plurality of monochromatic light beams and delivering the plurality of monochromatic light beams to the sample; and

[0054] a plurality of concentrically positioned annular photosensors carried by the substrate, wherein the plurality of concentrically positioned annular photosensors are progressively arranged radially outwardly of the low-absorption injection region, and further wherein each concentrically positioned annular photosensor generates an electrical signal corresponding to an amount of light received by the concentrically positioned annular photosensor;

[0055] directing the plurality of monochromatic light beams into a low-absorption injection region of the sample interface device such that the plurality of monochromatic light beams are delivered to the sample; and

[0056] The scattered light returning from the sample is detected using multiple concentrically positioned annular photosensors on the sample interface device. BRIEF DESCRIPTION OF THE DRAWINGS

[0057] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate preferred embodiments of the present invention and, together with the description, serve to explain the principles of the present invention. No attempt is made to show structural details of the present disclosure in greater detail than may be necessary for a basic understanding of the present disclosure and the various ways in which it can be practiced.

[0058] Figure 1 is a schematic depiction of a non-invasive spectroscopy system incorporating the disclosed subsystem.

[0059] Figure 2 is a graphical depiction of the concept of net attribute signal in a three-component system.

[0060] Figure 3is an embodiment of an electronic circuit designed to control the driving current of a solid-state light source, including means for turning the light source on and off.

[0061] Figure 4 is an embodiment of an electronic circuit designed to control the drive current of a solid-state light source, including means for turning the light source on and off and for varying the desired drive current.

[0062] Figure 5 yes Figure 1 An embodiment of an illumination / modulation subsystem includes a plurality of individual solid-state light sources arranged in an array, the outputs of which are directed into an internally reflecting light homogenizer having a hexagonal cross-section.

[0063] Figure 6 is an embodiment of a single laser emitter in a semiconductor chip.

[0064] Figure 7 is an embodiment of an illumination / modulation subsystem in which multiple laser emitters are mounted to a common carrier.

[0065] Figure 8 Figure 1 is an example of an illumination / modulation subsystem, depicting a laser bar consisting of a single semiconductor chip containing 24 emitters (2 emitters at 12 different wavelengths).

[0066] Figure 9 is a schematic diagram of an embodiment of a fiber optic coupler that collects Figure 8 The light emitted by each pair of emitters in the laser bar embodiment shown in FIG is combined into a single optical fiber into an output bundle or cable.

[0067] Figure 10 is an embodiment of combining the outputs of 4 different fiber couplers into a single output aperture / beam, where each coupler is coupled to a different laser rod.

[0068] Figure 11 is an exemplary embodiment of a light homogenizer suitable for homogenizing light from the output aperture / beam of an illumination / modulation subsystem.

[0069] Figure 12 yes Figure 1 A perspective view of the elements of the tissue sampling subsystem.

[0070] Figure 13 is a diagram of the ergonomic arrangement of the tissue sampling subsystem holding a sample (eg, a user's finger).

[0071] Figure 14 is an embodiment of a sampling surface of a tissue sampling subsystem showing the arrangement of illumination and collection fibers.

[0072] Figure 15is an alternative embodiment of a sampling surface of a tissue sampling subsystem.

[0073] Figure 16 is an alternative embodiment of the sampling surface of a tissue sampling subsystem that is optimized for the small emission area of ​​some solid-state light source based illumination / modulation subsystems.

[0074] Figure 17 is a schematic diagram of the interface between the sampling surface and tissue when local interferents are present on the tissue.

[0075] Figure 18 yes Figure 1 Schematic representation of the data acquisition subsystem.

[0076] Figure 19 is a diagram of the hybrid calibration formation process.

[0077] Figure 20 The effectiveness of the multivariate calibrated outlier metric for detecting the presence of local interferents is demonstrated.

[0078] Figure 21 The 1300 and 3000 K blackbody radiators are shown in the 100-33000 cm 1 (100-0.3 ) range.

[0079] Figure 22 A schematic diagram showing components of an exemplary embodiment of the present invention is shown.

[0080] Figure 23 Depicted are non-invasive tissue spectra acquired using 22 wavelengths.

[0081] Figure 24 Will be from Figure 23 Noninvasive tissue alcohol concentrations obtained from the spectra were compared with capillary blood alcohol concentrations over the same period.

[0082] Figure 25 Depicted are non-invasive tissue spectra acquired using 39 wavelengths.

[0083] Figure 26 Will be from Figure 25 Noninvasive tissue alcohol concentrations obtained from the spectra were compared with capillary blood alcohol concentrations over the same period.

[0084] Figure 27 One of many possible embodiments of a measurement timeline including system calibration, measurement, and counter-measurement time zones is depicted.

[0085] Figure 28 A non-intrusive monitoring system incorporated into a vehicle starter button in a vehicle dashboard is depicted.

[0086] Figure 29a Depicted is a side view of the non-invasive measurement inlet interface, where the emitter is a wavelength homogenizer directly connected to a wavelength light source.

[0087] Figure 29b Depicts Figure 29a Top view of the non-invasive measurement entrance interface, where the emitter is a wavelength homogenizer directly connected to a wavelength light source.

[0088] Figure 30 Depicted are components of a non-invasive monitoring system that utilizes widely tunable laser emitters to provide a means for spectrally separating absorption measurements.

[0089] Figure 31 One of many possible embodiments of a measurement timeline for improving the average required measurement time is depicted, where an initial measurement detects the presence of an analyte and subsequent measurements are taken to determine the actual concentration of the analyte.

[0090] Figure 32 A non-invasive monitoring system is depicted in which a primary analyte measurement is made by a touch system and a secondary measurement is made by a surrogate analyte detection system.

[0091] Figure 33 Depicted are components of a non-invasive monitoring system utilizing a blackbody light source with filtering elements to provide selection of discrete wavelengths to make up the emitted light source.

[0092] Figure 34 The intensity of the light source during the transition from the off state to the on state is depicted, where the measurement is taken before the intensity stabilizes.

[0093] Figures 35-40 A novel tissue interface device is described that combines the functions of sampling and data acquisition in a single unit disposed adjacent to a tissue surface. DETAILED DESCRIPTION

[0094] Before turning to the figures illustrating exemplary embodiments in detail, it should be understood that the present disclosure is not limited to the details or methods set forth in the specification or illustrated in the figures. It should also be understood that the terminology is for descriptive purposes only and should not be considered limiting. An effort has been made to use the same or like reference numerals throughout the drawings to refer to the same or like parts.

[0095] limited

[0096] For the purposes of this application, the term "analyte concentration" generally refers to the concentration of an analyte, such as alcohol. The term "analyte property" includes both analyte concentration and other properties, such as the presence or absence of the analyte, or the direction or rate of change in analyte concentration, or a bioassay that can be measured in conjunction with or in place of analyte concentration. Although this disclosure generally discusses alcohol as the "analyte" of interest, other analytes including, but not limited to, substances of abuse, alcohol biomarkers, and alcohol byproducts are also intended to be covered by the systems and methods disclosed in this application. The term "alcohol" is used as an example analyte of interest; the term is intended to include ethanol, methanol, ethylene glycol, or any other chemical commonly referred to as alcohol. For the purposes of this application, the term "alcohol byproducts" includes adducts and byproducts of alcohol metabolism by the body, including, but not limited to, acetone, acetaldehyde, and acetic acid. The term "alcohol biomarker" includes, but is not limited to, gamma glutamyltransferase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT), mean corpuscular volume (MCV), carbohydrate-deficient transferrin (CDT), ethyl glucuronide (EtG), ethyl sulfate (EtS), and phosphatidylethanolamine (PEth). The term "substance of abuse" includes, but is not limited to, THC (tetrahydrocannabinol or marijuana), cocaine, M-AMP (methamphetamine), OPI (morphine and heroin), oxycodone, oxycodone, and PCP (phencyclidine). The term "biological assay" refers to an analyte or biological characteristic that can be used to identify or verify the identity of a specific person or subject. This application discloses systems and methods that utilize spectroscopy to address the need for sample analyte measurement, where the term "sample" generally refers to biological tissue. The term "subject" generally refers to the person from whom the sample measurement is obtained.

[0097] The terms "solid-state light source" and / or "semiconductor light source" refer to all light sources based on semiconductors—whether narrow-spectrum (e.g., lasers) or broad-spectrum (e.g., LEDs)—including, but not limited to, light-emitting diodes (LEDs), vertical-cavity surface-emitting lasers (VCSELs), horizontal-cavity surface-emitting lasers (HCSELs), quantum cascade lasers, quantum dot lasers, diode lasers, or other semiconductor diodes or lasers. The term "diode laser" refers to any laser whose active medium is based on a semiconductor, and includes, but is not limited to, double heterostructure lasers, quantum well lasers, quantum cascade lasers, split-confined heterostructure lasers, distributed feedback (DFB) lasers, VCSELs, VECSELs, HCSELs, external-cavity emitting diode lasers, and Fabry-Perot lasers. Furthermore, plasma light sources and organic LEDs, while not strictly semiconductor-based, are contemplated within embodiments of the present invention and are therefore included within the definitions of "solid-state light source" and / or "semiconductor light source" for the purposes of this application.

[0098] For the purposes of this application, the term "dispersive spectrometer" refers to a spectrometer based on any device, component, or group of components that spatially separates one or more wavelengths of light from other wavelengths of light. Examples include, but are not limited to, spectrometers using one or more diffraction gratings, prisms, and / or holographic gratings. For the purposes of this application, the term "interferometry / modulation spectrometer" refers to a class of spectrometers based on the temporal optical modulation of light of different wavelengths to different frequencies, or based on the properties of optical interference to selectively transmit or reflect specific wavelengths of light. Examples include, but are not limited to, Fourier transform interferometers, Sagnac interferometers, analog interferometers, Michelson interferometers, one or more etalons, and / or acousto-optic tunable filters (AOTFs). Those skilled in the art will recognize that spectrometers based on a combination of dispersive and interferometric / modulation properties—such as spectrometers based on layered gratings—are also contemplated for use with the systems and methods disclosed herein.

[0099] This application discloses the use of a "signal" as absorbance or other spectral measurement in some examples. A signal can include any spectral measurement or change in a sample obtained at one or more wavelengths, such as absorbance, reflectance, intensity of returned light, fluorescence, transmittance, Raman spectroscopy, or various combinations of these measurements. Some embodiments utilize one or more "models," where such a model can be anything that relates a signal to a desired characteristic. Some examples of models include those derived from multivariate analysis methods such as partial least squares regression (PLS), linear regression, multiple linear regression (MLR), classical least squares regression (CLS), neural networks, discriminant analysis, principal component analysis (PCA), principal component regression (PCR), discriminant analysis, neural networks, cluster analysis, and K-nearest neighbors. Single-wavelength or multi-wavelength models based on the Beer-Lambert law are special cases of classical least squares and are therefore included in the term multivariate analysis for the purposes of this application. For the purposes of this application, the term "approximately" applies to all numerical values, whether or not expressly indicated. The term "approximately" generally refers to a range of numbers that one skilled in the art would consider equivalent to the stated value (i.e., having the same function or result). In some instances, the term "about" may include numbers rounded to the nearest significant figure.

[0100] Introduction to novel systems and methods

[0101] Spectroscopic measurement systems typically require some means to distinguish and measure light of different wavelengths in order to obtain a spectrum. Some common methods for achieving the desired spectrum include dispersive (e.g., grating and prism-based) spectrometers and interferometric (e.g., Michelson, Sagnac, or other interferometer) spectrometers. Non-invasive measurement systems that incorporate such methods are typically limited by the expensive nature of dispersive and interferometric measurement equipment and their inherent size, fragility, and sensitivity to environmental influences. The present application discloses systems and methods that can provide alternative methods for using solid-state light sources such as light-emitting diodes (LEDs), vertical-cavity surface-emitting lasers (VCSELs), horizontal-cavity surface-emitting lasers (HCSELs), diode lasers, quantum cascade lasers, or other solid-state light sources and using optical detectors such as photodiodes to generate, distinguish, and record the intensity of different wavelengths of light that interact with a sample.

[0102] Referring generally to the various figures, the disclosed system overcomes the challenges posed by the spectral properties of tissue by incorporating a design that, in some embodiments, includes an optimized subsystem. This design addresses the complexity of tissue spectra, high signal-to-noise ratio (SNR) and photometric accuracy requirements, tissue sampling errors, calibration maintenance issues, calibration transfer issues, and many other issues. The subsystems may include an illumination / modulation subsystem, a tissue sampling subsystem, a data acquisition subsystem, a computation subsystem, and a calibration subsystem.

[0103] This paper discloses an apparatus and method for noninvasively determining human tissue properties using quantitative near-infrared spectroscopy. The system includes subsystems optimized to address tissue spectral complexity, high signal-to-noise ratio and photometric accuracy requirements, tissue sampling errors, calibration maintenance issues, and calibration transfer issues. These subsystems include an illumination / modulation subsystem, a tissue sampling subsystem, a data acquisition subsystem, and a computational subsystem.

[0104] This application further discloses apparatus and methods that allow for the implementation and integration of each of these subsystems to maximize the net attribute signal-to-noise ratio. The net attribute signal is the portion of the near-infrared spectrum that is specific to the attribute of interest because it is orthogonal to all other sources of spectral variance. The orthogonal nature of the net attribute signal allows it to be perpendicular to the space defined by any interfering species and, therefore, uncorrelated with these sources of variance. The net attribute signal-to-noise ratio is directly related to the accuracy and precision of non-invasive attribute determination using quantitative near-infrared spectroscopy.

[0105] This application discloses the use of near infrared radiation for analysis. -1Radiation in the 1.0 to 2.5 micron wavenumber range) may be suitable for making some noninvasive measurements because such radiation has acceptable specificity for a number of analytes, including alcohol, and an optical penetration depth of up to several millimeters in tissue with acceptable absorption characteristics. In the spectral range of 1.0 to 2.5 microns, the large number of optically active substances that make up tissue complicates the measurement of any given substance due to the overlapping nature of their absorption spectra. Multivariate analysis techniques can be used to resolve these overlapping spectra so that accurate measurement of the substance of interest can be achieved. However, multivariate analysis techniques may require that the multivariate calibration remain robust over time ("calibration maintenance") and be applicable to multiple instruments ("calibration transfer"). Other wavelength regions, such as visible light and infrared, may also be suitable for use with the disclosed systems and methods.

[0106] This application discloses a multidisciplinary approach to designing spectroscopic instruments that incorporates an understanding of the instrument subsystems, tissue physiology, multivariate analysis, near-infrared spectroscopy, and overall system operation. Furthermore, the interactions between the subsystems have been analyzed, resulting in a good understanding of the behavior and requirements of the entire noninvasive measurement device and leading to the design of a commercial instrument that will perform noninvasive measurements with sufficient accuracy and precision at a commercially viable price and size.

[0107] This application also discloses systems and methods for use with the unique sensing requirements of transportation systems, including but not limited to motorcycles, automobiles, trucks, ships, trains, and aircraft, where the systems must operate across a wide range of temperature, barometric pressure, altitude, humidity, machine orientation, ambient lighting, and environmental composition (e.g., salt, sand, dust, smoke). The disclosed system can operate across the full range of potential users distinguishable by differences in weight, height, age, race, gender, health, fitness level, and other human distinguishing factors. The disclosed system can remain functional throughout the life of the vehicle and maintain diagnostics and telltales indicating required maintenance or replacement of serviceable units. The disclosed system can provide a human-machine interface that provides visual, tactile, and / or auditory feedback to inform system users of correct and incorrect measurements. The system can provide diagnostics and user feedback indicating plausible and implausible measurements, including detection of intentional and unintentional system tampering or measurement fraud. The system can maintain operating modes that can be enabled / disabled based on administrative controls (e.g., passwords). The system may provide one or more communication and / or power interfaces to external transport-enabling or human-machine interface systems using one or more existing or developed communication protocols to receive data and / or power required for system operation, or to enable, disable, or modify the operation of the external system. The system may support capabilities that allow measurement accuracy and precision verification or calibration during manufacturing, installation, and / or servicing via a prosthetic reference device.

[0108] The subsystems of the novel non-invasive system are highly optimized to provide reproducible and preferably uniform irradiation of tissue, low tissue sampling errors, deep targeting of tissue layers containing features of interest, efficient collection of diffuse reflectance spectra from tissue, high optical throughput, high photometric accuracy, large dynamic range, excellent thermal stability, efficient calibration maintenance, efficient calibration transfer, built-in quality control, and ease of use.

[0109] Now refer to Figure 1 A novel non-invasive system 5 is shown in a schematic diagram that is capable of achieving acceptable levels of accuracy and precision in analyte property measurements. For the purposes of discussion, the overall system 5 can be considered to include five subsystems; those skilled in the art will appreciate additional subdivisions of the disclosed functionality. The subsystems include an illumination / modulation subsystem 100, a tissue sampling subsystem 200, a data acquisition subsystem 300, a computation subsystem 400, and a calibration subsystem 500. It will be appreciated that the novel non-invasive system 5 can be embodied in or considered an instrument, and thus, hereinafter, the term "instrument" can be considered to refer to the novel non-invasive system 5 as the context so permits. It will also be appreciated that the novel non-invasive system 5 can be embodied in or considered an apparatus, and thus, hereinafter, the term "apparatus" can be considered to refer to the novel non-invasive system 5 as the context so permits (however, it should be appreciated that the term "apparatus" can also refer to a subsystem or element of the non-invasive system 5 as the context so permits).

[0110] Subsystems can be designed and integrated to achieve a desired net attribute signal-to-noise ratio. The net attribute signal is the portion of the NIR spectrum that is specific to the attribute of interest because it is orthogonal to other sources of spectral variance. Figure 2 It is a graphical representation of the net property signal in a three-dimensional system. The net property signal-to-noise ratio is directly related to the accuracy and precision of non-invasive property determination using quantitative near-infrared spectroscopy.

[0111] The subsystems provide reproducible and preferably spatially uniform radiance of the tissue, low tissue sampling error, depth targeting of the appropriate layer of tissue, efficient collection of diffuse reflectance spectra from the tissue, high optical throughput, high photometric accuracy, large dynamic range, excellent thermal stability, efficient calibration maintenance, efficient calibration transfer, built-in quality control, and ease of use. Each subsystem is discussed in more detail below.

[0112] Lighting / Modulation Subsystem 100

[0113] The illumination / modulation subsystem 100 generates light for interrogating a sample (eg, human skin tissue).

[0114] In classical spectroscopy using dispersive or interferometric spectrometers, the spectrum of a polychromatic light source (or light emitted from a sample of interest) is measured either by spatially dispersing the different wavelengths of light (e.g., using a prism or diffraction grating) or by modulating the different wavelengths of light to different frequencies (e.g., using a Michelson interferometer). In these cases, a spectrometer (a subsystem distinct from the light source) is required to perform the function of spatially or temporally "encoding" the different wavelengths so that each wavelength can be measured essentially independently of the others. While dispersive and interferometric spectrometers are known in the art and can be fully functional in some environments and applications, they can be limited by their cost, size, fragility, signal-to-noise ratio (SNR), and complexity in other applications and environments.

[0115] An advantage of the solid-state light sources incorporated into the disclosed system is that the light sources can be independently intensity modulated. Thus, multiple solid-state light sources emitting light of different wavelengths can be used, each modulated at a different frequency, or modulated together according to a predefined scheme (such as that defined by Hadamard or similar methods). The independently modulated solid-state light sources can be optically combined into a single beam and introduced into the sample. A portion of the light can be collected from the sample and measured by a single photodetector (sometimes also referred to herein as an optical detector). The result is a solid-state light source in the illumination / modulation subsystem that can offer significant benefits in size, cost, energy consumption, and overall system stability by eliminating the spectrometer from the measurement system. Furthermore, because all wavelengths are independently modulated and can be combined into a single beam, a single-element photodetector (rather than a photodetector array) can be used to detect all analyte light. This can represent a significant reduction in system complexity and cost relative to systems and embodiments having multiple photodetector elements.

[0116] Several parameters of a system for measuring analyte properties that incorporates solid-state light sources must be considered, including but not limited to the number of solid-state light sources required to perform the desired measurement, the emission profiles of the solid-state light sources (e.g., spectral width, intensity), the stability and control of the solid-state light sources, and their optical combination. Since each solid-state light source is a discrete component, it can be advantageous to combine the outputs of multiple solid-state light sources into a single beam so that they are uniformly introduced and collected from the sample.

[0117] In addition, the modulation scheme of the solid-state light source must also be considered, as some types of sources may be amenable to sinusoidal modulation of intensity, while other types of sources may be amenable to being turned on or off or square wave modulation. In the case of sinusoidal modulation, multiple solid-state light sources can be modulated at different frequencies based on the electronic design of the system. The light emitted by multiple sources can be optically combined, for example using a light pipe or other homogenizer, introduced and collected from the sample of interest, and then measured by a single optical detector. The resulting signal can be converted into a spectrum of intensity versus wavelength via a Fourier transform or similar transformation.

[0118] Alternatively, some solid-state light sources are switched between on and off states, or subjected to square wave modulation using a Hadamard transform method. However, in some embodiments, rather than a traditional Hadamard mask that blocks or passes different wavelengths at different times during a measurement, a Hadamard scheme can be implemented in electronics because the solid-state light source can be cycled at high frequencies. A Hadamard transform or similar transform can be used to determine a spectrum of intensity versus wavelength. Those skilled in the art will recognize that there are alternatives to the Hadamard encoding method that are equally suitable for use with the present invention.

[0119] In one embodiment, a 47-wavelength Hadamard encoding scheme is used and depicted as a binary matrix. Each row corresponds to a state of the Hadamard scheme, and each column corresponds to a wavelength in the measurement system. For each state, a value of "1" indicates that the wavelength (e.g., a laser diode) is on in that state, while a value of "0" indicates that the wavelength is off in that state. Each measurement of each state corresponds to a scan. Light emitted by the illumination / modulation subsystem 100 is transmitted to the sample by the tissue sampling subsystem 200. A photodetector in the data acquisition subsystem 300 collects, detects, digitizes, and records a portion of the light. The next state in the Hadamard scheme (e.g., a state in which a different set of wavelengths is on) is then measured and recorded. This process continues until all Hadamard states have been measured (referred to herein as a "Hadamard cycle"). Once the Hadamard cycle is complete, the intensity versus wavelength spectrum is determined by calculating the dot product of the recorded intensity versus state data and the matrix inverse of the Hadamard scheme. While the above example of Hadamard encoding includes 47 wavelengths, those skilled in the art will recognize that Hadamard schemes with other numbers of wavelengths are equally suitable for use with the present invention.

[0120] Another advantage of solid-state light sources is that many types (such as laser diodes and VCSELs) emit within a narrow range of wavelengths (which, in part, determines the effective resolution of the measurement). Therefore, there's no need to use optical filters or other methods to shape or narrow the emission profile of solid-state light sources, as they are already sufficiently narrow. This can be advantageous due to reduced system complexity and cost. Furthermore, the emission wavelength of some solid-state light sources (such as diode lasers and VCSELs) is tunable over a range of wavelengths via supplied drive current, drive voltage, or by varying the source's temperature. This approach offers the advantage that if a given measurement requires a specific number of wavelengths, the system can achieve this by tuning fewer discrete solid-state light sources within its feasible range. For example, if a non-invasive property measurement requires twenty wavelengths, ten discrete diode lasers or VCSELs can be used, each tuned to two different wavelengths during the measurement. In this type of approach, Fourier or Hadamard methods can still be used, either by varying the modulation frequency at each tuning point of the solid-state light source or by combining the modulation scheme with a scanning scheme.

[0121] Furthermore, if the emission wavelength of a given laser drifts or changes over time, the tuning properties of a diode laser allow it to be returned to its target emission wavelength by changing its drive current, drive voltage, temperature, or a combination thereof.

[0122] Analyte properties can be measured at a variety of wavelengths spanning the ultraviolet and infrared regions of the electromagnetic spectrum. For in vivo measurements in the skin, such as of alcohol or substances of abuse, the near-infrared (NIR) region from 1000 nm to 2500 nm can be important due to the sensitivity and specificity of the spectral signal for the analyte of interest as well as other chemicals present in human skin, such as water.

[0123] Furthermore, the absorption rate of the analyte is low enough that near-infrared light can penetrate several millimeters into the skin where the analyte of interest resides. The wavelength range of 2000 nm to 2500 nm can be particularly useful because it contains combined bands rather than the weaker, less distinct overtones encountered in the 1000 to 2000 nm portion of the NIR region.

[0124] Besides the commonly available LEDs, VCSELs and diode lasers in the visible region of the spectrum, there are also solid-state light sources available with emission wavelengths throughout the NIR region (1000 to 2500 nm).

[0125] These solid-state light sources are suitable for use with the disclosed analyte and bioassay property measurement systems. Some examples of useful NIR solid-state light sources are The VCSEL produced by Available VCSELs, quantum cascade lasers, and laser diodes, as well as lasers and diodes available from Roithner Laser, Sacher Lasertechnik, NanoPlus, Mitsubishi, Epitex, Dora Texas Corporation, MicrosensorTech, SciTech Instruments, Laser 2000, Redwave Labs, and Deep Red Tech. These examples are included for illustrative purposes and are not intended to limit the types of solid-state light sources suitable for use with the present invention.

[0126] In an embodiment of the illumination / modulation subsystem 100, a microcontroller can be used to control each solid-state light source. The microcontroller can be programmed to include states defined in a Hadamard or other encoding scheme (e.g., turning individual solid-state light sources off and on according to a set of states defined by the scheme). The microcontroller can then cycle through each state with a predetermined measurement time in each state. There is no restriction that the measurement time for each state must be equal. In addition to "off" and "on" control for each solid-state light source, the microcontroller can also provide global (across all solid-state light sources) and individual set points for the solid-state light source temperature, as well as the drive current and drive voltage. Such embodiments enable control of wavelength tuning and / or improve the stability of the illumination / modulation subsystem 100. Those skilled in the art will recognize that alternatives to the microcontroller are available that provide substantially the same functionality as the described microcontroller embodiment.

[0127] Measurement resolution and resolution enhancement

[0128] In a dispersive spectrometer, the effective resolution of a spectral measurement is typically determined by the width of the aperture in the system. The resolution-limiting aperture is typically the width of the entrance slit. At the focal plane where light is detected within the spectrometer, multiple images of the slit are formed, with different wavelengths located at different spatial locations on the focal plane. Therefore, the ability to detect a wavelength independently of its neighboring wavelengths depends on the slit width. A narrower slit width allows for better resolution between wavelengths at the expense of the amount of light that can pass through the spectrometer. Therefore, resolution and signal-to-noise ratio are often traded off.

[0129] Interferometry spectrometers have a similar trade-off between resolution and signal-to-noise ratio. In the case of a Michelson interferometer, the resolution of the spectrum is determined in part by the distance the moving mirror is translated, with longer distances resulting in greater resolution. Consequently, the greater the distance, the longer it takes to complete the scan.

[0130] In the case of the measurement system of the present invention, the spectral resolution is determined by the spectral width of each discrete solid-state light source (whether different solid-state light sources, light sources tuned to multiple wavelengths, or a combination thereof). For measurements of analyte properties requiring high resolution, diode lasers or other suitable solid-state lasers can be used. The width of the laser emission can be very narrow, which translates to high resolution. In measurement applications requiring medium to low resolution, LEDs may be suitable because they generally have a broader emission profile (output intensity distributed over a wider wavelength range) than solid-state laser alternatives.

[0131] The effective resolution of a solid-state light source can be enhanced by using or combining different types of optical filters. The spectral width of a solid-state light source can be narrowed or attenuated using one or more optical filters to achieve higher resolution (e.g., a tighter emission wavelength range). Examples of optical filters contemplated in embodiments of the present invention include, but are not limited to: linear variable filters (LVFs), dielectric stacks, distributed Bragg gratings, photonic crystal lattice filters, polymer films, absorption filters, reflection filters, etalons, dispersive elements such as prisms and gratings, and quantum dot filters.

[0132] Another means for improving the measurement resolution obtained from embodiments of the present invention is deconvolution. Deconvolution and other similar methods can be used to isolate signal differences between two or more wide overlapping solid-state light sources. For example, two solid-state light sources with partially overlapping emission profiles can be incorporated into a measurement system. Measurements can be acquired from the sample and the resulting spectrum (via a Hadamard scheme, Fourier transform, or other suitable transformation). When the emission profile of the solid-state light source is known, the profile can be deconvolved from the spectrum to enhance the resolution of the spectrum.

[0133] Stabilization and control of wavelength and intensity of solid-state light sources

[0134] The peak emission wavelength of solid-state light sources, particularly lasers, can be influenced by changing the thermal state or electrical properties (e.g., drive current or voltage) of the solid-state light source. In the case of semiconductor lasers, changing the thermal state and / or electrical properties alters the optical properties or physical dimensions of the semiconductor lattice structure. The result is a change in the cavity spacing within the device, which changes the peak emission wavelength. Because solid-state light sources exhibit these effects, the stability of the emission peak wavelength and its associated intensity can be important parameters when used in spectroscopic measurement systems. Therefore, controlling both the thermal state and electrical properties of each solid-state light source during measurement can be advantageous in terms of overall system robustness and performance.

[0135] Furthermore, changes in optical properties caused by thermal and electrical conditions can be exploited to allow a single solid-state light source to be tuned to multiple peak wavelengths. This can result in an analyte property measurement system that can measure a greater number of wavelengths than discrete solid-state light sources, which can reduce system cost and complexity.

[0136] Temperature stabilization can be achieved using a variety of methods. In some embodiments, one or more solid-state light sources can be stabilized by raising the temperature above (or cooling it below) ambient conditions without additional temperature control. In other embodiments, a control loop can be used to actively control one or more solid-state light sources to a set temperature (cooling or heating). For example, a temperature loop circuit suitable for use with embodiments of the present invention can include a thermoelectrically cooled (TEC) VCSEL package that includes a thermoelectric cooler and a precision thermistor. The precision thermistor can be connected to a Wheatstone bridge circuit, which can be connected to a current drive circuit configured to drive the thermoelectric cooler.

[0137] The electrical characteristics of a solid-state light source also affect its emission profile (e.g., the wavelength location of the emission). It may be advantageous to stabilize the current and / or voltage supplied to one or more solid-state light sources. For example, the peak emission of a VCSEL and many diode lasers depends on the drive current. For embodiments where peak wavelength stability is important, the stability of the drive current becomes an important figure of merit. In such cases, an electronic circuit can be designed to supply a stable drive current to the VCSEL or diode laser. The complexity and cost of the circuit may depend on the desired drive current stability. Figure 3 A current drive circuit suitable for use with embodiments of the present invention is shown. Figure 4 Another current drive circuit suitable for use with embodiments of the present invention is shown. Those skilled in the art will recognize that alternative embodiments of current control circuits are known in the art and may also be suitable for use with the present invention. In addition, some solid-state light sources require control of the drive voltage rather than the drive current; those skilled in the art will recognize that electronic circuits designed to control voltage rather than current are readily available.

[0138] In some embodiments, a single solid-state light source, such as a VCSEL or diode laser, is tuned to multiple wavelengths during the measurement process. To achieve tuning of the solid-state light source, the Figure 3 The circuit shown in FIG. 1 includes control of the temperature set point and current, respectively. In some embodiments, tuning the temperature or the drive current and drive voltage is sufficient to achieve the desired tuning of the peak emission wavelength. In other embodiments, it may be necessary to control both the temperature and the drive current and drive voltage to achieve the desired tuning range.

[0139] Furthermore, optical devices for measuring and stabilizing the peak emission wavelength can also be incorporated into the systems described in conjunction with embodiments of the present invention. A Fabry-Perot etalon can be used to provide a relative wavelength standard. The etalon's free spectral range and finesse can be specified to provide an optical passband that allows for active measurement and control of the peak wavelength of a VCSEL or diode laser.

[0140] An exemplary embodiment of the etalon uses a thermally stable flat fused silica plate with a partial mirror. For systems requiring multiple wavelengths from each VCSEL or diode laser, the free spectral range of the etalon can be selected so that its transmission peak coincides with the wavelength spacing desired for tuning. Those skilled in the art will recognize that there are many optical configurations and electronic control circuits that are feasible for this application. Alternative wavelength encoding schemes use dispersive gratings and secondary array detectors to encode the VCSEL or diode laser wavelength to a spatial position on the array. For either dispersion-based or etalon-based schemes, secondary optical detectors can be used that have less stringent performance requirements than the primary optical detector. Active control can reduce the stability requirements of the VCSEL temperature and current control circuitry by allowing real-time correction for any drift.

[0141] Embodiments and methods for multi-wavelength illumination / modulation subsystems

[0142] Figure 5 An exemplary embodiment of an illumination / modulation subsystem 100 is shown in which 10 individual solid-state light sources 101 are arranged in a planar array. In some embodiments, the solid-state light sources 101 are individually housed in their own packages such as TO-9, TO-56, or other standard packages. These packages may be sealed or unsealed with a transmission window. In other embodiments, the solid-state light sources 101 may be placed on a common carrier, and the resulting assembly may be placed in an enclosure. The enclosure may be sealed or unsealed. The temperature of each solid-state light source 101 may be independently controlled, with each solid-state light source 101 having its own device for controlling temperature, or a single device for controlling temperature may be used in common.

[0143] The light emitted by the solid-state light source 101 is homogenized by the homogenizer 102 ( Figure 5 ) is collected and homogenized and delivered to the input of the tissue sampling subsystem 200. In some embodiments of the present invention, packing density (how close together individual solid-state light sources 101 can be placed) is disadvantageous and limits the number of solid-state light sources 101 that can be used. In such embodiments, a means for concentrating the light emitted by the solid-state light sources 101 into a smaller area may be advantageous. Means for efficiently concentrating light and coupling it to the tissue sampling subsystem 200 are discussed in the following paragraphs.

[0144] In some embodiments, an alternative to a planar array of individual solid-state light sources is employed. An example of an individual solid-state light source 101 (laser diode) is shown in FIG. Figure 6 1 and includes a semiconductor chip 103 and a laser emitting aperture 104 .

[0145] In another embodiment, the cumulative number of individual solid-state light sources 101 are divided into one or more groups. Figure 7 As seen in the figure, each solid-state light source 101 within one or more groups is mounted on a common carrier 105 (one carrier per group) with a predefined spacing between other solid-state light sources 101. This approach is referred to as a light source "carrier". The carrier 105 can be formed from, for example, ceramic. In this embodiment, the different wavelengths can come from different sources, for example, different wafers cut into laser chips. Multiple laser chips can form the solid-state light source 101. This allows for multiple wavelengths to be accommodated by combining lasers from several sources (wafers, different suppliers, etc.). The advantages of this approach are a smaller number of solid-state light source assemblies and a known relationship of the solid-state light sources' positions relative to each other. This in turn allows for the potential for a reduced number of temperature-controlled packages relative to controlling individual solid-state light sources. Furthermore, because the solid-state light sources within the package are located in fixed and known positions relative to each other, a more efficient light coupling method is enabled.

[0146] In other embodiments, multiple solid-state light sources are located within the same physical semiconductor structure to further reduce the number of components in the illumination / modulation subsystem 100. In such embodiments, the solid-state light sources 101 within a single semiconductor structure can be of the same wavelength, different wavelengths, or a combination thereof. When the solid-state light source 101 is a laser diode or other solid-state laser, these embodiments are referred to as a "laser bar" 106 ( Figure 8 ). Similar to the carrier embodiment, the advantage of the laser bar 106 is the very good characterization and specific location of each solid-state light source 101. Overall, the laser bar 106 leads to a significant reduction in the number of individual semiconductors, the total number of system components, and therefore the subsystem complexity and cost.

[0147] Multiple solid-state light sources 101 of the same wavelength can be used to increase the optical power of that wavelength. In some embodiments, solid-state light sources 101 of the same wavelength are adjacent to each other and in close proximity to allow for efficient optical coupling. Figure 8A laser bar 106 is shown, consisting of 12 groups of two laser diodes (a total of 24 laser emitters). The two lasers forming pairs 107 share a common wavelength, and each pair 107 has a different wavelength than the other pairs (in this embodiment, there are 12 distinct wavelengths on bar 106). Each pair 107 is separated from the adjacent pairs 107 by 480 microns, and the spacing between the two emitters 101 of a pair 107 is 5 microns. In embodiments employing DFB diode lasers, different wavelengths are achieved using a single semiconductor chip by applying gratings with different pitches to each pair 107. The emission of DFB lasers is typically single-mode, which can be advantageous in some embodiments. Those skilled in the art will recognize a wide variety of permutations of the total solid-state light source 101 and its emission wavelengths encompassed by the carrier 105 and bar 106 embodiments. The embodiments disclosed herein are not intended to limit the scope of the invention.

[0148] In some embodiments, the cost and size of a dedicated thermoelectric cooler for each emitter may be prohibitive, and a single global cooler or temperature control may not provide adequate local temperature control. In such cases, localized temperature control within the semiconductor structure can be achieved using localized heating supplies near the solid-state light sources. An embodiment of a heating supply is a localized resistor near the solid-state light source that allows the applied current to be converted into localized heat. This approach allows a single temperature controlled supply to apply most of the heating / cooling load, while the localized temperature controlled supplies allow fine-tuning for each solid-state light source. This allows for a higher degree of stability and the ability to tune the emission wavelength of each laser by varying the local temperature.

[0149] Strategy for efficient coupling of solid-state light source with tissue sampling subsystem 200

[0150] Regardless of whether the solid-state light sources of an embodiment reside in individual packages or are grouped onto a smaller number of carriers or rods, the density of the solid-state light source emission apertures is not ideal because there is always a finite distance between adjacent solid-state light sources. For example, the spacing may be driven by the size of the individual solid-state light source packages and the need to allow for heat dissipation with limited spacing. In some embodiments of the present invention, the density of the emission apertures is not an issue, and a light homogenizer may be used to collect, combine, and homogenize the output of the individual solid-state light sources, the cross-section of the light homogenizer being large enough to encompass all of the solid-state light source emission apertures in the illumination / modulation subsystem 100. However, in this case, the photon flux at the output of the light homogenizer is lower than ideal because the light from the solid-state light source is already substantially evenly distributed across the entire cross-sectional area. This corresponds to a reduction in the system's etendue, which may be disadvantageous in some embodiments. In embodiments where the reduction in etendue should be minimized, there are a variety of strategies for more efficiently combining the outputs of the individual solid-state light source emission apertures. Several embodiments of the present invention incorporate optical fiber 108 ( Figure 8), the optical fiber 108 is a device for collecting light from a solid-state light source 101 or a pair of solid-state light sources 107 and combining it with light collected from other solid-state light sources 101 or a pair of solid-state light sources 107 in the system. Multiple individual optical fibers 108 can be bundled into a cable 109. In one embodiment, Figure 9 , an optical fiber 108 collects light from each of twelve solid-state light sources 101 or pairs of solid-state light sources 107. The twelve optical fibers 108 can be bundled into a cable 109. The diameter of the emission aperture of many solid-state light sources can be on the order of several microns. Some embodiments of the present invention may use large core multimode optical fiber (as opposed to the small core single mode optical fiber often used in telecommunications). The large fiber diameter relative to the small diameter of the emission aperture allows the optical fiber to collect light from the emission aperture with an alignment tolerance of tens of microns in all dimensions. Depending on the spacing of the emission apertures and the size of the optical fibers 108, light from more than one aperture can be collected by a given optical fiber (see Figure 9 ).

[0151] The advantage of this approach is that it allows the output of any number of solid-state light sources to be combined using an equivalent or smaller number of optical fibers. The opposing ends of the optical fibers can then be combined into a bundle. In some embodiments, the bundle is a circular hexagonal bundle. For a given number of optical fibers of a given diameter, this configuration minimizes cross-sectional area and, therefore, maintains maximum photon flux and etendue. Furthermore, optical fibers allow for the fabrication of linear or other geometric arrangements of solid-state light sources (e.g., such as laser bars) while maintaining the ability to combine their output into a small-area aperture, which allows for efficient coupling of the collected light into the tissue sampling subsystem 200. The laser bar assembly can include a laser bar 106, a ceramic carrier 105 with electrical contacts, a fiber coupler (not shown), a copper microstage (not shown), and a thermoelectric cooler (not shown). The assembly can be housed in a hermetic package, such as an industry-standard butterfly package. In some embodiments, a light homogenizer can be placed at the output of the fiber bundle to spatially and / or angularly homogenize the output of the individual fibers. In such embodiments, the cross-sectional area can be matched to the area of ​​the fiber bundle to minimize any reduction in photon flux and etendue. In some embodiments, the fiber arrangement at the output bundle can match the cross-section (eg, square, hexagonal, etc.) of the light homogenizer.

[0152] Fiber coupling methods also allow multiple assemblies with solid-state light source apertures to be combined into a single output aperture. For example, Figure 10 Four laser bars 106 are shown, each having twelve pairs of laser emitters 107 (see Figure 8 Multimode fiber 110 ( Figure 10) is used to collect light from each emitter pair 107 (a total of 48 optical fibers 108). The opposite ends of the 48 optical fibers 108 are then combined into a circular hexagonal output ferrule 111.

[0153] Method and apparatus for homogenizing the output of an illumination / modulation subsystem

[0154] Light homogenizer 112 (such as an optical diffuser, light pipe and other scrambler) Figure 11 ) may be incorporated into some embodiments of the illumination / modulation subsystem 100 to provide reproducible and preferably uniform radiation at the input of the tissue sampling subsystem 200. Figure 11 An example light homogenizer 112 is shown, comprising a ground glass diffuser and a hexagonal cross-section light pipe with two opposing bends. Uniform radiation can ensure good photometric accuracy and even illumination of tissue. Uniform radiation can also reduce errors associated with manufacturing variations between solid-state light sources. In various embodiments of the present invention, uniform radiation can be utilized to achieve accurate and precise measurements. See, for example, U.S. Patent No. 6,684,099, incorporated herein by reference.

[0155] A frosted glass plate is an example of an optical diffuser. The frosted surface of the plate effectively perturbs the angle of radiation emitted from a solid-state light source and its transfer optical device. A light pipe can be used to homogenize the radiation intensity so that it is spatially uniform at the output of the light pipe. In addition, a light pipe with a double bend will perturb the angle of the radiation. In order to create a uniform spatial intensity and angular distribution, the cross-section of the light pipe should not be circular. Square, hexagonal and octagonal cross-sections are effective scrambling geometries. The output of the light pipe can be directly coupled to the input of the tissue sampling subsystem 200, or it can be used in combination with additional transfer optical devices before the light is sent to the tissue sampling subsystem 200. See, for example, U.S. patent application serial number 09 / 832,586, "Illumination Device and Method for Spectroscopic Analysis," which is incorporated herein by reference.

[0156] Tissue sampling subsystem 200

[0157] Figure 1 The tissue sampling subsystem 200 is shown disposed between the illumination / modulation subsystem 100 and the data acquisition subsystem 300. Figure 1 , the tissue sampling subsystem 200 introduces radiation generated by the illumination / modulation subsystem 100 into a sample (e.g., tissue of a subject), collects the portion of the radiation not absorbed by the sample, and sends the radiation to an optical detector in the data acquisition subsystem 300 for measurement.

[0158] Figures 12 to 17 Elements of an exemplary tissue sampling subsystem 200 are depicted.

[0159] refer to Figure 12 The tissue sampling subsystem 200 has an optical input 202, a tissue interface 206 ( Figure 17 ) of the sampling surface 204 and the optical output 207 ( Figure 12 ). The subsystem is further included in Figure 13 The ergonomic device 210 depicted in FIG. 1 holds the sampling surface 204 and positions the tissue at the interface 206. Output 211 sends a signal to processing circuitry, which may be, for example, a microprocessor. In the exemplary subsystem, a device for thermostatting the tissue interface 206 is included. In other embodiments, an index-matching fluid may be used to improve the optical interface between the tissue and the sampling surface.

[0160] Improved interfaces can reduce errors and increase efficiency, thereby improving network attribute signals. See, for example, U.S. Patent Nos. 6,622,032, 6,152,876, 5,823,951, and 5,655,530, each of which is incorporated herein by reference.

[0161] The optical input 202 of the tissue sampling subsystem 200 receives radiation from the illumination / modulation subsystem 100 (e.g., light emitted from a light pipe) and transfers the radiation to the tissue interface 206. As an example, the optical input may include a bundle of optical fibers arranged in a geometric pattern that collects an appropriate amount of light from the illumination / modulation subsystem. Figure 14 An exemplary arrangement is depicted. The plan view depicts the ends of the input and output fibers in the geometry of the sampling surface, comprising six clusters 208 arranged in a circular pattern. Each cluster comprises four central output fibers 212 that collect diffusely reflected light from the tissue. Surrounding each group of four central output fibers 212 is a cylindrical material 215 that ensures approximately 100 nm of space between the edges of the central output fibers 212 and the inner ring of input fibers 214. Clearance. 100 The gap between the dermis and the ethanol can be important for measuring ethanol in the dermis. Figure 14 As shown in FIG, two concentric rings of input optical fibers 214 are arranged around a cylindrical material 215. As shown in one exemplary embodiment, 32 input optical fibers surround four output optical fibers.

[0162] Figure 15An alternative to the cluster geometry of the tissue sampling subsystem 200 is shown. In this embodiment, the illumination and collection fibers are arranged in a linear geometry. Each row can be used for either illumination or light collection and can be any length suitable for achieving a sufficient signal-to-noise ratio (SNR). Furthermore, to vary the physical area covered by the sampling subsystem, the number of rows can be two or more. The total number of potential illumination fibers depends on the physical size of the emission area of ​​the solid-state light source subsystem (e.g., the cross-sectional area of ​​the fiber bundle or light homogenizer of the embodiment) and the area of ​​each fiber. In some embodiments, multiple solid-state light source subsystems can be used to increase the number of illumination fibers. If the number of collection fibers results in an area larger than the photodetector of the data acquisition subsystem 300, a light pipe or other homogenizer followed by an aperture can be used to reduce the size of the output area of ​​the tissue sampling subsystem 200. The purpose of the light pipe or other homogenizer is to ensure that each collection fiber contributes substantially equally to the light passing through the aperture. In some embodiments, the light homogenizer can be omitted, and the aperture can be used on its own. In other embodiments, the active area of ​​the photodetector serves as the aperture (e.g., no distinct aperture is present). In this case, light not incident on the active area is effectively vignetted.

[0163] In some embodiments of the tissue sampling subsystem 200 of the present invention, the portion of the optical probe that interacts with the sample can be composed of a stack of two or more linear fiber optic ribbons. These arrangements allow the size and shape of the optical probe interface to be appropriately designed for the sample and measurement location of interest (e.g., hand, finger). Figure 16 An exemplary embodiment of a tissue sampling subsystem 200 based on a strip-like linear stack is shown. Additional details regarding suitable embodiments for use in the present invention can be found in co-pending U.S. patent applications Ser. Nos. 12 / 185,217 and 12 / 185,224, each of which is incorporated herein by reference.

[0164] In many embodiments of tissue analyte measurement devices, the photodetector is the limiting aperture of the system. In such systems, the system throughput (and correspondingly the signal-to-noise ratio (SNR)) can be optimized by incorporating an optical probe design that illuminates a larger area of ​​the sample (tissue) while collecting light from a smaller aperture that is consistent with the photodetector's solid angle of acceptance.

[0165] refer to Figure 16In the optical probe design, each collection fiber (black circle) is surrounded by eight illumination fibers (white circles). This geometric difference in area allows each of the eight illumination fibers to contribute to the collected light. The net effect of this approach is that it allows more light to be collected from the blackbody source and delivered to the sample without being limited by aperture vignetting. This can be advantageous for light sources that inherently have a large emitting area, such as many blackbody emitters.

[0166] However, the photon flux of semiconductor light sources such as diode lasers can be much higher than that of blackbody light sources. Therefore, a limited number of semiconductor light sources can deliver an equivalent or better photon flux at a smaller solid angle relative to their blackbody counterparts.

[0167] This can result in the solid angle of photon emission (the combined solid angle of all semiconductor light sources) being smaller than the solid angle of reception at the photodetector. In other words, the light source, not the photodetector, is the effective limiting aperture of the system. In this case, Figure 16 Optical probe designs such as the one shown in do not optimize the throughput and SNR of the system. While such optical probes are suitable for use in some embodiments of the present invention, alternative designs may be preferred. In other embodiments, the number of illumination fibers may be less than or equal to the number of collection fibers. These optical probe designs have a sampling surface that allows for a small illumination area consistent with the smaller area emitted by the solid-state light source, and a larger collection area consistent with the larger area of ​​the photodetector. Thus, the overall efficiency of the system is improved.

[0168] The tissue sampling subsystem 200 may also utilize one or more channels, where a channel refers to a specific orientation of the illumination and collection fibers. An orientation is comprised of the angle of the illumination fiber(s), the angle of the collection fiber(s), the numerical aperture of the illumination fiber(s), the numerical aperture of the collection fiber(s), and the separation distance between the illumination fiber(s) and the collection fiber(s). Multiple channels can be used simultaneously or sequentially to improve the accuracy of non-invasive measurements.

[0169] In one embodiment, a dual channel tissue sampling subsystem 200 is used. In this example, both channels are measuring the same tissue structure. Therefore, each channel provides a measurement of the same tissue from a different perspective. The second perspective helps provide additional spectral information that helps decouple signals due to scattering and absorption. Figure 17 , the fiber group (in this example, a source, a receiver #1, and a receiver #2) can be replicated 1 to N times to increase the sampling area and improve the optical efficiency. Each fiber can have a different numerical aperture and angle ( ). The distance between fibers X and Y determines the source-receiver separation. In addition, additional source channels can be added, which creates a 4-channel tissue sampling subsystem 200. Those skilled in the art will recognize the numerous possible variations in the number of channels and the relationship between the channels.

[0170] In experiments using a multichannel sampler for non-invasive glucose measurement, results indicate that the combination of two channels provides better measurement accuracy when compared to either channel alone. While this example uses two channels, additional channels can provide additional information that can further improve the measurement.

[0171] Another aspect of the multi-channel tissue sampling subsystem 200 is the improved ability to detect and mitigate localized interferents such as sweat or lotions present on the sample. Figure 17 is a diagram of the multi-channel tissue sampling subsystem 200 in the presence of local interferents. Figure 17 The sampling subsystem, local interferent layer, and tissue at the tissue interface are shown. In this example, the contribution of local interferents to each channel measurement is the same. This provides the potential to decouple common local interferent signals present in both channels from tissue signals that are different for the two channels.

[0172] Return Reference Figure 12 The clustered input and output fibers are mounted into clustered ferrules, which are mounted into a sampling head 216. The sampling head 216 includes a sampling surface 204 that is polished flat to allow for a good tissue interface. Similarly, the input fibers are clustered into a ferrule 218 connected to the input end for interfacing with the illumination / modulation subsystem 100. The output ends of the output fibers are clustered into a ferrule 220 for interfacing with the data acquisition subsystem 300.

[0173] Alternatively, the optical input may use a combination of light pipes, refractive optics, and / or reflective optics to divert the input light to the tissue interface. It is important that the input optics of the tissue sampling subsystem 200 collect enough light from the illumination / modulation subsystem 100 to achieve an acceptable net attribute signal.

[0174] The sampling head 216 illuminates the tissue in a manner that targets areas of the tissue associated with the property of interest and can discriminate between light that has not traveled a significant distance through those areas of the tissue. The gap can discriminate light that contains little attribute information. In addition, the sampling head 216 can average a region of the tissue to reduce errors due to tissue heterogeneity. The sampling head 216 can reject specular and short-path rays, and it can efficiently collect the portion of light that travels through the tissue with the desired path length to maximize the net attribute signal of the system. The sampling head 216 can use optical fibers to guide light from the input to the tissue in a predetermined geometry as discussed above. The optical fibers can be arranged in a pattern that targets certain layers of the tissue that contain good attribute information.

[0175] The spacing, angles, numerical apertures, and positions of the input and output optical fibers can be arranged to achieve an effective depth target. In addition to using optical fibers, the sampling head 216 can utilize a non-fiber-based arrangement that places a pattern of input and output areas on the tissue surface. Proper masking of the non-fiber-based sampling head 216 ensures that the input light travels a minimum distance in the tissue and contains valid property information. Finally, the sampling head 216 can be thermostated to control the temperature of the tissue in a predetermined manner. The temperature of the sampling head 216 can be set so that prediction errors due to temperature variations are reduced. Furthermore, by setting the temperature of the sampling head 216, reference errors are reduced when constructing a calibration model. These methods are disclosed in U.S. patent application Ser. No. 09 / 343,800, entitled “Method and Apparatus for Non-Invasive Blood Analyte Measurement With Fluid Compartment Equilibration,” which is incorporated herein by reference.

[0176] The tissue sampling subsystem 200 may employ an ergonomic device or guide 210 that positions tissue on the sampling surface 204 in a reproducible manner. Figure 13 An example ergonomic device 210 for reproducibly directing a finger to a sampling surface 204 is depicted in FIG. The ergonomic device 210 includes a base 217 having an opening 219 therethrough. The opening 219 is sized to receive a sampling head 216 ( Figure 12 ) to position the sampling surface 204 approximately coplanar with the upper surface of the base of the ergonomic device 210. Careful attention must be paid to the ergonomics of the tissue interface 206, otherwise significant sampling errors may result. Alternative sites such as the fingertips or the top or palm side of the forearm can also be accommodated using variations of the systems described herein.

[0177] The output of the tissue sampling subsystem 200 diverts the portion of light not absorbed by the tissue that has traveled an acceptable path through the tissue to an optical detector in the data acquisition subsystem 300. The output of the tissue sampling subsystem 200 can use any combination of refractive and / or reflective optics to focus the output light onto the optical detector. In some embodiments, the collected light is homogenized (see U.S. Patent No. 6,684,099, "Apparatus and Methods for Reducing Spectral Complexity in Optical Sampling," incorporated herein by reference) to mitigate spatial and angular effects that may be associated with the sample.

[0178] Data acquisition subsystem 300

[0179] The data acquisition subsystem 300 converts the optical signal from the tissue sampling subsystem 200 into a digital representation. Figure 18 is a schematic representation of data acquisition subsystem 300. Data acquisition subsystem 300 includes an optical detector (photodetector) 302, which receives light returning from tissue interface 206 and converts the light into an electrical signal representing the received light. An advantage of at least one embodiment of the present invention is that, similar to an interferometric spectrometer, only a single-element optical detector (sometimes also referred to herein as a photodetector) is required to measure all desired wavelengths. This reduces system cost. In contrast, array detectors and their supporting electronics are significantly disadvantaged by their expensive nature.

[0180] The optical detector (photodetector) 302 of the data acquisition subsystem 300 converts incident light into an electrical signal as a function of time.

[0181] Examples of optical detectors (photodetectors) sensitive in the 1.0 m to 2.5 m spectral range include InGaAs, InAs, InSb, Ge, PbS, and PbSe. Exemplary embodiments of the present invention utilize a 1 mm, thermoelectrically cooled (TEC), extended range InGaAs optical detector (photodetector) that is sensitive in the 1.0 to 2.5 m spectral range. Light sensitivity within the range of 2.5 The extended range InGaAs optical detector has low Johnson noise and, therefore, allows shot noise limited performance for the photon flux emitted from the tissue sampling subsystem 200. The extended range InGaAs optical detector has a range of 2.0 to 2.5 The spectral region has peak sensitivity between 2.0 and 2.5 There are three very important alcohol absorption features located in the spectral region. Compared with liquid nitrogen-cooled InSb optical detectors, thermoelectrically cooled (TEC), extended-range InGaAs photodetectors may be more practical for commercial products.

[0182] In addition, the extended range InGaAs optical detector is available in 1.0 to 2.5 Exhibits linearity exceeding 120 dBc across the spectral range. If the alcohol measurement system utilizes alternative wavelength regions, alternative optical detectors may be suitable. For example, if the wavelength range of interest is within the 300-1100 nm range, a silicon photodetector may be suitable. Any photodetector can be used as long as it meets the basic sensitivity, noise, and speed requirements.

[0183] The remainder of the data acquisition subsystem 300 amplifies and filters the electrical signal from the optical detector. An analog-to-digital converter (ADC) then converts the resulting analog electrical signal to its digital representation, performs digital filtering, and resamples the digital signal from equal temporal spacing to equal positional spacing. The analog electronics and ADC must support the high signal-to-noise ratio (SNR) and linearity inherent in the signal. To maintain the signal's SNR and linearity, the data acquisition subsystem 300 can support an SNR plus distortion of at least 100 dBc. The data acquisition subsystem 300 can generate a digitized representation of the signal. In some embodiments, a 24-bit delta-sigma ADC can operate at 96 or 192 kHz. In systems where only one signal channel is to be digitized (instead of the more common two signal channels in delta-sigma ADCs), the signal can be passed to both ADC inputs and averaged after digitization. This operation can help reduce any uncorrelated noise introduced by the ADC. If system performance requirements permit, an alternative analog-to-digital converter can be used in which sample acquisition is synchronized with the solid-state light source modulation, rather than capturing samples at equal time intervals. The digitized signal may be passed to computing subsystem 400 for further processing, as discussed below.

[0184] The constant-time sampling technique of data acquisition subsystem 300 offers several distinct advantages over other methods of digitizing signals. These advantages include greater dynamic range, lower noise, reduced spectral artifacts, noise-limited operation of the photodetector, and simpler and less expensive analog electronics. Furthermore, the constant-time sampling technique allows for digital compensation of frequency response distortions introduced by the analog electronics preceding the ADC. This includes nonlinear phase errors in the amplification and filtering circuitry, as well as nonideal frequency responses of the optical detector. The uniformly sampled digital signal allows for the application of one or more digital filters whose cumulative frequency response is the inverse of the transfer function of the analog electronics (see, for example, U.S. Patent No. 7,446,878, incorporated herein by reference).

[0185] Computing subsystem 400

[0186] The computing subsystem 400 performs various functions, such as converting the digitized data obtained from the data acquisition subsystem 300 into intensity-to-wavelength spectra, performing spectral outlier checks on the spectra, preprocessing the spectra to prepare for determining properties of interest, determining properties of interest, checking system status, display and processing requirements associated with the user interface, and data transfer and storage. In some embodiments, the computing subsystem 400 is contained in a dedicated personal computer or laptop computer connected to the other subsystems of the present invention. In other embodiments, the computing subsystem 400 is a dedicated embedded computer.

[0187] After converting the digitized data from the optical detector (photodetector) into an intensity versus wavelength spectrum, the computing subsystem 400 can examine the spectrum for outliers or bad scans. An outlier sample or bad scan is one that violates the assumed relationship between the measured signal and the characteristic of interest. Examples of abnormal conditions include operating the calibration instrument outside of the specified operating range for ambient temperature, ambient humidity, vibration tolerance, component tolerance, power level, etc. Additionally, outliers can occur if the composition or concentration of the sample differs from the composition or concentration range of the samples used to construct the calibration model. The calibration model will be discussed later in this disclosure. Any outliers or bad scans can be deleted, and the remaining good spectra can be averaged together to produce an average single-beam spectrum for the measurement. The intensity spectrum can be converted to absorbance by taking the negative base-10 logarithm (-log 10) of the spectrum. The absorbance spectrum can be scaled to renormalize for noise.

[0188] In conjunction with the calibration model obtained from the calibration subsystem 500, the zoomed absorption spectrum can be used to determine the attribute of interest. After determining the attribute of interest, the computing subsystem 400 can report the result to, for example, the subject, the operator or the administrator, the recording system or the remote monitor. The computing subsystem 400 can also report the confidence level of the result "good". If the confidence level is low, the computing subsystem 400 can retain the result and require the subject to retest. If necessary, the additional information guiding the user to perform corrective actions can be conveyed. See, for example, U.S. Patent Application Publication No. 20040204868, which is incorporated herein by reference. The result can be reported visually on a display, and / or reported by audio and / or in print. Additionally, the result can be stored to form a historical record of the attribute. In other embodiments, the result can be stored and transferred to a remote monitoring or storage facility via the Internet, a telephone line or a mobile phone service.

[0189] The computing subsystem 400 includes a central processing unit (CPU), memory, storage, a display, and preferably a communication link. An example of a CPU is an Intel Pentium microprocessor. Memory can be static random access memory (RAM) and / or dynamic random access memory. Storage can be implemented as non-volatile RAM or a disk drive. Liquid crystal displays, LEDs, or other displays may be suitable. The communication link can, for example, be a high-speed serial link, an Ethernet link, or a wireless communication link. The computer subsystem 400 can, for example, generate property measurements from received and processed interferograms, perform calibration maintenance, perform calibration transfers, run instrument diagnostics, store a history of measured alcohol concentrations and other relevant information, and, in some embodiments, communicate with a remote host to send and receive data and new software updates.

[0190] The computing system 400 may also include a communication link that allows the alcohol measurement record and corresponding spectrum of the subject to be transferred to an external database. In addition, the communication link can be used to download new software to the computer and update the multivariate calibration model. The computer system can be considered an information appliance.

[0191] Examples of information appliances include personal digital assistants, web-enabled cellular phones, and handheld computers.

[0192] Calibration subsystem 500

[0193] A calibration model is used in conjunction with spectral information to obtain alcohol measurements. In some embodiments, the calibration model is developed by acquiring blood reference measurements and contemporaneous spectral data from multiple subjects under a variety of environmental conditions. In these embodiments, spectral data can be acquired from each subject across a range of blood alcohol concentrations. In other embodiments, a hybrid calibration model can be used to measure alcohol concentration from the subject's spectra. In this context, the term hybrid model designates that a partial least squares (PLS) calibration model was developed using a combination of in vitro and in vivo spectral data. The in vitro portion of the data is a 0.1 mm pathlength transmission spectrum of 500 mg / dL alcohol in water, measured using a non-invasive measurement system configured for transmission measurements. The transmission spectrum is proportional to the 0.1 mm pathlength transmission spectrum of water, converted to absorbance, and normalized to unit pathlength and concentration.

[0194] Light propagation through tissue is a complex function of the diffuse optical tissue sampler design, physiological variables, and wavenumber. Therefore, the optical path length of light through tissue has a wavenumber dependence that is not encountered in scatter-free transmission measurements. To account for the wavenumber dependence, a commercial optical ray tracing software package (TracePro) was used to model the interaction of the optical tissue sampler with the scattering properties of human tissue via Monte Carlo simulations. Using the resulting model of photon-tissue interactions, an estimate of the effective optical path length of light through the dermis and subcutaneous tissue layers was generated as a function of wavenumber. The effective optical path length ( ) is defined as

[0195]

[0196] where v is the wave number, is the optical path traveled by the ith ray in the Monte Carlo simulation [mm], N is the total number of rays in the simulation, and a is the (wave number dependent) absorption coefficient [mm -1 Due to its large absorption in vivo, water is the only analyte that significantly affects the effective pathlength. Therefore, for the purposes of the effective pathlength calculation, the absorption coefficient used is that of water at physiological concentrations. The alcohol absorption spectrum (as measured in transmission) is then scaled by the calculated pathlength function to form a corrected alcohol spectrum that represents the wavenumber-dependent pathlength measured by the diffuse reflectance optical sampler. This correction spectrum forms the basis for the mathematical addition of alcohol to the calibration spectrum.

[0197] The in vivo data consisted of noninvasive tissue spectra collected from individuals who had not consumed alcohol. A hybrid model was formed by adding pure alcohol component spectra, weighted by various alcohol "concentrations" ranging from 0 to 160 mg / dL, to the noninvasive tissue spectral data. A PLS calibration model was constructed by regressing the hybrid spectral data on the synthetic alcohol concentrations. Figure 19is a schematic representation of the hybrid calibration formation process.The hybrid calibration in this work used approximately 1500 non-invasive tissue spectra collected from 133 subjects over a three-month period.

[0198] Using a hybrid calibration model, rather than one constructed from spectra acquired from subjects consuming alcohol, can offer significant advantages. The hybrid modeling process makes it possible to generate calibration spectra that contain higher alcohol concentrations (e.g., up to 160 mg / dL) than would be considered safe for consumption in human subject studies (120 mg / dL is considered the upper limit of safety). This can result in a stronger calibration with a wider analyte concentration range that can more accurately predict higher alcohol concentrations. This can be important, as alcohol concentrations observed in the field can be more than twice the maximum safe dose in a clinical research setting. The hybrid calibration process also prevents correlation between alcohol and spectral interferents in tissue. For example, randomly adding an alcohol signal to the calibration spectra prevents alcohol concentration from being correlated with water concentration. Thus, the hybrid approach prevents measurements from falsely tracking changes in tissue water content rather than alcohol concentration.

[0199] It is desirable that a calibration, once established, remain stable and produce accurate property predictions over extended periods of time. This process is known as calibration maintenance and can consist of a variety of approaches, which can be used individually or in combination. The first approach is to create a calibration in a way that inherently makes it robust. Several different types of instrumental and environmental variations can affect the predictive power of a calibration model. It is possible and desirable to reduce the magnitude of the impact of instrumental and environmental variations by incorporating them into the calibration model.

[0200] However, during the calibration period, it is difficult to span the entire range of possible instrument states. System perturbations may cause the instrument to operate outside the space of the calibration model.

[0201] Measurements taken when the instrument is in an inadequately modeled state can exhibit prediction errors. In the case of in vivo optical measurements of medically significant properties, these types of errors can lead to erroneous measurements that degrade the system's effectiveness. Therefore, it is often advantageous to employ additional calibration maintenance techniques during the instrument's lifespan to continually verify and correct the instrument's state.

[0202] Examples of problematic instrument and environmental changes include, but are not limited to, changes in the levels of environmental interferents such as water vapor or CO2 gas, changes in the alignment of instrument optical components, fluctuations in the output power of the instrument illumination / modulation subsystem 100, and changes in the spatial and angular distribution of light output by the instrument illumination / modulation subsystem 100.

[0203] Calibration maintenance techniques are discussed in the following U.S. Patents: U.S. Patent No. 6,983,176, “Optically Similar Reference Samples and Related Methods for Multivariate Calibration Models Used in Optical Spectroscopy”; U.S. Patent No. 7,092,832, “Adaptive Compensation for Measurement Distortions in Spectroscopy”; U.S. Patent No. 7,098,037, “Accommodating Subject and Instrument Variations in Spectroscopic Determinations”; and U.S. Patent No. 7,202,091, “Optically Similar Reference Samples”, each of which is incorporated herein by reference. In some disclosed methods, an environmentally inert non-tissue sample, such as an integrating sphere that may or may not contain properties of interest, is used to monitor the instrument over time. The sample can be incorporated into the optical path of the instrument or interfaced with the tissue sampling subsystem 200 in a manner similar to tissue measurements. The sample can be used in transmission or reflection and can contain a stable spectral signature or not contribute its own spectral signature. The material can be solid, liquid, or gel, as long as its spectrum is stable or predictable over time. Any unexplained changes in the spectrum acquired from the sample over time indicate that the instrument has experienced perturbations or drift due to environmental influences. These spectral changes can then be used to correct subsequent tissue measurements in humans to ensure accurate property measurements.

[0204] Another approach to achieving successful calibration maintenance is to update the calibration using measurements acquired over time on the instrument. Typically, performing such updates requires knowledge of a reference value for the analyte property of interest. However, in some applications, the known reference value is often, but not always, a specific value. In such cases, even if the specific value of the analyte property is unknown for each measurement, this knowledge can be used to update the calibration. For example, in alcohol screening at residential treatment centers, the vast majority of measurements are performed on individuals who adhere to their individual alcohol consumption limits and therefore have an alcohol concentration of zero. In such cases, alcohol concentration measurements or associated spectra obtained from devices disclosed according to various embodiments of the present invention can be used in conjunction with an assumed zero as a reference value. Thus, the calibration can be updated to include new information acquired in the field. This approach can also be used to perform calibration transfer, as assumed zero measurements can be used at system manufacturing or installation time to remove any system-specific bias in the measurement of the analyte property of interest. Calibration maintenance updates or calibration transfers can be implemented through a variety of approaches, such as, but not limited to, orthogonal signal correction (OSV), orthogonal modeling techniques, neural networks, inverse regression methods (PLS, PCR, MLR), direct regression methods (CLS), classification schemes, simple median or moving window, principal component analysis, or a combination thereof.

[0205] Once a calibration is established, it is often desirable to transfer the calibration to all existing and future units. This process is often referred to as calibration transfer. While not required, calibration transfer prevents the need to determine the calibration on every system manufactured. This represents a significant time and cost savings that can make the difference between the success or failure of a commercial product. Calibration transfer stems from the fact that optical and electronic components vary from unit to unit, which, in aggregate, can result in significant differences in the spectra obtained from multiple instruments. For example, two solid-state light sources can have different color temperatures, resulting in different light distributions from the two sources. The responsivity of two optical detectors can also differ significantly, which can result in additional spectral differences.

[0206] Similar to calibration maintenance, several approaches can be used to effectively achieve calibration transfer. The first approach is to construct a calibration using multiple instruments. The presence of multiple instruments allows the spectral changes associated with instrument differences to be determined during the calibration formation process and orthogonalized to the attribute signal. While this approach reduces the net attribute signal, it can be an effective means of calibration transfer.

[0207] Additional calibration transfer methods involve explicitly determining the difference in the system's spectral signature relative to the spectral signature used to construct the calibration. In this case, the spectral difference can then be used to correct the spectral measurements prior to property prediction on the system, or it can be used to directly correct the predicted property values. The instrument-specific spectral signature can be determined based on the relative difference between the spectrum of a stable sample acquired from the system of interest and the spectrum used to construct the calibration. The samples described in the calibration maintenance section are also suitable for calibration transfer; see, for example, U.S. Patent No. 6,441,388, "Method and Apparatus for Spectroscopic Calibration Transfer," which is incorporated herein by reference.

[0208] Alcohol measurement mode

[0209] Depending on the application of interest, two modalities can be considered for the measurement of analyte properties.

[0210] The first modality is "walk-up" or "generic" and represents analyte property determination where no previous measurements of the sample (e.g., subject) are used to determine the analyte property based on the current measurement of interest. In the case of measuring alcohol in the body, driving under the influence would fall into this modality because, in most cases, the person being tested will not have been previously measured on a breathalyzer.

[0211] Therefore, the person's prior knowledge is not available in the current determination of the analyte's characteristics.

[0212] The second modality is referred to as "registered" or "customized" and represents a situation in which a previous measurement from a sample or subject can be used to determine the analyte property of the current measurement. An example of an environment in which this modality can be applied is a vehicle interlock, where a limited number of people are permitted to drive or operate a vehicle or machine. Additional information about embodiments of registration and customized applications can be found in U.S. Patents Nos. 6,157,041 and 6,528,809, entitled "Method and Apparatus for Tailoring Spectroscopic Calibration Models," each of which is incorporated herein by reference. In registered applications, the combination of analyte property measurements with biometric measurements can be particularly advantageous because the same spectral measurement can assess whether the intended operator is authorized to use the device or vehicle via a biometric, while the analyte property can access their health level (e.g., sobriety).

[0213] Method for determining biometric authentication or identification from a spectral signal

[0214] Biometric identification describes the process of identifying a person or other biological entity using one or more physical or behavioral characteristics. There are two common biometric modes: identification and authentication.

[0215] Biometric identification attempts to answer the question “Do I know you?” Biometric measurement devices collect a biometric data set from a target individual. Based solely on this information, they assess whether the individual has previously been registered in a biometric system. Systems that perform biometric identification tasks, such as the FBI's Automated Fingerprint Identification System (AFIS), are typically very expensive (several million dollars or more) and require many minutes to detect a match between an unknown sample and a large database containing hundreds of thousands or millions of entries.

[0216] In biometric authentication, the relevant question is: “Are you who you say you are? This mode is used when an individual claims an identity using a code, magnetic card, or other means, and the device uses biometric data to confirm the person's identity by comparing the target biometric data with the registered data corresponding to the claimed identity. The present apparatus and method for monitoring the presence or concentration of alcohol or substances of abuse in a controlled environment may use the biometric mode.

[0217] There is at least one variation between these two modes, which is also suitable for use in various embodiments of the present invention. This variation arises when the registered database contains a small number of individuals, and the biometric application needs only to determine whether the target individual is in the registered set. In this case, the individual's exact identity is not required, and the task is therefore somewhat different (and generally easier) than the identification task described above. This variation may be useful in applications where the biometric system is used in a method where the individual being measured must be part of an authorized group and awake, but their specific identity is not required. The term "identity feature" includes all of the above modes, variations, and combinations or variants thereof.

[0218] There are three main data elements associated with bioassay measurements: calibration, registration, and target spectral data.

[0219] Calibration data is used to establish spectral signatures important for biometric determination. This dataset consists of a series of spectral tissue measurements collected from one or more individuals of known identity. Preferably, this data is collected over a time period and under a set of conditions such that multiple spectra are collected for each individual, spanning nearly the entire range of physiological states a person is expected to experience. Furthermore, the instrument or instruments used for spectral collection should typically also span the entire range of instrumental and environmental influences that it or its sister instruments are likely to see in actual use. This calibration data is then analyzed to establish spectral wavelengths or "factors" (i.e., linear combinations of wavelengths or spectral shapes) that are sensitive to inter-person spectral differences while minimizing sensitivity to intra-person, instrumental (both intra-instrument and inter-instrument), and environmental influences. These wavelengths or factors are then used to perform the biometric determination task.

[0220] The second major set of spectral data used for biometric determination is enrollment spectral data. The purpose of enrolling spectra for a given subject or individual is to generate a "representation" of that subject's unique spectral signature. Enrollment spectra are collected from individuals who are authorized or otherwise required to be recognized by the biometric system. Each enrollment spectrum can be collected over a period of seconds or minutes. Two or more enrollment measurements can be collected from an individual to ensure similarity between the measurements and to exclude one or more measurements if artifacts are detected. If one or more measurements are discarded, additional enrollment spectra can be collected. Enrollment measurements for a given subject can be averaged together, otherwise combined, or stored separately. In any case, the data is stored in an enrollment database. In some cases, each set of enrollment data is associated with an identifier (e.g., a password or keycode) of the person who measured the spectra. In the case of identification tasks, the identifier can be used for the ongoing purpose of recording who accessed the biometric system at what time. For verification tasks, the identifier is used to extract a reasonable set of enrollment data and perform verification on it.

[0221] The third major set of data used in biometric systems is spectral data collected when a person attempts to identify or authenticate using a biometric system. This data is referred to as the target spectrum. Using classification wavelengths or factors derived from a calibration set, it is compared to measurements stored in an enrollment database (or a subset of the database in the case of identity verification). In the case of biometric identification, the system compares the target spectrum to all enrollment spectra and reports a match if the data from one or more enrollment individuals is sufficiently similar to the target spectrum. If more than one enrollment individual matches the target, all matching individuals may be reported, or the best match may be reported as the identified person. In the case of biometric authentication, the target spectrum is accompanied by a declared identity collected using a magnetic card, a typed username or identifier, a transponder, a signal from another biometric system, or other means. The declared identity is then used to retrieve a corresponding set of spectral data from the enrollment database, a biometric similarity determination is performed against the corresponding set of spectral data, and the identity is either verified or rejected. If the similarity is insufficient, the biometric determination is canceled, and a new target measurement can be attempted.

[0222] In one verification method, principal component analysis is applied to calibration data to generate spectral factors. These factors are then applied to the spectral differences between the target spectrum and the registered spectra to generate Mahalanobis distances and spectral residual magnitudes as similarity measures. The identification is verified only if the distances and magnitudes are less than predetermined thresholds set for each distance and magnitude. Similarly, in an exemplary method for biometric identification, Mahalanobis distances and spectral residual magnitudes are calculated for the target spectrum relative to each database spectrum. The identity of the person providing the test spectrum is established as the person or persons associated with the database measurements that yield the smallest Mahalanobis distance and spectral residual magnitude that are less than predetermined thresholds set for each distance and magnitude.

[0223] In an exemplary method, an identification or verification task is implemented when a person attempts to perform an action for which a limited number of persons are authorized (e.g., performing a spectroscopic measurement, entering a controlled facility, passing through an immigration checkpoint, etc.). The person's spectral data is used to identify or verify the person's identity. In this method, a person is initially registered with the system by collecting one or more representative tissue spectra. If two or more spectra are collected during registration, they are checked for consistency and recorded only if they are sufficiently similar, thereby limiting the possibility of sample artifacts corrupting the registration data. For verification implementations, an identifier such as a PIN number, magnetic card number, username, badge, voice pattern, other biometric, or some other identifier may also be collected and associated with the confirmed registration spectra or spectra.

[0224] In subsequent use, biometric identification can be performed by collecting a spectrum from the person attempting to gain authorization. This spectrum can then be compared to spectra in a registered authorization database, and identification is performed if the match with an authorization database entry is better than a predetermined threshold. The verification task is similar, but in addition to the collected spectrum, the person may also be required to present an identifier. This identifier can then be used to select a specific registered database spectrum, and if the current spectrum is sufficiently similar to the selected registered spectrum, authorization can be granted. If the biometric task is associated with an operation for which only a single person is authorized, the verification and identification tasks are identical, and both are simplified to ensure that a uniquely authorized individual is attempting the operation, without the need for a separate identifier.

[0225] Regardless of the modality, biometric measurements can be performed in a variety of ways, including but not limited to linear discriminant analysis, quadratic discriminant analysis, K-nearest neighbors, neural networks, and other multivariate analysis or classification techniques. Some of these methods rely on establishing the underlying spectral shape (e.g., factors, loading vectors, eigenvectors, latent variables, etc.) in an in vivo calibration database and then using standard outlier methods (e.g., spectral F-ratio, Mahalanobis distance, Euclidean distance, etc.) to determine the consistency of the incoming measurement with the registration database. The underlying spectral shape can be generated by a variety of means, as disclosed herein.

[0226] First, the underlying spectral shape can be generated based on a simple spectral decomposition of the calibration data (e.g., eigenanalysis, Fourier analysis, etc.).

[0227] A second approach to generating the underlying spectral shape involves the development of a general model as described in U.S. Patent No. 6,157,041, entitled "Methods and Apparatus for Tailoring Spectroscopic Calibration Models," which is incorporated herein by reference. In this application, the underlying spectral shape is generated by a calibration procedure performed on spectral features within the human body. The underlying spectral shape can be generated by developing a calibration based on simulated compositional variations. The simulated compositional variations can model variations introduced by real physiological or environmental or instrumental variations, or can simply be artificial spectral variations.

[0228] It should be appreciated that other means of determining the underlying shape will be applicable to the identification and verification methods of the embodiments disclosed herein. These methods can be used in conjunction with the above-mentioned techniques, or in place of the above-mentioned techniques.

[0229] Calibration check samples

[0230] In addition to disposable items that ensure subject safety, disposable calibration check samples can be used to verify that the instrument is in normal working condition. In many commercial applications of alcohol measurement, the status of the instrument must be verified to ensure that subsequent measurements will provide accurate estimates of alcohol concentration or properties. The instrument status is typically checked immediately before the subject is measured. In some embodiments, the calibration check sample may include alcohol. In other embodiments, the check sample may be an environmentally stable and spectrally inert sample, such as an integrating sphere. The check sample may be a gas or liquid that is injected into or flows through the spectral sampling chamber. The check sample may also be a solid, such as a gel, that may contain alcohol. The check sample may be configured to interface with the tissue sampling subsystem 200, or it may be incorporated into another area of ​​the system's optical path. It is intended that these examples are illustrative and not limiting of the various possible calibration check samples.

[0231] Direction of Change (DOC) and Rate of Change (ROC)

[0232] Methods for using spectroscopy to measure the direction and magnitude of changes in the concentration of tissue components, such as alcohol, are considered within the scope of the present invention. The non-invasive measurements obtained from the present invention are inherently semi-time-resolved. This allows properties such as alcohol concentration to be determined as a function of time. The time-resolved alcohol concentration can then be used to determine the rate and direction of change of the alcohol concentration. In addition, the direction of change information can be used to partially compensate for any differences in blood and non-invasive alcohol concentrations caused by physiological dynamics. See U.S. Patent No. 7,016,713, "Determination of Direction and Rate of Change of an Analyte," and U.S. Application No. 20060167349, "Apparatus for Noninvasive Determination of Rate of Change of an Analyte," each of which is incorporated herein by reference. Various techniques have been developed for enhancing rate and direction signals. Some of these techniques include heating elements, red reactants, and index-matching media. The present invention is not limited to a specific form of enhancement or balancing. These and other enhancements are optional aspects of the present invention.

[0233] Subject safety

[0234] Another aspect of non-invasive alcohol measurement is subject safety during the measurement. To prevent measurement contamination or transfer of pathogens between subjects, the use of disposable cleansers and / or protective surfaces to protect each subject and prevent fluid or pathogen transfer between subjects is desirable, but not required. For example, in some embodiments, an isopropyl wipe can be used to clean each subject's sampling site and / or the sampling surfaces of the tissue sampling subsystem before measurement. In other embodiments, a disposable film (such as ACLAR) can be placed between the tissue sampling subsystem 200 and the subject before each measurement to prevent physical contact between the subject and the instrument. In other embodiments, both the cleansing and filming materials can be used simultaneously. As mentioned in the tissue sampling subsystem section of this disclosure, the film can also be attached to a positioning device and then applied to the subject's sampling site. In this embodiment, the positioning device can dock with the tissue sampling subsystem 200 and prevent the subject from moving during the measurement, while the film performs its protective function.

[0235] Local interferents

[0236] The presence of localized interferents at the sampling site is a significant problem in subject measurements. Many localized interferents have spectral signatures in the near infrared region and therefore can cause significant measurement errors when present. Certain embodiments of the present invention address the potential for localized interferents in three ways, which can be used alone or in combination with one another. First, a disposable cleaner similar to that described in the subject safety section can be used. The use of the cleaner can be determined by the system operator or be a mandatory step in the measurement process. Multiple cleaners that are specific to different types of localized interferents can also be used. For example, one cleaner can be used to remove grease and oil, while another cleaner can be used to remove consumer products such as cologne or perfume. The purpose of the cleaner is to remove localized interferents prior to attribute measurement to prevent them from affecting the accuracy of the system.

[0237] A second approach to mitigating the presence of localized interferents is to determine whether one or more interferents are present at the sampling site. The multivariate calibration model used in the calibration subsystem 500 provides inherent outlier metrics that yield important information about the presence of unmodeled interferents (local or otherwise). Therefore, they provide insight into the reliability of the attribute measurement. Figure 20Figure 1 shows example outlier metrics obtained from noninvasive measurements during a clinical study. All large metric values ​​(clearly separated from the majority of points) correspond to measurements intended to grease the subject's sampling site. These metrics do not explicitly identify the cause of the outliers, but they do indicate that the associated attribute measurement is questionable. Inflated outlier metric values ​​(e.g., values ​​exceeding a fixed threshold) can be used to trigger fixed responses, such as repeating the measurement, applying an alternative calibration model, or performing a sampling site cleaning procedure.

[0238] A third approach to mitigating localized interferents involves adjusting a calibration model to include the spectral signature of the localized interferent. Adjusted calibration models can be created on demand or selected from a library of existing calibration models. Each calibration in the library targets mitigating a different interferent or class of interferents, such as oil. In some embodiments, an appropriate calibration model can be selected based on the portion of the acquired spectrum that the original calibration model cannot account for. This portion of the spectrum is referred to as the calibration model residual. Because each localized interferent or class of interferents has a unique near-infrared spectrum, the calibration model residual can be used to identify the localized interferent.

[0239] The model residuals or pure spectra (obtained from a stored library) of the interferent can then be incorporated into the spectra used to form the calibration. The multivariate calibration is then reformulated using the new spectra, allowing the portion of the property signal orthogonal to the interferent to be determined. The new calibration model is then used to measure the property of interest, thereby reducing the effect of local interference on the accuracy of the property measurement. When the interferent is not present, the resulting model will reduce the effect of the interferent on the alcohol measurement at the expense of measurement accuracy. This process is known as calibration immunization. The immunization process is similar to Figure 19 The hybrid calibration formation process is similar to that shown in , but includes the additional step of mathematical addition of the spectral changes of the interferents. It should be noted that due to the effects of the immunity process on measurement accuracy, it may be desirable to identify possible interferents for each measurement and specifically immunize against them, rather than attempting to develop a calibration that is immune to all possible interferents. Additional details can be found in U.S. Patent Application Publication No. 20070142720, “Apparatus and methods for mitigating the effects of oreign interferents on analyte measurements in spectroscopy,” which is incorporated herein by reference.

[0240] Advantages of semiconductor light sources

[0241] Most light sources used in the NIR and IR spectra are blackbody radiators. The light emitted by a blackbody radiator is governed by Planck's law, which states that the intensity of the emitted light is a function of the wavelength and temperature of the blackbody. Figure 21 Shown 100-33000cm -1 (100-0.3 Normalized NIR spectra of blackbody radiators in the range of 1300 and 3000 K, with the 4000-8000 cm-1 range used by the alcohol measurement device. -1 (2.5-1.25 ) range is obscured. 1300 K is a reasonable temperature for ceramic-based blackbody light sources, and 3000 K is a reasonable temperature for quartz tungsten halogen (QTH) lamps often used in spectroscopy applications. Figure 21 It is indicated that the optical efficiency of both blackbody light sources is not ideal, as a significant amount of light is emitted at wavelengths outside the region of interest for measuring alcohol, with the ceramic light source having an optical efficiency of 58% and the QTH lamp only 18%.

[0242] In addition to optical efficiency, blackbody light sources can also have poor electrical efficiency. Practical blackbody light sources require a large amount of electrical energy, not all of which is converted into emitted light.

[0243] Measurements of electrical and optical power of hundreds of ceramic blackbody sources show that at an average electrical power of 24 W (4.4% electrical efficiency), the average optical power is 1.1 W. When combined with an optical efficiency of 58%, the overall efficiency of the ceramic blackbody is approximately 2.5%. In other words, at an electrical power of 24 W, the optical power is 1.1 W at the wavelength of interest, 4000 to 8000 cm 1 Approximately 0.6 W of optical power is emitted in the region. Additional losses are incurred because not all of the light emitted by the light source is collected by the rest of the optical system.

[0244] As indicated by low electrical efficiency, a large portion of the applied electrical energy is converted to heat, which can be detrimental to higher-than-desired power requirements. The heat generated by a blackbody light source can have an impact on the thermal state and stability of the spectroscopic measurement equipment. Therefore, in some cases, the equipment must be powered on and allowed to reach thermal equilibrium before performing measurements. The equilibration time associated with a blackbody light source can range from several minutes to several hours, which can be disadvantageous in some situations.

[0245] Blackbody light sources exhibit aging effects as the material resistance changes. From an optical perspective, there are two significant effects associated with light source aging.

[0246] First, as resistance increases, the amount of emitted light power decreases. In one experiment, measured intensity over time for an exemplary ceramic blackbody light source exhibited a 50% power reduction over 3500 hours. The degradation of intensity over time tends to be exponential in nature and may require the light source to be replaced at regular intervals, which may be disadvantageous in some deployment environments.

[0247] Secondly, the temperature of the light source changes, which alters the distribution of light as a function of wavelength. Depending on the severity of the color temperature change, the stability of the spectral device over time may be affected.

[0248] Solid-state light sources do not fail catastrophically in any similar manner to incandescent lamps and have typical lifetimes ranging from 50,000 to 100,000 hours. Thus, relative to blackbody light sources, solid-state light sources offer the potential for a 10X improvement in light source lifetime and a corresponding reduction in ongoing maintenance requirements.

[0249] Semiconductor light sources, such as diode lasers, can have a small emitting area when compared to their blackbody counterparts. The small emitting area of ​​a semiconductor light source is driven by the size of the semiconductor die itself. Photon emission cannot occur outside the die area because it is generated within the semiconductor structure. The small size (common emitting area is 0.3 mm × 0.3 mm square, or 0.09 mm 2 ) can be advantageous because any heterogeneity within this area is small relative to the output size of the lighting system (which can be several mm depending on the application). 2 or greater) will be insignificant. Therefore, as long as the die (or, if multiple semiconductors are employed, the multiple dies) do not physically move, the spatial output will be very stable. The goal of the subsequent spatial homogenizer is then to distribute the light emitted by the die evenly over the entire area of ​​the illumination system output.

[0250] Another advantage of semiconductor light sources such as diode lasers, VCSELs, and LEDs is the ability to incorporate more than one die into the same physical package. For example, additional solid-state light sources of the same type can be included to increase the optical power at the corresponding wavelength. Such an approach allows for an unprecedented level of control over both the specific wavelengths and the relative intensities emitted by the illumination system. This can be used to emphasize wavelengths that are important for a given analyte of interest (such as alcohol) while reducing output at less important wavelengths. Whether the set of solid-state light sources are all of the same type or a mix, up to hundreds of light sources can be incorporated into the same package while retaining an integrated optical area consistent with use in non-invasive measurements of analytes such as alcohol.

[0251] Another advantage of semiconductor light sources is the ability to select which light sources are active at a given time and to tune their output via voltage or current and temperature. Thus, a single lighting system can be optimized for measuring multiple analytes. For example, when measuring alcohol in tissue, a given set of solid-state light sources can be activated. Similarly, when measuring different analytes, such as cholesterol or glucose, a different set of solid-state light sources can be activated.

[0252] Methods for spatial and angular homogenization

[0253] Light homogenizers, such as optical diffusers, light pipes, and other scramblers, can be incorporated into some embodiments of the illumination / modulation subsystem 100 to provide reproducible and preferably uniform radiation at the input of the tissue sampling subsystem 200. Uniform radiation can ensure good photometric accuracy and uniform illumination of the tissue. Uniform radiation can also reduce errors associated with manufacturing variations between solid-state light sources. Uniform radiation can be utilized to achieve accurate and precise measurements. See, for example, U.S. Patent No. 6,684,099, which is incorporated herein by reference.

[0254] A frosted glass plate is an example of an optical diffuser. The frosted surface of the plate effectively perturbs the angle of radiation emitted from a solid-state light source and its transfer optical device. A light pipe can be used to homogenize the radiation intensity so that it is spatially uniform at the output of the light pipe. In addition, a light pipe with a double bend will perturb the angle of the radiation. In order to create a uniform spatial intensity and angular distribution, the cross-section of the light pipe should not be circular. Square, hexagonal and octagonal cross-sections are effective scrambling geometries. The output of the light pipe can be directly coupled to the input of the tissue sampling subsystem 200, or it can be used in combination with additional transfer optical devices before the light is sent to the tissue sampling subsystem 200. See, for example, U.S. patent application serial number 09 / 832,586, "Illumination Device and Method for Spectroscopic Analysis," which is incorporated herein by reference.

[0255] In an exemplary embodiment, the radiation homogenizer is a light pipe. Light pipes are typically made of metal, glass (amorphous), crystal, polymer, or other similar materials, or any combination thereof. Physically, a light pipe comprises a proximal end, a distal end, and the length therebetween. For this application, the length of a light pipe is measured by drawing a straight line from the proximal to distal ends of the light pipe. Therefore, the same section of a light pipe can have different lengths depending on the shape formed by the section. The length of the section varies depending on the intended application of the light pipe.

[0256] In an exemplary embodiment, the segments form an S-shaped light pipe. The S-shaped bend in the light pipe provides angular homogenization of the light as it passes through the light pipe. However, it is recognized that angular homogenization can be achieved in other ways. Multiple bends, or non-S-shaped bends, can be used. Furthermore, a straight light pipe can be used, provided that the inner surface of the light pipe includes a diffuse reflective coating over at least a portion of its length. The coating provides angular homogenization as the light passes through the pipe. Alternatively, the inner surface of the light pipe can be modified to include dimples or "microstructures," such as micro-optical diffusers or lenses, to achieve angular homogenization. Finally, a frosted glass diffuser can be used to provide some angular homogenization.

[0257] The cross-section of the light pipe can also include various shapes. In particular, the cross-section of the light pipe is preferably polygonal to provide spatial homogenization. Polygonal cross-sections include all polygonal shapes with three or more sides. Certain polygonal cross-sections have been shown to improve spatial homogenization of channel radiation. For example, a light pipe with a hexagonal cross-section provides improved spatial homogenization over its entire length when compared to a light pipe with a cylindrical cross-section of the same length.

[0258] Additionally, the cross-section of the light pipe can vary throughout its length. Thus, the shape and diameter of any cross-section at one point along the length of the light pipe can vary with a second cross-section at a second point along the same section. In some embodiments, the light pipe is a hollow structure between its ends. In these embodiments, at least one lumen or conduit can extend through the length of the light pipe. The lumen of a hollow light pipe typically has reflective features. These reflective features help guide radiation through the length of the light pipe so that it can be emitted at the distal end of the pipe. The inner diameter of the lumen can further have a smooth, diffuse, or textured surface. The surface features of the reflective lumen or conduit help to homogenize the radiation spatially and angularly as it traverses the length of the light pipe.

[0259] In additional embodiments, the light pipe is a solid structure. The solid core may be plated, coated, or clad. Similarly, solid structure light pipes typically provide internal reflections. This internal reflection allows radiation entering the proximal end of the solid light pipe to be guided through the length of the pipe. The guided radiation can then be emitted out the distal end of the pipe without a significant loss of radiation intensity.

[0260] A faceted elliptical reflector is an example of an embodiment of the present invention that produces only a portion of the desired characteristics in the output radiation. In the case of a faceted reflector, spatial homogenization is achieved, but angular homogenization is not. In other cases, such as passing the output of a standard system through ground glass, angular homogenization is achieved, but spatial homogenization is not. In embodiments such as these, where only angular or spatial homogenization is achieved (but not both), some improvement in the performance of the spectroscopic system can be expected. However, the degree of improvement is not expected to be as great as in systems that achieve both spatial and angular homogenization of the radiation.

[0261] Another approach for creating both angular and spatial homogenization is to use an integrating sphere in the illumination system. While integrating spheres are commonly used to detect light, especially from scattered light samples, they have not been used as part of the illumination system when attempting to non-invasively measure analytes. In practice, the radiant output from the emitter can be coupled into the integrating sphere, where it then illuminates the tissue passing through the outlet. The emitter can also be located within the integrating sphere. This will result in exceptional angular and spatial homogenization, but the efficiency of this system is significantly lower than the other previously specified embodiments.

[0262] It is also recognized that other modifications can be made to the disclosed system to achieve the desired light homogenization. For example, a solid-state light source can be placed inside a light pipe in a sealed arrangement, which would eliminate the need for a reflector. Furthermore, the light pipe can be replaced by an integrator, with the source placed inside the integrator. Furthermore, the system can be used in non-infrared applications to achieve similar results in different wavelength regions depending on the type of analysis being performed.

[0263] Description of Exemplary Embodiments

[0264] In an exemplary embodiment of the present invention (in Figure 22 The non-invasive alcohol measurement system consists of 13 diode lasers used to measure 22 discrete wavelengths. Table 1 below shows a list of each diode laser and the associated target peak wavelengths that will be interrogated during the measurement process.

[0265] Table 1

[0266] Light source # Measured wavelength (cm -1 )

[0267]

[0268] In this embodiment, each diode laser is stabilized at a constant temperature. Figure 5The circuitry shown in Figure 2 controls the peak wavelength of each diode laser (each diode laser has its own circuitry), which also enables the diode lasers to be turned on and off. During measurement, the specific state (on / off) of each diode laser at a given time is determined by a predetermined Hadamard or similar encoding matrix. In exemplary embodiments incorporating a solid-state light source, the Hadamard matrix is ​​a pattern of the on / off states of each diode laser versus time, stored in software and implemented in the electronics, rather than a physical mask or chopper that would mechanically modulate the solid-state light source. This allows the on / off states stored in the software to be communicated to the electronic control circuitry of each diode laser during measurement.

[0269] Since several diode lasers in Table 1 are responsible for measuring two wavelengths, implementing a Hadamard scheme that incorporates all wavelengths can be difficult. In this case, a combination of scanning and Hadamard coding can allow measurement of all target wavelengths. In this embodiment, all diode lasers are tuned to their first target wavelength (for those lasers with more than one target wavelength), and a Hadamard coding scheme is used to achieve the associated multiplexing benefits. The diode lasers can then be tuned to their second target wavelength, and the second Hadamard coding scheme is used. Diode lasers with only one target wavelength can be measured in one or two groups, or divided between groups.

[0270] Furthermore, the groups can be staggered in time. For example, for a two-second measurement, the first group can measure the first second, and the second group can measure the second second. Alternatively, the measurements can be performed alternately for two seconds at 0.5 second intervals. The measurement times need not be symmetrical between the groups. For example, it may be desirable to optimize the signal-to-noise ratio by weighting the measurement times of one group or the other. Those skilled in the art will recognize that many permutations of measurement times, the number of balanced groups, the ratio of balanced scans to Hadamards, and interleaving are possible and contemplated in embodiments of the present invention.

[0271] In an exemplary embodiment, the output of each diode laser is combined and homogenized using a hexagonal cross-section light pipe. In some embodiments, the light pipe may contain one or more bends to provide angular homogenization in addition to spatial homogenization.

[0272] Regardless, at the output of the light pipe, the emissions of all diode lasers are preferably spatially and angularly homogenized so that all wavelengths have substantially equal spatial and angular content when introduced into the input of the tissue sampling subsystem 200 .

[0273] The homogenized light is introduced into the input of the sampling head 216. In the exemplary embodiment, the input consists of 225 0.37 NA silica-silica optical fibers (referred to as illumination fibers) arranged in a geometry consistent with the cross-section of the light homogenizer. The light is then transferred to the sampling interface 204. The light exits the sampling interface 204 and enters the sample, where a portion of the light interacts with the sample and is collected by 64 collection fibers. In the exemplary embodiment, the collection fibers are 0.37 NA silica-silica fibers.

[0274] The output of sampling head 216 arranges the collection fibers into a geometry consistent with that of the homogenizer. For the exemplary embodiment, the homogenizer is a hexagonal light pipe. The homogenizer ensures that the content of each collection fiber contributes substantially equally to the measured optical signal. This can be important for samples that can be inherently heterogeneous, such as human tissue. The output of the homogenizer is then focused onto optical detector (photodetector) 302. In the exemplary embodiment, optical detector (photodetector) 302 is an extended-range InGaAs photodiode whose output current varies based on the amount of incident light.

[0275] System 5 then filters and processes the current and converts it into a digital signal using a two-channel delta-sigma ADC. In the exemplary embodiment, the processed analog photodetector signal is divided and directed to two ADC channels. Since the exemplary embodiment involves a VCSEL with two measurement groups (e.g., two target wavelengths), a Hadamard transform is applied to the spectral signal obtained from each group, and the subsequent transforms are combined to form an intensity spectrum. The intensity spectrum is then subjected to a base-10 logarithmic transformation prior to subsequent alcohol concentration determination.

[0276] This exemplary embodiment is suitable for use with "enrollment" or "walk-up / universal" modalities and applications combining alcohol with other analyte characteristics such as substances of abuse. Furthermore, any of the discussed modalities or combinations may be considered independently or in combination with measurements of biometric characteristics.

[0277] In one exemplary use, 3245 alcohol measurements were obtained from 89 people on five non-invasive alcohol systems that measured spectra incorporating 22 wavelengths in a "walk-up" modality. The measurements spanned a wide range of demographic and environmental factors. Figure 23 Near-infrared spectroscopy measurements obtained from the study are shown. Figure 24 Will be from Figure 23 Noninvasive alcohol concentrations obtained by spectroscopic measurements shown in were compared with contemporaneous capillary blood alcohol concentration (BAC).

[0278] Figure 25 Another exemplary embodiment is shown in and uses 39 wavelengths measured using 39 diode lasers. Table 2 shows the diode lasers and their target wavelengths.

[0279] Table 2

[0280] Target wavelength of laser diode

[0281]

[0282]

[0283] The remainder of the system parameters including the tissue sampling subsystem 200, light homogenizer, optical detector (photodetector), and processing are the same as in the earlier aforementioned embodiments. Figure 25 Shown are 8999 spectral measurements obtained from 134 people on 6 non-invasive measurement devices. Figure 26 The results obtained for non-invasive alcohol measurements are shown relative to venous blood alcohol results.

[0284] In some exemplary embodiments, calibration transfer can be performed using a small number of measurements on samples with known analyte characteristics. In the case of non-invasive alcohol measurement, each instrument can perform a small number of measurements on individuals without alcohol present. Any non-zero alcohol result on the instrument is converted into a measurement error, which can be used to correct subsequent measurements on that instrument. The number of measurements used to estimate the correction can vary and generally depends on the accuracy required for the calibration. Overall, the process is similar to an instrument-specific calibration that is consistent with an alcohol device such as a breathalyzer that is individually calibrated.

[0285] A similar approach can be applied to calibration maintenance. In many applications of breathalyzer testing, the majority of measurements are performed on individuals where alcohol is unlikely to be present. For example, in workplace safety where employees are regularly tested for alcohol, it is much more likely that an employee will be unintoxicated than intoxicated (e.g., most people entering the workplace are abstaining from alcohol). In this case, the true alcohol concentration can be assumed to be zero, and the median or other means can be used to exclude infrequent true alcohol events to estimate the instrument's calibration. This can be implemented as a running median filter, a moving window, or a more complex multivariate algorithm to determine the appropriate calibration at a given time.

[0286] Those skilled in the art will recognize that the present invention may be embodied in a variety of forms other than the specific embodiments described and contemplated herein, and therefore, departures may be made in form and detail without departing from the scope and spirit of the present invention.

[0287] System calibration in progress

[0288] In order to maintain maximum accuracy and precision over operating conditions and time, it is desirable to have information about the state of the alcohol measurement device (e.g., the optical and electronic components that contribute to the measurement) just before the tissue measurement. This is called a "calibration measurement." Although current and temperature-related controls are used for certain sensitive components of the system, there are a large number of mechanical and optical error contributors that may change over time and temperature. In addition, even if controls are in place, there may be errors associated with the operation of the electrical components, as well as factors related to surface treatment and possible light contamination from the sampling head 216, which also need to be considered. Therefore, it is desirable to measure the complete optical and electrical state of the device against a known standard sample just before measuring the tissue sample of interest. The measurement of the known standard sample then allows subsequent (or previous) tissue measurements to be corrected for the current state of the alcohol measurement device.

[0289] To obtain a calibration measurement, light from the illumination / modulation subsystem 100 is transmitted by the tissue sampling subsystem 200 to a known standard sample, where it interacts with the known standard sample. A portion of the light is collected by the tissue sampling subsystem 200 and coupled to a photodetector 302 in the data acquisition subsystem 300. One way to achieve this is to use an optical fiber that is different from the sampling surface (e.g., the surface measuring the skin tissue). In this case, the light transmitted to the known standard sample will travel a different optical path than the light interrogating the skin. In some embodiments, this difference in optical path may be acceptable. Furthermore, in other embodiments, the optical fiber itself can serve as the known standard sample (e.g., the optical fiber collects light from the illumination / modulation subsystem 100 and transmits it directly to the photodetector 302 in the data acquisition subsystem 300). In some embodiments of these methods, a gating mechanism can be implemented that selects which optical path the photodetector is measuring at a given time (the path to the skin sampling surface or the path to the calibration sample). While these methods are acceptable in some embodiments, they are not optimal in that they measure an optical path different from the optical path of the actual sampling head 216.

[0290] Therefore, in order to maintain substantially the same optical path length for the light interrogating the skin tissue and the calibration standard, a method is needed to place a removable calibration standard with known characteristics at the tissue interface 206 of the tissue sampling subsystem 200. The calibration sample can be measured shortly before the tissue measurement and then removed for the actual measurement. Although the calibration sample can be manually inserted into the path, in some embodiments, an automated method for insertion and removal is preferred.

[0291] It should be noted that one skilled in the art can devise any number of electromechanical or mechanical mechanisms to achieve this purpose.

[0292] In a first embodiment, the removable cover is coated with a suitable reflective calibration standard material on the proximal side and slides relative to the sampling head 216, thereby allowing the sampling head 216 to interrogate (i) the calibration standard material on the proximal side of the removable cover, or (ii) the surface of a finger.

[0293] In a second embodiment, the sliding button serves as a guide for a semi-flexible tape coated with a suitable reflective calibration standard surface.

[0294] Movement of the slide button allows the tape to be inserted between the sampling head 216 and the sample, or to be retracted from between the sampling head 216 and the sample. As a result, the sampling head 216 can interrogate (i) a calibration standard material on the proximal side of the tape, or (ii) the surface of a finger.

[0295] It should be further noted that the embodiments can be enhanced with styling features and finger guides to help facilitate placement without changing the basic concept, and that the mechanism and additional styling features will work equally well whether presenting the dorsal side of the finger, the Palmer side of the finger, or other skin surfaces.

[0296] refer to Figure 28 , Figure 1 The system described herein can be incorporated into the starting system of any transportation vehicle (including all forms of land, water, and air travel). For example, the system can be incorporated as an electromechanical component of an ignition system that includes a start button, key turn, or other typical use of driver-generated power to prepare the transportation vehicle for travel.

[0297] Such a system can be used to measure the presence or concentration of an analyte or biometric marker in a person attempting to start a transportation vehicle, where the measured information is used to alter the vehicle's subsequent electromechanical response. For example, the biometric marker can be used to identify a specific driver (from a pool of possible drivers) and modify the position or orientation of the driver's seat (and therefore the driver's position or orientation) and / or control settings such as infotainment settings or vehicle actuator settings. In another example, Figure 27 As illustrated in FIG, the system can be used to measure the concentration of an analyte to enable or disable the ability to start a transportation vehicle and / or initiate an alternative action. For example, an alcohol measurement in a vehicle driver above a legal threshold may restrict the ability to start a transportation vehicle and also trigger the telematics system to provide an automated call to an alternative mode of transportation, including a designated driver and / or a taxi.

[0298] In another embodiment, the system can be integrated into a transport vehicle control system that is in continuous or near-continuous contact with the operator, such as a steering wheel, handlebars, or yoke. As such, the system can continuously or periodically, or triggered by other control logic, take analyte and / or bioassay measurements that can be used to influence subsequent transport vehicle operation or trigger alternative actions.

[0299] In another embodiment, the system can be integrated into a transportation vehicle or facility entry system (e.g., door entry, trunk entry, etc.) and thereby perform analyte and / or bioassay measurements that are used to influence entry and / or subsequent levels of control after entry.

[0300] In another embodiment, the system can be incorporated into other transport vehicle subsystems in which direct contact between the operator's skin and the tissue sampling subsystem 200 is maintained temporarily, periodically, or continuously. Slightly modified embodiments in which semi-passive contact is maintained, as well as embodiments in which contact is made by an operator-initiated action, are also possible. In such cases, continuous or periodic analyte and / or bioassay measurements can be made that affect subsequent transport vehicle operations or trigger alternative actions.

[0301] exist Figure 28 In the case of the system described in the foregoing, the human-machine interaction between the operator and the tissue sampling subsystem 200 can be configured to inform the intended operator of the system's presence and the intended body part and / or location that must be coupled to the tissue sampling subsystem 200 to trigger a measurement. For example, the use of audible sound and / or voice and / or lighting and / or tactile feedback can be used to educate the operator, provide positive / negative feedback regarding the correct measurement procedure, and / or provide measurement results.

[0302] In an exemplary embodiment of the present invention (in Figure 29a and Figure 29b ), showing a different Figure 22 Another novel system depicted in FIG, which couples discrete solid-state light sources of varying wavelengths directly into a homogenizer composed of a material that minimizes losses at all supported wavelengths, thereby reducing the need for a coupling mechanism between the solid-state light sources and the homogenizer, as well as the tissue sensing subsystem 200. In this embodiment, the homogenizer material, size, shape, and coating can be controlled to optimize light transmission and minimize losses while directly providing the emitter of the tissue sampling subsystem 200.

[0303] Figure 7 A system using multiple different transmitters is depicted. In an alternative embodiment (in Figure 30As depicted in Figure 2, a single emitter can be created using several grating regions with different current paths that, when driven in combination, produce different wavelengths. By varying which grating combinations are driven, different wavelengths can be achieved in the time-domain signal. In this way, multiple wavelengths can be sampled in a predetermined pattern in time. Knowledge of the sampling sequence in the optical detector and processor can be used to obtain the spectral measurements described in subsequent examples.

[0304] In another embodiment, the system further includes one or more atmospheric, temperature, and relative humidity sensors, wherein measurements derived from these sensors may be used by the computing subsystem 400 to correct and / or improve analyte and / or bioassay measurements to correct for variations in the human body due to these environmental influences, and / or variations in individual subsystems due to extended systems (e.g., where the tissue measurement subsystem 200 is spatially or thermally distinct from the illumination / modulation subsystem 100; or where the system emitters and detectors are temperature compensated to a fixed value (independent of ambient conditions), but the optical fiber, homogenizer, and coupler require temperature compensation based on ambient conditions).

[0305] In the case of making some analyte measurements where the probability of the analyte being present in the pool of potential operators is low, it may be advantageous to make a faster and simpler measurement to first determine whether any analyte is evident, and only if so detected, and then make a subsequent measurement of the analyte concentration. Figure 31 For example, in the case of alcohol as the analyte, most expected vehicle operators will not have alcohol present in their system when attempting to start the vehicle. Presence measurement can be used to reduce the average measurement time.

[0306] In many safety applications, at least two dissimilar technology sensors must detect a signal before a decision is made to actuate a countermeasure. This greatly reduces the tendency for false positives due to undetected single sensor failures or errors. In similar scenarios, Figure 32 The systems described herein may be coupled to include one or more independent sensors to indicate the presence or concentration of an analyte and / or to confirm a bioassay measurement.

[0307] Figure 22 The system in describes a system utilizing a discrete wavelength solid-state light source; another embodiment (in Figure 33 The system (depicted in FIG) comprises a system that utilizes a single broad-spectrum blackbody source coupled to a discrete wavelength filter that passes only the intended wavelength. The subsequent processing steps remain the same as those previously indicated; however, undesirable system noise is avoided during detection and discrimination.

[0308] For the previously described system embodiments utilizing diode lasers, the rise and fall characteristics of those devices can be varied in a deterministic manner based on the driver and compensation circuitry, as well as based on the ambient temperature and electromechanical characteristics of the devices themselves (e.g., laser grating structure, material, size, shape, and heating / cooling components). Figure 34 As shown in Figure 2, waiting until the solid-state light source intensity has settled to a desired level (T2) can reduce the modulation time. To improve the modulation rate that can be used to multiplex light of different wavelengths, the a priori rise / fall characteristics can be compensated in the detector logic, thereby shortening the settling time (Tl).

[0309] It is to be understood that both the foregoing general description and detailed description are exemplary and explanatory only and are not restrictive of the invention.

[0310] For the purposes of this disclosure, the term "coupled" refers to the connection of two electrical or mechanical components directly or indirectly to one another. Such a connection may be static in nature or dynamic in nature. Such a connection may be achieved by the two components (electrical or mechanical) and any additional intermediate components being integrally formed as a single unit with one another, or by the two components or the two components and any additional components being attached to one another. Such a connection may be permanent in nature or, alternatively, removable or releasable in nature.

[0311] The structure and arrangement of the diffuser as shown in the preferred and other exemplary embodiments are illustrative only. Although only a few embodiments of the present system are described in detail in this disclosure, those skilled in the art who review this disclosure will readily appreciate that many modifications are possible (e.g., changes in the size, dimensions, structure, shape and proportions of the various elements, parameter values, mounting arrangements, material use, orientation, etc.) without materially departing from the novel teachings and advantages of the subject matter described in this disclosure. Therefore, all such modifications that are achievable by those skilled in the art from this disclosure are intended to be included as additional embodiments of the present invention within the scope and spirit of the present invention. The order or sequence of any process or method steps may be changed or reordered according to alternative embodiments. Other substitutions, modifications, changes, and omissions may be made in the design, operating conditions, and arrangement of the preferred and other exemplary embodiments without departing from the spirit of the present application.

[0312] New tissue interface device

[0313] In the foregoing description, a novel system 5 for non-invasive measurement of an analyte in a vehicle driver is disclosed, wherein the system comprises:

[0314] (i) an illumination / modulation subsystem 100 for generating a plurality of monochromatic light beams, wherein the plurality of monochromatic light beams constitute a plurality of different wavelengths;

[0315] (ii) a tissue sampling subsystem 200 for receiving a plurality of monochromatic light beams (from the illumination / modulation subsystem 100) and delivering those monochromatic light beams to the vehicle driver's tissue, and for receiving a return light beam (sometimes referred to herein as "scattered light") back (from the vehicle driver's tissue), wherein the return light beam is a modification of the monochromatic light beam delivered to the vehicle driver's tissue; and

[0316] (iii) A data acquisition subsystem 300 for receiving return light beams (from the tissue sampling subsystem 200) and converting those return light beams into corresponding electrical signals for subsequent processing and analyte evaluation.

[0317] As previously described, tissue sampling subsystem 200 includes an optical input 202 comprising multiple optical fibers, an optical output 207 comprising multiple optical fibers, and a sampling surface 204 (carried by sampling head 216) comprising the output ends of the optical input fibers and the input ends of the optical output fibers. Multiple lasers tuned to different wavelengths transmit monochromatic light beams to the optical fibers of optical input 202, and the optical fibers of optical output 207 transmit return light beams (i.e., "scattered light") to optical detectors (photodetectors) 302 (e.g., one or more photodiodes) provided in data acquisition subsystem 300, where corresponding electrical signals are generated. These electrical signals are then processed for analyte assessment.

[0318] As will be discussed below, in another form of the invention, the invention comprises a novel tissue interface device that combines the functionality of the tissue sampling subsystem 200 and the data acquisition subsystem 300 in a single unit that is disposed adjacent a tissue surface.

[0319] Notably, the new tissue interface device is not limited to use in the non-invasive measurement of analytes in vehicle drivers, but may also be used in other analyte detection systems, as will be apparent to those skilled in the art in view of this disclosure.

[0320] The goal of new tissue interface devices

[0321] The novel tissue interface device is designed to facilitate rapid and reliable interfacing for spectroscopic analysis of tissues, liquids, gels and composite materials placed on, or dense gases directed to, the detector surface of the novel tissue interface device.

[0322] Uses of the novel tissue interface device include, but are not limited to, detecting blood alcohol by measurement on a human fingertip.

[0323] The specific use of the new tissue interface device will determine the details of the light sources (e.g., their wavelengths) and spectroscopic devices connected to the new tissue interface device. The target analyte being analyzed will also determine the details of the light sources (e.g., their wavelengths) and spectroscopic devices connected to the tissue interface device. In other words, and as will be appreciated by those skilled in the art, the specific light sources connected to the new tissue interface device and the specific configuration of the spectroscopic devices connected to the new tissue interface device will vary depending on the target analyte being evaluated.

[0324] Disadvantages of the method used in the tissue sampling subsystem 200 described above

[0325] The tissue sampling subsystem 200 described above utilizes a combination of two fiber optic systems, the first of which directs monochromatic light (generated by an array of laser sources) to the tissue, and the second of which collects scattered light from the tissue and directs it to an optical detector (photodetector), such as one or more photodiodes, where the collected scattered light is converted into a corresponding electrical signal and then processed for analyte evaluation. This approach suffers from several drawbacks.

[0326] First, the sampling surface 204 of the tissue sampling subsystem 200 is a relatively large and bulky object, and it is unclear whether the approach can be scaled to a device of a size and with material and production costs that would be commercially acceptable for certain applications.

[0327] Another disadvantage of the method used in the above-described tissue sampling subsystem 200 stems from high optical losses due to (1) the manner in which the reference intensity (i.e., the reference signal) is measured and (2) the inefficient manner in which scattered light (emitted from the tissue) is collected using optical fibers. The use of optical fibers is not only inefficient for light collection, it also creates a significant cost factor and is a source of additive noise.

[0328] A further disadvantage of the approach used in the above-described tissue sampling subsystem 200 is the very inefficient way in which the reference signal is generated and utilized.

[0329] Description of the new tissue interface device

[0330] The new tissue interface device is a highly integrated device, resulting in a much smaller design than the tissue sampling subsystem 200 described above and limiting the use of expensive optical fibers. Furthermore, the new tissue interface device generates data and reference signals in a straightforward and efficient manner. The entire design results in a size of only a few cubic centimeters.

[0331] More particularly, according to the present invention, and now looking at Figures 35-40A novel tissue interface device 600 is provided. Tissue interface device 600 comprises a monolithic, semiconductor-based sensor comprising four concentrically positioned annular photosensors 605, 610, 615, and 620 mounted on a transparent substrate 625 surrounding a low-absorption injection region 630. Together, they serve as an interface for performing measurements on a human fingertip or surrogate object. As discussed below, the four concentrically positioned annular photosensors 605, 610, 615, and 620 preferably comprise photodiodes that generate electrical signals corresponding to the light received by those photodiodes. A protective cover (e.g., a sapphire glass element) 632, combined with a diffuser plate 640 (see below), preferably covers the front of transparent substrate 625 (and, therefore, the four concentrically positioned annular photosensors 605, 610, 615, and 620). The geometry of the four concentrically positioned annular photosensors 605, 610, 615, and 620 can be adapted to the specific geometry of the target (as discussed below).

[0332] Monochromatic light at different frequencies is coupled into the waveguide 642 ( Figure 40 ), the monochromatic light can be generated by multiple fixed wavelength lasers or by one or more tunable lasers or different light sources. The waveguide 642 is designed to guide the monochromatic laser light to the low absorption rate injection zone 630 of the tissue interface device 600 without loss. The diffuser plate 640 is arranged in front of the low absorption rate injection zone 630 so that part of the incident light (guided into the low absorption rate injection zone 630 by the waveguide 642) is guided into the finger of the vehicle driver, and part of the incident light (guided into the low absorption rate injection zone 630) is directly scattered to the innermost photosensor ring 605, thereby generating a corresponding electrical signal used as a reference signal. By providing a coating 645 ( Figure 38 ), the innermost photosensor ring 605 is preferably shielded to prevent scattered light returning from the fingertips. Preferably, the periphery of the diffuser plate 640 is also coated with a coating 650 to prevent light from radially emerging from the diffuser plate 640. In a preferred form of the present invention, the diffuser plate 640 is mounted in a central opening 655 ( Figure 37). Scattered light returning from the fingertip is collected by three outer photosensor rings 610, 615, and 620 and converted into corresponding electrical signals, which are then unloaded from tissue interface device 600 for subsequent processing for analyte assessment. The scattered light collected by each of the three outer photosensors 610, 615, and 620 takes a different path through the tissue, so the measurements taken by the three outer photosensor rings 610, 615, and 620 provide data points for the spectrum measured at different paths through the tissue. Because this generates data at different effective depths in the sample, it provides additional relative intensity information. This relative intensity information can render the reference signal provided by central photosensor ring 605 unnecessary in certain applications. In such cases, the optimized design described below can be used.

[0333] The tissue interface device 600 preferably has a diameter of approximately six millimeters, and the entire tissue interface device can be miniaturized to occupy only a few cubic centimeters, including a laser (not shown), a waveguide 642 and the above-mentioned tissue interface components, such as the transparent substrate 625, the concentrically positioned annular photosensors (e.g., photodiodes) 605, 610, 615 and 620, the low absorption rate injection region 630, the diffuser plate 640, etc.

[0334] In a preferred form of the invention, the tissue interface device 600 is configured to be mounted to the ergonomic device 210, for example, such that the protective cover 632 is received in the opening 219 of the ergonomic device 210, so that when the user's finger is seated in the base 217 of the ergonomic device 210, the tissue interface device 600 can transmit multiple monochromatic light beams to the user's finger and receive backscattered light from the user's finger.

[0335] It will be appreciated that appropriate electrical contacts are provided to the four concentrically positioned annular photosensors (e.g., photodiodes) 605, 610, 615, and 620 so that the electrical output of these photosensors can be communicated to the computing subsystem 400. Thus, in one preferred form of the invention, the tissue interface device 600 comprises a transparent substrate 625 comprising a low-absorption injection region 630 surrounded by four concentric photosensor rings 605, 610, 615, and 620. These four concentric photosensor rings 605, 610, 615, and 620 convert received light into corresponding electrical signals. In one preferred form of the invention, the photosensor rings 506, 610, 615, and 620 comprise photodiodes. A diffuser plate 640 is disposed within an opening 655 formed in a protective cover 632, which covers the front of the semiconductor structure, such that the diffuser plate 640 covers the low-absorption injection region 630 and the innermost concentric photosensor ring 605, and the protective cover 632 covers the three outer concentric photosensor rings 610, 615, and 620 (as well as the remainder of the semiconductor device). A coating 645 is disposed on the front of the diffuser plate 640 to prevent scattered light returning from the tissue from reaching the innermost concentric photosensor ring 605 (which provides the reference signal), and a coating 650 is disposed around the periphery of the diffuser plate 640 to prevent light from escaping the periphery of the diffuser plate 640. It will be appreciated that appropriate electrical contacts are provided to the four concentrically positioned photosensors (e.g., photodiodes) 605, 610, 615, and 620 so that their electrical outputs can be communicated to the computing subsystem 400.

[0336] In use, monochromatic laser light at different frequencies is injected into waveguide 642, passes through low-absorption injection region 630, passes through diffuser plate 640, and enters the tissue of the vehicle driver. The monochromatic light also passes from diffuser plate 640 into the innermost concentric photosensor ring 605 to provide a reference signal. Scattered light returning from the vehicle driver's tissue is received by three outer concentric photosensor (e.g., photodiode) rings 610, 615, and 620 to provide data signals. Note that the scattered light received by the three outer concentric photosensor (e.g., photodiode) rings 610, 615, and 620 travels through different paths through the tissue, generating data at different effective depths to provide additional relative intensity information. The electrical signals provided by the four annular photosensors (e.g., photodiodes) 605, 610, 615, and 620 are then processed for analyte assessment, with the innermost photosensor ring 605 providing the reference and the three outer photosensor rings 610, 615, and 620 providing the data signals.

[0337] Importantly, by forming the signal-acquisition photosensors (e.g., photodiodes) into three outer photosensor rings 610, 615, and 620, the signal-acquisition photosensors (e.g., photodiodes) include successively larger surface areas as their distance from the low-absorption injection region 630 increases. Thus, for example, the outermost photosensor ring 620, which acquires reflected light with the greatest light loss due to its extended path through the tissue, has the largest surface area to collect additional scattered light.

[0338] And importantly, because waveguide 642 (carrying multiple monochromatic beams on multiple optical fibers) generally injects different monochromatic beams at different locations in low-absorption injection region 630 (i.e., due to the spatial distribution of the multiple optical fibers), each signal acquisition photosensor (e.g., photodiode) forming the ring balances out variations in the injection point of a particular monochromatic beam, e.g., if the injection point is farther away from one side of a given photosensor ring, it is automatically closer to the other side of the same photosensor ring.

[0339] Alternative Constructions of New Tissue Interface Devices

[0340] As noted above, in some cases, the relative intensity information obtained by the three outer photosensor rings 610, 615, and 620 may already contain sufficient information for a given spectroscopic application, such as detecting blood alcohol levels in a human finger, since these generate data at different effective depths in the tissue. If this is the case, the design can be optimized and the diffuser plate 640 can also be omitted, with the innermost concentric photosensor ring 605 being reused to provide additional data points, resulting in even higher collection efficiency and a potentially smaller design.

[0341] A second possibility for optimization is to adapt the geometry of the photodetector rings 605, 610, 615, and 620 to the geometry of a specific target. Ideally, the photosensor (e.g., photodiode) rings 605, 610, 615, and 620 are designed as concentric circles, which is preferred due to symmetry (which helps provide the advantages discussed above). This symmetry ensures that all parts of the ring receive scattered light from the same depth. However, this symmetry advantage can be compensated by using an elliptical ring geometry, which can better adapt to the geometry of a specific target, such as the shape of the impression of a human fingertip when placed on a tissue interface device. The elliptical ring photosensor (e.g., photodiode) can then be split into several (four or more) parts, so that each part receives scattered light from a well-defined depth.

[0342] Furthermore, if desired, the reference photodetector ring need not be the innermost photodetector ring 605. More specifically, it may be convenient to use the innermost photodetector ring 605 as the reference photodetector ring because it is relatively straightforward to pass light from the low-absorption injection region 630 to the innermost photodetector ring 605 (i.e., by using the diffuser plate 640) in order to provide a known light signal to the reference photodetector ring. However, if desired, another photodetector ring (e.g., photodetector ring 610, or photodetector ring 615, or photodetector ring 620) may be used as the reference photodetector ring, so long as an optical path is provided between the diffuser plate 640 and the photodetector ring (e.g., photodetector ring 610, or photodetector ring 615, or photodetector ring 620) that will serve as the reference photodetector ring, thereby providing a known light signal to the reference photodetector ring. In this case, the coating 645 ( Figure 38 ) would be positioned differently on tissue interface device 600, i.e., coating 645 would not be positioned on diffuser plate 640 so as to cover innermost photodetector ring 605 (which no longer serves as a reference photodetector ring), and would instead be positioned on a photodetector ring serving as a reference photodetector ring (e.g., photodetector ring 610, photodetector ring 615, or photodetector ring 620), thereby preventing light returning from the tissue from reaching the reference photodetector ring. And in this case, diffuser plate 640 would have a smaller diameter so that it does not cover innermost photodetector ring 605.

[0343] Furthermore, if desired, where photodetector rings 605, 610, 615, and 620 include photodiodes, the ring metallization on the photodiodes can also be used as a capacitive sensor to detect the presence of the vehicle driver's finger (or the presence of another sample). If a negative bias is applied in such a way that the photodiodes are non-conductive, these metallized rings are insulating. The RF impedance of these metallized rings can then be measured. If a finger is brought close to the metallized rings, the impedance changes measurably, and spectroscopic measurements using tissue interface device 600 can be initiated. By providing a non-optical, in-situ "start trigger," the system's standby power consumption is reduced, which can be a substantial advantage. Furthermore, by providing a non-optical, in-situ "start trigger," an optical "start trigger" can be avoided, which may be desirable in some applications (e.g., for eye safety reasons, etc.).

[0344] Advantages gained through the use of the new tissue interface device

[0345] The new tissue interface device has several advantages over existing technologies: (1) the system generates an intrinsic reference signal, which means high intensity because the new device avoids the collection of scattered light, which is associated with low efficiency (i.e., high loss of intensity);

[0346] (2) The inherent generation of the reference signal also increases the stability of the system, since the reference signal is generated within the device itself – this means high strength of the reference signal and avoids additional noise that would be introduced by intermediate optics when the reference signal is generated indirectly;

[0347] (3) the device is very compact (only a few cubic centimeters compared to a volume of several liters) and is therefore very lightweight; and

[0348] (4) The device reduces the use of high-cost fiber optic systems and can therefore be produced at significantly lower costs.

[0349] Modifications of the Preferred Embodiment

[0350] It will be understood that those skilled in the art may make numerous additional changes in details, materials, steps, and arrangements of parts while remaining within the principles and scope of the invention, which changes have been described and illustrated herein to explain the essence of the invention.

Claims

1. A sample interface device for use in identifying the presence of an analyte in a sample, wherein the sample interface device transmits a plurality of monochromatic light beams to the sample and receives backscattered light from the sample, the sample interface device comprising: substrate; a low absorption rate injection region carried by the substrate, for receiving the plurality of monochromatic light beams and transmitting the plurality of monochromatic light beams to the sample; and a plurality of concentrically positioned annular photosensors carried by a substrate, wherein the plurality of concentrically positioned annular photosensors are progressively arranged radially outside of a low-absorption injection region, wherein each concentrically positioned annular photosensor generates an electrical signal corresponding to an amount of light received by the concentrically positioned annular photosensor, wherein each of the plurality of concentrically positioned annular photosensors is optically isolated from the other photosensors in the plurality of concentrically positioned annular photosensors, wherein one of the plurality of concentrically positioned annular photosensors comprises a reference photosensor for measuring light transmitted to the sample, and the remainder of the plurality of concentrically positioned annular photosensors comprises a signal photosensor for measuring scattered light returned from the sample, and wherein the reference photosensor receives only light from the low absorption rate injection region, and the signal photosensor receives only light from the sample, Further including: a diffuser disposed distal to the low-absorption injection region, wherein the diffuser receives the plurality of monochromatic light beams and directs those monochromatic light beams to a reference photosensor; a first mask disposed around a perimeter of the diffuser to prevent the monochromatic light beam from passing to the signal photosensor; and A second mask is disposed between the reference photosensor and the sample, wherein the second mask prevents scattered light from the sample from passing to the reference photosensor.

2. The sample interface device according to claim 1, wherein: The substrate includes a transparent substrate.

3. The sample interface device of claim 1, further comprising a transparent protective cover mounted to the base plate.

4. The sample interface device according to claim 3, wherein: The transparent protective cover includes a sapphire glass element.

5. The sample interface device according to claim 3, wherein: The transparent protective cover includes an opening, wherein the diffuser is disposed in the opening.

6. The sample interface device according to claim 1, wherein: The innermost concentrically positioned annular photosensor comprises the reference photosensor.

7. The sample interface device according to claim 1, wherein: The plurality of concentrically positioned annular photosensors include photodiodes.

8. The sample interface device according to claim 1, wherein: The sample interface device is incorporated into an ergonomic arrangement configured to receive a user's finger.

9. The sample interface device according to claim 1, wherein: The sample interface device is configured to detect alcohol.

10. A method for transmitting a plurality of monochromatic light beams to a sample and detecting scattered light returning from the sample, the method comprising: A sample interface device is provided, the sample interface device comprising: substrate; a low absorption injection region carried by the substrate for receiving the plurality of monochromatic light beams and transmitting the plurality of monochromatic light beams to the sample; and a plurality of concentrically positioned annular photosensors carried by a substrate, wherein the plurality of concentrically positioned annular photosensors are progressively arranged radially outward of a low-absorption injection region, wherein each concentrically positioned annular photosensor generates an electrical signal corresponding to an amount of light received by the concentrically positioned annular photosensor; directing the plurality of monochromatic light beams into a low-absorption injection region of a sample interface device such that the plurality of monochromatic light beams are delivered to the sample; and detecting scattered light returning from the sample using the plurality of concentrically positioned annular photosensors on the sample interface device, wherein each of the plurality of concentrically positioned annular photosensors is optically isolated from the other photosensors in the plurality of concentrically positioned annular photosensors, wherein one of the plurality of concentrically positioned annular photosensors comprises a reference photosensor for measuring light transmitted to the sample, and the remainder of the plurality of concentrically positioned annular photosensors comprises a signal photosensor for measuring scattered light returned from the sample, and wherein the reference photosensor receives only light from the low absorption rate injection region, and the signal photosensor receives only light from the sample, Wherein, the sample interface device further comprises: a diffuser disposed distal to the low-absorption injection region, wherein the diffuser receives the plurality of monochromatic light beams and directs those monochromatic light beams to a reference photosensor; a first mask disposed around a perimeter of the diffuser to prevent the monochromatic light beam from passing to the signal photosensor; and A second mask is disposed between the reference photosensor and the sample, wherein the second mask prevents scattered light from the sample from passing to the reference photosensor.

11. The method according to claim 10, wherein: The substrate includes a transparent substrate.

12. The method according to claim 10, wherein: The sample interface device further includes a transparent protective cover mounted to the base plate.

13. The method according to claim 12, wherein: The transparent protective cover includes a sapphire glass element.

14. The method according to claim 12, wherein: The transparent protective cover includes an opening, wherein the diffuser is disposed in the opening.

15. The method according to claim 10, wherein The innermost concentrically positioned annular photosensor comprises the reference photosensor.

16. The method according to claim 10, wherein The plurality of concentrically positioned annular photosensors include photodiodes.

17. The method according to claim 10, wherein The sample interface device is incorporated into an ergonomic arrangement configured to receive a user's finger.

18. The method according to claim 10, wherein The sample interface device is configured to detect alcohol.

19. A system for non-invasive measurement of an analyte in a sample, wherein the system comprises: an illumination unit for generating a plurality of monochromatic light beams, wherein the plurality of monochromatic light beams constitute a plurality of different wavelengths; and A sampling unit is configured to receive the multiple monochromatic light beams from the illumination unit, transmit those monochromatic light beams to the sample, receive scattered light returned from the sample, and convert the scattered light into corresponding electrical signals for subsequent processing and analyte evaluation, wherein the sampling unit comprises: A sample interface device, the sample interface device comprising: substrate; a low absorption rate injection region carried by the substrate, for receiving the plurality of monochromatic light beams and transmitting the plurality of monochromatic light beams to the sample; and a plurality of concentrically positioned annular photosensors carried by a substrate, wherein the plurality of concentrically positioned annular photosensors are progressively arranged radially outside of a low-absorption injection region, wherein each concentrically positioned annular photosensor generates an electrical signal corresponding to an amount of light received by the concentrically positioned annular photosensor, wherein each of the plurality of concentrically positioned annular photosensors is optically isolated from the other photosensors in the plurality of concentrically positioned annular photosensors, wherein one of the plurality of concentrically positioned annular photosensors comprises a reference photosensor for measuring light transmitted to the sample, and the remainder of the plurality of concentrically positioned annular photosensors comprises a signal photosensor for measuring scattered light returned from the sample, and wherein the reference photosensor receives only light from the low absorption rate injection region, and the signal photosensor receives only light from the sample, Wherein, the sample interface device further comprises: a diffuser disposed distal to the low-absorption injection region, wherein the diffuser receives the plurality of monochromatic light beams and directs those monochromatic light beams to a reference photosensor; a first mask disposed around a perimeter of the diffuser to prevent the monochromatic light beam from passing to the signal photosensor; and A second mask is disposed between the reference photosensor and the sample, wherein the second mask prevents scattered light from the sample from passing to the reference photosensor.

20. The system of claim 19, wherein: The substrate includes a transparent substrate.

21. The system of claim 19, wherein: The sample interface device further includes a transparent protective cover mounted to the base plate.

22. The system of claim 21, wherein: The transparent protective cover includes a sapphire glass element.

23. The system of claim 22, wherein: The transparent protective cover includes an opening, wherein the diffuser is disposed in the opening.

24. The system of claim 19, wherein: The innermost concentrically positioned annular photosensor comprises the reference photosensor.

25. The system of claim 19, wherein: The plurality of concentrically positioned annular photosensors include photodiodes.

26. The system of claim 19, wherein: The sample interface device is incorporated into an ergonomic arrangement configured to receive a user's finger.

27. The system of claim 19, wherein: The sample interface device is configured to detect alcohol.

28. A method for detecting an analyte in a sample, the method comprising: A system is provided, wherein the system comprises: an illumination unit for generating a plurality of monochromatic light beams, wherein the plurality of monochromatic light beams constitute a plurality of different wavelengths; and A sampling unit is configured to receive the multiple monochromatic light beams from the illumination unit, transmit those monochromatic light beams to the sample, receive scattered light returned from the sample, and convert the scattered light into corresponding electrical signals for subsequent processing and analyte evaluation, wherein the sampling unit comprises: A sample interface device, the sample interface device comprising: substrate; a low absorption rate injection region carried by the substrate, for receiving the plurality of monochromatic light beams and transmitting the plurality of monochromatic light beams to the sample; and a plurality of concentrically positioned annular photosensors carried by a substrate, wherein the plurality of concentrically positioned annular photosensors are progressively arranged radially outward of a low-absorption injection region, wherein each concentrically positioned annular photosensor generates an electrical signal corresponding to an amount of light received by the concentrically positioned annular photosensor; directing a plurality of monochromatic light beams into a low-absorption injection region of a sample interface device such that the plurality of monochromatic light beams are delivered to the sample; and detecting scattered light returning from the sample using the plurality of concentrically positioned annular photosensors on the sample interface device, wherein each of the plurality of concentrically positioned annular photosensors is optically isolated from the other photosensors in the plurality of concentrically positioned annular photosensors, wherein one of the plurality of concentrically positioned annular photosensors comprises a reference photosensor for measuring light transmitted to the sample, and the remainder of the plurality of concentrically positioned annular photosensors comprises a signal photosensor for measuring scattered light returned from the sample, and wherein the reference photosensor receives only light from the low absorption rate injection region, and the signal photosensor receives only light from the sample, Wherein, the sample interface device further comprises: a diffuser disposed distal to the low-absorption injection region, wherein the diffuser receives the plurality of monochromatic light beams and directs those monochromatic light beams to a reference photosensor; a first mask disposed around a perimeter of the diffuser to prevent the monochromatic light beam from passing to the signal photosensor; and A second mask is disposed between the reference photosensor and the sample, wherein the second mask prevents scattered light from the sample from passing to the reference photosensor.

29. The method according to claim 28, wherein The substrate includes a transparent substrate.

30. The method of claim 28, wherein the sample interface device further comprises a transparent protective cover mounted to the base plate.

31. The method according to claim 30, wherein The transparent protective cover includes a sapphire glass element.

32. The method according to claim 30, wherein The transparent protective cover includes an opening, wherein the diffuser is disposed in the opening.

33. The method of claim 28, wherein: The innermost concentrically positioned annular photosensor comprises the reference photosensor.

34. The method of claim 28, wherein The plurality of concentrically positioned annular photosensors include photodiodes.

35. The method of claim 28, wherein The sample interface device is incorporated into an ergonomic arrangement configured to receive a user's finger.

36. The method of claim 28, wherein The sample interface device is configured to detect alcohol.

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