Abstract:
A non-invasive imaging and analysis system suitable for measuring concentrations of specific components, such as blood glucose concentration and suitable for non-invasive analysis of defects or malignant aspects of targets such as cancer in skin or human tissue, includes an optical processing system which generates a probe and composite reference beam. The system also includes a means that applies the probe beam to the target to be analyzed and modulates at least some of the components of the composite reference beam by means of a micro-mirror array, such that signals corresponding to different depths within the target can be separated by electronic processing. The system combines a scattered portion of the probe beam and the composite beam interferometrically to concurrently acquire information from multiple depths within a target. It further includes electronic control and processing systems.

Description:
CROSS REFERENCES TO RELATED APPLICATIONS  
       [0001]     This application, docket number JH050818US1, is a continuation in part of U.S. utility application Ser. No. 11/025,698 filed on Dec. 29, 2004 titled “Multiple reference non-invasive analysis system”, the contents of which are incorporated by reference as if fully set forth herein. This application, docket number JH050818US1, claims priority from provisional application Ser. No. 60/602,913 filed on Aug. 19, 2004 titled “Multiple reference non-invasive analysis system”. This application also relates to U.S. utility application Ser. No. 10/949,917 filed on Sep. 25, 2004 titled “Compact non-invasive analysis system”, the contents of which are incorporated by reference as if fully set forth herein. This application also relates to U.S. utility patent application Ser. No. 10/870,121 filed on Jun. 17, 2004 titled “A Non-invasive Analysis System”, the contents of which are incorporated by reference as if fully set forth herein. This application also relates to U.S. utility patent 10/870,120 filed on Jun. 17, 2004 titled “A Real Time Imaging and Analysis System”, the contents of which are incorporated by reference as if fully set forth herein. 
     
    
     FIELD OF THE INVENTION  
       [0002]     The invention relates to non-invasive optical imaging and analysis and in particular to quantitative analysis of concentrations specific components or analytes in a target. Such analytes include metabolites, such as glucose. This invention also relates to non-invasive imaging or analysis of defects or malignant aspects of targets such as cancer in skin or human tissue.  
       BACKGROUND OF THE INVENTION  
       [0003]     Non-invasive analysis is a valuable technique for acquiring information about systems or targets without undesirable side effects, such as damaging the target or system being analyzed. In the case of analyzing living entities, such as human tissue, undesirable side effects of invasive analysis include the risk of infection along with pain and discomfort associated with the invasive process.  
         [0004]     In the particular case of measurement of blood glucose levels in diabetic patients, it is highly desirable to measure the blood glucose level frequently and accurately to provide appropriate treatment of the diabetic condition as absence of appropriate treatment can lead to potentially fatal health issues, including kidney failure, heart disease or stroke. A non-invasive method would avoid the pain and risk of infection and provide an opportunity for frequent or continuous measurement. Non-invasive glucose analysis based on several techniques have been proposed. These techniques include: near infrared spectroscopy using both transmission and reflectance; spatially resolved diffuse reflectance; frequency domain reflectance; fluorescence spectroscopy; polarimetry and Raman spectroscopy.  
         [0005]     These techniques are vulnerable to inaccuracies due to issues such as, environmental changes, presence of varying amounts of interfering contamination and skin heterogeneity. These techniques also require considerable processing to de-convolute the required measurement, typically using multi-variate analysis. These techniques have heretofore produced insufficient accuracy and reliability to be clinically useful.  
         [0006]     More recently optical coherence tomography (OCT), using a super-luminescent diode (SLD) as the optical source, has been proposed in Proceedings of SPIE, Vol. 4263, pages 83-90 (2001). The SLD output beam has a broad bandwidth and short coherence length. The technique involves splitting the output beam into a probe and reference beam. The probe beam is applied to the system to be analyzed (the target). Light scattered back from the target is combined with the reference beam to form the measurement signal.  
         [0007]     Because of the short coherence length only light that is scattered from a depth within the target such that the total optical path lengths of the probe and reference are equal combine interferometrically. Thus the interferometric signal provides a measurement of the scattering value at a particular depth within the target. By varying the length of the reference path length, a measurement of the scattering values at various depths can be measured and thus the scattering value as a function of depth can be measured.  
         [0008]     The correlation between blood glucose concentration and the scattering coefficient of tissue has been reported in Optics Letters, Vol. 19, No. 24, Dec. 15, 1994 pages 2062-2064. The change of the scattering coefficient correlates with the glucose concentration and therefore measuring the change of the scattering value with depth provides a measurement of the scattering coefficient which provides a measurement of the glucose concentration. Determining the glucose concentration from a change, rather than an absolute value provides insensitivity to environmental conditions.  
         [0009]     In conventional OCT systems depth scanning is achieved by modifying the relative optical path length of the reference path and the probe path. The relative path length is modified by such techniques as electromechanical based technologies, such as galvanometers or moving coils actuators, rapid scanning optical delay lines and rotating polygons. All of these techniques involve moving parts, which have limited scan speeds and present significant alignment and associated signal to noise ratio related problems.  
         [0010]     Motion occurring within the duration of a scan can cause significant problems in correct signal detection. If motion occurs within a scan duration, motion related artifacts will be indistinguishable from real signal information in the detected signal, leading to an inaccurate measurement. Long physical scans, for larger signal differentiation or locating reference areas, increase the severity of motion artifacts. Problematic motion can also include variation of the orientation of the target surface (skin) where small variations can have significant effects on measured scattering intensities.  
         [0011]     Non-moving part solutions, include acousto-optic scanning, can be high speed, however such solutions are costly, bulky and have significant thermal control and associated thermal signal to noise ratio related problems.  
         [0012]     Optical fiber based OCT systems also use piezo electric fiber stretchers. These, however, have polarization rotation related signal to noise ratio problems and also are physically bulky, are expensive, require relatively high voltage control systems and also have the motion related issues. These aspects cause conventional OCT systems to have significant undesirable signal to noise characteristics and present problems in practical implementations with sufficient accuracy, compactness and robustness for commercially viable and clinically accurate devices.  
         [0013]     Therefore there is an unmet need for commercially viable, compact, robust, non-invasive device with sufficient accuracy, precision and repeatability to image or analyze targets or to measure analyte concentrations, and in particular to measure glucose concentration in human tissue.  
       SUMMARY OF THE INVENTION  
       [0014]     The invention provides a method, apparatus and system for a non-invasive imaging and analysis suitable for measuring concentrations of specific components or analytes within a target, such as the concentration of glucose within human tissue and suitable for non-invasive analysis of defects or malignant aspects of targets such as cancer in skin or human tissue. The invention includes an optical source and an optical signal processing system which provides a probe and a composite reference beam. It includes a micro-mirror array that enables sequentially switched mirrors having a large physical separation to be switched at high speed, thus avoiding motion artifacts. It also includes a means that applies the probe beam to the target to be analyzed, recombines the scattered probe beam and the composite reference beam interferometrically and concurrently acquires information from different locations within the target. It further includes electronic control and processing systems. 
     
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0015]      FIG. 1  is an illustration of the non-invasive analysis system according to the invention.  
         [0016]      FIG. 2A  is a more detailed illustration of the multiple reference generator.  
         [0017]      FIG. 2B  is an illustration of an alternative embodiment of a design using a MEMS device.  
         [0018]      FIG. 3A  illustrates yet another embodiment involving a beam-splitter a micro-mirror array and a modulating reflective element.  
         [0019]      FIG. 3B  illustrates yet another embodiment involving two beam-splitters, two modulating reflective elements and a micro-mirror array.  
     
    
     DETAILED DESCRIPTION OF THE INVENTION  
       [0020]     Optical coherence tomography is based on splitting the output of a broadband optical source into a probe beam and a reference beam and of varying the optical path length of the reference beam to scan the target. This imaging and analysis technology has problems and limitations including problems and limitations related to motion occurring within the duration of a scan.  
         [0021]     The present invention is a novel interferometric approach, which addresses these problems and limitations, by concurrently acquiring multiple meaningful interferometric signals from multiple depths within the target, thus avoiding relative motion artifacts. For purposes of this invention “concurrently acquiring” includes simultaneously acquiring and acquiring at a speed that is significantly higher than motion artifacts. Similarly “concurrent” includes “simultaneous” and “at high speed with respect to motion artifacts” and “concurrently” includes “simultaneously” and “at high speed with respect to motion artifacts”. With the present invention the interferometric information from the different depths within the target can be distinguished from each other and separated by electronic processing.  
         [0022]     The invention involves generating a composite reference beam consisting of multiple beams (or component reference beams) each corresponding to a different path length. In addition to corresponding to different path lengths, at least some components of the composite reference beam are also modulated in a different manner to allow the interferometric information corresponding to different component reference beams to be separated by electronic processing. This enables a compact imaging and analysis system which can concurrently acquire and analyze information from different depths within a target and thereby avoid undesirable motion related artifacts.  
         [0023]     A preferred embodiment of this invention is illustrated in and described with reference to  FIG. 1  where a non-invasive optical analysis system is shown. The analysis system includes an optical processing system that generates a probe beam and a reference beam from a broadband optical source  101 , such as a super-luminescent diode or a mode-locked laser, whose collimated output  102 , consists of a broad band, discrete or continuous, set of wavelengths.  
         [0024]     The output beam  102 , is passed through a beam splitter  103 , to form a probe beam  104  and a reference beam  105  (which also becomes the composite reference beam on its return path). The probe beam  104  passes through an optional focusing lens  106 . The focusing probe beam  108  is directed by an optional angled mirror  109  and applied to the target  110  below the angled mirror.  
         [0025]     At least part of the radiation of the beam applied to the target is scattered back and captured by the lens  106  to form captured scattered probe radiation. Scattering occurs because of discontinuities, such as changes of refractive index or changes in reflective properties, in the target. The captured scattered probe radiation passes through the lens  106  back to the beam splitter  103 .  
         [0026]     The reference beam  105  is applied to a composite reference generator  111  (which is illustrated in more detail in  FIG. 2 ) where multiple components reference beams are generated that each are related to different depths within the target. component reference beams related to different depths are modulated in a different manner, such that interferometric information can be detected which relates to different depths within the target and can be separated by electronic processing. This provides a mechanism for concurrently analyzing information from different depths within the target, thereby avoiding motion artifacts.  
         [0027]     At least a part of the component reference beams are re-combined to form the generated composite reference beam which returns along the path of the reference beam  105  and is referred to as a composite reference beam. The reflected re-combined reference beam, or composite reference beam, is combined interferometrically with the captured scattered probe radiation in the beam splitter  103 . (Although typically referred to as a beam splitter the optical element  103  also operates as an optical combining element, in that it is in this element that reflected re-combined reference beam and captured scattered probe radiation combine interferometrically.) The resulting composite interference signal  107  is detected by the opto-electronic detector  112  to form a composite electronic signal.  
         [0028]     A meaningful interferometric signal only occurs with interaction between the reference beam and light scattered from a distance within the target such that the total optical path lengths of both reference and probe paths are equal or equal within the coherence length of the optical beam. In this preferred embodiment concurrent information from different depth locations is acquired either simultaneously or with time delay that is small compared to any motion related to the target or components within the target.  
         [0029]     The preferred embodiment also includes an electronic processing module,  113 , which interacts with an electronic control module  114  by means of electronic signals  115 . The control module  114  provides timing signals, included in signals  115 , to provide the electronic processing module  113  with timing signals to assist the processing module with filtering and processing the detected composite interferometric signals. The control module  114  also generates control and drive signals for the system, including signals  116  to control and drive the optical source and signals  117  which modulate and control various aspects of the composite reference generator  111 .  
         [0030]     A preferred embodiment of composite reference generator  111  is illustrated in more detail in  FIG. 2 , where a MEMS (Micro-Electro-Mechanical System) mirror array is used to generate the composite reference beam. In this illustration, the reference beam  201  corresponds to the reference beam  105  of  FIG. 1 . The reference beam  201  is routed through a set of switchable micro mirrors, one of which  202  is shown in a position to reflect all or part of the reference beam  201 . Other switchable micro mirrors, such as  203  are shown in a non reflecting position. An optional modulating reflective element  204  can provide a component of the composite reference signal.  
         [0031]     Individual micro mirrors, such as  214  or  215  can be rapidly switched in and out of the reference beam. The speed with which the micro mirrors come into the reflective position can be used to determine the frequency content of the resulting interferometric signal or the micro-mirror array unit  205  could be translated to generate a specific frequency content. An effective long physical scan can be accomplished by switching into reflective positions micro mirrors that have a large physical separation, thus avoiding the requirement of a long physical scan.  
         [0032]     Many configurations are possible, for example, switching of widely separated mirrors can be done simultaneously but at different speeds to allow the resulting interferometric signals to be separable by filtering in the electronic domain, or switching can occur one mirror at a time and the signal used in conjunction with the signal simultaneously available from the modulating reflective element  205  to determine relative depth information, or in yet another configuration, switching could occur one mirror at a time but at high speed (concurrently) and with sequentially switched mirrors having a large physical separation, thus avoiding motion artifacts.  
         [0033]     The resulting composite reference signal generates interference signals when combined with the captured scattered probe radiation. The resulting interference signals can be separated in the electronic domain by digital electronic processing involving various combinations of high speed sequential signal sampling in the time domain and electronic filtering. Many variations of the multiple reference generator are possible. For example, in  FIG. 2B  and additional modulated partially reflective element  206 . Signals from the partially reflective element  206  or the modulating reflective element  205  could be continuously available and used to locate reference surfaces in the target and to position the analysis system with respect to them.  
         [0034]     Alternatively the modulating signals applied to the modulated partially reflective element  206  or the modulating reflective element  205  and individual micro-mirrors could be switched on one at a time, but at high speed (concurrently) thereby avoiding motion artifacts, but with the advantage of only having to process one set of frequency content at a time. Again sequentially switched (closely switched in time) micro-mirrors can have a large physical separation but enable acquiring information over a large physical range in a manner that is insensitive to motion artifacts.  
         [0035]     The micro-mirror array can have a large number of micro-mirrors of the order of thousands which can span a physical distance of the order of milli-meters. The ability to switch physically distant mirrors concurrently (either simultaneously or within a short time period) enables acquiring sets of information that are insensitive to motion. This motion insensitive information can be processed to analyze or image the target. Analyzing such acquire information of targets can provide information relating to the concentration of components within the target, for example, to determine the concentration of components or analytes, such as glucose, within the tissue or to generate an image of the target.  
         [0036]     An alternative embodiment of the composite reference generator is illustrated in  FIG. 3A , where there are separate optical paths for the modulating reflective element and the micro-mirror array. In this illustration, the reference beam  301  corresponds to the reference beam  105  of  FIG. 1  and is applied to a beam-splitter  302 . A portion  303  of the reference beam is reflected by the modulating reflective element  304  to the beam splitter  302 . Another portion  305  of the reference beam is applied to the micro mirror array  306  as described before.  
         [0037]     Many variations involving techniques and configurations are described in the U.S. utility application Ser. No. 11/025,698 filed on Aug. 19, 2004 titled “A Multiple Reference Non-Invasive Analysis System”, whose contents are incorporated by reference as if fully set forth herein and in the patent application Ser. No. 10/949,917 referenced by and incorporated into this application. For example, multiple modulating reflective elements separated by additional beam-splitters; phase modulators or piezo devices could be used to modulate these elements.  
         [0038]     Another such possible configuration is illustrated in  FIG. 3B  which is similar to the configuration in  FIG. 3A  in many respects, but has an additional beam-splitter  307  separates the reference beam  308  into two portions which are applied to modulating reflective elements  309  and  310 . The path lengths to these elements  309  and  310  may, for example, be selected to correspond to the approximate locations of known surfaces in the target. Conventional feedback position control systems could be used to lock on to these locations and thereby align the analysis system.  
         [0039]     For purposes of this invention a source of broadband optical radiation, includes but is not limited to, optical sources of, such as SLDs, mode-locked laser, LEDs, other regions of the electromagnetic spectrum.  
         [0040]     It is understood that the above description is intended to be illustrative and not restrictive. Many of the features have functional equivalents that are intended to be included in the invention as being taught. Many of the features have functional equivalents that are intended to be included in the invention as taught. For example, the optical source could include multiple SLDs with either over-lapping or non-overlapping wavelength ranges, or, in the case of a mode-locked laser source could be an optically pumped mode-locked laser, it could be a solid state laser, such as a Cr:LiSAF laser optically pumped by a diode laser.  
         [0041]     The optical source could be an actively mode-locked laser diode or a passively mode locked by a Kerr lens or a semiconductor saturable absorber mirror. Gain switched optical sources, with optical feedback to lock modes may also be used. For purposes of this invention, mode-locked lasers will include gain switched optical sources. The optical source could be a VCSEL (vertical cavity surface emitting laser), or an LED (light emitting diode) or an incandescent or fluorescent light source or could be arrays of the above sources.  
         [0042]     Other examples will be apparent to persons skilled in the art. The scope of this invention should be determined with reference to the specification, the drawings, the appended claims, along with the full scope of equivalents as applied thereto.