Concurrent scanning non-invasive analysis system

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

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

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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

FIG. 1 is an illustration of the non-invasive analysis system according to the invention.

FIG. 2A is a more detailed illustration of the multiple reference generator.

FIG. 2B is an illustration of an alternative embodiment of a design using a MEMS device.

FIG. 3A illustrates yet another embodiment involving a beam-splitter a micro-mirror array and a modulating reflective element.

FIG. 3B illustrates yet another embodiment involving two beam-splitters, two modulating reflective elements and a micro-mirror array.

DETAILED DESCRIPTION OF THE INVENTION

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Claims

1. A method for non-invasive analysis of a target comprising:

generating a probe beam and a reference beam;

separating the reference beam into multiple component reference beams;

modulating at least some of the multiple component reference beams;

re-combining at least part of some of the multiple component reference beams to form a composite reference beam;

applying the probe beam to the target to be analyzed;

capturing at least part of said probe beam scattered from within the target to form captured scattered probe radiation;

combining the captured scattered probe radiation and the composite reference beam;

detecting the resulting composite interferometric signal to form a composite electronic signal;

separating the composite electronic signal into signals related to concurrent information from different locations within the target; and

processing said concurrent information to achieve non-invasive analysis of the target.

2. The method of claim 1, wherein the probe and reference beams are generated by at least one super-luminescent diode.

3. The method of claim 1, wherein the probe and reference beams are generated by at least one source of broadband radiation.

4. The method of claim 1, wherein the reference beam is separated into component reference beams by at least one beam-splitter.

5. The method of claim 1, wherein the reference beam is separated into component reference beams by a partially reflective element.

6. The method of claim 1, wherein the reference beam is separated into component reference beams by a MEMS based mirror array.

7. The method of claim 1, wherein at least one component reference beam is modulated by the motion of at least one micro-mirror of the MEMS based mirror array.

8. The method of claim 1, wherein at least one component reference beam is modulated by sequentially switching micro-mirrors at least some of which have a large physical separation.

9. The method of claim 1, wherein at least one component reference beam is modulated by the motion of the MEMS based mirror array.

10. The method of claim 1, wherein at least some of the different component reference beams are modulated in a manner that results in interferometric signals with different frequency content.

11. The method of claim 1, wherein at least some of the different component reference beams are modulated in a manner that results in interferometric signals that occur at different time intervals.

12. The method of claim 1, wherein the signals related to different component reference beams are separated by electronic processing of the detected composite electronic signal.

13. The method of claim 1, wherein the concurrent information from different locations within the target is processed to provide scattering information.

14. The method of claim 13, wherein the scattering information is analyzed to determine a measurement of an analyte.

15. The method of claim 14, wherein the measurement of an analyte is the concentration level of glucose in tissue.

16. The method of claim 1, wherein the concurrent information from different locations is analyzed to provide imaging information.

17. A system for non-invasive analysis of a target, said system comprising:

means for generating a probe beam and a reference beam;

means for separating the reference beam into multiple component reference beams;

means for modulating at least some of the multiple component reference beams;

means for re-combining at least part of some of the multiple component reference beams to form a composite reference beam;

means for applying the probe beam to the target to be analyzed;

means for capturing at least part of said probe beam scattered from within the target to form captured scattered probe radiation;

means for combining the captured scattered probe radiation and the composite reference beam;

means for detecting the resulting composite interferometric signal to form a composite electronic signal;

means for separating the composite electronic signal into signals related to concurrent information from different locations within the target; and

means for processing said concurrent information to achieve non-invasive analysis of the target.

18. An apparatus for non-invasive analysis of a target, said apparatus comprising:

means for generating a probe beam and a reference beam;

means for separating the reference beam into multiple component reference beams;

means for modulating at least some of the multiple component reference beams;

means for re-combining at least part of some of the multiple component reference beams to form a composite reference beam;

means for applying the probe beam to the target to be analyzed;

means for capturing at least part of said probe beam scattered from within the target to form captured scattered probe radiation;

means for combining the captured scattered probe radiation and the composite reference beam;

means for detecting the resulting composite interferometric signal to form a composite electronic signal;

means for separating the composite electronic signal into signals related to concurrent information from different locations within the target; and

means for processing said concurrent information, wherein said means for processing said concurrent information enables non-invasive analysis of the target.

19. The apparatus of claim 18, wherein the probe and reference beams are generated by at least one super-luminescent diode.

20. The apparatus of claim 18, wherein the probe and reference beams are generated by at least one source of broadband radiation.

21. The apparatus of claim 18, wherein the reference beam is separated into component reference beams by at least one beam-splitter.

22. The apparatus of claim 18, wherein the reference beam is separated into component reference beams by a partially reflective element.

23. The apparatus of claim 18, wherein the reference beam is separated into component reference beams by a MEMS based mirror array.

24. The apparatus of claim 18, wherein at least one component reference beam is modulated by the motion of at least one micro-mirror of the MEMS based mirror array.

25. The apparatus of claim 18, wherein at least one component reference beam is modulated by sequentially switching micro-mirrors at least some of which have a large physical separation.

26. The apparatus of claim 18, wherein at least one component reference beam is modulated by the motion of the MEMS based mirror array.

27. The apparatus of claim 18, wherein at least some of the different component reference beams are modulated in a manner that results in interferometric signals with different frequency content.

28. The apparatus of claim 18, wherein at least some of the different component reference beams are modulated in a manner that results in interferometric signals that occur at different time intervals.

29. The apparatus of claim 18, wherein the signals related to different component reference beams are separated by electronic processing of the detected composite electronic signal.

30. The apparatus of claim 18, wherein the concurrent information from different locations within the target is processed to provide scattering information.

31. The apparatus of claim 30, wherein the scattering information is analyzed to determine a measurement of an analyte.

32. The apparatus of claim 31, wherein the measurement of an analyte is the concentration level of glucose in tissue.

33. The apparatus of claim 18, wherein the concurrent information from different depth locations is analyzed to provide imaging information.