Classifications

• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01J—MEASUREMENT OF INTENSITY, VELOCITY, SPECTRAL CONTENT, POLARISATION, PHASE OR PULSE CHARACTERISTICS OF INFRARED, VISIBLE OR ULTRAVIOLET LIGHT; COLORIMETRY; RADIATION PYROMETRY
  • G01J3/00—Spectrometry; Spectrophotometry; Monochromators; Measuring colours
  • G01J3/28—Investigating the spectrum
  • G01J3/44—Raman spectrometry; Scattering spectrometry ; Fluorescence spectrometry
  • G01J3/4412—Scattering spectrometry
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/0059—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
  • A61B5/0075—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence by spectroscopy, i.e. measuring spectra, e.g. Raman spectroscopy, infrared absorption spectroscopy
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/72—Signal processing specially adapted for physiological signals or for diagnostic purposes
  • A61B5/7235—Details of waveform analysis
  • A61B5/7253—Details of waveform analysis characterised by using transforms
  • A61B5/7257—Details of waveform analysis characterised by using transforms using Fourier transforms
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01B—MEASURING LENGTH, THICKNESS OR SIMILAR LINEAR DIMENSIONS; MEASURING ANGLES; MEASURING AREAS; MEASURING IRREGULARITIES OF SURFACES OR CONTOURS
  • G01B9/00—Measuring instruments characterised by the use of optical techniques
  • G01B9/02—Interferometers
  • G01B9/02041—Interferometers characterised by particular imaging or detection techniques
  • G01B9/02044—Imaging in the frequency domain, e.g. by using a spectrometer
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01B—MEASURING LENGTH, THICKNESS OR SIMILAR LINEAR DIMENSIONS; MEASURING ANGLES; MEASURING AREAS; MEASURING IRREGULARITIES OF SURFACES OR CONTOURS
  • G01B9/00—Measuring instruments characterised by the use of optical techniques
  • G01B9/02—Interferometers
  • G01B9/02083—Interferometers characterised by particular signal processing and presentation
  • G01B9/02084—Processing in the Fourier or frequency domain when not imaged in the frequency domain
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01B—MEASURING LENGTH, THICKNESS OR SIMILAR LINEAR DIMENSIONS; MEASURING ANGLES; MEASURING AREAS; MEASURING IRREGULARITIES OF SURFACES OR CONTOURS
  • G01B9/00—Measuring instruments characterised by the use of optical techniques
  • G01B9/02—Interferometers
  • G01B9/02083—Interferometers characterised by particular signal processing and presentation
  • G01B9/02087—Combining two or more images of the same region
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01B—MEASURING LENGTH, THICKNESS OR SIMILAR LINEAR DIMENSIONS; MEASURING ANGLES; MEASURING AREAS; MEASURING IRREGULARITIES OF SURFACES OR CONTOURS
  • G01B9/00—Measuring instruments characterised by the use of optical techniques
  • G01B9/02—Interferometers
  • G01B9/0209—Low-coherence interferometers
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01J—MEASUREMENT OF INTENSITY, VELOCITY, SPECTRAL CONTENT, POLARISATION, PHASE OR PULSE CHARACTERISTICS OF INFRARED, VISIBLE OR ULTRAVIOLET LIGHT; COLORIMETRY; RADIATION PYROMETRY
  • G01J3/00—Spectrometry; Spectrophotometry; Monochromators; Measuring colours
  • G01J3/28—Investigating the spectrum
  • G01J3/45—Interferometric spectrometry
  • G01J3/453—Interferometric spectrometry by correlation of the amplitudes
  • G01J3/4531—Devices without moving parts
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
  • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
  • G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
  • G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
  • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
  • G01N21/47—Scattering, i.e. diffuse reflection
  • G01N21/4795—Scattering, i.e. diffuse reflection spatially resolved investigating of object in scattering medium
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/0059—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
  • A61B5/0062—Arrangements for scanning
  • A61B5/0066—Optical coherence imaging
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/0059—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
  • A61B5/0082—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence adapted for particular medical purposes
  • A61B5/0084—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence adapted for particular medical purposes for introduction into the body, e.g. by catheters
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
  • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
  • G01N21/47—Scattering, i.e. diffuse reflection
  • G01N2021/4704—Angular selective
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
  • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
  • G01N21/47—Scattering, i.e. diffuse reflection
  • G01N2021/4704—Angular selective
  • G01N2021/4709—Backscatter
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
  • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
  • G01N21/47—Scattering, i.e. diffuse reflection
  • G01N2021/4735—Solid samples, e.g. paper, glass
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N2201/00—Features of devices classified in G01N21/00
  • G01N2201/08—Optical fibres; light guides

Definitions

• faLCI Fourier domain angle-resolved low coherence interferometry
• the a/LCI technique has been successfully applied to measuring cellular morphology and to diagnosing intraepithelial neoplasia in an animal model of carcinogenesis.
• the inventors of the present application described such a system in Determining nuclear morphology using an improved angle-resolved low coherence interferometry system in Optics Express, 2003, 11(25): p. 3473-3484, incorporated herein by reference in its entirety.
• the a/LCI method of obtaining structural information about a sample has been successfully applied to measuring cellular morphology in tissues and in vitro as well as diagnosing intraepithelial neoplasia and assessing the efficacy of chemopreventive agents in an animal model of carcinogenesis.
• a/LCI has been used to prospectively grade tissue samples without tissue processing, demonstrating the potential of the technique as a biomedical diagnostic.
• Figure 4B is an illustration of an angular distribution plot of raw and filtered data regarding scattered sample signal intensity as a function of angle in order to recover size information about the sample;
• Figure 7A is a cutaway view of an a/LCI fiber-optic probe tip that may be employed by the faLCI system illustrated in Figure 6;
• Figure 7B illustrates the location of the fiber probe in the faLCI system illustrated in Figure 7A;
• Figure 8 A is an illustration of an alternative fiber-optic faLCI system that may be employed with the present invention.
• the present invention involves a new a/LCI technique called Fourier domain a/LCI (faLCI), which enables data acquisition at rapid rates using a single scan, sufficient to make in vivo applications feasible.
• faLCI Fourier domain a/LCI
• the present invention obtains angle-resolved and depth-resolved spectra information about a sample, in which depth and size information about the sample can be obtained with a single scan, and wherein the reference arm can remain fixed with respect to the sample due to only one scan required.
• a reference signal and a reflected sample signal are cross-correlated and dispersed at a multitude of reflected angles off of the sample, thereby representing reflections from a multitude of points on the sample at the same time in parallel.
• the faLCI technique of the present invention uses the Fourier domain concept to acquire depth resolved information. Signal-to-noise and commensurate reductions in data acquisition time are possible by recording the depth scan in the Fourier (or spectral) domain.
• the faLCI system combines the Fourier domain concept with the use of an imaging spectrograph to spectrally record the angular distribution in parallel. Thereafter, the depth-resolution of the present invention is achieved by Fourier transforming the spectrum of two mixed fields with the angle-resolved measurements obtained by locating the entrance slit of the imaging spectrograph in a Fourier transform plane to the sample.
• FIG. 1 An exemplary apparatus, as well as the steps involved in the process of obtaining angle and depth-resolved distribution data scattered from a sample, are also set forth in Figure 2.
• the faLCI scheme in accordance with one embodiment of the present invention is based on a modified Mach-Zehnder interferometer as illustrated in Figure IA.
• Broadband light 10 from a superluminescent diode (SLD) 12 is directed by a mirror 13 (step 60 in Figure 2) and split into a reference beam 14 and an input beam 16 to a sample 18 by beamsplitter BSl 20 (step 62 in Figure 3).
• SLD superluminescent diode
• the path length of the reference beam 14 is set by adjusting retroreflector RR 22, but remains fixed during measurement.
• the reference beam 14 is expanded using lenses Ll (24) and L2 (26) to create illumination (step 64 in Figure 2), which is uniform and collimated upon reaching a spectrograph slit 48 in an imaging spectrograph 29.
• Ll may have a focal length of 1.5 centimeters
• L2 26 may have focal length of 15 centimeters.
• Lenses L3 (31) and L4 (38) are arranged to produce a collimated pencil beam 30 incident on the sample 18 (step 66 in Figure 2).
• the input beam 30 is made to strike the sample at an angle of 0.10 radians relative to the optical axis.
• This arrangement allows the full angular aperture of lens L4 (38) to be used to collect scattered light 40 from the sample 18.
• Lens L4 (38) may have a focal length of 3.5 centimeters.
• the light 40 scattered by the sample 18 is collected by lens L4 (32) and relayed by a 4/ imaging system comprised of lenses L5 (43) and L6 (44) such that the Fourier plane of lens L4 (32) is reproduced in phase and amplitude at the spectrograph slit 48 (step 68 in Figure 2).
• the scattered light 40 is mixed with the reference field 14 at a second beamsplitter BS2 42 with the combined fields 46 falling upon the entrance slit (illustrated in Figure IB as element 48) to the imaging spectrograph 29 (step 70 in Figure 2).
• the imaging spectrograph 29 may be the model SP2150i, manufactured by Acton Research for example.
• Figure IB illustrates the distribution of scattering angle across the dimension of the slit 48.
• the mixed fields are dispersed with a high resolution grating (e.g. 1200 I/mm) and detected using a cooled CCD 50 (e.g. 1340 X 400, 20 ⁇ m X 20 ⁇ m pixels, Sped 0:400, manufactured by Princeton Instruments) (step 72 in Figure 2).
• the detected signal 46 is a function of vertical position on the spectrograph slit 48, y, and wavelength ⁇ once the light is dispersed by the spectrograph 29.
• the detected signal at pixel (m, n) can be related to the signal 40 and reference fields 16 (E S ⁇
• ⁇ is the phase difference between the two fields 30, 16 and ⁇ ' denotes an ensemble average in time.
• the interference term is extracted by measuring the intensity of the signal 30 and reference beams 16 independently and subtracting them from the total intensity.
• Figure 3 A shows typical data representing the total detected intensity (Equation (1), above) of the sum of the reference field 16 and the field scattered 40 by a sample of polystyrene beads, in the frequency domain given as a function of wavelength and angle, given with respect to the backwards scattering direction. In an exemplary embodiment, this data was acquired in 40 milliseconds and records data over 186 mrad, approximately 85% of the expected range, with some loss of signal at higher angles.
• Figures 3B and 3 C illustrate the intensity of the reference and signal fields 14, 30 respectively. Upon subtraction of the signal and reference fields 14, 30 from the total detected intensity, the interference 46 between the two fields is realized as illustrated in Figure 3D.
• the sample is contained in a round well (8mm diameter, lmm deep) behind a glass coverslip (thickness, d ⁇ 170 ⁇ m) (not shown).
• the sample beam 30 is incident on the sample 18 through the coverslip.
• the data are ensemble averaged by integrating over one mean free path (MFP).
• MFP mean free path
• the spatial average can enable a reduction of speckle when using low-coherence light to probe a scattering sample.
• the scattering distribution is low pass filtered to produce a smoother curve, with the cutoff frequency chosen to suppress spatial correlations on length scales above 16 ⁇ m.
• a/LCI data As an alternative to processing the a/LCI data and comparing to Mie theory, there are several other approaches which could yield diagnostic information. These include analyzing the angular data using a Fourier transform to identify periodic oscillations characteristic of cell nuclei. The periodic oscillations can be correlated with nuclear size and thus will possess diagnostic value.
• Another approach to analyzing a/LCI data is to compare the data to a database of angular scattering distributions generated with finite element method (FEM) or T-Matrix calculations. Such calculations may offer superior analysis as there are not subject to the same limitations as Mie theory. For example, FEM or T-Matrix calculations can model non-spherical scatterers and scatterers with inclusions while Mie theory can only model homogenous spheres.
• FEM finite element method
• T-Matrix calculations can model non-spherical scatterers and scatterers with inclusions while Mie theory can only model homogenous spheres.
• the present invention can also employ optical fibers to deliver and collect light from the sample of interest to use in the a/LCI system for endoscopic applications.
• This alternative embodiment is illustrated in Figure 6.
• the fiber optic a/LCI scheme for this alternative embodiment makes use of the Fourier transform properties of a lens. This property states that when an object is placed in the front focal plane of a lens, the image at the conjugate image plane is the Fourier transform of that object.
• the Fourier transform of a spatial distribution (object or image) is given by the distribution of spatial frequencies, which is the representation of the image's information content in terms of cycles per mm.
• the wavelength retains its fixed, original value and the spatial frequency representation is simply a scaled version of the angular distribution of scattered light.
• the angular distribution is captured by locating the distal end of the fiber bundle in a conjugate Fourier transform plane of the sample using a collecting lens. This angular distribution is then conveyed to the distal end of the fiber bundle where it is imaged using a 4f system onto the entrance slit of an imaging spectrograph. A beamsplitter is used to overlap the scattered field with a reference field prior to entering the slit so that low coherence interferometry can also be used to obtain depth resolved measurements.
• FIG. 6 the fiber optic faLCI scheme is shown.
• Light 12' from a broadband light source 10' is split into a reference field 14' and a signal field 16' using a fiber splitter (FS) 80.
• FS fiber splitter
• a splitter ratio of 20:1 is chosen in one embodiment to direct more power to a sample 18' via the signal arm 82 as the light returned by the tissue is typically only a small fraction of the incident power.
• the sample 18' is located in the front focal plane of lens L2 (98) using a mechanical mount 100.
• the sample is located in the front focal plane of lens L2 (98) using a transparent sheath (element 102).
• scattered light 104 emerging from a proximal end 105 of the fiber probe F4 (94) is recollimated by lens L4 (104) and overlapped with the reference field 14' using beamsplitter BS (108).
• the two combined fields 110 are re-imaged onto the slit (element 48' in Figure 7) of the imaging spectrograph 29' using lens L5 (112).
• the focal length of lens L5 (112) may be varied to optimally fill the slit 48'.
• the resulting optical signal contains information on each scattering angle across the vertical dimension of the slit 48' as described above for the apparatus of Figures IA and IB.
• the above-described a/LCI fiber-optic probe will collect the angular distribution over a 0.45 radian range (approx. 30 degrees) and will acquire the complete depth resolved scattering distribution 110 in a fraction of a second.
• There are several possible schemes for creating the fiber probe which are the same from an optical engineering point of view.
• One possible implementation would be a linear array of single mode fibers in both the signal and reference arms.
• the reference arm 96 could be composed of an individual single mode fiber with the signal arm 82 consisting of either a coherent fiber bundle or linear fiber array.
• the fiber probe tip can also have several implementations which are substantially equivalent. These would include the use of a drum or ball lens in place of lens L2 (98).
• a side-viewing probe could be created using a combination of a lens and a mirror or prism or through the use of a convex mirror to replace the lens-mirror combination. Finally, the entire probe can be made to rotate radially in order to provide a circumferential scan of the probed area.
• the sample arm delivery fiber 16" can consist of either of the following for example: (1) a single mode fiber with polarization control integrated at the tip; or (2) a polarization maintaining fiber.
• the angular distribution is sampled by approximately 130 individual fibers for example, across a vertical strip of the fiber bundle 116", as depicted by the highlighted area in Figure 8C.
• the example of the present invention herein uses 130 fibers to simultaneously collect scattered light across a range of angles in parallel, resulting in rapid data collection.
• the theoretical magnification of the 4f imaging system is (/j/j6) 6.67 in this example.

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