JP2021526035A - Molecular Chemistry Imaging Endoscopic Imaging System - Google Patents

Abstract

The present disclosure provides a medical imaging system that can be used with an intraoperative medical device such as an endoscope. Generally, the disclosed medical imaging system includes an illumination source configured to generate illumination photons for illuminating a biological sample. A second optical signal modulator having a first optical signal having a first plurality of passband wavelengths and a second plurality of passband wavelengths for one or more of the illuminated photons and photons interacting with the biological sample. It is configured to separate into two optical signals. At least one detector is configured to detect one or more of the first optical signal and the second optical signal and generate at least one image data set. The processor is configured to analyze at least one of the image datasets. In some embodiments, the processor is configured to distinguish between the structures of the biological sample, such as between the ureter and surrounding tissue. [Selection diagram] Fig. 1

Description

When performing surgery on the human body, it is essential that the surgeon does not accidentally cut or damage organs, passages, or other anatomical structures such as the urethra or ureter. The presence of intervening tissues such as blood, fat, arteries, veins, muscles or fascia, and other highly interspersed and absorptive media, such organs, passages, anatomy in the immediate vicinity of the surgical site. Can be very difficult to identify with high accuracy. Luminescent catheters are used to detect irregularities in tubes, blood vessels, or organs, helping surgeons identify the anatomy of the subject and enable the proper performance of surgical procedures. .. However, in helping surgeons perform delicate surgery without damaging the tissue surrounding the surgical site, there is a need for improved intraoperative imaging tools that allow real-time detection of anatomical structures.

The present disclosure provides a medical imaging system. The medical imaging system can be used with an endoscope. In general, medical imaging systems include illumination sources that are configured to produce illumination photons. Illumination photons are transmitted to one or more filters, the one or more filters filtering the first plurality of illumination photons and the first plurality having a first passband wavelength. It is configured to generate filtered photons and a second plurality of filtered photons having a second passband wavelength. The sample is then illuminated with the first plurality of filtered photons and the second plurality of filtered photons to produce a first plurality of interacting photons and a second plurality of interacting photons. do. The one or more detectors are configured to detect the first plurality of interacting photons and the second plurality of interacting photons and generate one or more image datasets. ..

In another embodiment, the imaging system includes an illumination source configured to illuminate the sample and generate interacting photons. One or more filters filter one or more of the first plurality of interacting photons to transmit the first passband wavelength and one or more of the second plurality of interacting photons. It is configured to filter and transmit a second passband wavelength. The first and second passband wavelengths are transmitted to one or more detectors, and the one or more detectors have the first passband wavelength and the second passband wavelength. Is configured to detect and generate one or more image datasets.

In yet yet another embodiment, the imaging system is a source of illumination, the first plurality of illuminated photons having a first wavelength for producing the first plurality of interacting photons and the second. It features said illumination source configured to illuminate a sample with one or more of a second plurality of illumination photons having a second wavelength for producing a plurality of interacting photons. One or more detectors are configured to detect the first plurality of interacting photons and the second plurality of interacting photons to generate one or more image datasets. ing.

FIG. 1 shows an endoscope according to an embodiment having an imaging system having a plurality of conformal filters having a dual polarization configuration. FIG. 1A is an end view of the endoscope according to the embodiment of FIG. FIG. 1B shows a patterned conformal filter configuration with a CCD detector according to one embodiment. FIG. 2 shows an endoscope having an imaging system with a plurality of multivariate optical element (MOE) filters according to one embodiment. FIG. 2A is an end view of the endoscope according to the embodiment of FIG. FIG. 2B is a cross-sectional view of the tip of the endoscope according to the embodiment of FIG. FIG. 3 shows an endoscope having an imaging system with a conformal filter according to one embodiment. FIG. 3A is an end view of the endoscope according to the embodiment of FIG. FIG. 4 shows an endoscope according to an embodiment having an imaging system having a plurality of conformal filters having a dual polarization configuration for light source illumination modulation. FIG. 4A is an end view of the endoscope according to the embodiment of FIG. FIG. 4B is an end view of an alternative embodiment of the endoscope according to the embodiment of FIG. FIG. 5 shows an endoscope having an imaging system with an acoustic optical filter according to one embodiment. FIG. 5A is an end view of the endoscope according to the embodiment of FIG. FIG. 6 shows an endoscope having an imaging system with a MOE filter wheel according to one embodiment. FIG. 6A is an end view of the endoscope according to the embodiment of FIG. FIG. 7 shows an endoscope having an imaging system with a patterned etalon filter arrangement according to one embodiment.

The disclosure features an intraoperative imaging system that can assist the surgeon in a variety of medical procedures. The systems disclosed herein are suitable for use as stand-alone devices or can be incorporated into other medical imaging devices such as robot platforms. In one embodiment, the system disclosed herein can be used with an endoscope. The medical imaging systems disclosed herein can provide real-time detection of tumors and anatomical structures during endoscopic surgery. Generally, the systems disclosed herein illuminate a biological sample, collect photons that interact with the sample, detect the interacting photons, generate an image dataset of the sample, and image. Analyze the dataset. The interacting photons can have one or more of the photons absorbed by the sample, the photons reflected by the sample, the photons scattered by the sample, and the photons emitted by the sample. In one embodiment, the medical imaging system provides multivariate imaging. Multivariate imaging functions to generate two or more wavelengths corresponding to the first image data set (T1) and the second image data set (T2). These first and second image datasets can be analyzed using optical calculations. Multivariate imaging improves image contrast and enhances the distinction between the target and the background. In certain embodiments, the first image dataset and the second image dataset feature hyperspectral image data. In another embodiment, the medical imaging system features an image frame rate of> 10 Hz (hypercubes / second).

The systems disclosed herein can be used in a variety of biological samples such as tissues, organs, anatomical structures, physiological systems, cells, blood, fat, nerves, muscles and the like. In certain embodiments, the system may be used in various areas of the body, which will be apparent to those skilled in the art in light of the present disclosure. For example, the system can be used to perform gastrointestinal tract examination and / or surgery. In such applications, the system may be used in any of the esophagus, stomach, duodenum, small intestine, large intestine / colon, bile duct, rectum, anus and the like. The system may further be used in the construction of the airways, including but not limited to the nose, sinuses and lower respiratory tract. In other embodiments, the systems disclosed herein may be used to investigate and / or perform surgery on structures including the urinary tract, such as the bladder, ureters, and kidneys. In yet other embodiments, the system may be used in structures that include the female reproductive system, such as the cervix, uterus, and fallopian tubes. In addition, the system may be used for medical procedures performed during pregnancy, such as to investigate and / or perform amniotic and fetal medical procedures. In another embodiment, the system described herein is a structure comprising a musculoskeletal system, i.e. a hand, knee, elbow, including epidural space, synovial bursa, muscles, ligaments, connective tissue, and the like. It may be used to investigate and / or perform orthopedic structures, including shoulder and spinal structures.

In addition, the system may be configured to distinguish between two or more different biological samples. For example, the system disclosed herein can be configured to distinguish between the ureter and surrounding tissues and fat. In one embodiment, the system disclosed herein can be used to distinguish cancer from normal tissue and to determine one or more of the stage of the cancer, the progression of the cancer and the grade of the cancer. .. In another embodiment, the system can be used during a surgical procedure to remove cancerous tissue or tumor found in a biological sample. In yet another embodiment, the systems described herein can be used to distinguish anatomical structures by identifying body fluids associated with such anatomical structures. Examples of body fluids include urine, saliva, sputum, blood, feces, mucus, pus, semen, lymph, wound exudate, breast fluid, vaginal fluid and the like. Anatomical structures with associated fluids will be apparent to those of skill in the art. As disclosed herein, the systems of the present disclosure provide illumination to living tissue. It is known that such illumination can penetrate a biological sample up to several centimeters, depending on the wavelength and type of tissue. Therefore, such illumination penetration allows imaging of body fluids contained within the anatomical structure. In addition, body fluids can be imaged directly where their presence is outside the anatomy or other biological samples. In another embodiment, the ureter can be identified by detecting urine in or around the ureter using the system disclosed herein.

In another embodiment, the system can be used with the use of one or more contrast enhancers. The contrast enhancer may include one or more dyes or dyes. If only one dye or dye is used, the procedure is called dyeing. Multiple dyeings include the use of multiple dyes or dyes. As used herein, a "dye" or "staining agent" is any chemical or biological compound that can bind to a substance in a biological sample to induce color. For example, dyes or stains bind to specific cells or biochemical structures (eg, cell membranes, small cell organs, nucleic acids, proteins) and produce contrast when viewed using the systems described herein. Can be made to. In some embodiments, the dye or dye can produce color when excited (ie, fluorescent) by emitting electromagnetic radiation at one or more wavelengths.

One or more dyes or dyes can be used, for example, in vivo or in vitro. In some embodiments, the dye or stain is any dye or stain suitable for use in an organism / individual that does not kill cells, i.e. a biological dye. Examples of biological dyes include, but are not limited to, azo dyes, arylmethane dyes, cyanine dyes, thiazine dyes, xanthene dyes (eg eosin), natural dyes (eg Alizarin Red), steroids, tripan blue, Examples include Janus Green, Indocyanine Green, Alizarin Red, Propidium Iodide, Eosinsin, 7-Aminotinomycin D, and Nile Blue. In one embodiment, the contrast enhancer is a fluorescence contrast enhancer. In one embodiment, the contrast enhancer can include a fluorescent material. Suitable fluorescent substances include immunofluorescent compounds, basic compounds, acidic compounds, neutral dyes, and naturally luminescent molecules.

When using one or more dyes or stains with the systems and methods described herein, the user (eg, a surgeon) may use tissue, pathology, morphology, location, chemicals, in or around a biological sample. And chemical reactions can be identified during surgery. For example, some (one or more) biological dyes can identify cancerous cells so that the surgeon can resect the tumor. Other biological dyes can also distinguish between living cells (tissues) and non-living cells. When a contrast enhancer is applied to a biological sample in order to obtain a spectral image as described in the present disclosure, the sample can be irradiated with photons having wavelengths within the illumination wavelength range of the applied contrast enhancer. ..

In another embodiment, the contrast enhancer may be ingested by the subject, in which case the contrast enhancer will appear in the body fluid. In one embodiment, the contrast enhancer can be taken orally via IV or via other means, as will be apparent to those skilled in the art in light of the present disclosure. When the contrast enhancer is ingested, the target biological sample can be examined by the system disclosed herein. The system may be configured to detect contrast enhancers in body fluids and provide contrast between structures containing body fluids and surrounding biological samples such as surrounding tissues. For example, a patient can orally ingest a solution containing a contrast enhancer, after which the contrast enhancer appears in the patient's urine at a specific time. The system according to the present disclosure can be used to perform endoscopic treatment on the renal region of a patient. The system is configured to detect contrast enhancers present in the urine in the ureter to distinguish between the ureter and other surrounding tissues.

In another embodiment, the biological tissue can be imaged in vitro using the system according to the present disclosure. In such applications, the biological sample may be removed from the surgical site and analyzed. Conventional staining methods can be applied to the resected tissue to determine one or more biological properties of the sample. In vitro technology is known in the art and will be apparent to those skilled in the art given this disclosure.

In another embodiment, the biological sample can be enhanced by applying digital staining to the sample. Apply digital staining to the image dataset using an algorithm. The use of digital staining eliminates the need to apply physical and / or chemical staining to biological samples. Digital staining can be applied to any of the image datasets obtained via the systems disclosed herein. An example of the application of digital staining to a set of Raman data was filed on September 30, 2011 by Drach et al. As US Patent Application No. 13 / 200,779 and transferred to Chemimage, Pittsburgh, Pennsylvania. It can be found in US Patent Application Publication No. 2012/0083678, entitled "Systems and Methods for Raman Chemical Analysis of Lung Cancer by Digital Staining," which is incorporated herein by reference in its entirety.

Although not intended to limit this disclosure, this disclosure relates to the analysis of the ureter through an endoscope. Detection of other medical imaging devices and other types of biological samples is further articulated by the present disclosure and will be apparent to those skilled in the art in light of the present disclosure.

The medical imaging apparatus disclosed herein provides real-time multivariate imaging by generating a multivariate signal using one or more detectors. The detector detects multivariate signals and produces one or more image datasets. Here, two methods for achieving this result are shown. One such method includes a step of illuminating the sample, a step of collecting photons interacting with the sample, and a step of modulating the collected signal before sending the signal to the detector. The second method includes a step of modulating the illumination source signal before the interaction with the sample, a step of collecting the interacting photons of the modulated signal, and a step of detecting the interacting photons of the signal. including. Both processes provide modulated signals to generate contrast-enhanced multivariate chemical images in real time to assist surgeons in performing delicate medical procedures. The embodiments included herein can be further configured to provide real-time images displayed in stereoscopic view. Such a configuration will be apparent to those skilled in the art given this disclosure. Stereoscopic vision further assists surgeons by providing the depth perception required for medical procedures using medical imaging techniques such as endoscopic procedures. The systems and methods described herein provide exemplary embodiments of the present disclosure and are not intended to limit the disclosure to any particular embodiment.

In the embodiments shown below, similar reference characters refer to similar parts.

Modulation of Collected Optical Signals The following embodiments are characterized in that the optical signal is modulated after the collection of photons interacting with the sample.

Systems with Conformal Filters in a Double Polarized Arrangement With reference to FIG. 1, the biological sample 100 can be illuminated and / or excited by the illumination source 103. In one embodiment, the illumination source 103 may have a quartz tungsten halogen light source. In other embodiments, the illumination source has a metal halide light source, a light emitting diode (LED), an LED array with uniformly selected emitters emitting over a range of wavelengths, or multiple emitters emitting over a variety of wavelength ranges. It may have an LED array, a pulsed LED, a pulsed LED array, a laser, a pulsed laser, and / or a broadband illumination light source and the like. The illumination source 103 generates illumination photons, and the illumination photons are directed from the illumination source 103 to the tip of the endoscope 102 via an optical fiber bundle 104. The endoscope 102 is configured to direct the photons 101 that interact with the biological sample 100 to the polarizing beam splitter 107. Two independently adjustable conformal filters 105a, 105b are arranged along separate orthogonal beam paths to filter the orthogonal polarization components emerging from the polarization beam splitter 107. As a conformal filter suitable for use in the present disclosure, a US patent application entitled "Conformal Filter and its Usage", which was filed by Priore et al. On January 4, 2013 and assigned to ChemImage, was published. Examples include those disclosed in No. 2013/0176568.

In this arrangement, the path of the filtered beam is not parallel through the conformal filters 105a, 105b, but is directed to the beam combiner 111 by a suitable reflector, ie mirrors 109a, 109b. In an alternative embodiment, the beam combiner can be a polarizing cube or a polarizing beam splitter. In another embodiment, the orthogonal component may have a plurality of same or different passband wavelengths Σλ ₁ and Σλ ₂ . In an exemplary embodiment, the conformal filter 105a is _{configured to produce a plurality of polarized passband wavelengths Σλ 1,} and the conformal filter 105b is configured to produce a plurality of polarized passband wavelengths Σλ _2. It is configured. In an exemplary embodiment, the plurality of passband wavelengths Σλ ₁ and Σλ ₂ are directed to the detector 115 via a lens assembly (not shown). In another embodiment, the plurality of passband wavelengths Σλ ₁ and Σλ ₂ may be coupled so that they are directed to the detector 115. In some embodiments, the beam path from the polarizing beam splitter 107 to the beam combiner 111 can be symmetrical, eg, to avoid the need for infinity correction optics.

The illustrated detector 115 has a CCD detector. However, according to the present disclosure, the detector 115 is, for example, a complementary metal oxide semiconductor, a (CMOS) detector, an indium gallium arsenide (InGaAs) detector, a platinum silicate (PtSi) detector, and an indium antimonide (PtSi) detector. It is contemplated that it may have "InSb") detectors, mercury cadmium telluride ("HgCdTe") detectors, or other suitable detectors comprising combinations thereof. Continuing with reference to FIG. 1, the two conformal filters 105a and 105b can be simultaneously adjusted to _{the same plurality of passband wavelengths (Σλ 1} = Σλ _{2) using the controller 117.} In another embodiment, the controller 117 may be configured to independently adjust the _{plurality of passband waves Σλ 1} and Σλ ₂ in order to process the orthogonal components of the input respectively. Therefore, with proper control, the conformal filters 105a and 105b can be simultaneously adjusted to the same multiple passband wavelengths or two different different passband wavelengths (Σλ ₁ ≠ Σλ _2). Controller 117 can be programmed to allow the user to selectively adjust each conformal filter as desired, or can be implemented in software. In the embodiment of FIG. 1, a fast switching mechanism (not shown) is provided to switch between two figures (or spectral images) corresponding to the spectral data from the respective conformal filters 105a and 105b collected by the detector 117. You can switch. Alternatively, the two such spectral diagrams or images may be combined or superposed into a single image in order to increase contrast or intensity, or for comparison purposes. An exemplary embodiment of FIG. 1 has a single CCD detector 115 that acquires the filtered signal received from the conformal filters 105a and 105b.

FIG. 1B shows an alternative embodiment of the present disclosure. In this embodiment, the beam combiner 111 and the mirror 109a may be removed, or two detectors may be used. The first conformal filter 105a is configured to filter and transmit a plurality of first passband wavelengths corresponding to the T1 state to the first detector 115a, wherein the first detector 115a is the first. The first image data set (T1) is generated by detecting a plurality of passband wavelengths. Similarly, the second conformal filter 105b is configured to filter and transmit a plurality of second passband wavelengths corresponding to the T2 state to the second detector 115b, which second detector 115b. Detects a second plurality of passband wavelengths and generates a second image data set (T2).

US Patent Application Publication No. 2014 / entitled "Systems and Methods for Evaluating Analysts Using Conformal Filters and Double Polarized Lights" filed by Tradedo et al. On January 15, 2014 and transferred to Chemimage. 0198315 discloses the use of conformal filters in dual polarization configurations as described above. This reference is incorporated herein by reference in its entirety.

FIG. 1A shows an end view of the tip end portion of the endoscope 102. The tip is characterized by a lens 119 that collects the interacting photons 101 and a fiber end 121 of an optical fiber bundle 103 that illuminates the biological sample 100 to generate the interacting photons 101. The detector 115 is configured to detect a plurality of passband wavelengths from the conformal filters 105a and 105b and generate one or more image datasets. The image data set may have a T1 image corresponding to the first plurality of passband wavelengths Σλ ₁ and a T2 image corresponding to the second plurality of passband wavelengths Σλ ₂ . In one embodiment, the image dataset has a Raman image dataset. One or more image datasets generated by the detector 115 can be further analyzed as described below.

System with MOE Filter Arrangement FIG. 2 shows another embodiment characterized in that the collected optical signal is modulated. In FIG. 2, the illumination source 103 passes through the endoscope 102 along the optical fiber bundle 104 and produces an illumination photon ending at a series of fiber ends 121 at the tip of the endoscope 102 (shown in FIG. 2A). The fiber end 121 emits illumination photons to illuminate the sample 100 and generate a plurality of interacting photons 101. The interacting photons are focused by the first collection optical system 231 and the second collection optical system 233. The first collecting optical system 231 collects the first portion of the interacting photons 101 and passes these photons to the first multivariate optical element "(Multivariate Optical Element: MOE" filter 237. The "MOE" filter filters the first portion of the interacting photon 101 to produce a first portion of the filtered photon. The first portion of the filtered photon is the first detector. Detected by 241. In addition, the second collection optics 233 collects a second portion of the interacting photons 101 and produces these photons into a second portion of the filtered photons. Passed to the second MOE filter 238. The second portion of the filtered photons is detected by the second detector 239. In one embodiment, the first detector 239 and the second detector 241 are CCDs. Detectors. In other embodiments, the detectors 239 and 241 are, for example, complementary metal oxide semiconductors, (CMOS) detectors, indium gallium arsenide (InGaAs) detectors, platinum silicate (PtSi). ) Detectors, indium antimonized (“InSb”) detectors, mercury cadmium telluride (“HgCdTe”) detectors, or other suitable detectors containing combinations thereof may be available.

In one embodiment, the first MOE filter 237 may be configured to produce a first filtered passband. In one embodiment, the first MOE filter 237 is configured to produce a first filtered passband that matches a randomized target or background. In one embodiment, the second MOE filter 238 may be configured to produce a second filtered passband that matches the target or sample 100. In an embodiment in which the first MOE filter 231 is configured to generate a first filtered passband corresponding to a randomized target or background, the second MOE filter 238 corresponds to the target or sample. It may be configured to generate a second filtered passband. This type of embodiment allows for both target and background identification.

MOE is generally known in the art. MOE features a wideband optical interference filter encoded with target-specific, application-specific regression (or pattern). MOE provides multivariate optical calculations by performing optical calculations based on the pattern of the filter. That is, MOE does not process this information by taking multiple measurements at different wavelengths to estimate the complete spectrum of the target and applying multivariate statistics to that spectrum, but rather multivariate analysis of the filter. Is uniquely adjusted to the pattern that needs to be measured. Therefore, MOE can improve throughput and efficiency and improve analysis speed as compared with conventional filters. Given this disclosure, suitable MOEs will be apparent to those of skill in the art.

The first detector 241 is configured to detect the first filtered passband from the first MOE filter 237 to generate the first image data set (T1) and the second detector 239. Is configured to detect the second filtered passband from the second MOE filter 238 and generate a second image data set (T2). As described below, the first image dataset and the second image dataset may be further analyzed.

Modulation of Illumination Source Signals The following embodiments are characterized in that the illumination source signal is modulated prior to interaction with the sample.

A system with a conformal filter arrangement FIG. 3 shows an illumination source 103 configured to generate illumination photons that pass through the filter 305. In one embodiment, the filter 305 has a conformal filter as disclosed herein. In another embodiment, the filter 305 may have a liquid crystal tunable filter ("Lquid Crystal Tuner Filter: LCTF"), or other filter such as a filter apparent to those skilled in the art given the present disclosure. good. In one embodiment, the filter 305 may include a multiple conjugated filter. The filter 305 switches the filter configuration so as to pass the first plurality of passband wavelengths (Σλ ₁ ), and then configures the filter so as to pass the second plurality of passband wavelengths (Σλ ₂ ). It is controlled by a controller (not shown) configured to switch between them. In one embodiment, the speed at which the controller switches between the two states is on the order of milliseconds. The filter 305 transmits each of the plurality of passband wavelengths Σλ ₁ and Σλ ₂ to the tip of the endoscope 102 via the optical fiber bundle 309, where the plurality of passband wavelengths are set as shown in FIG. 3A. It exits the tip of the endoscope 102 through the fiber end 321 and illuminates the sample 100 to generate interacting photons 329. The interacting photons 329 are collected by a first detector 331 and a second detector 335 located at the tip of the endoscope 102. The detectors 331 and 335 of the illustrated embodiment have a CCD detector. However, other detectors as disclosed herein may be used. The first detector 331 may be configured to detect substantially only the first plurality of passband wavelengths. In one embodiment, the first detector 331 is timed so that the filter 305 transmits the first plurality of passband wavelengths and at the same time detects the first plurality of passband wavelengths, i.e. off-on. can do. Similarly, the second detector 335 may be configured to detect substantially only the second plurality of passband wavelengths. In one embodiment, the second detector 335 is timed, or off-on, so that the filter 305 transmits the second plurality of passband wavelengths and simultaneously detects the second plurality of passband wavelengths. be able to. In another embodiment, a timing sequence of modulation between the first passband wavelength and the second passband wavelength and the first passband wavelength and the second passband by the corresponding detector. The detection of the passband wavelength of is controllable by a controller (not shown). The first detector 231 detects the first plurality of passband wavelengths to generate the first image data set (T1), and the second detector detects the second plurality of passband wavelengths. A second image data set (T2) is generated. In one embodiment, the first image dataset and the second image dataset may be further analyzed as described below.

System with Conformal Filter with Dual Polarization Arrangement FIG. 4 shows another embodiment of illumination source modulation. In this embodiment, the illumination source 103 generates an optical signal to be transmitted to the polarizing beam splitter 405, which splits the optical signal into a first polarization signal and a second polarization signal. The first polarized signal is transmitted to the first filter 409, and the second polarized signal is transmitted to the second filter 411. In one embodiment, the first filter 409 and the second filter 411 each have a conformal filter as described herein. In another embodiment, the first filter 409 and the second filter 411 have an LCTF. In one embodiment, the first filter 409 and the second filter 411 may each have a multi-conjugated filter. The first filter 409 is configured to filter the first polarized signal and transmit the first plurality of passband wavelengths (Σλ ₁ ), and the second filter 411 is a second filter. It is configured to filter the polarization signal and transmit a _{second plurality of passband wavelengths (Σλ 2).} The first plurality of passband wavelengths and the second plurality of passband wavelengths are transmitted from the respective filters 409, 411 to the endoscope 102 via the first optical fiber bundle 417 and the second optical fiber bundle 419. It is transmitted to the tip. In one embodiment, the first optical fiber bundle 417 and the second optical fiber bundle 419 have a polarization-holding optical fiber bundle.

4A and 4B show different embodiments of the tip of the endoscope 102. The first fiber bundle 417 and the second fiber bundle 419 cross through the endoscope 102 to the tip portion. The first fiber bundle 417 terminates at the first fiber end 423, and the second fiber bundle 417 terminates at the second fiber end 425. FIG. 4A shows an example of the arrangement of the first fiber end 423 with respect to the second fiber end 425. In this embodiment, the first fiber end 423 is collectively distributed to one side of the tip of the endoscope 102, and the second fiber end 425 is collectively distributed to the opposite side of the tip of the endoscope 102. .. FIG. 4B shows another embodiment in which the first fiber end 423 and the second fiber end 425 alternate around the tip of the endoscope 102. Suitable arrangements for fiber ends will be apparent to those of skill in the art given this disclosure. Sample 100 is illuminated by a plurality of first passband wavelengths and a second plurality of passband wavelengths emitted from the first fiber end 423 and the second fiber end 425, respectively, and interacts with photons 435. Generate. The interacting photons 435 are detected by a first detector 437 and a second detector 441 located at the tip of the endoscope 102. In the illustrated embodiment, the first detector 437 and the second detector 441 are CCD detectors. However, other suitable detectors as disclosed herein may be used, such detectors will be apparent to those skilled in the art given this disclosure. In one embodiment, the first fiber bundle 417 and the second fiber bundle 419 have a polarization-maintaining fiber bundle. In such an embodiment, polarizers (not shown) may be placed in front of the detector 437 and detector 441, which are placed for stereoscopic viewing and are in the T1 and T2 states based on polarization. It is configured to distinguish between. In one embodiment, the first detector 437 is configured to substantially detect only interacting photons generated from the first plurality of passband wavelengths, and the second detector 441 is substantially. It is configured to detect only interacting photons generated from a second plurality of passband wavelengths. Therefore, the positions of the first fiber end 423 and the second fiber end 425 with respect to the first detector 437 and the second detector 441 are the first plurality of passband wavelengths by the first detector 437. It can be configured to optimize the detection of the interacting photons corresponding to and the detection of the interacting photons corresponding to the second plurality of passband wavelengths by the second detector 441. When the first detector 437 and the second detector 441 detect an interacting photon 435, the first detector 437 is configured to generate a first image dataset (T1) and a second detector. 441 is configured to generate a second image data set (T2). In one embodiment, the first image dataset and the second image dataset may be further analyzed.

System with Acoustic-Optical Filter Arrangement FIG. 5 shows an embodiment of the present disclosure using an acoustic-optical tunable filter (AOTF). This embodiment features an illumination source 103 that produces illumination photons for illuminating the sample 100. The filter 507 is configured to filter the photons emitted from the illumination source 103. In one embodiment, the filter 507 has an AOTF, in which case the AOTF transmits a single passband wavelength. To achieve sampling rates in excess of 10 fps, the AOTF is quickly switched between the target passband wavelength and the background passband wavelength. In another embodiment, the filter comprises a conformal filter based on AOTF technology, in which the AOTF simultaneously transmits multiple passband wavelengths. To switch between the T1 and T2 states, the conformal filter AOTF is switched in series at a microsecond switching speed. In other embodiments, a plurality of conformal AOTFs in which the T1 state and the T2 state are selected at the same time may be used. In an embodiment using a plurality of acoustic and optical filters, each filter can be adjusted to various wavelengths, and each filter simultaneously transmits a plurality of different passband wavelengths.

Acoustic optical filters are known in the art and generally operate by passing a beam of light from a source light through a substrate, usually quartz. The substrate is vibrated by a piezoelectric transducer modulator. The RF frequency is applied to the modulator, which causes the substrate to vibrate. The source light or radiation passes through the vibrating substrate, which diffracts the source light passing through the substrate, thus creating a filter gradient for the source light. The light source light emitted from the acoustic-optical filter can be filtered to the desired passband wavelength by the RF frequency applied to the piezoelectric transducer. For more information on the operation of acoustic and optical filters, see Turner, John F, and Tradeo, Patrick J. et al. "Near Infrared Acoustic Optics Tunerable Filter Hadamard Transform Spectroscopy" Applied Spectroscopy, 50.2 (1996), 277-284, which is incorporated herein by reference in its entirety.

The passband wavelength transmitted from the filter 507 is transmitted to the tip of the endoscope 102 through the optical fiber bundle 515. FIG. 5A shows the tip of the endoscope 102 and features a plurality of fiber ends 519 from the optical fiber bundle 515. The fiber end 519 illuminates the sample 100 to transmit the passband wavelength from the filter 507 to generate the interacting photons 521, and the interacting photons 521 are located at the tip of the endoscope 102. It is detected by the detector 525 of 1 and the detector 529 of the second. In one embodiment, only one detector, i.e. the first detector 525, is used to detect a plurality of interacting photons 521. In another embodiment, the interacting photons 521 are detected by both detector 525 and detector 259. In another embodiment, a plurality of acoustic optical filters are used to generate a first passband wavelength and a second passband wavelength. The first detector 525 can be configured to detect the first passband wavelength and generate a first image data set (T1), and the second detector 529 has a second passband wavelength. Can be configured to detect and generate a second image data set (T2). In one embodiment, the first image dataset and the second image dataset may be further analyzed as described below.

System with MOE Filter Wheel Arrangement FIG. 6 shows another embodiment according to the present disclosure. The illumination source 103 produces illumination photons, which are transmitted to the filter wheel 605, where they are filtered to produce filtered photons. The filter wheel 605 has a plurality of filter elements 609. In one embodiment, each filter element 605 has a MOE. Suitable MOEs for use in this disclosure are known to those of skill in the art and are described herein. Each filter element 609 may be different and may be configured to filter and transmit different passband wavelengths. For example, the filter element 609a can be configured to transmit wavelengths corresponding to the background, such as certain types of tissue or anatomical structures, and the filter element 609b can be used for abnormalities in tissue samples such as cancerous tumors of tissue. It can be configured to transmit the corresponding passband wavelength. In this type of embodiment, the filter wheel 605 can be rotated during the surgical procedure to help the surgeon distinguish normal tissue from cancerous tissue. In another embodiment, the filter element 609 is configured to detect a plurality of different samples. In one embodiment, the filter element 609 is configured to identify background tissue from an anatomical structure such as the ureter.

The filtered photons are transmitted to the tip of the endoscope 102 via the optical fiber bundle 603 and exit the tip of the endoscope through the plurality of fiber ends 621 as shown in FIG. 6A. The filtered photons illuminate the sample 100 to produce a plurality of interacting photons 601. The interacting photons 601 are detected by one or more detectors 619, and one or more detectors 619 are configured to generate an image dataset (T1). In one embodiment, the image dataset may be further analyzed as described below.

System with Patterned Etalon Filter Arrangement FIG. 7 shows another embodiment of the present disclosure. The illumination source 103 generates illumination photons, and the illumination photons are transmitted to the tip of the endoscope 102 and to the fiber end 121 via the optical fiber bundle 104. The illumination photon exits the fiber end 121 to illuminate the sample 100 and generate an interacting photon 101 from the sample 100. The interacting photons 101 are detected by a first detector 705 and a second detector 707 located at the tip of the endoscope 102. In one embodiment, the first detector 705 and the second detector 707 have a hyperspectral camera. In one embodiment, the detector 705 and the detector 707 include a Fabry-Perot interference (patterned etalon) filter configuration located on each pixel of the detector. Suitable examples of patterned etalon filter arrangements and related detectors are available from Ximea Corporation. The filter for each pixel is configured to transmit one or more passband wavelengths for each pixel. In one embodiment, the first detector 705 has a patterned etalon filter arrangement in a mosaic snapshot arrangement. Mosaic snapshots can be taken over 1088 x 2048 pixels. In one embodiment, the mosaic snapshot has a 4x4 mosaic with 16 wavelength bands. In another embodiment, the mosaic snapshot has snapshots of the sample from 465 nm to 630 nm at 11 nm intervals. In another embodiment, the mosaic snapshot may have a 5x5 mosaic with 25 bands over a wavelength range of about 600 nm to 1,000 nm. Mosaic snapshots may include spatial resolution per band of about 512 x 272 and interpolation of up to 2 megapixels, which can collect up to 170 data cubes / second.

In another embodiment, the first detector 705 and the second detector 707 may have a patterned etalon filter arrangement for acquiring snapshot tile configurations. In one embodiment, the snapshot tile configuration transmits a passband wavelength at each pixel. The patterned Etalon snapshot tile filter configuration can capture up to 1088 × 2048 pixels. In one embodiment, the tiled snapshot has a spectral resolution of up to 32 bands and can detect wavelengths in the range of 600 nm to 1,000 nm in 12 incremental steps. In another embodiment, the spatial resolution per band is about 256 × 256. In another embodiment, the tiled snapshot can detect up to 170 data cubes / second. The patterned etalon filter arrangement can also be customized to produce a given response based on the sample to be analyzed and the desired result. Such customization will be apparent to those skilled in the art given this disclosure.

In one embodiment, the first detector 705 and the second detector 707 have an IMEC mosaic filter arrangement. In such an embodiment, the patterned etalon mosaic filter arrangement of the first detector 705 and the second detector 707 is configured to transmit one or more different wavelength bands at each pixel. There is. In another embodiment, the first detector 705 and the second detector 707 have a patterned etalon tiled filter arrangement. In such an embodiment, the patterned tiled etalon filter arrangement of the first detector 705 and the second detector 707 is configured to detect different wavelength bands at each pixel. In another embodiment, the second detector is eliminated, which embodiment has either a snapshot mosaic patterned etalon filter arrangement or a snapshot tile-like patterned etalon filter arrangement. The first detector 705 is used.

The detector 705 and the detector 707 are configured to generate one or more image data sets for each passband wavelength transmitted from the filter arrangement. In one embodiment, the detector 705 and the detector 707 are configured to generate a first image data set (T1) and a second image data set (T2). In one embodiment, the image dataset may be further analyzed as described below.

In yet another embodiment, the illumination source may be configured to generate illumination photons at a particular wavelength. For example, the illumination source can have a plurality of LEDs, in which case the first portion of the LEDs is configured to produce a first wavelength and the second portion of the LEDs is a second portion to illuminate the sample. It is configured to generate two wavelengths. In such an embodiment, the first detector can be configured to detect the interacting photons from the first wavelength and generate a first image data set (T1), and also The detector 2 can be configured to detect the interacting photons from the second wavelength and generate a second image data set (T2). Other sources or arrangements capable of producing illumination photons at multiple wavelengths may be used. In one embodiment, the illumination source has a modulated laser capable of producing multiple wavelengths.

The image datasets described herein are ultraviolet (UV) image datasets, fluorescent image datasets, visible (VIS) image datasets, Raman image datasets, near infrared (NIR) image datasets, short wave infrared. It may have one or more of the (SWIR) dataset, the mid-infrared (MIR) dataset, and the long-wave infrared (LWIR) dataset. In another embodiment, the image dataset has a hyperspectral image dataset. The image datasets of the present disclosure may be further analyzed. In one embodiment, the system disclosed herein may include a fiber array spectrum transducer (FAST). Suitable FAST devices were filed by Nelson et al. On April 13, 2010 and assigned to ChemImage, Inc., "Spatial and Spectral Parallelized Fiber Array Spectral Converter System and Usage". It is disclosed in US Pat. No. 8,098,373, the disclosure of which is incorporated by reference in its entirety.

In one embodiment, the system disclosed herein may have a processor and a non-transitory processor-readable storage medium that operably communicates with the processor. The storage medium can include one or more programming instructions that cause the processor to analyze the image dataset at run time. In one embodiment, the analysis may include the step of applying optical calculations to a dataset. In another embodiment, the optical calculation may have one or more T1 and (T1-T2) / (T1 + T2). Other optical calculations known in the art may be applied. In one embodiment, the analysis may include the step of applying one or more chemometrics techniques to an image dataset. Chemometric analysis includes multivariate curve decomposition analysis, principal component analysis (PCA), partial least squared discrimination analysis (PLSDA), k-mean clustering analysis, band-targeted entropy analysis, adaptive subspatial detector analysis, cosine correlation analysis, and Euclidean distance. It may have one or more of analysis, partial least squared regression analysis, mixed spectrum resolution analysis, spectral angle mapper metric analysis, spectral information divergence metric analysis, Maharanobis distance metric analysis, and non-mixed spectrum analysis. In some embodiments, the processor may be configured to control the operation of the system. For example, in embodiments where a tunable filter is used, the process can be configured such that the controller applies a voltage to the tunable filter to provide transmission of the desired passband. In addition, the processor may be configured to control the lighting source and the timing of the detector so that the correct detector operates for a particular light. Other processor configurations are intended and will be apparent to those of skill in the art given this disclosure.

The system according to the present disclosure may further include a display. In some embodiments, the display may include one or more results from one or more detectors. In another embodiment, the display may include one or more results from analysis by the processor. In one embodiment, the display may include one or more results from one or more detectors and one or more results from analysis by a processor.

When performing surgery on the human body, it is essential that the surgeon does not accidentally cut or damage organs, passages, or other anatomical structures such as the urethra or ureter. The presence of intervening tissues such as blood, fat, arteries, veins, muscles or fascia, and other highly interspersed and absorptive media, such organs, passages, anatomy in the immediate vicinity of the surgical site. Can be very difficult to identify with high accuracy. Luminescent catheters are used to detect irregularities in tubes, blood vessels, or organs, helping surgeons identify the anatomy of the subject and enable the proper performance of surgical procedures. .. However, in helping surgeons perform delicate surgery without damaging the tissue surrounding the surgical site, there is a need for improved intraoperative imaging tools that allow real-time detection of anatomical structures.
Prior art document information related to the invention of this application includes the following (including documents cited at the international stage after the international filing date and documents cited when domestically transferred to another country).
(Prior art document)
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Claims (55)

It ’s an intraoperative device,
It ’s an imaging system,
An illumination source configured to generate multiple illuminated photons to illuminate a biological sample and generate multiple interacting photons.
An optical signal modulator configured to receive one or more of the plurality of illumination photons and the plurality of interacting photons and generate a first optical component and a second optical component.
With at least one detector configured to detect one or more of the first optics and one or more of the second optics and generate at least one image data set.
An intraoperative device having an imaging system including a processor configured to analyze at least one image data set. In the device of claim 1, the illumination source includes one or more of a halogen light source, a metal halide light source, a light emitting diode (LED), an LED array, a pulsed LED, a pulsed LED array, a laser, and a pulsed laser. A device that is a waste. In the device according to claim 1, the optical signal modulator is one of a plurality of conformal filters, a liquid crystal tunable filter, a multiple conjugate filter, a plurality of multivariate optical elements, and an acoustic optical tunable filter. A device that has the above. In the device according to claim 1, the detector includes a CCD detector, a complementary metal oxide semiconductor (CMOS) detector, an indium gallium arsenide (InGaAs) detector, a platinum silicate (PtSi) detector, and an antimonide. A device having one or more of an indium antimonide (InSb) detector and a mercury cadmium telluride (HgCdTe) detector. The device of claim 1, wherein the at least one detector is configured to generate a first image data set (T1) and a second image data set (T2). In the device of claim 5, the processor applies at least one optical calculation to one or more of the first image data set (T1) and the second image data set (T2). A device that is configured to analyze two datasets. In the device of claim 1, the processor is further configured to apply digital staining to said at least one image dataset. In the device of claim 1, the processor is configured to analyze at least one image dataset to distinguish the structure of the biological sample. The device of claim 8, wherein the structure comprises a ureter and surrounding tissue. In the device of claim 1, the processor includes multivariate curve decomposition analysis, principal component analysis (PCA), partial least squared discrimination analysis (PLSDA), k-mean clustering analysis, band-targeted entropy analysis, adaptive subspace detection. Selected from the group consisting of instrumental analysis, cosine correlation analysis, Euclidean distance analysis, partial least squared regression analysis, spectral mixed resolution analysis, spectral angle mapper metric analysis, spectral information divergence metric analysis, Maharanobis distance metric analysis, and spectral non-mixed analysis. A device configured to analyze at least one image data set by applying one or more chemometrics techniques. The device of claim 1, wherein the at least one image dataset comprises a hyperspectral image. In the device according to claim 1, the first optical component has a first plurality of passband wavelengths, and the second optical component has a second plurality of passband wavelengths. ,device. The device of claim 1, wherein the optical signal modulator has a patterned etalon filter arrangement configured to receive said plurality of interacting photons. The device according to claim 1, wherein the optical signal modulator is configured to modulate the plurality of illumination photons. The device according to claim 14, wherein the optical signal modulator has one or more of a plurality of conformal filters with a dual polarization arrangement and a plurality of multivariate optics. The device of claim 1, wherein the optical signal modulator is configured to modulate a plurality of interacting photons. In the device of claim 16, the optical signal modulator is one of a conformal filter, a liquid crystal tunable filter, a multiple conjugate filter, an acoustic optical filter, a plurality of multi-optical elements, and a patterned etalon filter. A device that has or more. In the device according to claim 1, the at least one detector is configured to detect the first optical component and the first detector configured to detect the first optical component. A device that has a second detector that has been made. It ’s an endoscope device,
The tubular body, which has a lumen passing through the tubular body and has a proximal end and an operable end.
An illumination source that is optically coupled to the operable end and is configured to illuminate a biological sample to generate a plurality of interacting photons.
The collection optics located at the operable end and
Optical signal modulation configured to be optically coupled to the collecting optical system, receive the plurality of interacting photons, and separate the plurality of interacting photons into a first optical component and a second optical component. With a vessel
With at least one detector configured to detect one or more of the first optics and one or more of the second optics and generate at least one image data set.
An endoscope apparatus having a processor configured to analyze at least one image data set. In the apparatus of claim 19, the illumination source includes one or more of a halogen light source, a metal halide light source, a light emitting diode (LED), an LED array, a pulsed LED, a pulsed LED array, a laser, and a pulsed laser. A device that is a waste. The device according to claim 19, wherein the optical signal modulator has one or more of a plurality of conformal filters with a dual polarization arrangement and a plurality of multivariate optical elements. In the apparatus according to claim 19, the at least one detector is a CCD detector, a complementary metal oxide semiconductor (CMOS) detector, an indium gallium arsenide (InGaAs) detector, and a platinum silicate (PtSi) detection. A device having one or more of a device, an indium antimonide (InSb) detector, and a mercury cadmium telluride (HgCdTe) detector. The device of claim 19, wherein the at least one detector is configured to generate a first image data set (T1) and a second image data set (T2). In the apparatus of claim 23, the processor applies the optical calculation to the first image data set (T1) and the second image data set (T2) to obtain the at least one image data set. A device that is configured to analyze. In the apparatus of claim 19, the processor is further configured to apply digital staining to said at least one image dataset. In the apparatus of claim 19, the processor is configured to analyze the at least one image dataset to distinguish the structure of the biological sample. The device of claim 19, wherein the structure comprises a ureter and surrounding tissue. In the apparatus of claim 19, the processor includes multivariate curve decomposition analysis, principal component analysis (PCA), partial least squared discrimination analysis (PLSDA), k-mean clustering analysis, band-targeted entropy analysis, adaptive subspace detection. Selected from the group consisting of instrumental analysis, cosine correlation analysis, Euclidean distance analysis, partial least squared regression analysis, spectral mixed resolution analysis, spectral angle mapper metric analysis, spectral information divergence metric analysis, Maharanobis distance metric analysis, and spectral non-mixed analysis. An apparatus configured to analyze at least one image data set by applying one or more chemometrics techniques. The device of claim 19, wherein the at least one image dataset comprises a hyperspectral image. In the apparatus according to claim 19, the first optical component has a first plurality of passband wavelengths, and the second optical component has a second plurality of passband wavelengths. ,Device. The device of claim 19, wherein the optical signal modulator has a patterned etalon filter arrangement. In the apparatus according to claim 19, the at least one detector is configured to detect the first optical component and the first detector configured to detect the first optical component. An apparatus having a second detector. It ’s an endoscope device,
The tubular body, which has a lumen passing through the tubular body and has a proximal end and an operable end.
With an illumination source configured to generate multiple illumination photons,
An optical signal modulator configured to receive the plurality of illumination photons and separate the plurality of illumination photons into a first optical component and a second optical component.
An optical fiber configured to illuminate a biological sample by transmitting the first optical component and the second optical component to the operable end through the lumen.
The collection optics located at the operable end and
At least one configured to be optically coupled to the collection optics to detect one or more of the first optical component and the second optical component and generate at least one image dataset. With the detector
An endoscope apparatus having a processor configured to analyze at least one image data set. In the apparatus of claim 33, the illumination source comprises one or more of a halogen light source, a metal halide light source, a light emitting diode (LED), an LED array, a pulsed LED, a pulsed LED array, a laser, and a pulsed laser. A device that is a waste. The device according to claim 33, wherein the optical signal modulator has one or more of a plurality of conformal filters with a dual polarization arrangement and a plurality of multivariate optical elements. In the apparatus according to claim 33, the at least one detector is a CCD detector, a complementary metal oxide semiconductor (CMOS) detector, an indium gallium arsenide (InGaAs) detector, and a platinum silicate (PtSi) detection. A device having one or more of a vessel, an indium antimonide (InSb) detector, and a mercury cadmium telluride (HgCdTe) detector. The device of claim 33, wherein the at least one detector is configured to generate a first image data set (T1) and a second image data set (T2). In the apparatus of claim 37, the processor applies the optical calculation to the first image data set (T1) and the second image data set (T2) to obtain the at least one image data set. A device that is configured to analyze. In the apparatus of claim 33, the processor is further configured to apply digital staining to said at least one image dataset. 33. The apparatus of claim 33, wherein the processor is configured to analyze at least one image dataset to distinguish the structure of the biological sample. The device of claim 40, wherein the structure comprises a ureter and surrounding tissue. In the apparatus of claim 33, the processor comprises multivariate curve decomposition analysis, principal component analysis (PCA), partial least squared discriminant analysis (PLSDA), k-mean clustering analysis, band-targeted entropy analysis, adaptive subspace detection. Selected from the group consisting of instrumental analysis, cosine correlation analysis, Euclidean distance analysis, partial least squared regression analysis, spectral mixed resolution analysis, spectral angle mapper metric analysis, spectral information divergence metric analysis, Maharanobis distance metric analysis, and spectral non-mixed analysis. An apparatus configured to analyze at least one image data set by applying one or more chemometrics techniques. The device of claim 33, wherein the at least one image dataset comprises a hyperspectral image. In the apparatus according to claim 33, the first optical component has a first plurality of passband wavelengths, and the second optical component has a second plurality of passband wavelengths. ,Device. In the apparatus according to claim 33, the at least one detector is configured to detect the first optical component and the first detector configured to detect the first optical component. An apparatus having a second detector. A method of distinguishing the anatomy of a biological sample,
A step of illuminating the biological sample with a plurality of irradiated photons in order to generate a plurality of interacting photons, and a process of illuminating the biological sample with a plurality of irradiated photons.
A step of modulating one or more of the plurality of illumination photons and the plurality of interacting photons into a first optical component and a second optical component.
The detection step, which is a step of detecting one or more of the first optical component and the second optical component to generate at least one image data set. ,
A method having a step of analyzing, wherein the at least one image data set is analyzed to distinguish the anatomical structure. In the method of claim 46, the step of modulating one or more of the plurality of illumination photons and the plurality of interacting photons is a plurality of tunable conformal filters, a plurality of multivariate optical elements, and the like. A method comprising the step of passing one or more of a liquid crystal tunable filter, a multi-conjugated filter, an acoustic optical filter, a plurality of multivariate optical elements, and a patterned etalon filter. The method according to claim 46, wherein the detecting step includes a step of generating a first image data set (T1) and a second image data set (T2). The method of claim 48, wherein the step of analysis comprises applying an optical calculation to the first image data set (T1) and the second image data set (T2). The method of claim 46, wherein the step of analysis comprises applying digital staining to said at least one image dataset. The method of claim 46, wherein distinguishing the anatomical structure comprises distinguishing the ureter from surrounding tissue. In the method of claim 46, the steps of analysis include multivariate curve decomposition analysis, principal component analysis (PCA), partial least-squared discriminant analysis (PLSDA), k-mean clustering analysis, band-targeted entropy analysis, adaptive subspace. Select from the group consisting of detector analysis, cosine correlation analysis, Euclidean distance analysis, partial minimum square regression analysis, spectral mixed resolution analysis, spectral angle mapper metric analysis, spectral information divergence metric analysis, Maharanobis distance metric analysis, and spectral non-mixed analysis. A method comprising the step of applying one or more chemometrics techniques to the at least one image data set. In the method according to claim 46, the step of detecting the first optical component includes a step of detecting a first plurality of passband wavelengths, and the step of detecting the second optical component is a step of detecting the second optical component. A method comprising the step of detecting a second plurality of passband wavelengths. The method of claim 46, wherein the modulation step comprises a step of modulating the plurality of illumination photons. The method of claim 46, wherein the modulation step comprises a step of modulating the plurality of interacting photons.

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