Arrangements and methods for providing multimodality microscopic imaging of one or more biological structures

Cross-reference of related applications This application is based on US Patent Application No. 60 / 721,802, filed September 29, 2005, incorporated herein by reference, and claims its priority.

The present invention relates to devices and methods for obtaining broad optical images of epithelial organs and other biological structures by spectral coding.

Radiological methods such as computed tomography (CT), magnetic resonance imaging (MRI) and ultrasound provide non-invasive visualization of human lesions at the organ level. Although these modality can identify large lesions, cancer diagnosis may require microscopic tissue assessment beyond the resolution of traditional imaging methods. For this reason, biopsy and histopathological examination may be required for diagnosis. Proliferation and early stage cancer of the precancerous state often occur on the microscopic scale, so their identification and diagnosis are sometimes very difficult. Traditionally, screening and testing of these pathologies has relied on random biopsies and morphological analysis of hematoxylin and eosin (H & E) stained slides. This method is currently regarded as the standard for microscopic diagnosis, but requires excision of tissue from the patient and requires considerable processing time to produce slides. More importantly, since histopathological examination is essentially a point extraction method, only a small portion of the diseased cell tissue is often examined, and pathologists sometimes examine less than 1% of biopsy specimens.

It is preferable to obtain a microscopic diagnosis from the entire organ of a living patient, or the entire biological system. However, due to the lack of suitable imaging techniques, methods for screening preneoplastic conditions (eg, metaplasia), dysplasia, etc. are limited. In addition, the difficulty in identifying areas of dysplasia and carcinoma in situ results in random biopsies of the prostate, large intestine, esophagus, bladder, etc., which is also indiscriminate and preferable. Absent. Much of the diagnostic work today called frozen section testing, such as tumor boundary assessment, can be improved by diagnostic modality that allows rapid imaging of large volumes of cell tissue on a microscopic scale. Technology that bridges the gap between pathology and radiology would bring significant benefits to patient care and healthcare.

Innovations have improved the resolution of non-invasive imaging methods such as micro CT, micro PET, and magnetic resonance imaging (MRI) microscopy. Although these techniques have achieved resolutions close to 20 μm, they have not yet been applied to patients due to the underlying physical constraints. In recent years, in-situ microscopic student examination has been advanced for non-resectable histopathological diagnosis. Reflective confocal microscopy (RCM) can measure microscopic structures without contact with cell tissue and without the need for external contrast medium administration, making it suitable for non-invasive microscopy of patients. Especially suitable. The RCM can reject out-of-focus light and selectively detect backscattered photons emanating from a single surface within the cell tissue. For example, when RCM is performed by scanning the plane parallel to the surface of the cell tissue with an electromagnetic radiation focusing beam at high speed, a lateral image or a front image of the cell tissue can be obtained. If a large numerical aperture (NA) is used for the RCM, a very high spatial resolution (1-2 μm) can be obtained and the intracellular structure can be visualized. However, high NA images are often particularly sensitive to aberrations caused by the passage of light through non-uniform cell tissue. Further, high resolution imaging by RCM is typically limited to a depth of 100-400 μm.

RCM has been extensively demonstrated as a promising imaging method for skin cell tissue. The development of a confocal microscope scanning endoscope system has faced many difficulties due to the large technical challenges for miniaturizing the scanning microscope. How to design a mechanism for rapidly scanning a focused beam at the distal end of a small-diameter, flexible probe is a major challenge in applying the concept of confocal microscopy directly to an endoscope. Various proposals have been made to solve this problem, one of which is to use a micromachine technology (MEMS) beam scanning device distally and a single-mode fiber bundle scanning proximally. .. The RCM can also provide images of individual locations only, i.e. microscopic images of the point extraction method. Current methods limit the field of view to equal to or less than that of excisional biopsy, and the imaging speed is too slow for wide-field large-field microscopy, which can make point extraction unique to RCM.

Another difficulty in applying confocal microscopy endoscopically is the miniaturization of high NA objectives that can be used for optical sectioning. Such miniaturization can be achieved by providing, for example, a refractive index distribution lens system, a biaxial objective lens, or a custom-made small objective lens. For example, a bundle of optical fibers coupled to a small objective lens can be used to obtain detailed morphological images of the cervical epithelium in vivo, and fluorescent images of colorectal lesions can be obtained from commercially available devices such as Olympus optics and Pentax / Optiscan. Can be obtained using.

Despite these advances, there is a need for imaging methods that can present biological structures in place over large areas with microscopic resolution.

One object of the present invention is to overcome the shortcomings and deficiencies of conventional systems and methods (including those described above) and to broaden microscopic optics for anatomical structures such as epithelial organs and other somatic tissues. To provide specific examples of methods and devices for obtaining images.

For example, the device according to an exemplary embodiment of the invention may be in the form of a probe or assembly and may be disposable. The probe or assembly is configured, for example, with one or more waveguides capable of sending electromagnetic radiation to the probe or assembly to form a light beam and converging the light beam at the distal end. It comprises one or more arranged focusing devices and a scanning device configured to scan the light beam across a portion of the anatomical structure. The above electromagnetic radiation may include multiple wavelengths, and these wavelengths may change over time. The probe also includes one or more diffracting devices configured to diffract or spectrally disperse the beam, one or more correction devices configured to correct optical aberrations, and the interior of the anatomical structure to be imaged. May include a mechanism capable of centering or aligning the probe or assembly with, and / or a guide wire device capable of translating and / or rotating the probe or assembly. The waveguide may be, for example, an optical fiber, a bundle of optical fibers, or another waveguide. The probe or aggregate may further include a spectral coding device and / or a correction device such as a curved transparent surface that can be used to correct aberrations such as astigmatism in the optical path.

The probe or assembly in one exemplary embodiment of the invention is approximately 1 mm.²A region of the anatomical structure having a larger area is configured to be scannable, and this region includes the surface, volume, or subsurface position of the anatomical structure. The probe or assembly can be configured to obtain data that can be used to generate an image of the region with a resolution less than approximately 10 μm.

In another exemplary embodiment of the invention, the probe or assembly can be provided so that the optical beam can be aligned and / or focused with respect to the anatomy. The above alignment and / or focusing can be based on, for example, an interference signal, a time-of-flight signal, or an electromagnetic radiation intensity. The probe or assembly can include confocal optics.

The probe or assembly in yet another exemplary embodiment of the invention is a location location device capable of determining the location of the probe or assembly relative to a location within the anatomy and the movement of the probe based on this location. , And / or any alignment device capable of controlling the position.

Another exemplary embodiment of the invention provides a method for obtaining a wide range microscopic image of the anatomical structure, which method is about 1 mm of the anatomical structure to be imaged.²This image comprises scanning a larger area with electromagnetic radiation, such as an optical beam, receiving a signal based on this radiation, and forming an image based on this signal. It can have a lateral resolution less than 10 μm.

Yet another exemplary embodiment of the invention provides a method for aligning or guiding electromagnetic radiation within an anatomical structure, which method uses at least the electromagnetic radiation of the anatomical structure. It involves scanning a portion and using a signal based on this electromagnetic radiation to control the position and / or focus of this radiation. Methods for controlling the position or focus of the confocal beam within this anatomical structure are also provided based on the signal obtained by scanning the electromagnetic radiation over the area of the anatomical structure.

Other features and advantages of the invention will become apparent by reading the detailed description of the embodiments set forth below, along with the appended claims.

<figref num="1">It is a schematic diagram which shows the example of the spectrum coding confocal microscopy (SECM) system.</figref><figref num="2A">This is an example of a SECM image from 100 μm below the surface of porcine intestinal epithelial cell tissue obtained in vitro using a single-mode light source-single-mode detection (SM-MM) configuration.</figref><figref num="2B">This is another example of a SECM image of porcine intestinal epithelial cell tissue obtained using a single-mode light source-multi-mode detection (SM-MM) configuration.</figref><figref num="2C">It is an enlarged display of the SECM image of the intestinal epithelial cell tissue of a pig.</figref><figref num="3A">This is an example of a SECM image of porcine intestinal epithelial cell tissue obtained in vitro after compressing the intestinal wall at an image depth of 50 μm.</figref><figref num="3B">This is an example of a SECM image of porcine intestinal epithelial cell tissue obtained in vitro after compressing the intestinal wall at an image depth of 100 μm.</figref><figref num="4">It is a schematic diagram of the SECM apparatus example.</figref><figref num="5">This is an example of a SECM image of a USAF test pattern.</figref><figref num="6A">This is an example in which a SECM image based on data collected from a lens paper sample is displayed at 1x.</figref><figref num="6B">This is an example of displaying a SECM image based on data collected from a lens paper sample at a magnification of 4.5.</figref><figref num="6C">This is an example in which a SECM image based on data collected from a lens paper sample is displayed at 16.7 times.</figref><figref num="6D">This is an example in which a SECM image based on data collected from a lens paper sample is displayed at a magnification of 50.</figref><figref num="6E">This is an example in which a SECM image based on data collected from a lens paper sample is displayed at a magnification of 125.</figref><figref num="7">It is a series of SECM images including SECM data collected from five different focal positions of a lens paper sample and a combined image obtained by combining the data in these five individual images.</figref><figref num="8A">This is an example in which a SECM image based on data collected from a piece of porcine intestinal cell tissue is displayed at 1x.</figref><figref num="8B">This is an example in which a SECM image based on data collected from a piece of porcine intestinal cell tissue is displayed at a magnification of four.</figref><figref num="8C">This is an example in which a SECM image based on data collected from a piece of porcine intestinal cell tissue is displayed at a magnification of 20.</figref><figref num="8D">This is an example in which a SECM image based on data collected from a piece of porcine intestinal cell tissue is displayed at a magnification of 40.</figref><figref num="9">It is a schematic diagram of the SECM system example which can image a large cell tissue volume.</figref><figref num="10">It is a schematic diagram of the distal end of an exemplary catheter used for imaging according to an exemplary embodiment of the present invention.</figref><figref num="11">It is a schematic diagram of an exemplary catheter including an external rotary scanning apparatus that can be used for imaging according to an exemplary embodiment of the present invention.</figref><figref num="12A">It is a schematic diagram which shows the optical effect of a curved window and a negative cylindrical lens.</figref><figref num="12B">It is a schematic diagram of astigmatism correction using a curved window.</figref><figref num="13A">FIG. 6 is a schematic diagram showing an example of a method used to obtain a desired depth range by stepping through a focus depth range.</figref><figref num="13B">It is a schematic diagram of an example of a method used for imaging a cell tissue at a specific depth by actively adjusting the focal plane.</figref><figref num="14A">It is a schematic diagram of a dual bimorph piezoelectric bender.</figref><figref num="14B">It is a schematic diagram which shows the example of the device which can move a motor in a transparent outer sheath using a bending actuating device.</figref><figref num="15">It is a schematic diagram which shows the example of the balloon catheter structure which was configured to move a collimating lens to adjust a focus.</figref><figref num="16">It is a photograph of a specific varifocal lens.</figref><figref num="17A">It is a schematic diagram of the cylindrical inner housing structure having a transparent cylindrical shape.</figref><figref num="17B">It is a schematic diagram of a cylindrical inner housing structure having a transparent window.</figref><figref num="17C">It is a schematic diagram of the cylindrical inner housing structure with some openings in the housing wall.</figref><figref num="17D">It is a schematic diagram of a cylindrical inner housing structure having an opening at a connection portion between a housing and a motor.</figref><figref num="18">FIG. 5 is a schematic diagram of electrical and data connections between various components and an exemplary imaging system.</figref><figref num="19A">It is a figure which shows the example of the probe scanning pattern which formed the spiral imaging pattern by rotating a beam fast and moving slowly in an axial direction at the same time.</figref><figref num="19B">It is a figure which shows the example of the probe scanning pattern which rotates a beam fast and then rearranges in an axial direction.</figref><figref num="19C">It is a figure which shows the example of the probe scanning pattern which scans a beam fast in an axial direction, and then rearranges in a rotation direction.</figref><figref num="19D">It is a figure which shows the example of the probe scanning pattern which a beam scans on a concentric path covering a circular cell tissue region.</figref><figref num="20A">FIG. 6 is a schematic representation of a rapid exchange balloon catheter containing a guide wire device at the distal end of the housing.</figref><figref num="20B">FIG. 6 is a schematic diagram of a secondary channel type rapid exchange balloon catheter including a guide wire device located at the distal end of the housing.</figref><figref num="20C">FIG. 6 is a schematic diagram of a secondary channel type rapid exchange balloon catheter including a guide wire device located at the proximal end of the housing.</figref><figref num="21A">FIG. 5 is a schematic diagram of a first step involving insertion of a guide wire in an exemplary alignment method of a wire balloon catheter.</figref><figref num="21B">FIG. 6 is a schematic diagram of a second step involving placing a balloon catheter on a guide wire in an exemplary alignment method of a wire balloon catheter.</figref><figref num="21C">FIG. 5 is a schematic diagram of a third step involving placing an optical device within a balloon catheter in an exemplary alignment method of a wire balloon catheter.</figref><figref num="22A">FIG. 5 is a schematic diagram illustrating an example of a balloon catheter containing a single channel configured to deliver an inflatable material from a location away from the balloon.</figref><figref num="22B">It is a schematic diagram which shows the example of the balloon catheter containing two sheaths, and the expansion material is provided between the sheaths.</figref><figref num="23A">It is a schematic diagram which shows that this device is housed in the outer sheath in the centering device which has a wire cage shape.</figref><figref num="23B">It is a schematic diagram which shows in the centering apparatus which has a wire cage shape, this apparatus partially protrudes from an outer sheath.</figref><figref num="23C">It is a schematic diagram which shows in the centering apparatus which has a wire cage shape, this apparatus extends sufficiently from an outer sheath.</figref><figref num="24A">It is a schematic diagram which shows the example of the SECM / SD-OCT system including the wavelength division multiplexer and the dispersion compensator.</figref><figref num="24B">It is a schematic diagram which shows the example of the spectrum provided by the SECM / SD-OCT system using a linear CCD array.</figref><figref num="25">It is a schematic diagram which shows the example of SECM / SD-OCT probe.</figref><figref num="26">FIG. 5 is a schematic diagram showing an example of a SECM / SD-OCT probe containing a single optical fiber used for both SECM and SD-OCT configurations.</figref><figref num="27">FIG. 5 is a flow chart of an example method used for adjusting the focus of a SECM image using SD-OCT data.</figref><figref num="28">It is a schematic diagram which shows the cross section of the exemplary catheter cable.</figref><figref num="29">It is a schematic diagram which shows the example of the probe including the beam deflection optical apparatus which miniaturizes the probe structure.</figref><figref num="30A">It is a schematic diagram of the translational scanning method which shows the miniaturized probe structure at the time of sending a probe to an imaging part.</figref><figref num="30B">It is a schematic diagram of the translational scanning method in which the inner housing of the probe is at the distal limit of the translational range.</figref><figref num="30C">It is a schematic diagram of the translational scanning method in which the inner housing of the probe is at the proximal limit of the translational range.</figref><figref num="31">It is a schematic diagram of the outer housing including a transparent opening.</figref><figref num="32">It is a schematic diagram which shows the example of the small probe including the collimating optical apparatus deviated from the center which can perform rotary scanning from the outside.</figref><figref num="33A">FIG. 5 is a schematic diagram showing an example of a probe including a forward inflatable balloon and an inner housing configured to perform scanning while in contact with the inner wall of the balloon.</figref><figref num="33B">FIG. 33A is a schematic view showing a state in which the probe is in contact with the inner wall of an inflated balloon in the probe of FIG. 33A.</figref><figref num="34A">FIG. 5 is a schematic diagram showing an example of a probe comprising an inflatable outer balloon and an inflatable inner balloon and configured to maintain contact between the probe and the wall surface of the outer balloon when these are inflated.</figref><figref num="34B">In the probe shown in FIG. 34A, it is a schematic diagram showing a probe in which an inflated inner balloon is provided around the probe and is configured to maintain contact between the probe and the inflated outer balloon.</figref><figref num="35A">FIG. 5 is a schematic diagram showing an example of another probe comprising an inflatable outer balloon and an inflatable inner balloon, which are configured to maintain contact between the probe and the wall surface of the outer balloon when they are inflated.</figref><figref num="35B">In the probe shown in FIG. 35A, it is a schematic diagram showing a probe in which an inflated inner balloon is provided between the probe and the outer balloon and is configured to maintain contact between the probe and the inflated outer balloon.</figref><figref num="36A">FIG. 5 is a schematic bottom view of a probe configured to scan along a pullback axis while in contact with the inner wall of an inflatable balloon.</figref><figref num="36B">FIG. 6 is a schematic side view of the probe shown in FIG. 36A.</figref><figref num="36C">It is a side view of the probe shown in FIG. 36A in which the probe is in contact with the inner wall of the inflated balloon.</figref><figref num="36D">It is a front view of the probe shown in FIG. 36C.</figref>

Further objects, features, and advantages of the present invention will become apparent from the following detailed description, along with accompanying drawings showing descriptive embodiments of the present invention.

The same reference numbers and symbols throughout the drawings are used to indicate similar features, elements, parts or parts of the embodiments described unless otherwise specified. Further, a detailed description of the present invention will be made in association with an exemplary embodiment with reference to the figures. It is intended that the following embodiments may be modified or modified without departing from the scope and spirit of the invention as defined in the appended claims.

According to an exemplary embodiment of the present invention, there is provided an endoscopic confocal microscopy that does not require a compact, high-speed scanning mechanism in the probe. Spectral coded confocal microscopy (SECM) can be used as a wavelength split multiple confocal method. SECM can use a broadband light source to encode one dimension of spatial information in the optical spectrum.

An example of SECM is shown in FIG. For example, the output from the single-mode optical fiber 100 located at the distal end of the probe can be parallelized by the collimating lens 110 and irradiated with a dispersed optical element (for example, a transmission diffraction grating 120). The objective lens 130 then focuses each diffraction wavelength at an individual spatial position in the subject, resulting in a crossing line focus 140. Each point on this line is characterized by its own wavelength. For example, an optical signal reflected from a test object such as a cell tissue of an organism can be re-superposed by a diffraction element 120 and collected on the single mode fiber 100. The core aperture of the single mode fiber 100 can act as a spatial filter mechanism that rejects out-of-focus light. The return light spectrum can be measured outside the probe (and optionally inside the system console) and converted to confocal reflectance as a function of lateral displacement within the subject. Decoding of the spectrum is quick. Image formation by beam scanning in the direction perpendicular to the line focal point can be performed by a relatively slow and simple mechanical operation.

In the SECM method, an endoscope RCM can be used, and image data can be provided at a very high speed by using a high-speed linear CCD camera. Commercially available linear CCD arrays can acquire data at speeds of about 60 million pixels or more per second. When these CCD arrays are incorporated into a SECM spectrometer, confocal images can be formed at speeds of 10 times or more that of a typical video rate and up to 100 times that of other endoscopy methods. The high imaging speed and fiber optic design of typical SECM systems enable wide-range microscopy through endoscopic probes.

Optical coherence tomography (OCT) and methods using its variants can be used to screen a wide range of structures. By collecting OCT signals in the wavelength region instead of the time domain, it is possible to obtain an image quality that is orders of magnitude faster while maintaining high image quality. When the spectral region OCT (SD-OCT) method is used, high-resolution ranging of biological tissue can be performed by detecting spectrally decomposed interference between a cell tissue sample and a standard sample. Since the same high-speed linear CCD as the SECM system can be used for the SD-OTC system, images can be captured at 60 million pixels / second, which is faster than the conventional time domain OCT (TD-OCT) system. Is two orders of magnitude faster. This capture rate and resolution allow the SD-OCT system to be used as a structural-level wide-range three-dimensional microscopy in a clinical environment.

Information from exemplary SD-OTC and SECM systems can be utilized in a complementary manner, and hybrid systems utilizing both methods can provide information on cell tissue structure essential for accurate diagnosis. Combinations of different technologies usually require extensive technological development and may sacrifice performance, but SECM and SD-OCT systems can share key components, complicating and increasing costs for each system. It is possible to provide a high-performance multi-modality system substantially without the need for.

A SECM system according to an exemplary embodiment of the invention can utilize a light source with a wavelength scan of 1300 nm and a single element photodetector to obtain spectrally encoded information as a function of time. With this system, it is possible to obtain images with directional resolution (1.4 μm) and distance resolution (6 μm) at a speed of up to about 30 frames per second for a field of view of 400 μm. To show that the SECM system can identify intracellular changes in special intestinal metaplasia (SIM) and Barrett's esophageal metaplasia, some images of the newly resected porcine duodenum are in vitro using a high-speed system. Taken at.

2A-2C show two imaging modes and their corresponding fiber configurations: single-mode illumination-single-mode detection (SM-SM) and single-mode illumination-multimode detection (SM-MM). An example of a SECM image of the intestinal epithelial tissue of a pig obtained in vitro is shown. The SM-SM image of FIG. 2A shows the epithelial tissue structure at 100 μm from the surface of the cell tissue structure using single-mode light source-single-mode detection. The image of the same cell tissue portion obtained by using the single-mode light source-multi-mode detection (SM-MM) with a core opening ratio of 1: 4 shown in FIG. 2B has a smooth appearance and less speckle noise. It may be easier to interpret. FIG. 2C is a magnified image of the image shown in FIG. 2B, showing the presence of villi containing a weakly reflective core (eg, lamina propria or lp) and more scattered epithelial tissue. Bright spots (indicated by arrows) visible at the roots of columnar cells corresponding to the nucleus are shown in FIG. 2C.

The thickness of the esophageal wall imaged in vivo using the OCT method can be reduced to about half by using, for example, an inflated balloon. The thickness of the porcine intestinal specimens shown in FIGS. 2A to 2C was reduced to about the same amount, but the intracellular characteristics observed using the SECM method were well maintained. 3A and 3B are images of this thinned specimen, obtained at depths of 50 μm and 100 μm, respectively.

It was observed that the penetration depth of a commercially available 800 nm laser scanning confocal microscope was reduced by about 20% compared to the 1300 nm SECM system. This decrease in penetration depth is believed to be the result of increased scattering of short wavelength light. Therefore, it is considered that the use of a SECM system using an 840 nm light source provides a sufficient penetration depth to identify intracellular structures such as intestinal epithelial tissue.

FIG. 4 schematically illustrates an apparatus according to an exemplary embodiment of the invention configured to provide a wide range of SECM images. This exemplary device can be configured to obtain an image of a cylindrical specimen 2.5 cm long and 2.0 cm in diameter, which corresponds to the approximate dimensions of the lower esophagus. A 2.0 mW ultra-bright diode 200 (QSSL-790-2, qPhotonics, Chesapeake, VA) with a center wavelength of 800 nm and a bandwidth of 45 nm coupled to the fiber is used to irradiate the 50/50 single-mode fiber optical beam splitter 405. Can be configured. The light transmitted through one port of the splitter is parallelized by the collimator 410 and sent to the focusing device 415 through the fiber 412, and further, the diffraction grating 420 (1780 lpmm, Hologramix, LLC, Hudson, MA) and the focal length (f). 350230-B aspherical lens 425 (Thor Labs, Inc., Newton, 4.5 mm, aperture 5.0 mm, NA 0.55) It is sent to a diffraction grating-lens pair containing NJ). The device can form a focused, spectrally coded, 500 μm long, longitudinal linear array of points 430, or lines, on the inner surface of a columnar specimen. The grating-lens pair may be fixed to the shaft of a motor 435 beside the housing 440 (eg, a motor with a diameter of 15 mm available from MicroMo Electronics, Inc., Clearwater, FL, 1516SR, etc.). As the motor 435 rotates, the entire inner circumference of the columnar specimen can be scanned by the spectrally coded lines. The motor 435, housing 440 and grating-lens pair were mounted using, for example, a computer-controlled linear stage 445 (eg, Nanomotion II with a width of 2.5 cm, obtained from Melle's Griot, Rochester, NY). The columnar specimen may be translated in the longitudinal axis direction during rotation. By this operation, the entire inner surface of the columnar specimen can be scanned in a spiral shape.

The light reflected from the specimen can be returned to the single mode fiber 412 through the optical system and sent from the fiber 412 to the spectrometer 450 and the linear CCD 455. The linear CCD455 may have, for example, 2048 pixels, a linear velocity of 30 kHz, or the like (for example, obtained from Basler Vision Technologies, Exton, PA). The computer 460 can store, analyze, and display image data from the spectrometer 450 and the CCD 455. About 60,000 points can be digitized per motor revolution at 0.5 Hz, or 30 rpm, to obtain a circumferential sample density of about 1.0 μm. The longitudinal speed of the motor can be about 0.25 mm / sec, and the time required to complete scanning of the columnar specimen can be about 100 seconds.

1 / e of a parallel beam in a diffraction grating-lens pair²The diameter can be about 4.0 mm. As a result, the effective NA of this exemplary device is about 0.4, which theoretically corresponds to a spot diameter of about 1.2 μm and a confocal parameter of about 2.5 μm. The theoretical spectral resolution on the sample in a system without optical aberrations is 0.8 Å, which allows up to about 630 decomposable points to be formed on the spectrally coded line 430. The spectrometer 450 in the detection arm can be designed to exceed the expected spectral resolution of the probe.

FIG. 5 shows the results of SECM scanning of the 1951 USAF (US Air Force) resolution test pattern using this device. The smallest bars in this figure are separated at intervals of 2.2 μm, but these were also resolved. The full width at half maximum (FWHM) of the lateral line image distribution function and the FWHM of the axial line image distribution function obtained using a mirror scanning through the focal point were 2.1 μm and 5.5 μm, respectively. The field of view was observed to be approximately 500 μm. These values are slightly lower than the corresponding theoretical values, which is considered to be due to the aberration of the optical path. These parameters indicate that the apparatus of the present invention can exhibit sufficient resolution for confocal microscopy of biological cell tissues.

FIG. 6 shows an example of SECM image data of a pullback image of a 2.5 cm simulated test object. Polar coordinates were converted to Cartesian coordinates before forming the image displayed here. As the simulated test object, a Teflon (registered trademark) tube having an inner diameter of 2.1 cm with a lens paper attached to the inner surface was used. In the low-magnification image of FIG. 6A, the macrostructure of the paper including creases and voids is observed. The visible fringes on the outer circumference are believed to be due to low spectral power and lens aberrations present on or near the edges of the spectrally coded lines. Each fiber and the microstructure of the fiber is clearly resolved in the region of this dataset shown at high magnification in FIGS. 6B-6E.

The focusing device 415 of FIG. 4A was adjusted to obtain cylindrical two-dimensional (2D) images of this simulated sample at five different focal depths up to 120 μm. The five images 710 to 750 of FIG. 7 were added to create an integrated image 760. The integrated image shows almost the entire surface of the simulated specimen.

Image formation of a biological specimen using a SECM device as described here may be complicated because the optical scanning head does not have a centering device. To further improve the generation of wide-field microscopic images and data, porcine intestinal specimens were placed on top of a 2.0 cm diameter transparent cylinder. A 360 degree scan of this sample was completed within 1 second. The photograph is shown in FIG. 8A. The imaged cell tissue is found in only one location on the cylinder scan because the specimen was off center of the probe and did not completely wrap around the cylinder. 8B-8D are a series of magnified images of the cell tissue specimen. The image shown in FIG. 8B is a magnified image of a 1.5 cm square portion surrounded by the dotted line in FIG. 8A. Similarly, the image of FIG. 8C is an enlarged image of the square portion of FIG. 8B, and FIG. 8D is an enlarged image of the square portion of FIG. 8C. The enlarged image of the cell tissue in FIG. 8B suggests a glandular structure. Enlarged images from FIGS. 8C to 8D show villus and nuclear tissue similar to those observed using the 1300 nm SECM system as shown in FIGS. 2 and 3. The other SECM scanning regions shown in FIG. 8A show artifacts (unnatural results) such as specular reflection from the transparent cylinder and lack of signal, due to improper alignment of the SECM convergent beam. Conceivable.

Performing extensive confocal microscopy in the patient's body presents various technical challenges. Such issues include, for example, increasing the imaging speed, downsizing the optical and mechanical parts of the probe, integrating the centering mechanism, and introducing technology for dynamically changing the focal plane.

The image acquisition speed of the SECM system can be improved by about 2 to 4 times as compared with the above-mentioned exemplary system. Such improvements can be made by adding some kind of improvement. For example, a high power semiconductor light source (eg, Superlum Diode, T-840 HP: 25 mW, 840 nm, 100 nm spectral bandwidth) can provide approximately 1000 spectrally decomposable points. Since such optical intensity improves sensitivity and a large bandwidth widens the field of view, scanning of the SECM beam can be made approximately twice as fast. Also, optical circulators such as OC-3-850 (Optics for Research, Caldwell, NJ) can increase the efficiency of light transmitted to and collected from the probe. A faster and more sensitive linear CCD, such as an AVIIVA M4-2048 (Atmel) with 2048 pixels and a read speed of 60 kHz. The use of Corporation) or the like doubles the data acquisition rate and improves the response spectrum of the entire wavelength range used for image data formation. Further, for example, the performance can be improved by using a camera link interface having a data transfer speed of about 120 MB / sec from the camera to the hard drive array of the storage device.

Sensitivity is a system parameter that affects confocal image quality and penetration depth, and can be understood as indicating the minimum detectable reflectance. When using the near-infrared RCM method, a part of the incident light, that is, about 10^-4〜１０^-7Degree is reflected from a depth of up to approximately 300 μm of the skin. Based on the NA of the objective lens used in the exemplary system according to the exemplary embodiments of the invention described herein and the observation that the skin attenuates light more significantly than non-keratinized epithelial cells. The exemplary probe objective described in is a 3 × 10 irradiation light reflected from a deep part of the cell tissue.^-4〜３×１０^-7A considerable amount of light can be collected. A 25 mW light source can be separated into, for example, approximately 1000 independent beams. The maximum double-pass insertion loss can be estimated to be approximately 10 dB, including probe loss of 6 dB and fiber optics and spectrometer loss of 4 dB. Thus, for each line formation time based on these estimated parameters, each pixel in the array will be illuminated by approximately 50 to 50,000 photons / pixel.

Using the multimode detection method, a signal gain of about 10 times is obtained, resulting in approximately 500 to 500,000 photons / pixel per scan for such a configuration. For example, one pixel of an Atmel AVIIVA M4 camera reliably detects light if the signal is greater than or equal to the dark current fluctuations that occur at approximately 240 photons. Assuming the device has a quantum efficiency of approximately 50% for these wavelengths, the smallest detectable signal would be approximately 480 photons / pixel per scan. Based on the above estimates, the Atmel camera will have sufficient sensitivity to capture SECM images of deeper cell tissue. Detection of the minimum expected reflectance constrained by quantum noise can be achieved by using multimode for collection or by increasing the output of the light source.

FIG. 9 shows a schematic view of an apparatus according to an exemplary embodiment of the invention capable of widespread microscopic imaging of epithelial organs. The light source 900 may be a broadband light source or a wavelength scanning light source, supplying light through a circulator 910, or instead a fiber splitter. This light is sent to the imaging catheter 930 through the scanning mechanism 920. Scanning is done outside the catheter or inside the catheter. In certain preferred exemplary embodiments, pullback scans may be performed outside the catheter and rotational scans may be performed inside the catheter. The collected reflected light is detected by a detector 940 such as a spectrometer when, for example, wideband light is used. The detector 940 may be a single detector when a wavelength scanning light source is used. The data from the detector 940 is processed, displayed and / or stored by the computer 950. The computer 950 may be configured to control and synchronize the scanning procedure.

When examining large luminal organs, the distal portion of the catheter is placed in the inner center of the lumen, with a constant focal length and / or depth relative to the tissue, and a circumferential orientation over a length of several centimeters. It is preferable to obtain the image of. These conditions are satisfied by integrating the circumferential scanning imaging probe in the centering device. Placing the imaging optics on or near the centering device can otherwise occur, for example, in eliminating surface height fluctuations and simplifying focusing conditions, as well as in the physical coupling between the imaging system and the patient. , Motion artifacts can be significantly reduced, and other advantages are added.

FIG. 10 shows a schematic diagram of the distal end of a SECM catheter according to an exemplary embodiment of the present invention. Light is supplied through the optical fiber 1000 and parallelized using the collimating lens 1010. The optical fiber 1000 may be fixed by the fiber chuck 1005. This light passes through a varifocal mechanism 1015 and a cylindrical lens 1020 configured to pre-compensate the optical path to correct astigmatism. The light is then diffracted by a diffraction grating 1025 configured to diffract the center wavelength at, for example, an angle of about 90 degrees, and focused on line 1035 spectrum coded by the imaging lens 1030.

Speckle-like artifacts can be reduced by performing multimode detection with increased pinhole apertures associated with the optical fiber 1000. This method increases the signal throughput and reduces speckle-like artifacts, although the spatial resolution is slightly reduced. When performing this method in spectral coding, a double clad optical fiber can be used, the cell tissue can be irradiated with a single mode core, and reflected light can be detected by a multimode internal clad.

The imaging lens 1030 preferably has a relatively long working distance of, for example, about 2 to 7 mm, and holds a large NA of about 0.25 to 0.5. Further, the imaging lens 1030 can be thinned so as not to exceed a thickness of preferably about 5 mm. Conventional lenses such as aspherical or achromatic may be used for the imaging lens.

The inner housing 1040 can enclose some or all of the various optical components and the motor 1045 so that the components can be longitudinally aligned within the outer housing 1060. If some of the characteristics of the inner housing 1040 have high light transmission characteristics and small distortion of the wave surface, high image quality can be obtained while maintaining the structural rigidity of the motor shaft 1050 at the center of the probe. Materials used to make part or all of the inner housing 1040 transparent windows include, for example, glass or plastic materials such as Pevacs and high density polyethylene (HDPE).

The outer housing 1060 can be configured to surround the inner housing 1040 and be placed at a fixed position with respect to the imaged cell tissue 1080 using the centering mechanism 1065. The inner housing 1040 can be moved by the pullback cable 1065 through the opening in the wall of the outer housing 1060. A translation device available from a computer-controlled translation device (eg, Newport Corp., Irvine, CA) while holding the outer housing 1060 in a fixed position relative to the cell tissue 1080 to image. By connecting to), linear scanning can be performed. Such a pullback method can be used, for example, to obtain an OCT image in the longitudinal direction of the esophagus. All or part of the outer housing 1060 may be made transparent so that light can pass through it. The optical characteristics of the transparent portion of the outer housing 1060 can be similar to that of the inner window 1055.

The cylindrical lens 1020, the diffraction grating 1025, and the imaging lens 1030 may be housed in, for example, a rotating housing 1070 fixed to the motor shaft 1050. As the motor 1045, a conventional small motor having a diameter of about 1.5 mm or less may be used. The use of encoders improves image quality and registration, but at the same time can increase the diameter of the motor to 6-10 mm. Such motors are described, for example, by MicroMo Electronics, Inc. (Clearwater, FL). The dimensions of the motor wire can be minimized so as not to obstruct the field of view of the device. Circumference scanning can be performed by rotating the rotating housing 1070 inside the inner housing 1040 via the motor shaft 1050 of the motor 1045.

FIG. 11 schematically illustrates a catheter according to an exemplary embodiment of the invention configured to rotate the inner housing 1040 with respect to the outer housing 1060 from a position outside the distal end of the catheter. The rotational motion is transmitted through the optical rotary junction 1100, allowing light to be introduced into the rotating optical fiber 1110. The rotary junction may also hold an electrical connection via one or more wires 1120 and a mechanical connection via a rotatable pullback cable 1030 configured to control the pullback and focusing mechanisms. it can. Since the inner housing 1140 in the exemplary device configuration of FIG. 11 does not surround the motor, it can be made smaller and lighter.

Cylindrical lenses can be used to correct astigmatism caused by the walls of balloons or other centering devices and / or transparent windows or transparent portions of the inner or outer housing. Curved glass produces astigmatism, similar to that of negative cylindrical lenses. For example, the astigmatism caused by the two curved transparent walls shown in FIG. 12A is optically similar to the negative cylindrical lens shown on the right side of the figure. In any of the objects shown in FIG. 12A, astigmatism occurs because the light passing through the central dashed line has a shorter optical path than the light passing through the upper or lower dashed line. In order to correct this optical distortion efficiently and accurately, for example, as shown in FIG. 12B, a curved window similar to a window that induces astigmatism may be installed on the optical path. In order to perform optical correction of astigmatism, it is necessary to make the curved axis of the curved window for correction perpendicular to the axis of the curved housing window.

Another exemplary embodiment of the invention provides an endoscopic SECM system capable of imaging a wide range of organs without the need for user intervention during image data acquisition. The system has the ability to consider movements such as heartbeat, respiration and / or peristalsis. By utilizing some kind of centering mechanism, the artifacts caused by the movement of the imaged cell tissue can be significantly reduced. For example, the variation in distance between the imaging system device and the cell tissue to be imaged can range as much as ± 250 μm during a single wide scan. This change in distance is slower in time (for example, a few seconds) than the circumferential scan, but it is the time required to scan the length of the cell tissue region during the longitudinal pullback of the imaging system device. It is remarkable in comparison.

In certain exemplary embodiments of the invention, methods are used to reduce or eliminate the effects of tissue movement during sampling. This method can include the procedure of acquiring image data over a wide range of depth of focus, as shown in FIG. 13A. If the desired image depth is, for example, 200 μm and the variation in distance between the imaging system device and the cell tissue is, for example, ± 250 μm, the image data can be acquired from a focal range of about 700 μm. This procedure makes it possible to obtain image data from the entire volume of desired cell tissue. Upon imaging, many parts of the volumetric image may not contain cell tissue, but it is likely that at least one good image will be obtained from most areas of the volume of cell tissue of interest.

A second exemplary method used to compensate for tissue movement during imaging is shown in FIG. 13B. The method may include a procedure for determining the distance between the imaging lens and the tissue to be imaged. This distance can be tracked and the focus of the lens can be adaptively controlled to align a known focal length with respect to the tissue surface to collect image data of the tissue volume of interest. Since adaptive control of focus can reduce the number of focal scans required, it can also reduce the time required to cover a large area of tissue volume of interest. The focus of light can be controlled by using, for example, an interference signal, a flight time signal, the intensity of electromagnetic radiation, and the like.

A mechanism for adjusting the focal length of the imaging system device can be utilized in the above-mentioned exemplary method for coping with the movement of the cell tissue to be imaged. There are several examples of ways to adjust the depth of focus within the volume of tissue imaged. For example, the inner housing of the imaging system device including the focus lens can be moved relative to the outer housing. To achieve such movement, the multilayer bimorph piezoelectric actuator 1410 shown in FIG. 14A (eg, D220-A4-103YB, Piezo Systems, Inc., Cambridge, MA, etc.) may be attached, for example, to the metal sheets 1420 at both ends to bend the ceramic material. By installing these actuating devices back to back as shown in FIG. 14A, these free motion ranges can be effectively doubled. Four such actuating devices 1430 can be placed between the outer sheath 1440 and the assembly 1450 containing the motor and the focus optics surrounding the motor, as shown in FIG. 14B. By controlling and moving the assembly 1450 with respect to the outer housing 1440 using these actuating devices 1430, the focal position can be changed over the entire required range. This method may require electrical wiring due to the high voltage used within the probe, which crosses the field of view, blocks, and / or the overall diameter of the probe that houses the imaging system, for example. It may be several mm larger.

FIG. 15 shows an alternative example of a method that can be used to adjust the focal length of the imaging system device. A cable housing 1510 is provided that surrounds the cable 1530. The cable 1530 is attached to the collimating lens 1540 at one end thereof. The collimating lens 1540 may be configured to be movable in the longitudinal direction with respect to the housing 1550. The focal length can be changed by moving the collimating lens 1540 with respect to the housing 1550 and other optical components. This translation can be controlled, for example, from outside the imaging catheter using a cable 1530 as shown in FIG. Alternatively, the movement of the collimating lens 1540 can be controlled, for example, by an electric motor or piezoelectric motor provided inside the catheter. The focal length can also be changed by moving the optical fiber 1520, which irradiates the light required for imaging the cell tissue, with respect to the collimating lens 1540. Alternatively, both the optical fiber 1520 and the collimating lens 1540 may be relatively moved to change the focal length.

When the magnification of the image pickup device is M, the distance between the optical fiber 1520 and the collimating lens 1540 is approximately M.²When the distance of Δz is changed, the focal length changes by Δz. For example, assume that the magnification of the exemplary imaging device is approximately 3. In order to change the focal length by about ± 450 μm, it is necessary to move the distance between the optical fiber 1520 and the collimating lens 1540 by about ± 4.0 mm. It is also possible in the above method.

An electrically adjustable varifocal lens can be utilized as an example of yet another method for varying the focal length. For example, a commercially available lens for a camera-equipped mobile phone shown in FIG. 16 (Variotropic AMS-1000, Lyon, France) can be used to change the focal length of the imaging device according to the exemplary embodiment of the present invention. The lens 1600 uses the principle of electrowetting to change the focal length between about -200 mm and 40 mm, and the optical quality is limited only by the diffraction effect. The effective opening (CA) of this exemplary lens 1600 is 3.0 mm and the outermost diameter (OD) is 10 mm. Similar lenses with CA 4.0 mm and OD 6.0 mm can also be manufactured. The full range response time of this exemplary lens 1600 is about 150 ms, which is fast enough to track the distance between the optics and the surface of the cell tissue and adjust the focal length accordingly. It would also be possible to make a lens of the same type with a response time of about 10 ms. By using a variable lens as described above between the collimator and the SECM diffraction grating, a variable focal length can be obtained with a width of about ± 300 μm or more.

According to an exemplary embodiment of the present invention, the inner housing can be configured in various ways. For example, as shown in FIG. 17A, the housing 1700 can be formed from a transparent material. Alternatively, as shown in FIG. 17B, the housing may be provided with a transparent window 1710. Further, as shown in FIG. 17C, an opening 1720 may be provided between the two walls, or as shown in FIG. 17D, an opening may be provided in the vicinity of the motor 1730 attached to the housing.

An exemplary schematic diagram of a control and data recording device that can be used in the exemplary system shown in FIG. 9 is shown in FIG. The apparatus shown in FIG. 18 is configured to record the position of the beam while acquiring the image data 1800, and can more accurately register the spatial position of the image data 1800. As shown in FIG. 18, the image data 1800 is acquired by the data acquisition control unit 1810. The catheter scanning device can scan the beam using, for example, a rotary motor 1820 for angular movement of the beam and a pullback motor 1830 for moving the beam in the longitudinal direction. The rotary motor 1820 can be controlled by the rotary motor control unit 1840, and the pullback motor 1830 can be controlled by the pullback motor control unit 1850. Each control may be performed by a closed loop operation. Data acquisition and control units 1810 can command motor control units 1840 and 1850 to specify specific motor speeds and / or positions. Encoder signals generated from the motors 1820 and 1830 are sent to both the motor control units 1840 and 1850 and the data acquisition control unit 1810. In this way, the encoder signals associated with the 1820 and 1830 motors are recorded as the lines of image data 1800 are collected, thereby allowing accurate beam positions to be associated with each line of data 1800.

FIG. 19 shows various scanning sequences that can be used for an imaging catheter according to an exemplary embodiment of the present invention. For example, FIG. 19A shows an example of a scanning method in which rotary scanning is performed as the first order and axial (pullback) scanning is performed as the second order. This method gives a dataset with a spiral array. As shown in FIG. 19B, another scanning method can perform axis scanning in small increments, followed by one rotation of each axis scanning. Instead, if the axis (pullback) scan is performed as the first rank and the rotary scan is performed as the second rank, a scan pattern as shown in FIG. 19C is formed. Higher image quality can be obtained in the direction of the first scanning order. Therefore, the selection of the scanning order can be determined depending on whether a landscape (rotation) image or an axial image is preferable. Imaging of organs and cell tissues with different symmetries can be performed in several ways. For example, a circular scanning pattern as shown in FIG. 19D can be used to image certain organs.

In yet another exemplary embodiment of the invention, a balloon catheter as shown in FIG. 10 can be configured to allow for a procedure of rapid replacement and installation using a guide wire. In one rapid replacement, installation procedure, the guidewire can be placed first in the organ to be imaged and then the catheter can be advanced along the guidewire. This procedure allows the catheter to be installed more easily and more accurately in many applications. Various configurations can be used to guide the catheter by the rapid replacement procedure. For example, FIG. 20A shows an exemplary guide wire 2000 through a hole 2010 at the distal end of the outer housing 2040. In the second exemplary configuration shown in FIG. 20B, the guide wire 2000 passes through a tube 2020 attached to the distal end of the outer housing 2040. Alternatively, as shown in FIG. 20C, the guide wire 2000 can be configured to pass through a tube 2020 attached to the proximal end of the outer housing 2040.

Examples of the procedure for aligning the catheter using a guide wire at the center of the lumen of the catheter are shown in FIGS. 21A to 21C. First, as shown in FIG. 21A, the guide wire 2100 is installed inside the organ 2150. Then, as shown in FIG. 21B, the outer housing 2110 of the catheter is passed over the guide wire 2100 together with the balloon 2120. Finally, as shown in FIG. 21C, the inner housing 2130 is passed through the center of the lumen of the catheter. The inner housing 2130 may include an optical device, and the optical device can be used for imaging.

Two configuration examples of the balloon catheter are shown in FIG. In FIG. 22A, the balloon 2210 can be inflated using a device 2200 containing a compressed air or gas source. A tube or small diameter passage 2230 is provided connected to the balloon 2210 surrounding the catheter to allow pressurized air or gas to be delivered to the balloon 2210. The pressure inside the inflating balloon 2210 can be monitored using a pressure gauge 2220. This pressure optimizes the expansion of the balloon and allows the catheter placement to be confirmed by monitoring the pressure in the surrounding organs with which the inflated balloon comes into contact. Alternatively, a passage 2240 may be provided along the outer sheath of the catheter as shown in FIG. 22B to deliver pressurized air or gas to the balloon 2210. A balloon whose diameter can be changed in response to a change in pressure may be used. The depth of focus can be controlled by changing the diameter of the balloon by supplying pressurized air or gas to the balloon 2210 and moving the surrounding cell tissue with respect to the imaging lens.

Examples of catheter structures used in another exemplary embodiment of the invention are shown in FIGS. 23A-23C. This catheter design can be configured to use one or more stretchable stranded wires 2300 to align the optical core inside the imaging device with the center within the luminal organ. As shown in FIG. 23A, the catheter can include an additional sheath 2310 and a set of expandable stranded wires 2300 provided around the outer housing 2320 and located inside the sheath 2310. After installing the catheter, the wire 2300 can be pushed into the sheath 2310 as shown in FIG. 23B so that the stranded wire protrudes from the end of the outer sheath. Alternatively, the sheath 2310 can be retracted from the outer housing 2320. A stranded wire 2300 of sufficient length is exposed around the outer housing 2320 so that the wire 2300 expands the surrounding organ or cell tissue and allows the housing 2320 to be centered, as shown in FIG. 23C. After the imaging procedure is complete, the stranded wire 2300 can be pulled back into the sheath 2310 to remove the catheter.

The OTC and RCM method examples can exclude or ignore multiple scattered light from the sample of cell tissue to be imaged, so that backscattered photons that may contain structural information can be detected alone. .. However, these methods eliminate multiple scattered light by different methods.

For example, the RCM method employs a method of confocal selection of light reflected by a cell tissue imaged from a strongly focused incident light. The RCM method is performed by fast scanning the focused light on a plane parallel to the surface of the cell tissue, thereby obtaining a lateral or front view of the cell tissue. Using a large numerical aperture (NA) as used in conventional RCM methods, very high spatial resolution (eg, a resolution of approximately 1-2 μm that allows visualization of intracellular structures) can be obtained. However, imaging procedures with high NA are often particularly sensitive to aberrations caused by the propagation of light through non-uniform cell tissue. Therefore, high resolution images produced by the RCM method are typically limited to a depth of 100-400 μm.

Since the OCT method utilizes the principle of a coherent diffraction grating for optical sections, it is not necessary to rely on the use of high NA lenses. Therefore, the OCT method can be performed using an imaging lens having a relatively large confocal parameter. This increases the penetration depth into the imaged cell tissue (eg, approximately 1-3 mm) and provides a cross-sectional image format. These advantages may come at the expense of reduced lateral resolution, with lateral resolution typically on the order of about 10-30 μm.

Therefore, in consideration of the above-mentioned contrast, the exemplary OCT method and the RCM method can provide complementary and different image information. For example, the RCM method provides intracellular details, while the OTC method provides, for example, structural morphology. Image information from these two dimensional regions is very important for histopathological diagnosis, and in many cases it is difficult, if not impossible, to make an accurate diagnosis without both. The combination of these different imaging methods usually involves extensive development efforts and performance compromises, but the SECM and SD-OCT methods can share several components. Therefore, it is possible to provide a high-performance multi-modality system that employs both of these imaging methods without causing a substantial increase in complexity and cost as compared with a system that uses only one of these methods.

FIG. 24A shows an outline of an example of a system in which both the SECM method and the SD-OCT method can be executed according to an exemplary embodiment of the present invention. In this system example, a part of the bandwidth of the broadband light source can be used for acquiring SECM image data, and another part of the bandwidth can be used for acquiring, for example, SD-OCT data. For example, a light source 2400 can be used to supply electromagnetic energy with a bandwidth greater than about 100 nm. Examples of devices that can be used as light source 2400 are diode-excited ultrafast lasers (eg, available from ArrayOCT, Femtorers Productions GmbH, Vienna, Germany), or superluminescent diodes (Superlumin, Lussia). There is an array of things such as

A portion of the light source spectrum used for SD-OCT data (eg, light having a wavelength of about 81-910 nm) is separated from the portion of the spectrum used for SECM data using a wavelength division multiplexing (WDM) 2410. Can be sent to the catheter 2420 and the reference arm 2445. Light returning from the catheter 2420 through the SECM fiber optics 2430 and SD-OCT fiber optics 2440 can be sent to the spectrometer 2450. The spectrometer 2450 is configured such that approximately half of the elements of the CCD array 2460 illustrated in FIG. 24B can detect signals associated with SECM data and approximately half of the CCD elements can detect signals associated with SD-OCT data. Can be done. For example, SD-OCT data can be converted into axial structural data by performing a Fourier transform from the wavelength space to the wave number space (k space) after interpolating the SD-OCT data. For example, if the spectrometer 2450 has a resolution of about 0.1 nm, the total distance measurement depth of the SD-OCT may be deeper than about 2.0 mm. The resolution of the axial image using SD-OCT is about 5 μm.

An outline of an example of a SECM / SD-OCT probe is schematically shown in FIG. This probe is similar to, for example, the probe shown in FIG. 15 and further includes an apparatus configured to form an SD-OCT beam path. In order to obtain the SD-OCT beam, the OCT optical fiber 2500 can be inserted into the inner housing together with the SECM optical fiber 2510. The OCT optical fiber 2500 can be configured to illuminate the small lens 2520. The confocal parameters and spot size of the SD-OCT beam are selected so that a tomographic image of the entire distance measurement depth is formed. The confocal parameter and spot size values are, for example, about 1.1 mm and 25 μm, respectively. The NA of the SD-OCT lens 2520 can be selected, for example, to be approximately 0.02, and the diameter of the parallelized SD-OCT beam can be selected, for example, to approximately 200 μm. A dichroic mirror 2530 can be installed in front of the SECM diffraction grating to reflect the SD-OCT light beam 2540 and pass through the SECM light beam 2550. The dichroic mirror 2530 shown in FIG. 25 is arranged at an angle of about 45 degrees with respect to the SD-OCT light beam 2540. Increasing this angle by applying an appropriate coating to the mirror 2530 allows the SD-OCT beam 2540 to be superimposed on the SECM beam 2550, allowing more accurate spatial position registration of these two images. it can. The optical aberration of the SD-OCT beam 2540 caused by a curved window, balloon, or the like can be corrected by using a cylindrical element for preliminarily correcting astigmatism as shown in FIG. 12B.

Another exemplary embodiment of a catheter probe that can be used for both SECM imaging and SD-OCT imaging is shown in FIG. Broadband light can be supplied through a single optical fiber 2600 instead of the two different fibers 2500 and 2510 shown in FIG. Part of the light used to form the SD-OCT beam 2640 is reflected out of the optical path of the SECM beam 2650 by the dichroic mirror 2610. The diameter of the SD-OCT beam 2640 is reduced by focusing the SD-OCT beam 2640 with the aperture 2620 and / or the lens 2630. Although the depth resolution of SD-OCT is between about 20-100 μm, the SD-OCT device can still be used to identify the surface location of cell tissue imaged by the SECM method. This can be done even if the bandwidth of the SD-OCT beam 2640 is insufficient to obtain a high quality SD-OCT image.

The data obtained from the exemplary SD-OCT images can be used to adjust the focal plane of the SECM beam. FIG. 27 shows an example of a flow chart of this method. For example, SD-OCT image data may be acquired by depth scanning (step 2700) and then processed (step 2710). This image data may be analyzed and displayed as an SD-OCT image (step 2720). This image data can also be used to locate the cell tissue surface using, for example, an edge detection algorithm (step 2730). Once the location of the cell tissue has been identified, the position of the focal plane of the SECM device can be adjusted using a variable focus mechanism (step 2740). This focus adjustment method can be performed at high speed (for example, within about 100 ms), which enables real-time tracking and focusing of the cell tissue surface. The position of the cell tissue edge can be adjusted by the angle formed with respect to the SECM beam.

A cross section of a catheter cable 2800 that can be used in certain exemplary embodiments of the invention is shown in FIG. Cable 2800 is, for example, a pullback cable 2810, multiple wires 2820 configured to power a motor, a focus control cable 2830, a channel configured to send gas or other fluid to an inflatable balloon or membrane. 2840, SECM fiber optic 2850 and / or SD-OCT fiber optic 2860 may be included.

An example of an exemplary probe 2900 is schematically shown in FIG. The probe 2900 includes two prisms 2910 configured to refract the beam 2920 before passing through the grating 2930 and the imaging lens 2940. According to this configuration example, a large space for arranging the objective lens 2940 can be taken inside the probe 2900, and as a result, high NA and / or the probe 2900 can be miniaturized.

The probe length can be further reduced by using the exemplary probe configuration 3000 shown in FIGS. 30A-30C. The probe 3000 includes an inner housing 3010 that is installed inside the outer housing 3020 as shown in FIG. 3A when the probe 3000 is sent to the imaging position. When the probe is placed in the tissue or organ to be imaged and centered, the inner housing 3010 slides inside the outer housing 3020, extending the pullback range, as shown in FIGS. 30B and 30C. can do. For example, if the imaging lens 3020 is provided near the center of the inner housing 3010, the position stability is increased even at the extreme scanning positions shown in FIGS. 30B and 30C.

An example of the outer housing 3100 is shown in FIG. The outer housing 3100 can be made of a rigid material such as stainless steel or plastic. The outer housing may include one or more gaps 3110 that allow light to pass through and generate image data without causing aberrations. Optionally, the gap 3110 may include a transparent window.

FIG. 32 shows an example of a probe according to an exemplary embodiment of the present invention. The probe 3200 has a small component configuration, and the probe size can be reduced as a whole. For example, the cylindrical inner housing 3210 can be configured to freely rotate and move inside the cylindrical outer housing 3220, with the collimating lens 3230 and the optical fiber 3240 separated from the center of the inner housing 3210. It can be installed. The scanning of the cell tissue to be imaged is performed from the outside, and the movement of the inner housing 3210 is controlled by the pullback cable 3250.

In one exemplary embodiment of the invention, a fluid such as water or refractive index matching oil can fill the space between the imaging lens and the cell tissue to be imaged. The use of such fluids can improve optical parameters such as NA and / or reduce the back reflection of the light beam used to acquire the image data.

An example of the probe configuration 3300 in which high NA can be used for image data acquisition is shown in FIGS. 33A and 33B. For example, the inner housing 3310 is provided inside the outer housing 3320. At this time, an uninflated balloon 3330 may be included. The uninflated balloon 3330 may be inflated so that it inflates in front of the outer housing 3320. After that, the inner housing 3310 is arranged inside the balloon 3340 inflated outside the outer housing 3310. As shown in FIG. 33A, the elastic device 3350 can be provided between the inner housing 3310 and the outer housing 3320 in a compressed state. The elastic device 3350 can be configured to align the inner housing 3310 with respect to the inner wall of the inflated balloon 3340 when the inner housing 3310 is arranged as shown in FIG. 33B. The inner housing 3310 can be configured to scan the outer cell tissue region of the inflated balloon 3340 with a pullback cable 3360. The cable 3360 may be capable of controlling both the rotation of the inner housing 3310 and the longitudinal translation (eg, pullback) inside the inflated balloon 3340. Spacers 3370 can be used to improve contact between the imaging optics and the inflated balloon 3340 or near the surface of the cell tissue.

Examples of another exemplary probe configuration 3400 according to one exemplary embodiment of the invention are shown in FIGS. 34A and 34B. In this configuration, the inner housing 3410 of the probe can be held on the inner wall of the outer balloon 3420. For example, these can be provided so that the outer balloon 3420 and the inner balloon 3430, which are shown in the uninflated state in FIG. 34A, surround the inner housing 3410. Each balloon can be inflated as shown in FIG. 34B. In this configuration example, the inner housing 3410 may be attached to one surface of the inner balloon 3430. Rotational and translational scanning within the outer balloon 3420 may be performed by moving the inner housing 3410 together with the inner balloon 3430 with respect to the outer balloon 3420.

Yet another probe configuration 3500 according to one exemplary embodiment of the invention is shown in FIGS. 35A and 35B. In this configuration, the inner housing 3510 of the probe can be held on the inner wall of the outer balloon 3520. The outer balloon 3520, shown as uninflated in FIG. 35A, can be inflated inside the organ or tissue region to be imaged. The inner balloon 3530, which is shown as uninflated in FIG. 35A, may be provided between the inner housing 3510 and the outer balloon 3520. As shown in FIG. 35B, the inner balloon 3530 can be inflated and the pressure of the inner balloon 3530 can maintain contact between the inner housing 3510 and the inner wall of the outer balloon 3520. The probes 3400 and 3500 exemplified in FIGS. 34 and 35, respectively, may be used without an outer housing. The uninflated balloons 3420, 3430, 3520, 3530 may be packed in an outer package used to feed the probes 3400, 3500 into the desired position. Optionally, such an outer packaging can be formed, for example, from a meltable material.

Configuration examples of the SECM probe are shown in FIGS. 36A to 36D. This configuration can provide a spectrum-coded line 3610 that lies perpendicular to the axis of the organ or balloon cylinder. A bottom view of this probe configuration is shown in FIG. 36A, and a corresponding side view is shown in FIG. 36B. FIG. 36C shows another side, where the probe housing 3640 is located within the inflated balloon 3650, as in FIG. 33B. In this configuration example, the longitudinal direction (for example, pullback) can be the main scanning direction, and the probe housing 3640 moves in this longitudinal direction at a relatively high speed. Scanning in the rotational direction around the longitudinal axis is performed at a slower speed than scanning in the longitudinal direction. The probe 3600 can be provided with an alignment device as shown in any of FIGS. 33 to 35. The probe housing 3640 includes a mirror 3620 configured to deflect light towards an appropriately arranged diffraction grating to form a spectrally coded line 3610 configured as shown in FIGS. 36A and 36D. be able to.

The combination of SD-OCT and SECM imaging system devices in the probe provides an effective device for acquiring structural information of different scales using different image formats. The data obtained by both imaging methods can be acquired at the same time because the resolutions of these two methods are different. However, the available scan speeds for these two methods may not be compatible with each other. For example, a typical SECM scanning speed is given by a rotation speed of about 1 Hz and a longitudinal pullback speed of about 1 mm / s. On the other hand, a typical scanning speed for obtaining SD-OCT image data is, for example, about 50 to 100 Hz in the rotation direction and about 0.2 to 0.5 mm in the longitudinal direction.

One method used to obtain well-sampled wide-range image data for both methods is to additionally perform a well-sampled wide-range SD-OCT scan after collecting the SECM dataset. There is a way. With this method, the data collection time for the cell tissue region may be increased by, for example, 1 to 2 minutes. Encoder signals obtained from both rotary motors and linear moving motors can be digitized for each scan. Quantitative correlation between SD-OCT images can be performed to determine the angle and rotational offset of each scan, and the encoder signal can be corrected for the balloon position shift. This method makes it possible to register SD-OCT and SECM datasets accurately, i.e. spatially within a range of about 500 μm.

In another exemplary embodiment of the invention, for example, an organ or organ in which an imaging system device provided within a probe is operated in a simple imaging mode (eg, a scout image) and the catheter used to deliver the probe is imaged. It can be determined whether or not it is properly placed in the cell tissue. After confirming that the catheter is properly installed, a wide range image dataset can be obtained.

In yet another exemplary embodiment of the invention, the balloon centering catheter may be inflated with an optically transparent material other than air, such as water, heavy water (D2O) oil. Lubricants can also be used to assist in catheter insertion. If the presence of mucus reduces image quality in certain exemplary embodiments of the invention, a secretory inhibitor may be administered prior to image data acquisition to reduce mucus in the organ being imaged.

The above is merely a description of the principle of the present invention. Various improvements and changes to the embodiments described above will be apparent to those skilled in the art from what is taught herein. In fact, the devices, systems and methods according to the exemplary embodiments of the invention can be used with any of the OCT, OFDI, SD-OCT systems or other imaging systems, eg, all of which are here by reference. International patent application number PCT / US2004 / 029148 filed September 8, 2004, US patent application number 11/266,779 filed November 2, 2005, and US patent application filed July 9, 2004. It can also be used for the system described in numbers 10 / 501,276. Therefore, it is understood that a number of systems, devices and methods not explicitly stated or specified herein can be devised by those skilled in the art and embody the principles of the present invention and are therefore included in the spirit and scope of the present invention. To. Moreover, the findings of the prior art are explicitly incorporated above by reference, but these are those that clearly incorporate the whole. The publications referenced above are also referenced in their entirety and incorporated here.