Single-axis confocal endoscope based on ultra-compact microsystem

Abstract

A compact single-axis confocal endoscope is provided that is capable of meeting the space requirements of a 2.8 mm diameter endoscope. The single-axis confocal endoscope uses a folded path design implemented between a fixed mirror and a transverse plane scanning mirror, thereby producing a high numerical aperture that allows diffraction-limited resolution with subsurface depth. The scanning mirror is formed on a scanning MEMS assembly in a fixed position and has a central aperture that allows expansion of the illumination beam in the folded path design. A series of spacers are used to maintain the beam focusing optics in a fixed position relative to the scanning MEMS assembly for coupling with a single mode optical fiber.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Patent Application No. 62 / 820,256, filed on March 18, 2019, which is incorporated herein by reference in its entirety.

[0003] Government Support Statement

[0004] This invention was made with government support under Grant No. CA 142750 from the National Institutes of Health. The government has certain rights in this invention. Technical Field

[0005] The present disclosure relates generally to techniques for imaging tissue using optical instruments, and more particularly to techniques for imaging tissue using an ultra-compact single-axis confocal configuration endoscope. Background Art

[0006] The background description provided herein is for the purpose of generally presenting the background of the present disclosure. To the extent described in this background section, the work of the presently named inventors and aspects of the description that may not otherwise be considered prior art at the time of application are not admitted, either explicitly or implicitly, as prior art against the present disclosure.

[0007] Medical endoscopes have been developed to use white light illumination to perform wide-field in vivo imaging of epithelia in hollow organs throughout the human body. In other examples, endoscopes have been used to remotely generate fluorescence imaging by delivering light via flexible optical fibers.

[0008] Endoscopes are moving toward a thinner overall diameter, and most endoscopes are equipped with an instrument channel measuring 2.8 mm. Instruments that can advance through this channel have a wide range of clinical applications. The large bend angle at the entrance of the channel requires the size of the rigid tip to be less than 2.4 mm in diameter and less than 10 mm in length. This small size requirement presents significant challenges for packaging and alignment.

[0009] Confocal microscopy is an example type of endoscope used in medical imaging applications to examine tissue at a specific depth or focal plane. Confocal microscopy typically uses a pinhole to collect only light from the focal plane while blocking light scattered by tissue. Confocal laser endoscopy (CLE) is an example endoscopic technology that uses the core of an optical fiber as a pinhole. CLE has been developed for real-time in vivo imaging with some success.

[0010] CLE techniques have been used in clinical settings to visualize living tissue with subcellular resolution. For example, these techniques have been used in clinical settings to collect "optical biopsies" in vivo in real time. Ideally, these techniques can provide physicians with rapid histological evaluation at the bedside (point-of-care), thereby minimizing the number and cost of physical tissue biopsies. Overdiagnosis can be reduced and diagnostic yield can be improved. In addition, surgical risks such as bleeding, infection, and perforation can be reduced.

[0011] However, despite the promise of CLE technology, current designs are limited. There is a need for MEMS-based CLE systems capable of real-time in vivo imaging using a compact 2.8 mm or lower instrument form factor. Summary of the invention

[0012] This application describes a single-axis confocal endoscope of compact design that can be used for in vivo tissue imaging. The technology described can be used to provide a handheld optical device for real-time tissue scanning and 3D optical imaging for "optical biopsy" and other applications.

[0013] In some examples, the present technology includes microsystem-based confocal laser endoscopy (CLE) devices that use folded optical paths to achieve high numerical aperture (NA) in an ultra-compact package. In some examples, the size of the distal tip of these devices can be reduced to provide easy forward passage through the 2.8 mm instrument channel of a standard medical endoscope, allowing for widespread clinical use by community physicians.

[0014] According to an example, an endoscope assembly includes: a flexible conduit having a sleeve and a single-mode optical fiber extending into the sleeve, the flexible conduit having a distal end positioned to emit an illumination beam when provided to the single-mode optical fiber; a compact scanning assembly mounted to the flexible conduit, the compact scanning assembly having a folded beam configuration to receive the illumination beam, convert the illumination beam into a higher numerical aperture illumination beam, and scan the higher numerical aperture illumination beam across a lateral sample area, the compact scanning assembly including: a rigid housing; a lateral scanning assembly fixedly positioned within the rigid housing and adjacent to the distal end of the flexible conduit, the lateral scanning assembly having a scanning mirror having an aperture aligned with the single mode optical fiber to receive the illumination beam into a folded beam path for conversion into the higher numerical aperture illumination beam, the folded beam path being defined by the scanning mirror and a fixed mirror, a rear scanning assembly having a comb filter driver for scanning the scanning mirror; a lens assembly fixedly positioned within the rigid housing, the lens assembly being positioned distal to the transverse scanning assembly to scan the higher numerical aperture illumination beam across a rear sample area; and a spacer fixedly positioned within the rigid housing and distal to the transverse scanning assembly, the spacer having a spring member fixedly suspending the fixed mirror. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] For a more complete understanding of the present disclosure, reference should be made to the following detailed description and accompanying drawings, in which like reference numerals represent like elements throughout the figures, and in which:

[0016] Figure 1 A schematic diagram of an endoscopic imaging system with a single-axis confocal endoscope is shown according to an example.

[0017] Figure 2A-2G According to the example Figure 1 Simulation of the optical properties of an example embodiment of a single-axis confocal endoscope.

[0018] Figure 3 is used for Figure 1 Top plan view of an example scanning unit of a single-axis confocal endoscope.

[0019] Figure 4 is used to form according to the example Figure 3 Side view of the deep reactive ion etching (DRIE) process of the scanning unit.

[0020] Figure 5 An endoscope having a scanning unit assembled to a holder and fixed using a cannula according to an example is shown.

[0021] Fig. 6A and6B Based on the example Figure 3 A graph of the frequency response of the scanning unit on the x- and y-axes.

[0022] Fig. 7A A cross-sectional side view of a single-axis confocal endoscope is shown according to an example.

[0023] Figures 7B-7D The images taken at different positions of the endoscope according to the example are shown. Fig. 7A Cross-sectional view of a single-axis confocal endoscope.

[0024] Fig. 7E According to the example Fig. 7A A cross-sectional perspective view of a schematic diagram of a single-axis confocal endoscope.

[0025] Figure 8 An ultra-compact medical imaging endoscope having a standard 2.8 mm diameter for optical biopsy and implemented using a single-axis confocal endoscope is shown according to an example.

[0026] Fig.9A and 9B The optical elements L2, L3 and L4 are shown in a single-axis confocal endoscope design according to an example along the lateral direction ( Fig.9A ) direction and axial direction ( Fig. 9B ) direction shows a graph of the full width half maximum (FWHM) of sub-resolution (100 nm) fluorescent beads, the graphs showing a resolution of 1.5 μm and 12 μm, respectively.

[0027] Fig. 9C The example shown is 350×350μm 2 Image of scattered 10 mm beads across the field of view (FOV).

[0028] Fig. 10A and 10B is an in vivo fluorescence image of a mouse colon taken using a single-axis confocal endoscope according to an example, and shows a normal colon ( Fig. 10A ) and dysplasia in CPC; Apc colon ( Fig. 10B ). Fig. 10C and 10D Based on the example of a normal colon ( Fig. 10C ) and dysplastic colon ( Fig. 10D ) histological (H&E) images.

[0029] Fig.11A and 11B is an in vitro fluorescent image of a mouse taken using a single-axis confocal endoscope according to an example, which shows the villi (v) present in the small intestine ( Fig.11A), and shows a kidney with renal tubules (t) and glomeruli (g) ( Fig. 11B ). Fig. 11C and 11D These are histological (H&E) images of the small intestine and kidney, respectively.

[0030] Fig.12 Depicted is an example block diagram of an example single-axis endoscope system according to an example.

[0031] Fig.13A is an image showing the blurring result of poorly registered pixels in an uncorrected confocal image collected in vivo from a mouse colon in an example. Fig. 13B is a phase-corrected image that distinguishes subcellular features including cell membranes (arrows) and goblet cells (g) from adenomatous crypts (arrowheads).

[0032] The skilled person will appreciate that the elements in the figure are illustrated only for simplicity and clarity, and are not necessarily drawn to scale. For example, the size and / or relative positioning of some of the elements in the figure may be enlarged relative to other elements to help improve the understanding of the various embodiments of the present invention. In addition, common but well-understood elements that are useful or necessary in commercially feasible embodiments are generally not depicted so as to less hinder the views of these various embodiments. It should also be understood that certain actions and / or steps may be described or depicted in a specific order of occurrence, and those skilled in the art will understand that such specificity regarding the sequence is not actually required. It should also be understood that, except for different specific meanings to be otherwise set forth herein, the terms and expressions used herein have the common technical meanings given to such terms and expressions by those skilled in the art as described above. DETAILED DESCRIPTION

[0033] In general, according to these various embodiments, an optical instrument has an actuator mechanism that produces high image resolution by being able to quickly scan deep into tissue to produce volumetric images. The size of the optical components of the instrument can be small enough to be easily moved and manipulated in the desired tissue. By using piezoelectric actuation, a low-profile scanning device can achieve large, high-speed displacement of an optical component (e.g., a mirror) through micro-actuation, which allows real-time cross-sectional and / or 3D images of tissue.

[0034] Figure 1 A schematic diagram 100 of an optical imaging system is shown. The system 100 includes a single-axis confocal endoscope 102 for performing an optical scan on a sample. The optical scan may be performed on the outer surface of the tissue sample. However, in this document, Figure 1 In the detailed examples, the endoscope scans at a subsurface focal plane in tissue, thereby allowing subsurface in vivo scanning, including optical biopsy scanning.

[0035] In the example shown, a single-axis confocal endoscope 102 is coupled to a single-mode optical fiber (SMF). The SMF is coupled to receive an illumination beam (also referred to as an excitation beam) provided from a laser source, which is configured to provide the illumination beam via a dichroic mirror (DM) and a focusing element L1, thereby focusing the illumination beam into the SMF. The illumination beam is focused by the single-axis confocal endoscope 102 to a subsurface focal plane in the tissue, and the illumination beam can be scanned on the focal plane as further described.

[0036] The collected fluorescence reflected from the focal plane is collected by the single-axis confocal endoscope 102 and provided to a photomultiplier tube (PMT) through a first focusing element L1, DM, an optical long-pass edge filter (LPF), a second focusing element L5, and a multimode optical fiber (MMF). The fluorescence collected from the PMT is provided to an amplifier coupled to an analog-to-digital converter (ADC), which is coupled to an image processing unit. The image processing unit analyzes the collected fluorescence and processes the collected fluorescence beam to produce an output image provided to a medical professional on a display. In some examples, the image processing unit can be part of a diagnostic system, wherein the image processing unit analyzes the collected fluorescence to identify lesions and lesion sites in the image data. In some examples, the image processing unit can be part of a treatment system, wherein the image processing unit generates a treatment response based on the identified lesion information.

[0037] In the example shown, the image processing unit also controls the operation of the single-axis confocal endoscope 102. The image processing unit is coupled to a digital-to-analog converter (DAC) and generates scan control signals that are sent to the DAC, which sends these scan control signals to the MEMS actuator of the endoscope 102. The scan control signals control the scanning operation of the single-axis confocal endoscope 102. For example, the MEMS actuator can control the scanning of the single-axis confocal endoscope 102 by controlling the scanning of the scanning mirror M1, as discussed further below.

[0038] In operation, according to the example, in λ ex=488nm wavelength provides fluorescence excitation (also known as illumination beam). The illumination beam is reflected from the DM and focused by L1 to the SMF. The illumination beam at the distal end of the SMF is reflected from the fixed mirror M2 through the central aperture in the scanning mirror M1 and is scanned laterally in the tissue sample. For example, the illumination beam is scanned along the X-axis and the Y-axis to define a lateral scanning plane. This illumination beam scanning can be performed by a MEMS driver controlling the scanning of the mirror M1 through lenses (L2, L3, and L4). The fluorescence from the tissue sample is collected by the same optical device (i.e., lenses L4, L3, and L2), scanned by M1, and focused back to the SMF as a fluorescence beam. The fluorescence beam passes through the DM and the LPF (e.g., the 488nm edge LPF) and is focused into the MMF through the lens L5. The fluorescence beam is detected by the PMT. The signal is amplified and digitized via the ADC and reconstructed in the image processing unit.

[0039] Figure 2A An example beam propagation through the lenses of endoscope 102 is shown, including scanning operation of mirror M1. The illumination beam is present in the SMF and passes through the central aperture in mirror M1 and hits the fixed mirror M2. The illumination beam expands when it reflects from the fixed mirror M1 and returns to the mirror M1 for scanning, where M1 is scanned at a scanning angle θ. The illumination beam reflected from scanning mirror M1 is focused by achromatic lenses L2 (65568, Edmund Optics) and L3 (65567, Edmund Optics) and then by plano-convex lens L4 (90858, Edmund Optics) such that the total NA = 0.41. In the example shown, the optical system is diffraction limited, with spot sizes ranging from <0.71 μm to as large as 150 μm from the center of the image, as shown in FIG. Figure 2B-2F As shown. Figure 2B-2F As shown, spot sizes (RMS radius) of 0.23μm, 0.7μm, 1.56μm, 2.02μm and 2.77μm are available at distances of 0μm, 88μm, 124μm, 152μm and 175μm from the center, respectively. The shift of the chromatic focus in the Z axis is <1.42μm in the wavelength range of 480-600nm to be compatible with a wide range of excitation wavelengths. As an example, in the example shown, when M1 is deflected at a mechanical scan angle of θ = ±8.25 degrees, a 350×350μm 2 Field of view (FOV), such as Figure 2G shown.

[0040] refer to Figure 3 , 4 , 5, 6A and 6B further discuss the scanning operation of an example implementation of the endoscope 102. Figure 3An example implementation of a MEMS scanning mirror assembly 200 is shown, in this example the outer diameter of the MEMS scanning mirror assembly is 2 mm to allow for an ultra-compact endoscope design. In the example, at the center of the MEMS assembly 200, the diameter of the reflector mirror M1 is 550 μm. In the example, to make the reflector surface of the mirror M1, aluminum is sprayed on the front side of the MEMS assembly 200 to achieve a reflectivity of >90% between 400-700 nm. An aperture of 50 μm in diameter is etched in the center of the mirror M1 to allow the illumination beam leaving the SMF to pass through. The mirror M1 is mounted on a gimbal.

[0041] In order to achieve an ultra-compact design, many other design features have been developed and implemented in some of the example endoscopes described herein. For example, the MEMS assembly 200 includes a plurality of wire clamp structures etched on the edge of the MEMS assembly 200 to connect the drive wires and maintain the MEMS assembly 200 in place during operation, specifically during scanning. Even during scanning, the drive wires can be wound around or bonded to the wire clamps to provide a fixed anchor. The wire clamps greatly improve stability and the service life of the endoscope. In some examples, four wire clamp structures are used and in a relative configuration, each of which has a pair of wire clamp structures on the opposite side of the MEMS assembly 200, thereby providing reaction force stability for the entire device during operation. In fact, by having a pair of wire clamp structures in a relative configuration, the MEMS assembly 200 exhibits relatively low noise across the entire lateral scanning plane, i.e., on the X-axis and Y-axis.

[0042] Other design features include spring members, as shown, for suspending the mirror M1 for rotational motion about the Y axis. In the example shown, two spring members are shown, one on each side of the mirror M1. The two spring members are positioned on the outer region of the actuator configuration of the MEMS assembly 200.

[0043] In the example shown, the MEMS assembly 200 employs an actuator configuration including two actuation axes around which the mirror M1 can rotate independently. The definition of the X-axis is shown in the figure. The mirror M1 is scanned around the X-axis via an internal comb filter driver. The definition of the Y-axis is shown in the figure, and the mirror M1 is scanned around the Y-axis using an external comb filter driver. The internal side and the external side can be used as parts of the internal comb filter driver and the external comb filter driver, respectively. The internal comb filter driver and the external comb filter driver provide electrostatic actuation so that when driven by a drive signal, the mirror M1 rotates around the inner axis (X axis) and the outer axis (Y axis), respectively. The comb filter driver is formed by an electrostatic comb drive, which is arranged on the side of M1 to provide a driving force that causes M1 to rotate. The comb filter driver can be configured to provide rotation in response to, for example, an in-phase or out-of-phase drive signal. The comb drive actuator can be a serpentine spring, the geometry of which can determine the resonant frequency used for scanning.

[0044] Each of the internal comb filter driver and the external comb filter driver can be operated at a resonant frequency, for example, a resonant frequency selected between about 1 kHz and about 4 kHz. In addition, the MEMS assembly 200 can be driven using the selected resonant frequency drive signal to each comb driver so that the mirror M1 undergoes a sinusoidal scanning pattern. In an example, the MEMS assembly 200 is driven by the resonant frequency to perform imaging at ≥5 frames / second using a Lissajous scanning pattern and scanning at 400×400 pixels per frame.

[0045] Figure 4 An example deep reactive ion etching (DRIE) process cross section is shown for forming the MEMS component 200 in an example. In an example, the MEMS component is fabricated using a silicon-on-insulator 3-step deep reactive ion etching DRIE process with 3 masks. Figure 5 An example endoscope is shown having a MEMS assembly 200 (labeled MEMS chip) at the distal end mounted on a 2 mm outer diameter fixed tube connected to an optical fiber via a cannula as shown.

[0046] Fig. 6A and 6B 2 is a graph of the frequency response of the MEMS component 200 in the X-axis and Y-axis. By sweeping the drive signal from high frequency to low frequency (sweeping down) in the X-axis or Y-axis, M1 can achieve a large scanning angle, such as Fig. 6A and 6BAs shown. Sweeping in the opposite direction from low frequency to high frequency (sweeping up) produces a smaller scan angle. In some examples, the drive frequency is selected to produce a dense Lissajous scan pattern at a high repetition rate. In the example, an amplitude of 60V is used. pp The frequency is close to 24kHz and 6kHz sine waves, and the tilt frequencies of the X and Y axes are 12kHz and 3kHz respectively. 2 The field of view (FOV) is covered by 300 × 300 or 400 × 400 pixels at 20 or 10 frames per second, respectively, with a pixel pitch of 1.17 μm or 0.875 μm. Motion artifacts can be reduced by imaging at higher speeds, but with fewer pixels.

[0047] Figures 7A-7E Various cross-sectional views of the distal end of the endoscope 102 assembled in an exemplary embodiment are provided. Fig. 7A As shown, the distal end of the endoscope 102 is fixed in a stainless steel outer tube with an outer diameter (OD) and an inner diameter (ID) of 2.4 mm and 2.0 mm, respectively, and a length of 10 mm. As shown, the MEMS fixing tube is used to align the MEMS assembly 200 with the fiber optic ferrule. Specifically, due to the MEMS fixing tube, the SMF is axially aligned with the central aperture of the mirror M1. In the example, the MEMS assembly 200 is mechanically isolated by inserting a stainless steel end tube with an OD and ID of 2.0 mm and 1.6 mm, respectively, and a length of 3 mm between the rigid outer tube and the flexible tubing to isolate the scanner from unwanted mechanical vibrations, and specifically the scanning mechanism from unwanted vibrations.

[0048] In some examples, the MEMS assembly 200 may include a position sensing detector (PSD) configured to measure tilt angles about one or both of the X and Y axes during scanning. Thus, the PSD may detect misalignment errors when the illumination beam is no longer aligned with the aperture in M1. In other examples, the comb filter driver may be driven in a closed-loop control configuration that allows the MEMS driver to determine the scan angle for scanning and prevent misalignment. In some examples, a piezoresistive sensor may be coupled to an actuator of the comb filter driver to provide an indication of the scan angle. Through closed-loop control, such a sensor may provide feedback that the MEMS driver uses to adjust the drive signal to achieve the desired scan through M1.

[0049] As shown in the figure, micromachining methods are used to manufacture the fixed mirror M2 and the spacer for mounting the distal optics L2-L3. The upper surface of the fixed mirror M2 is coated with an aluminum layer of about 70nm to achieve a reflectivity of >90% at 488nm. The diameter of 0.29mm covers the size of the illumination beam and is designed to completely cover the beam emitted from the SMF and achieve a fluorescence collection efficiency of >80%. Figure 7B As shown, in order to facilitate the handling and precise assembly of this tiny component, the fixed mirror M2 is supported by a straight rod 8 μm wide via a pair of flexible springs connected to a ring bracket. The ring bracket ( Figure 7B ) has an OD and ID of 1.97 mm and 1.6 mm respectively, and the ring bracket is designed to match the optical device and not block the illumination or output beam. Figure 7C As shown, the OD and ID of the spacer between lenses L2 and L3 are 1.97 mm and 1.8 mm, respectively. Fig.7D As shown, the OD and ID of the spacer between lenses L3 and L4 are 1.97 mm and 1.7 mm, respectively. All spacers are fabricated on a silicon wafer with a thickness of 0.5 mm. The distance between the MEMS component and the optical device is adjusted by moving the MEMS component with a 3D translation stage to achieve WD = 50 μm. Fig. 7E A cut-away view of an example configuration is shown. Figure 8 A medical endoscope 300 is shown having an inner diameter channel, specifically an ID instrument channel having an inner diameter of 2.8 mm, through which the ultra-compact single axis endoscope 102 is drawn. In the example, the medical endoscope 200 is an Olympus GIF-HQ190 endoscope.

[0050] Fig.9A and 9B The optical elements L2, L3 and L4 are used in a single-axis confocal endoscope 102 to extend along the lateral direction ( Fig.9A ) direction and axial direction ( Fig. 9B ) direction shows a graph of the full width half maximum (FWHM) of sub-resolution (100 nm) fluorescent beads, the graphs showing a resolution of 1.5 μm and 12 μm, respectively. Fig. 9C The diagram shows the use of 350 × 350 μm 2 Image of 10 mm beads dispersed in a sample of the endoscope's field of view.

[0051] Example

[0052] In λ ex In vivo fluorescence images were collected from the colon of CPC;Apc mice using an ultra-compact single-axis confocal endoscope according to the present teachings under excitation with λ = 488 nm. Fig. 10A and 10BFigure 2 shows representative images of normal and dysplastic development after intravenous injection of fluorescein. The distinct crypt structures (arrows) with central lumen (l), goblet cells (g), and surrounding lamina propria (lp) can be identified in the image. Fig. 10C and 10D Representative histological hematoxylin and eosin (H&E) stained images of normal and dysplastic proliferations are shown.

[0053] According to the example in this article, Figures 11A-11D Figure 2 shows fluorescence images collected in vitro using an ultra-compact single-axis confocal endoscope. Fig.11A and 11B As can be seen, the small intestine image shows the villi, and the kidney image shows the tubules and glomeruli. Fig.11D and 11D Representative histological hematoxylin and eosin (H&E) staining images of normal small intestine and dysplastic small intestine are shown in FIG.

[0054] In some examples, a confocal image can be reconstructed based on a Lissajous scan pattern. A time series of discrete data can be mapped to each pixel location as an intensity. The Lissajous track can be derived from the scanning frequency f between the input drive voltage and the sinusoidal motion of the mirror in the X-axis and Y-axis. x 、f y and phase delay The pixel position (x, y) can be mapped using the following equation, where P x , P y Image dimensions expressed in pixels:

[0055]

[0056]

[0057] In these examples, the Lissajous scan pattern is sparse in the center of the image and increases in density toward the periphery. Unsampled pixels (empty spaces where the beam is not scanned) can be calculated by counting the number of pixels with zero intensity. These unsampled pixels are filled with the average intensity of eight adjacent pixels, a process performed in real time during in vivo imaging. Thus, in these examples, the dense scan area results in multiple intensity values ​​being assigned to pixels, which are averaged to obtain a processed image.

[0058] In some examples, the deflection amplitude and phase delay of the scanning mirrors are calibrated as a function of drive voltage under laboratory environmental conditions prior to in vivo imaging. These parameters may vary over time after the instrument is inserted into a subject. In vivo images may appear blurry due to environmental effects on the scanning mirror dynamics, such as perturbations in the phase delay caused by temperature changes. In some examples, these phase shifts may cause errors in assigning intensity values ​​to pixel locations. A phase correction algorithm is used to recover the actual phase delay of the scanner during in vivo use by optimizing a sharpness metric S defined by the following equation:

[0059]

[0060] Where I(i,j) is the grayscale intensity of the reconstructed image, and I avg is the average of all pixel intensities in the image. M and N are the total number of pixels along the height and width of the image. The phase corresponding to the sharpest image is selected as the new estimate for subsequent reconstructed images and videos. Phase correction can be performed at regular time intervals or as needed. The resulting image is further processed using gamma correction to enhance image brightness and contrast. In the example, a Wiener filter is used to reduce shot noise and Gaussian noise from the PMT and amplifier. This filter suppresses noise without blurring to minimize image degradation. In some experiments, the phase shift observed during in vivo experiments was approximately 2-3°. Compared to Fig. 13B In comparison, see Fig.13A , the corrected images are sharper, allowing the distinction of subcellular features. Therefore, phase correction can be performed without loss of image quality during in vivo imaging.

[0061] Fig.124 is an example block diagram 400 of various components for implementing an example embodiment of a single-axis confocal endoscope system. A single-axis confocal endoscope 402 may be positioned adjacent to or operably coupled to a sample 401. A control device 403 may have a controller 404 operably connected to a database 414 via a link 422 connected to an input / output (I / O) circuit 412. It should be noted that, although not shown, additional databases may be linked to the controller 404 in a known manner. The controller 404 includes a program memory 406, a processor 408 (which may be a microcontroller or microprocessor), a random access memory (RAM) 410, and an input / output (I / O) circuit 412, all interconnected via an address / data bus 420. It should be understood that, although only one microprocessor 408 is shown, the controller 404 may include multiple microprocessors 408. Similarly, the memory of the controller 404 may include multiple RAMs 410 and multiple program memories 406. Although I / O circuitry 412 is shown as a single block, it should be appreciated that I / O circuitry 412 may include multiple different types of I / O circuitry. For example, RAM 410 and program memory 406 may be implemented as semiconductor memory, magnetically readable memory, and / or optically readable memory. Link 424 may operably connect controller 404 to endoscope 402 via I / O circuitry 412. I / O circuitry 412 may be connected to a network interface 434 that provides a wired or wireless connection to a network 436.

[0062] The program memory 406 and / or RAM 410 may store various applications (i.e., machine-readable instructions) for execution by the microprocessor 408. For example, the operating system 430 may generally control the operation of the endoscope 402 and provide a user interface to the test device to implement the processes described herein. The program memory 406 and / or RAM 410 may also store various execution instructions 432 for accessing specific functions of the endoscope 402. By way of example and not limitation, the execution instructions 432 may include, among other things: instructions for controlling the operation of the endoscope 402 or other endoscopic devices as described herein; instructions for capturing images using the endoscope 402 as described herein; and other instructions, such as implementing software keyboard functions, instructions for interfacing with other hardware in the endoscope 402, and the like. The program memory 406 and / or RAM 410 may further store data related to the configuration and / or operation of the endoscope 402, and / or related to the operation of one or more instructions. For example, the data may be data collected by the endoscope 402, data determined and / or calculated by the processor 408, and the like. In addition to the controller 404, the endoscope 402 may also include other hardware resources. The endoscope 402 may also be coupled to various types of input / output hardware, such as a visual display 426 and an input device 428 (e.g., a keypad, keyboard, etc.) to fine-tune the actuation of the lateral scan. In an embodiment, the display 426 is touch-sensitive and may cooperate with a software keyboard routine as one of the software routines 432 to accept user input.

[0063] The inventive technology provides an ultra-compact design for microsystem-based confocal endoscopes. Using the inventive technology, a 2.4mm diameter microsystem-based confocal laser endoscope that can easily pass through the 2.8mm biopsy channel of a standard medical endoscope can be realized. To our knowledge, this is the smallest caliber microsystem-based instrument to date. The ultra-compact distal end contains a fast MEMS scanner and compression lens assembly packaged in a short rigid length of 10mm and 2mm diameter to navigate large bending angles at the channel entrance.

[0064] The optical design uses a folded path to expand the beam and achieves NA = 0.41 to achieve on-axis diffraction limited resolution. Using intravenous fluorescein, real-time images can be collected from in vivo tissue (or in some examples, in vitro tissue) to, for example, distinguish normal mucosa from precancerous (dysplastic) mucosa using intravenous fluorescein for contrast. The resulting endoscope can be used at the bedside to avoid the long processing time required for physical biopsies and provide physicians with immediate lesion feedback during surgery.

[0065] The ultra-compact form factor presented here is compatible with a variety of medical endoscopes used by community physicians and can be used in a wide range of clinical applications.

[0066] We demonstrate advances in microsystem packaging to reduce the size of the instrument for endoscope compatibility. For example, a MEMS chip can be designed with a wire clip structure instead of bond pads to facilitate the connection and routing of drive and signal lines. In addition, the drive signal can be tuned to the scanner to achieve a hybrid softening / hardening effect to increase the mechanical scanning angle, thereby improving the performance of the reflector. Microfabrication techniques are used to produce spacers with tight tolerances to align the optics. In addition, end tubes are inserted to isolate the scanner from the bending motion induced by the flexible tubing protecting the optical fiber. As a result, the large stresses present when the endoscope is passed through the instrument channel for in vivo imaging are compensated.

[0067] Throughout the entire specification, multiple instances can implement the parts, operations or structures described as single instances. Although the individual operations of one or more methods are shown and described as individual operations, one or more of the individual operations can be performed simultaneously, and do not need to perform the operations in the order shown. The structure and function presented as independent components in the example configuration can be implemented as a combined structure or components. Similarly, the structure and function presented as a single component can be implemented as an independent component. These and other changes, modifications, additions and improvements all fall within the scope of this paper theme.

[0068] In addition, certain embodiments are described herein as comprising logic or a number of routines, subroutines, applications, or instructions. These may constitute software (e.g., code embodied on a non-transitory machine-readable medium) or hardware. In hardware, routines, etc. are tangible units that are capable of performing certain operations and may be configured or arranged in some manner. In example embodiments, one or more computer systems (e.g., independent client or server computer systems) or one or more hardware modules of a computer system (e.g., a processor or a group of processors) may be configured by software (e.g., an application or an application portion) to be a hardware module that operates to perform certain operations as described herein.

[0069] In various embodiments, hardware modules may be implemented mechanically or electronically. For example, a hardware module may include dedicated circuits or logic that are permanently configured to perform certain operations (e.g., a dedicated processor such as a field programmable gate array (FPGA) or an application specific integrated circuit (ASIC)). A hardware module may also include programmable logic or circuits that are temporarily configured to perform certain operations by software (e.g., as contained in a dedicated processor or other programmable processor). It should be understood that the decision to implement a hardware module mechanically in a dedicated and permanently configured circuit or in a temporarily configured circuit (e.g., configured by software) may be driven by cost and time considerations.

[0070] Thus, the term "hardware module" should be understood to encompass tangible entities, referring to entities that are physically constructed, permanently configured (e.g., hardwired), or temporarily configured (e.g., programmed) to operate in a certain manner or to perform certain operations described herein. In view of embodiments in which hardware modules are temporarily configured (e.g., programmed), it is not necessary to configure or instantiate each hardware module at any one time. For example, where the hardware modules include a general-purpose processor configured using software, the general-purpose processor can be configured into corresponding different hardware modules at different times. Thus, software can configure a processor, for example, to constitute a particular module at one time and to constitute a different module at a different time.

[0071] A hardware module can provide information to other hardware modules, or receive information from other hardware modules. Therefore, the hardware modules can be considered to be communicatively coupled. In the case of multiple such hardware modules being present at the same time, communication can be achieved by signal transmission (e.g., by appropriate circuits and buses) connecting the hardware modules. In embodiments where multiple hardware modules are configured or instantiated at different times, communication between such hardware modules can be achieved, for example, by storing and retrieving information in a memory structure accessible to multiple hardware modules. For example, a hardware module can perform an operation and store the output of such operation in a memory device to which it is communicatively coupled. Then, another hardware module can access this memory device at a later time to retrieve and process the stored output. A hardware module can also initiate communication with an input or output device, and can operate on a resource (e.g., a collection of information).

[0072] The various operations of the example methods described herein may be performed, at least in part, by one or more processors that are temporarily configured (e.g., by software) or permanently configured to perform the relevant operations. Such processors, whether temporarily or permanently configured, may constitute processor-implemented modules that operate to perform one or more operations or functions. In some example embodiments, the modules referred to herein may include processor-implemented modules.

[0073] Similarly, the methods or routines described herein may be implemented at least in part by a processor. For example, at least some operations of a method may be performed by one or more processors or a hardware module implemented by the processor. Some of the executions in the operation may be distributed between one or more processors that not only reside in a single machine but also across multiple machine deployments. In some example embodiments, one or more processors may be located at a single location (e.g., in a home environment, in an office environment, or as a server farm), but in other embodiments, the processor may be distributed across multiple locations.

[0074] The execution of some of the operations may be distributed between one or more processors that reside not only in a single machine but also deployed across multiple machines. In some exemplary embodiments, one or more processors or processor-implemented modules may be located in a single geographic location (e.g., in a home environment, an office environment, or a server farm). In other exemplary embodiments, one or more processors or processor-implemented modules may be distributed in multiple geographic locations.

[0075] Unless otherwise expressly stated, discussions herein using terms such as "processing," "computing," "calculating," "determining," "presenting," "displaying," and the like may refer to the action or process of a machine (e.g., a computer) to manipulate or transform data represented as physical (e.g., electrical, magnetic, or optical) quantities in one or more memories (e.g., volatile memory, non-volatile memory, or a combination thereof), registers, or other machine components that receive, store, transmit, or display information.

[0076] As used herein, any reference to "one embodiment" or "an embodiment" means that a particular element, feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. The phrase "in one embodiment" appearing in various places in the specification does not necessarily all refer to the same embodiment.

[0077] For example, some embodiments may be described using the term "coupling" to indicate that two or more elements are in direct physical contact or electrical contact. For example, some embodiments may be described using the term "coupling" to indicate that two or more elements are in direct physical contact or electrical contact. However, the term "coupling" may also refer to two or more elements that are not in direct contact with each other, but still cooperate or interact with each other. The embodiments are not limited to this context.

[0078] Those skilled in the art will appreciate that various modifications, changes and combinations may be made to the embodiments described above without departing from the scope of the present invention, and such modifications, changes and combinations are considered to be within the scope of the inventive concept.

Claims

1. An endoscope assembly, comprising: a flexible conduit having a sleeve and a single mode optical fiber extending into the sleeve, the flexible conduit having a distal end positioned to emit an illumination beam when presented to the single mode optical fiber; a compact scanning assembly mounted to the flexible conduit, the compact scanning assembly having a folded beam configuration to receive the illumination beam, convert the illumination beam into a higher numerical aperture illumination beam, and scan the higher numerical aperture illumination beam across a lateral sample area, the compact scanning assembly comprising: Rigid housing; a transverse scanning assembly fixedly positioned within the rigid housing and adjacent the distal end of the flexible conduit, the transverse scanning assembly having a scanning mirror having an aperture aligned with the single mode optical fiber to receive the illumination beam into a folded beam path for conversion into the higher numerical aperture illumination beam, the folded beam path being defined by the scanning mirror and a fixed mirror, a rear scanning assembly having a comb filter drive for scanning the scanning mirror; a lens assembly fixedly positioned within the rigid housing, the lens assembly being positioned distal to the transverse scanning assembly to scan the higher numerical aperture illumination beam across a rearward sample region; and A spacer is fixedly positioned within the rigid housing and distal to the lateral scanning assembly, the spacer having a spring member that fixedly suspends the fixed mirror.

2. The endoscope assembly of claim 1, wherein the lateral scanning assembly further comprises one or more clamp elements for securing an attachment drive line connecting the lateral scanning assembly to a scan driver processing unit.

3. The endoscope assembly of claim 1, wherein the lens assembly comprises a plurality of lens elements and one or more secondary spacers positioned to space adjacent lens elements.

4. The endoscope assembly of claim 3, wherein the plurality of lens elements comprises two achromatic doublet lenses.

5. The endoscope assembly of claim 4, wherein the plurality of lens elements comprise plano-convex lenses.

6. The endoscope assembly of claim 1, wherein the rigid housing of the compact scanning assembly has an outer diameter of 2.4 mm.

7. The endoscope assembly of claim 1, wherein the rigid housing of the compact scanning assembly has an outer diameter of less than 2.4 mm.

8. The endoscope assembly according to claim 1 further includes a rigid end tube connector, the outer diameter of which matches the inner diameter of the rigid shell and the inner diameter of the flexible tube, and the rigid end tube connector is positioned to engage the rigid shell with the flexible tube while allowing rotational movement therebetween.

9. An endoscope assembly according to claim 1, wherein the comb filter driver includes an internal comb filter driver and an external comb filter driver, each of which is configured to provide electrostatic actuation to rotate the scanning mirror around an X-axis and a Y-axis respectively in response to a drive signal.

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