Ultra-compact Folding Beam Path Confocal Endomicroscope

Abstract

The present invention provides a compact single-axis confocal endomicroscope that can meet the endoscopic space requirements of a 2.8 mm diameter. The single-axis confocal endomicroscope uses a folded path design implemented between a fixed mirror and a laterally scanning mirror, thereby producing a high numerical aperture that allows diffraction-limited resolution in subsurface scanning. The scanning mirror has a central aperture that allows for the expansion of the illumination beam in the folded path design.

Description

[0001] Cross - reference to related applications

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 820,023, filed Mar. 18, 2019, the entire content of which is hereby incorporated by reference. Technical Field

[0003] The present disclosure generally relates to techniques for imaging tissue using optical instruments, and more particularly, to techniques for using a compact confocal endomicroscope. Background Art

[0004] The background description provided herein is for the purpose of generally presenting the background of the disclosure. To the extent that the work of the presently named inventors is described in this background art section, and aspects of the description that may not otherwise have been considered prior art at the time of filing, are neither expressly nor impliedly admitted as prior art against the present disclosure.

[0005] Many human diseases originate within the epithelium of hollow organs and ducts. This thin tissue layer has dimensions of only a few hundred microns, a simple repetitive architecture, and strong self - renewal kinetics. Optical sectioning techniques have been developed to visualize the molecular expression patterns within the epithelium. These techniques attempt to visualize the unique biological processes driving disease progression at sub - cellular resolution.

[0006] For in - vivo imaging of the epithelium, an optical scanning instrument must be small enough and provide fast scanning. Confocal endomicroscopes have been developed for this purpose and are now routinely used in clinics. A confocal endomicroscope uses the core of a single - mode optical fiber to act as a “pinhole” that rejects light scattered from epithelial tissue.

[0007] Unfortunately, current clinical endomicroscopes are limited in imaging performance by the scanning mechanism, which is either too slow, resulting in motion artifacts, or too large in size, requiring a fiber bundle that reduces resolution, flexibility, and increases cost.

[0008] There is a need for a fast and compact scanner mechanism that can be placed at the distal end of an endomicroscope to provide improved instrument control performance and flexibility. Summary of the Invention

[0009] This application describes a single - axis confocal endomicroscope in a compact design form that can be used for in - vivo tissue imaging. These techniques can be used to provide hand - held optical devices for real - time tissue scanning, for “optical biopsies,” and other applications.

[0010] We previously developed a miniature scanner for performing high-speed in-vivo imaging that has a design using parametric resonance, where the drive signal is applied at a frequency close to 2ω o / n (ω o is the natural frequency of the vibration mode, and n is an integer ≥ 1). These electrostatic devices are fabricated using microelectromechanical systems (MEMS) processes to have a compact size.

[0011] Using the techniques of the present invention, a MEMS-based confocal endomicroscope has now become a reality, having a compact design that, in some examples, achieves a much smaller outer diameter of 2.4 mm or less. This diameter enables an endomicroscope to be properly incorporated with the 2.8 mm biopsy channel of a standard medical endoscope.

[0012] The techniques of the present invention include a single flexible optical fiber configured to deliver and collect light using a folded beam path configuration that enables a compact design. In some examples, the folded beam path configuration is achieved using a fast-scanning assembly located at the distal probe tip of the endomicroscope. The fast-scanning assembly can be a scanning mirror positioned to facilitate a high numerical aperture in the endomicroscope. This facilitation occurs in part due to the folded beam path configuration of the scanning mirror, and particularly because the folded beam path is coordinated with the exit surface of the single-mode optical fiber without being obstructed by the scanning mirror.

[0013] In some examples, the scanning assembly includes two mirrors, one a fast-scanning mirror and the other a fixed mirror, both positioned to fold both the incident (illumination beam path) and reflected (detected beam path) beams passing through the endomicroscope. The scanning assembly further includes a compact lens assembly having a high numerical aperture (NA) facilitated by these mirrors. As an example, an NA of 0.4 or better, a working distance of 50 μm, and a field of view of 250×250 μm 2 have been achieved.

[0014] According to an example, an endoscopic microscope assembly includes: an optical fiber ferrule and a single-mode optical fiber extending into the optical fiber ferrule, the optical fiber ferrule having a distal end positioned to emit an illumination beam when provided to the single-mode optical fiber; a compact scanning assembly mounted to a flexible tube, the compact scanning assembly having a folded beam configuration to receive the illumination beam, convert the illumination beam into an illumination beam with a higher numerical aperture, and scan the illumination beam with the higher numerical aperture across a transverse sample area, the compact scanning assembly including: a housing; a dual-mirror transverse scanning assembly fixedly positioned within the housing and adjacent to the distal end of the flexible tube, the dual-mirror transverse scanning assembly having a first 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 an illumination beam with a higher numerical aperture, the folded beam path being defined by the first scanning mirror and a second mirror; and a lens assembly fixedly positioned within the rigid housing, the lens assembly being positioned distally to the transverse scanning assembly to scan the illumination beam with the higher numerical aperture across the transverse sample area and collect fluorescence from the transverse sample area. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] To more fully understand the present disclosure, reference should be made to the following detailed description and the drawings, in which like reference numerals represent like elements in the figures, and in which:

[0016] Figure 1 A schematic diagram showing an imaging system having a single-axis confocal endoscopic microscope according to an example.

[0017] Figure 2 Shows according to an example Figure 1 The schematic design of the single-axis confocal endoscopic microscope of the imaging system.

[0018] Figure 3 For the Figure 2 Cross-sectional view of the single-axis confocal endoscopic microscope according to an example.

[0019] Figures 4A - 4D Respectively show the collected reflection images of 0.1 μm fluorescent beads according to an example ( Figure 4A ), a graph showing the intensity distribution along the 0.1 μm fluorescent bead showing the lateral resolution defined by the full width at half maximum ( Figure 4B ), the collected reflection image of a standard resolution target ( Figure 4C ), and the collected reflection image of lens paper showing individual optical fibers ( Figure 4D ). In these examples, the collected reflection images are fluorescence images collected using the single-axis confocal endoscopic microscope according to an example.

[0020] Figure 5A A fluorescence image collected in vitro from a mouse colon using a single-axis confocal endoscopic microscope according to an example herein.Figure 5B A fluorescence image collected in vitro from a mouse kidney. Figure 5C A fluorescence image collected in vitro from a mouse stomach.

[0021] Figure 6 A block diagram of an exemplary single-axis endoscopic microscope imaging system according to the example.

[0022] Those skilled in the art should understand that the elements in the figures are illustrated only for simplicity and clarity and are not necessarily drawn to scale. For example, the dimensions and / or relative positioning of some of the elements in the figures may be enlarged relative to other elements to facilitate understanding of the various embodiments of the present invention. Additionally, common but well-understood elements that are useful or necessary in commercially viable embodiments are typically not depicted so as to less obstruct the view of these various embodiments. It should further be understood that certain actions and / or steps may be described or depicted in a particular order of occurrence, and those skilled in the art will understand that such particularity of sequence is not actually required. It should also be understood that, unless otherwise specifically defined herein, the terms and expressions used herein have the ordinary technical meaning ascribed to such terms and expressions by those skilled in the art of the above-described technical field. Detailed Description

[0023] A forward-viewing confocal endomicroscope is provided having a fast compact distal scanner configured to collect real-time in vivo optical sections. The confocal endomicroscope is designed using a single fiber and a single-axis folded beam path configuration. To form the folded beam path, two mirrors are used, one a fixed mirror and the other a scanning mirror. Implemented through dual-mirror MEMS component technology, the folded beam path configuration allows us to scale down the size of the device for efficient packaging and enables fast beam scanning. Compared to other endomicroscope designs currently used in clinical practice, this capability provides significantly improved imaging performance in terms of speed and resolution. The inventive technology demonstrates stable operation at fast frame rates (e.g., 20 frames per second and higher), with minimal interference from mechanical vibrations during imaging. In an example, using fluorescein staining, we were able to collect bright optical sections of the epithelium at a depth of ~50 μm. Further, the inventive technology provides continuous image collection without any significant phase shift at a fixed drive frequency. Utilizing the position sensing of the device allows for further control of stable operation in a more general environment.

[0024] Figure 1 FIG. 100 shows a schematic diagram of an optical imaging system. System 100 includes a single-axis confocal endomicroscope 102 for performing optical scanning of a sample. Optical scanning can be performed on the outer surface of a tissue sample. However, herein with respect to Figure 1In the example detailed, the endoscopic microscope scans at a surface subfocal plane in tissue, thereby allowing subsurface in-vivo scanning, including optical biopsy scanning.

[0025] In the illustrated example, the single-axis confocal endoscopic microscope 102 is coupled to a single-mode fiber (SMF). The SMF is coupled to receive an illumination beam provided from a light source, such as a laser source, which is configured to provide the illumination beam via a dichroic mirror (DM) and a focusing element—a lens L1—that focuses the illumination beam into the SMF. The illumination beam can be focused by the endoscopic microscope to a surface subfocal plane in tissue, and the illumination beam can be scanned across the focal plane as further described.

[0026] The light source is controlled by a data processing unit, such as an image processor or other computer device. A display is coupled to the data processing unit along with a user input device, which is, for example, a keyboard, keypad, touchpad, touch screen, microphone, and / or other input devices.

[0027] The collected fluorescence reflected from the focal plane in tissue is collected by the single-axis confocal endoscopic microscope 102 and provided to a detector, such as a photomultiplier tube, through the SMF and a first focusing element L1, DM, and an optical bandpass filter (BPF). The filtered collected fluorescence is coupled to a second focusing element L2, which focuses the fluorescence into a multimode fiber (MMF). The collected fluorescence is received at the detector, and a digital output signal is provided to the data processing unit for analysis.

[0028] The data processing unit can analyze the collected fluorescence and process the collected fluorescence beam to generate an output image on the display provided to a medical professional. In some examples, the data processing unit can be part of a diagnostic system, where the data processing unit analyzes the collected fluorescence to identify lesions and lesion sites in the image data, and thus identify lesions and lesion sites in the sampled tissue area. In some examples, the image processing unit can be part of a treatment system, where the image processing unit generates a treatment response based on this identified lesion information.

[0029] The data processing unit can also control the operation of the single-axis confocal endoscopic microscope 102. The data processing unit can be coupled to a digital-to-analog converter (DAC) (not shown) and can generate a scan control signal that is sent to the DAC, amplified, and used to drive two-dimensional (2D) scanning of a MEMS actuator of the endoscopic microscope 102. For example, the MEMS actuator can control the scanning of the single-axis confocal endoscopic microscope 102 by controlling the scanning of a scanning mirror M1 discussed further below.

[0030] Figure 2Shows a schematic design of a single - axis confocal endomicroscope 200 as may be used in an endoscope microscope 102. An SMF is fed to the distal end of the endomicroscope 200, which has a MEMS scanning assembly formed by two mirrors M1 and M2 adjacent to the exit surface of the SMF and configured to provide a folded beam path that expands the illumination beam before the illumination beam from the SMF is collimated by a lens assembly formed by lens elements L1, L2, and L3, as shown. These lens elements are different from those described above with reference to Figure 1 The lens elements described. Mirror M1 is a scanning mirror, and mirror M2 can be a fixed mirror or a scanning mirror. Thus, the scanning mirror M1 is used to scan the illumination beam across a 2D sample area within the tissue and to scan the fluorescence capture beam across the 2D sample area. In the example shown, mirror M2 can be used for static or off - plane scanning, thereby allowing full 3D tissue area illumination and fluorescence capture scanning.

[0031] To develop Figure 2 the schematic design, we performed ray - tracing simulations to design the optical elements specifically for a 2.4 - mm form - factor confocal endomicroscope. The design criteria included on - axis diffraction - limited resolution, with a working distance of 50 μm and a field of view of 250×250 μm 2 . Of course, other design criteria can be used for other size constraints on the overall endomicroscope design.

[0032] In the schematic shown, the illumination beam delivered by the SMF passes through the aperture in the MEMS scanning mirror M1, impinges on the second scanning mirror M2, and is reflected back into the actual scanning mirror surface of mirror M1 by the second MEMS scanner M2, which laterally scans the illumination beam in a two - dimensional form. Thus, the scanning assembly formed by mirrors M1 and M2 is an example of a lateral scanning assembly. A converging lens L3 with a high refractive index is used to increase the effective numerical aperture (NA), i.e., increase to a higher numerical aperture, and two achromatic doublets L1 and L2 are used to correct for aberrations and chromatic dispersion.

[0033] Fluorescence is collected by the same optics and travels in the opposite direction along the same path, is de - scanned by the scanning mirror M2, and is focused into the same SMF. For desired endoscope outer - diameter compatibility, L2, L3, and L4 are designed to all have an outer diameter of or about 2 mm. In an embodiment, Figure 2 the schematic design is for generating an effective numerical aperture (NA) of 0.41 and a field of view (FOV) of 250×250 μm 2 .

[0034] Figure 3A cross-sectional view of an assembled single-axis confocal endomicroscope 300 according to an example of the schematic diagram 200 is shown. An optical fiber (e.g., SMF) is connected to an optical fiber ferrule at its distal end, and the optical fiber ferrule engages an optical fiber fixture that holds the ferrule within the housing of the MEMS scanning assembly. Adjacent to the distal end of the optical fiber ferrule is a two-mirror scanning assembly having a 2D scanning mirror M1 and a mirror M2, and the mirror M2 can be a fixed mirror or a scanning mirror. Similar to the optical fiber fixture, the MEMS scanning assembly abuts the inner diameter of the housing and is held in the housing to prevent displacement. Lenses L1, L2, and L3 are also positioned in the housing and are held in the housing by the engagement of their outer diameter surfaces with the inner surface of the housing.

[0035] The scanning mirror M1 is a compact scanner designed and fabricated using MEMS technology. The mirror M1 has a reflector surface at the end of its exit surface that faces the mirror M2 and thus faces away from the optical fiber ferrule. The mirror M1 can be mounted on a gimbal frame to minimize vibration crosstalk between the orthogonal scanning axes (i.e., the X-axis and the Y-axis). The mirror can be rotated about either axis by a drive signal that is applied to the panel of the electrostatic comb drive actuator that forms the scanning mirror M1. For example, internal and external torsion springs can be designed to achieve resonance frequencies of approximately 12 kHz and 3 kHz. The reflective surface is formed using aluminum sputtered on the front-side silicon surface to achieve a reflectivity of >90% between 400 nm and 700 nm. Other reflectivity values in other frequency ranges can be achieved as needed. It is worth noting that the reflective surfaces of the scanning mirror M1 and the mirror M2 should be optimized for both the illumination beam and the collected fluorescence beam.

[0036] For in vivo imaging, we used drive frequencies of 24.64 kHz and 6.36 kHz to generate tilt frequencies of 12.32 kHz and 3.18 kHz for scanning. Lissajous scan patterns were generated at 20 frames per second with 300×300 pixels or at 10 frames per second with 400×400 pixels to cover a FOV of 250×250 μm 2 The pixel pitch is 0.83 μm, and at a 20 Hz frame rate, we performed a small amount of sampling to maintain a higher frame rate to produce fewer motion artifacts. Custom software developed in LabView was used to drive the MEMS scanner and reconstruct the image by remapping the time series signal in a 2D matrix.

[0037] In Figure 4B we plotted the intensity distribution ([[]] Figure 4A ) along a 0.1 μm fluorescent bead to measure the lateral resolution of 1.59 μm defined by the full width at half maximum (FWHM) of the intensity distribution. In addition, as shown, we collected reflection images from a standard resolution target to qualitatively estimate a lateral resolution of <2 μm (element 6 in the enlarged view of group 7, box).Figure 4C The fluorescence image of the lens paper shows that individual optical fibers can be visualized by an endoscope microscope, Figure 4D .

[0038] Figure 5A Fluorescence images showing in vitro analysis of the mouse colon. We performed an intravenous injection of 10% sodium fluorescein with a volume of 10 μL on a 10-week-old mouse. After the injection, the mouse was euthanized and the excised colon tissue was imaged under the endoscope microscope designed in the present invention, as Figure 5A shown. Representative image data from the mouse are shown for comparison Figure 5B (kidney) and Figure 5C (stomach).

[0039] Figure 6 FIG. 400 is an example block diagram showing various components for implementing an example embodiment of a uniaxial confocal endoscope microscope system. The uniaxial confocal endoscope microscope 402 can be positioned adjacent to or operatively coupled to the sample 401. The control device 403 can have a controller 404 that is operatively connected to the database 414 via a link 422 connected to the input / output (I / O) circuit 412. Although not shown, additional databases can be linked to the controller 404 in a known manner. The controller 404 includes a program memory 406, a processor 408 (which can be a microcontroller or a microprocessor), a random access memory (RAM) 410, and an input / output (I / O) circuit 412, all of which are interconnected via an address / data bus 420. Although only one microprocessor 408 is shown, the controller 404 can include multiple microprocessors 408. Similarly, the memory of the controller 404 can include multiple RAMs 410 and multiple program memories 406. Although the I / O circuit 412 is shown as a single block, it should be understood that the I / O circuit 412 can include multiple different types of I / O circuits. For example, the RAM 410 and the program memory 406 can be implemented as semiconductor memories, magnetically readable memories, and / or optically readable memories. The link 424 can operatively connect the controller 404 to the endoscope microscope 402 through the I / O circuit 412.

[0040] The program memory 406 and / or the RAM 410 may store various application programs (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 microscope 402 and provide a user interface to the testing device to implement the processes described herein. The program memory 406 and / or the RAM 410 may also store various execution instructions 432 for accessing specific functions of the endoscope microscope 402. By way of example and not limitation, the execution instructions 432 may particularly include: instructions for controlling the operation of the endoscope microscope 402 or other endoscope devices as described herein; instructions for capturing images using the endoscope microscope 402 as described herein; and other instructions, such as implementing a software keyboard function, interfacing with other hardware in the endoscope microscope 402, etc. The program memory 406 and / or the RAM 410 may further store data related to the configuration and / or operation of the endoscope microscope 402 and / or related to the operation of one or more instructions. For example, the data may be data collected by the endoscope microscope 402, data determined and / or calculated by the processor 408, etc. In addition to the controller 404, the endoscope microscope 402 may further include other hardware resources. The endoscope microscope 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, a 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.

[0041] The present invention technology provides a super-compact single-axis confocal endoscope microscope design. Using the present invention technology, a 2.4-mm diameter micro-system-based confocal laser endomicroscopy capable of easily passing through a 2.8-mm biopsy channel of a standard medical endoscope can be achieved. The optical design uses a folded path to expand the beam and achieve NA = 0.41 for achieving on-axis diffraction-limited resolution. The resulting endoscope microscope can be used for point-of-care testing to avoid the long processing time required for physical biopsies and provide immediate lesion feedback to the doctor during surgery.

[0042] Throughout the specification, multiple instances may implement components, operations, or structures described as a single instance. Although individual operations of one or more methods are illustrated and described as separate operations, one or more of the individual operations may be performed simultaneously, and the operations need not be performed in the illustrated order. Structures and functions presented as separate components in an example configuration may be implemented as a combined structure or component. Similarly, structures and functions presented as a single component may be implemented as separate components. These and other variations, modifications, additions, and improvements fall within the scope of the subject matter herein.

[0043] Additionally, certain embodiments are described herein as including logic or a number of routines, subroutines, applications, or instructions. These can constitute software (e.g., code embodied on a non-transitory machine-readable medium) or hardware. In hardware, a routine, etc. is a tangible unit capable of performing certain operations and can be configured or arranged in a certain manner. In an example embodiment, one or more computer systems (e.g., stand-alone client or server computer systems) or one or more hardware modules of a computer system (e.g., a processor or a group of processors) can be configured by software (e.g., an application or a portion of an application) to operate as a hardware module that performs certain operations as described herein.

[0044] In various embodiments, the hardware module can be implemented mechanically or electronically. For example, the hardware module can include dedicated circuitry or logic that is permanently configured to perform certain operations (e.g., as a dedicated processor, such as a field programmable gate array (FPGA) or an application specific integrated circuit (ASIC)). The hardware module can also include programmable logic or circuitry that is temporarily configured by software to perform certain operations (e.g., as encompassed within a general-purpose processor or other programmable processor). It should be appreciated that the decision to implement the hardware module mechanically in dedicated and permanently configured circuitry or in temporarily configured circuitry (e.g., configured by software) can be driven by cost and time considerations.

[0045] Accordingly, the term "hardware module" should be understood to encompass a tangible entity that refers to an entity that is physically constructed, permanently configured (e.g., hard-wired) or temporarily configured (e.g., programmed) to operate in a certain manner or to perform certain operations as described herein. Considering embodiments in which the hardware module is temporarily configured (e.g., programmed), it is not necessary to configure or instantiate every hardware module at any given time. For example, in the case where the hardware module includes a general-purpose processor that is configured by 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 hardware module at one time and different hardware modules at different times.

[0046] A hardware module can provide information to other hardware modules or receive information from other hardware modules. Thus, the described hardware modules can be considered to be communicatively coupled. In the case where multiple such hardware modules are present simultaneously, communication can be achieved through signal transmission that connects the hardware modules (e.g., via appropriate circuitry and buses). 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 the multiple hardware modules. For example, one hardware module can perform an operation and store the output of the operation in a memory device to which it is communicatively coupled. Then, another hardware module can access the 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 resources (e.g., a collection of information).

[0047] The various operations of the example methods described herein can 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. Whether temporarily or permanently configured, such processors can constitute processor-implemented modules that operate to perform one or more operations or functions. In some example embodiments, the modules referred to herein can include processor-implemented modules.

[0048] Similarly, the methods or routines described herein can be implemented, at least in part, by a processor. For example, at least some of the operations of a method can be performed by one or more processors or processor-implemented hardware modules. The execution of some of the operations can be distributed among one or more processors that reside not only within a single machine but also across multiple machines. In some example embodiments, one or more processors can be located at a single location (e.g., within a home environment, within an office environment, or as a server farm), but in other embodiments, the processors can be distributed across multiple locations.

[0049] The execution of some of the operations can be distributed among one or more processors that reside not only within a single machine but also across multiple machines. In some example embodiments, one or more processors or processor-implemented modules can be located at a single geographical location (e.g., within a home environment, an office environment, or a server farm). In other example embodiments, one or more processors or processor-implemented modules can be distributed across multiple geographical locations.

[0050] Unless otherwise explicitly stated, discussions herein using words such as "processing", "computing", "calculating", "determining", "presenting", "displaying", etc. may refer to actions or processes of a machine (e.g., a computer) to manipulate or transform data represented as physical (e.g., electrical, magnetic, or optical) quantities within 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.

[0051] As used herein, any reference to "an embodiment" or "embodiments" means that the particular elements, features, structures, or characteristics described in connection with the embodiment are 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.

[0052] Some embodiments may be described using the expressions "coupled" and "connected" along with their derivatives. For example, some embodiments may use the term "coupled" to describe two or more elements in direct physical or electrical contact. However, the term "coupled" may also mean that two or more elements are not in direct contact with each other, but still cooperate or interact with each other. The embodiments are not limited to this context.

[0053] Those skilled in the art will recognize that various modifications, changes, and combinations can be made to the embodiments described above without departing from the scope of the invention, and such modifications, changes, and combinations are considered to be within the scope of the inventive concept.

Claims

1. An endoscope microscope assembly, comprising: An optical fiber ferrule and a single-mode optical fiber extending into the optical fiber ferrule, the optical fiber ferrule having a distal end positioned to emit an illumination beam when provided to the single-mode optical fiber; A compact scanning assembly mounted to a flexible tube, the compact scanning assembly having a folded beam configuration to receive the illumination beam, convert the illumination beam into an illumination beam with a higher numerical aperture, and scan the illumination beam with the higher numerical aperture across a transverse sample area, the compact scanning assembly comprising: A housing body; A two-mirror transverse scanning assembly fixedly positioned within the housing body and adjacent to the distal end of the flexible tube, the two-mirror transverse scanning assembly having a first 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 illumination beam with the higher numerical aperture, the folded beam path being defined by the first scanning mirror and a second mirror; and A lens assembly fixedly positioned within the housing body, the lens assembly being positioned distally to the transverse scanning assembly to scan the illumination beam with the higher numerical aperture across the transverse sample area and collect fluorescence from the transverse sample area, wherein the two-mirror transverse scanning assembly and the lens assembly are axially aligned with the axis of the single-mode optical fiber.

2. The endoscope microscope assembly according to claim 1, wherein the housing body of the compact scanning assembly has an outer diameter of 2.4 mm.

3. The endoscope microscope assembly according to claim 1, wherein the housing body of the compact scanning assembly has an outer diameter less than 2.4 mm.

4. The endoscope microscope assembly according to claim 1, wherein the lens assembly comprises a plurality of lens elements.

5. The endoscope microscope assembly according to claim 4, wherein the plurality of lens elements comprises two achromatic doublets.

6. The endoscope microscope assembly according to claim 5, wherein the plurality of lens elements comprises a plano-convex lens.

7. The endoscope microscope assembly according to claim 1, wherein the second mirror is an axial scanning mirror.

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