CA2959410C

CA2959410C - Biopsy control system and methods

Info

Publication number: CA2959410C
Application number: CA2959410A
Authority: CA
Inventors: Thanh Vinh Voung; Michael Francis Buxton; Kresimir Franjic; Siu Wai Jacky MAK
Original assignee: Synaptive Medical Inc
Current assignee: Synaptive Medical Inc
Priority date: 2017-03-02
Filing date: 2017-03-02
Publication date: 2021-11-02
Anticipated expiration: 2037-03-02
Also published as: CA2959410A1

Abstract

A biopsy control system for providing telepathology involving a biopsy apparatus having a positioning mechanism, a removable sample holder, the removable sample holder having a tissue sample storage extension configured to incubate a tissue sample of interest, the tissue sample storage extension configured to couple with the positioning mechanism, detectors disposed in relation to the removable sample holder, and a processor operable with the biopsy apparatus and configured to receive a measurement parameter associated with the tissue sample of interest, the measurement parameter having a sample type; retrieve, from a database, past measurement data associated with the sample type, determine an optimal position of the removable sample holder in relation to the tissue sample of interest for sampling by the detectors based on the measurement parameter and the past measurement data, and generate instructions for moving the removable sample holder to an optimal position.

Description

BIOPSY CONTROL SYSTEM AND METHODS
TECHNICAL FIELD

[0002] The present disclosure relates to biopsy tissue analysis systems. More particularly, the present disclosure relates to biopsy tissue analysis systems for use in operating rooms. Even more particularly, the present disclosure relates to biopsy tissue analysis systems for use in operating rooms that are remotely accessible.
BACKGROUND

[0003] During a surgical procedure in the related art, a need exists for intra-operative pathology consultation in order to guide immediate surgical decisions, such as establishing a diagnosis, confirming a diagnosis; or delineating margins of diseases. These pathological assessments are vital for successful surgical outcomes. Yet, typical intra-operative pathology procedures are time-consuming since tissue biopsy samples must be transferred to a pathology lab where the tissue biopsy samples must be correctly prepared and analyzed, wherein the results must be adequately communicated to a remote operating room. This long process may cause discontinuities in surgical workflows and delays in surgical actions. Under ideal circumstances, performing a biopsy analysis typically requires approximately 20 minutes. However, this period of time is usually longer during a surgery and waiting times of more than 60 minutes are not unusual for a variety of reasons. Reasons for such delays comprises a large distance between the operating room and the pathology lab, limited capacity of the pathology lab to analyze the biopsy sample(s), or inefficient setup of the pathology equipment.

[0004] Further, various types of optical imaging can provide information about tissue disease states.
Examples of such optical imaging modalities include optical coherence tomography (OCT), incoherent Raman spectroscopy, coherent Raman spectroscopy, auto-florescence intensity imaging, fluorescence lifetime imaging, diffuse optical imaging, confocal microscopy, multi-spectral imaging, hyperspectral imaging, 3D imaging, super-resolution microscopy, second harmonic imaging microscopy, third harmonic imaging microscopy, dark field imaging, phase-contrast microscopy, and white light imaging, e.g. traditional microscopy.

Date Recue/Date Received 2020-05-29

[0005] The imaging information can be further improved by injecting imaging contrast agents into an examined tissue. Insights about examined tissue can be enhanced if the tissue is probed with several optical imaging modalities and the data from different imaging modalities are correlated. The reason for the success of such multi-modal imaging approaches is that these optical imaging techniques examine different tissue properties, so they are complementary in nature. Some related art multi-modal optical imaging systems have also been described in Egodage, Kokila, et al., "The combination of optical coherence tomography and Raman spectroscopy for tissue characterization," Journal of Biomedical Photonics & Engineering, 1.2 (2015): 169-177, and disclosed in the following patent documents: DE19854292C2, US6507747B1, U57508524B2.

[0006] A shared feature of all the related art multi-modal optical systems for tissue imaging is that their optical sub-systems relate to individual imaging modalities, e.g. OCT, Raman spectroscopy, and fluorescence spectroscopy, share a certain number of optical elements such as optical beam splitters, lenses, or mirrors. Such an approach is conducive to compact optical systems;
however, such an approach is a potential disadvantage as the characteristics choice of shared optical elements is a compromise among different requirements for individual imaging sub-systems.
For example, in Raman spectroscopy, signals are very weak in relation to background noise and the pump laser power, necessitating the use of optical elements with sharp optical filtering characteristics; however, such optical filtering characteristics may not be optimal for other imaging modalities for which excitation and signal spectra may partially overlap with the Raman ones.

[0007] Therefore, a need exists for a biopsy analysis system that is useful in an operating room, is easily operated, and can provide faster and more reliable relevant pathological assessments than is currently available in the related art.
SUMMARY

[0008] To address at least the challenges experienced in the related art, in an embodiment of the present disclosure, a system and method for organic sample analysis is presently disclosed involving an optical multi-modal imaging platform in which various optical imaging modalities do not share Date Recue/Date Received 2020-05-29 common optical elements, whereby individual optical imaging data is provided with better quality imaging than that of the related art and, thus, improve overall information content of the multi-modal imaging process, wherein the better quality imaging can be remotely analyzed by expert personnel to provide rapid tissue analysis. To further address some of the related art challenges, the subject matter of the present disclosure involves a biopsy control system that is specifically configurable in relation to a given medical environment or environments, e.g., via an Internet-of Things (IoT) arrangement.
The biopsy control system comprises a processor that is configured to analyze and interpret biopsy analysis data in an operating room in real time, e.g., via an informatics system.

[0009] The present disclosure generally involves a sample holder mounted on a motorized positioning mechanism underneath a probe support rack containing a plurality of bio-imaging probes, with at least one bio-imaging probe having a field of view independent of all other bio-imaging probes. The system includes a computer controller connected to the motorized positioning mechanism and the at least one bio-imaging probe. The at least one bio-imaging probe and the motorized positioning mechanism are fully controllable and accessible via remote secure connection to a remote user, the remote user being at least one of a pathology professional and an automated graphics-recognition or visual-recognition system, who may perform the necessary tissue analysis commands from anywhere in the world, regardless of the physical location of the system. A further understanding of the detailed aspects of the present disclosure can be realized by reference to the following Detailed Description and Brief Description of the Drawing and to the several figures of the appended Drawing.

[0010] In accordance with an embodiment of the present disclosure, a biopsy control system for providing telepathology generally comprises: a biopsy apparatus, the biopsy apparatus comprising: a positioning mechanism; a removable sample holder for accommodating at least one tissue sample of interest, the removable sample holder disposed in relation to the positioning mechanism, the removable sample holder comprising a tissue sample storage extension configured to incubate the at least one tissue sample of interest, the tissue sample storage extension configured to couple with the positioning mechanism; and a plurality of detectors disposed in relation to the removable sample holder; and a processor operable with the biopsy apparatus, the processor configured to: receive at least one measurement parameter associated with the tissue sample of interest, the at least one measurement parameter comprising a sample type; retrieve, from a database, past measurement data Date Recue/Date Received 2020-05-29 associated with the sample type; determine at least one optimal position of the removable sample holder in relation to the tissue sample of interest for sampling by the plurality of detectors based on the at least one measurement parameter and the past measurement data; and generate a set of instructions for moving the removable sample holder to at least one optimal position.

[0011] In accordance with an embodiment of the present disclosure, a method of fabricating a biopsy control system for providing telepathology generally comprises: providing a biopsy apparatus, the biopsy apparatus providing comprising: providing a positioning mechanism;
providing a removable sample holder for accommodating at least one tissue sample of interest, providing the removable sample holder comprising disposing the removable sample holder in relation to the positioning mechanism, providing the removable sample holder comprising providing a tissue sample storage extension configured to incubate the at least one tissue sample of interest, the tissue sample storage extension configured to couple with the positioning mechanism; and providing a plurality of detectors disposed in relation to the removable sample holder; and providing a processor operable with the biopsy apparatus, providing the processor comprising configuring the processor to: receive at least one measurement parameter associated with the tissue sample of interest, the at least one measurement parameter comprising a sample type; retrieve, from a database, past measurement data associated with the sample type; determine at least one optimal position of the removable sample holder in relation to the tissue sample of interest for sampling by the plurality of detectors based on the at least one measurement parameter and the past measurement data; and generate a set of instructions for moving the removable sample holder to at least one optimal position.

[0012] In accordance with an embodiment of the present disclosure, a method of providing telepathology, by way of biopsy control system, generally comprises: providing the biopsy control system, providing the system comprising: providing a biopsy apparatus, the biopsy apparatus providing comprising: providing a positioning mechanism; providing a removable sample holder for accommodating at least one tissue sample of interest, the removable sample holder disposed in relation to the positioning mechanism, providing the removable sample holder comprising providing a tissue sample storage extension configured to incubate the at least one tissue sample of interest, the tissue sample storage extension configured to couple with the positioning mechanism;
and providing a plurality of detectors disposed in relation to the removable sample holder;
and providing a processor Date Recue/Date Received 2020-05-29 operable with the biopsy apparatus, providing the processor comprising configuring the processor to:
receive at least one measurement parameter associated with the tissue sample of interest, the at least one measurement parameter comprising a sample type; retrieve, from a database, past measurement data associated with the sample type; determine at least one optimal position of the removable sample holder in relation to the tissue sample of interest for sampling by the plurality of detectors based on the at least one measurement parameter and the past measurement data; and generate a set of instructions for moving the removable sample holder to at least one optimal position; commencing a biopsy session; receiving the at least one measurement parameter; retrieving, from the database, past measurement data; determining the at least one optimal position; and generating the set of instructions, thereby moving the removable sample holder to the at least one optimal position.
BRIEF DESCRIPTION OF THE DRAWING

[0013] The above, and other, aspects and features of several embodiments of the present disclosure will be more apparent from the following Detailed Description as presented in conjunction with the following several figures of the Drawing.

[0014] FIG. 1 is a schematic diagram illustrating a portable multi-modal tissue imaging system, implementable with a biopsy control system, in accordance with an embodiment of the present disclosure.

[0015] FIG. 2 is a schematic diagram illustrating a control computer system used in relation to representing a probe imaging volume discretization, implementable with a biopsy control system, in accordance with an embodiment of the present disclosure.

[0016] FIG. 3 is a diagram illustrating a side elevation view of a tissue sample with highlighted sample sections of interest that are selected after the sample has been observed with an optical probe, implementable with a biopsy control system, in accordance with an embodiment of the present disclosure.
Date Recue/Date Received 2020-05-29

[0017] FIG. 4 is a diagram illustrating a perspective view of a sample holder and motorized positioning assembly of a portable multi-modal tissue imaging system, implementable with a biopsy control system, in accordance with an embodiment of the present disclosure.

[0018] FIG. 5 is a schematic diagram illustrating a probe registration module in relation to the portable multi-modal tissue imaging system, implementable with a biopsy control system, in accordance with an embodiment of the present disclosure.

[0019] FIG. 6A is a diagram illustrating a cutaway side view of a pinhole registration module as an example of a probe registration module, implementable with a biopsy control system, in accordance with an embodiment of the present disclosure.

[0020] FIG. 6B is a diagram illustrating a cutaway side view of a pinhole registration module localization with white light imaging probes, implementable with a biopsy control system, in accordance with an embodiment of the present disclosure.

[0021] FIG. 7 is a diagram illustrating a side elevation view of localization of sampling volumes of interest, implementable with a biopsy control system, in accordance with an embodiment of the present disclosure.

[0022] FIG. 8A is a diagram illustrating a general portable multi-modal tissue imaging system for vertical coordinate determination in relation to sampling volume definition using a 2D optical probe and two guide lasers with crossed beams, implementable with a biopsy control system, in accordance with an embodiment of the present disclosure.

[0023] FIG. 8B is a diagram illustrating the general portable multi-modal tissue imaging system, as shown in FIG. 8A, implementable with a biopsy control system, in the case when alignment is achieved and the vertical coordinate determined, in accordance with an embodiment of the present disclosure.

Date Recue/Date Received 2020-05-29

[0024] FIG. 9A is a diagram illustrating a multi-modal optical imaging system for tissue analysis, implementable with a biopsy control system, in accordance with an embodiment of the present disclosure.

[0025] FIG. 9B is a diagram illustrating the multi-modal optical imaging system, as shown in FIG.
9A, that is mounted on a mobile unit, implementable with a biopsy control system, in accordance with an embodiment of the present disclosure.

[0026] FIG. 9C is a diagram illustrating the multi-modal optical imaging system, as shown in FIG.
9B, that includes an additional enclosure box for the multi-modal probe system, implementable with a biopsy control system, in accordance with an embodiment of the present disclosure.

[0027] FIG. 10 is a flow diagram illustrating a method of using the multi-modal optical imaging system, as shown in FIG. 9C, implementable with a biopsy control system, comprising non-limiting process steps, in accordance with an embodiment of the present disclosure.

[0028] FIG. 11A is a flow diagram illustrating detailed start and initialization steps in the method of using the multi-modal optical imaging system, implementable with a biopsy control system, as shown in FIG. 10, in accordance with an embodiment of the present disclosure.

[0029] FIG. 11B is a flow diagram illustrating detailed Raman setup steps in the method of using the multi-modal optical imaging system, implementable with a biopsy control system, as shown in FIG.
10, in accordance with an embodiment of the present disclosure.

[0030] FIG. 11C is a flow diagram illustrating detailed OCT scan setup and preview steps in the method of using the multi-modal optical imaging system, implementable with a biopsy control system, as shown in FIG. 10, in accordance with an embodiment of the present disclosure.

[0031] FIG. 11D is a flow diagram illustrating detailed 3D OCT scan setup steps in the method of using the multi-modal optical imaging system, implementable with a biopsy control system, as shown in FIG. 10, in accordance with an embodiment of the present disclosure.

Date Recue/Date Received 2020-05-29

[0032] FIG. 11E is a flow diagram illustrating detailed data acquisition steps in the method of using the multi-modal optical imaging system, implementable with a biopsy control system, as shown in FIGS. 11B, 11C, and 11D, in accordance with an embodiment of the present disclosure.

[0033] FIG. 12 is a schematic diagram illustrating a biopsy control system for providing telepathology, in accordance with an embodiment of the present disclosure.

[0034] FIG. 13 is a flow diagram illustrating a method of fabricating a biopsy control system for providing telepathology, in accordance with an embodiment of the present disclosure.

[0035] FIG. 14 is a flow diagram illustrating a method of providing telepathology, by way of a biopsy control system, in accordance with an embodiment of the present disclosure.

[0036] FIG. 15 is a flow diagram illustrating a method of performing telepathology, by way of a biopsy control system, in accordance with an embodiment of the present disclosure.

[0037] Corresponding reference numerals or characters indicate corresponding components throughout the several figures of the Drawing. Elements in the several figures are illustrated for simplicity and clarity and have not necessarily been drawn to scale. For example, the dimensions of some of the elements in the figures may be emphasized relative to other elements for facilitating understanding of the various presently disclosed embodiments. Also, common, but well-understood, elements that are useful or necessary in commercially feasible embodiment are often not depicted in order to facilitate a less obstructed view of these various embodiments of the present disclosure.
DETAILED DESCRIPTION

[0038] Various embodiments and aspects of the disclosure will be described with reference to details discussed below. The following description and drawings are illustrative of the disclosure and are not to be construed as limiting the disclosure. Numerous specific details are described to provide a thorough understanding of various embodiments of the present disclosure.
However, in certain Date Recue/Date Received 2020-05-29 instances, well-known or conventional details are not described in order to provide a concise discussion of embodiments of the present disclosure.

[0039] As used herein, the terms "comprises" and "comprising" are to be construed as being inclusive and open ended, and not exclusive. Specifically, when used in the specification and claims, the terms "comprises" and "comprising" and variations thereof mean the specified features, steps or components are included. These terms are not to be interpreted to exclude the presence of other features, steps or components.

[0040] As used herein, the term "exemplary" means "serving as an example, instance, or illustration,"
and should not be construed as preferred or advantageous over other configurations disclosed herein.

[0041] As used herein, the terms "about" and "approximately" are meant to cover variations that may exist in the upper and lower limits of the ranges of values, such as variations in properties, parameters, and dimensions.

[0042] As used herein, the tenn "patient" is not limited to human patients and may mean any organic sample such as human tissue, animal tissue, plant tissue, cells, and food samples.

[0043] As used herein, the term "bio-imaging probe" includes probes that acquire signals from visible, ultraviolet, infrared, terahertz, X-rays, microwave, and radio frequency part of the electromagnetic spectrum as well as acoustic probes.

[0044] As used herein, the imaging probes are of various dimensions, such as zero-dimensional, i.e., single point, 1-dimensional (1D), 2-dimensional (2D), 3-dimensional (3D), and 4-dimensional (4D).

[0045] Referring to FIG. 1, this schematic diagram illustrates a portable multi-modal tissue imaging system 10, implementable with a biopsy control system S, in accordance with an embodiment of the present disclosure. The portable biopsy multi-modal tissue imaging system 10 which includes plurality of optical probes P1, P2, , PN, wherein N = an integer, arranged in a fixed geometry relative to each other; a motorized positioning assembly 14; a sample holder 16 attached to the Date Recue/Date Received 2020-05-29 motorized positioning assembly 14 on which a sample 18 is mounted; control electronics 15 that drives the motorized positioning assembly 14 and the optical probes P1, P2, PN; a controller, such as a computer or processor 20, a microprocessor, and microcontroller, that controls the control electronics 15 and which is programmed with instructions to acquire and store data from these optical probes P1, P2, PN; and a power supply 19 that provides appropriate power for the control electronics 15 and the computer or processor 20.

[0046] Still referring to FIG. 1, the contents of the portable multi-modal tissue imaging system 10, implementable with a biopsy control system S, or, at least, the optical probes P1, P2, , PN and the motorized positioning assembly 14 is enclosable within a light-tight enclosure 12 to prevent any ambient light from contaminating the optical signals detected by any one or combination of the sensitive optical probes P1, P2,..., PN, wherein the optical probes P1, P2,..., PN are sensitive.

[0047] Still referring to FIG. 1, the contents of the portable multi-modal tissue imaging system 10, implementable with a biopsy control system S, or, at least, the optical probes P1, P2, PN and the motorized positioning assembly 14 are mountable on a vibrationally-damped base (not shown) to prevent mechanical vibrations, otherwise causing noise in the optical signals.

[0048] Still referring to FIG. 1, a housing 10a, encloses all the components forming part of the portable multi-modal tissue imaging system 10, implementable with a biopsy control system S, and comprises a ventilation system (not shown) to prevent deterioration of sensitive biological samples due to the presence of any air contamination inside the light-tight enclosure 12. Air contamination is detrimental if long-term sample preservation is required due to the need for an extended period to do the tissue analysis. Similarly, the portable multi-modal tissue imaging system 10 comprises a sample cooling system (not shown) for retarding deterioration of the biological samples by cooling the biological samples below room temperature. A non-limiting exemplary cooling system comprises a thermoelectric cooler (TEC) system within the sample holder 16.

[0049] Still referring to FIG. 1, for each probe Pi among probes P1, P2, PN, a probe imaging volume Vi is defined that is stationary relative to probe Pi, whereby a region of space is defined that is probed with each probe Pi. Also, for each probe imaging volume Vi, a coordinate system CSi exists Date Recue/Date Received 2020-05-29 which is fixed relative to each probe Pi and which defines the coordinates of the points within the given probe imaging volume V. In the remaining text, assumed is, without loss of generality, that the coordinate systems CSi are Cartesian coordinate systems with axes xi, yi, zi.
If alternative coordinate systems, such as cylindrical coordinate systems or spherical coordinate systems, are used, the alternative coordinate systems are transformable to Cartesian coordinate systems through coordinate transformations.

[0050] Referring to FIG. 2, this schematic diagram illustrates a computer or processor 20 used in relation to representing a probe imaging volume discretization, implementable with a biopsy control system S, in accordance with an embodiment of the present disclosure. Each probe imaging volume Vi is divided into a virtual spatial array 22 of sampling discrete cells 24.
The minimum useful size of the sampling discrete cells 24 is determined by the imaging resolution of the corresponding probe Pi.
The dimension Ns of the virtual spatial array 22 can be 0, 1, 2, 3, depending on the type of probe Pi.
For example, spatial arrays related to simple point base probes (such as Raman probes with static laser excitation beams) are zero-dimensional (scalars), while those related to OCT
probes are three-dimensional (3D). Also, for a probe with any spatial array dimension, recording an additional time coordinate, indicating the moment when the imaging measurement occurs is possible, at a specific discrete cell. Recording time coordinates can be useful in case when dynamic phenomena are observed in a sample. The virtual spatial array 22 is mapped into a data array 28 in the memory storage device of the computer or processor 20 such that data array 28 has at least a dimension Ns + 1 where its Ns dimensions correspond to Ns dimensions of virtual spatial array 22 while additional > Ns dimensions are related to imaging data acquired in a particular discrete cell of sampling discrete cells 24 in the virtual spatial array 22. The number and size of additional > Ns dimensions correspond to the number of data types acquired in individual discrete cells.

[0051] Still referring to FIG. 2, for computational convenience, the informational content of data arrays 28 can be represented by a set of several data arrays with smaller dimensions and size.
Hereinafter, assumed is that the spatial array is mapped into a single data array with dimension (Ns +
1). For each set of coordinates xi, yi, zi in physical coordinate system CSi, there are unique coordinates of data array 28 along Ns dimensions and a vector of imaging data along the (Ns + 1)-th dimension where imaging data are acquired from the discrete spatial cell overlapping with xi, yi, zi coordinates.

Date Recue/Date Received 2020-05-29 Using data from data array 28, it is possible to assign values of imaging data to any point with coordinates xi, yi, zi using interpolation methods that will be known to those of ordinary skill in the art. Imaging data from a particular discrete cell of the virtual spatial array 22 is mapped to a corresponding element of data array 28 by controlling the position of the volume element being excited by the excitation optical signal of probe Pi.

[0052] Still referring to FIG. 2, for example, in the event when detector of probe Pi is an array element whose dimension is equal to the dimension of the virtual spatial array 22, e.g., as in the event of white light imaging with a charge-coupled device (CCD) camera, such excitation position control can be accomplished by simple switching on/off the excitation source such that all cells of the virtual spatial array 22 will be imaged and mapped to data array 28 simultaneously. Another example involves scanning with optical probes, such as by OCT, wherein the optical probe Pi comprises an optical scanner controlled by the computer or processor 20, and wherein the position of optical scanner mirrors define the position of the excitation laser beam, and, thus, define the position of the excitation volume. To simplify further discussion, we will relate imaging data to physical coordinate system CSi and continuous coordinates xi, y, zi assuming tacitly that all data and positions are recorded and processed in the computer or processor 20 in the form of discrete data arrays.

[0053] Still referring to FIG. 2, during a probe registration process, coordinate transformation equations are established that relate coordinates xi, yi, zi of each probe imaging volume V; to the corresponding Cartesian coordinates of all other probe imaging volumes Vi, V2, ..., VN. These coordinate transformation equations are recorded and stored by the computer or processor 20. A few practical and non-limiting embodiments for such optical probe registration processes are herein below described. The optical probe registration process can be performed only occasionally assuming the optical probes Pl, P2, PN remain fixed at their positions relative to each other.

[0054] Referring to FIG. 3, this diagram illustrates a side elevation view of a tissue sample with highlighted sample sections of interest that are selected after the sample has been observed with an optical probe, implementable with a biopsy control system S, in accordance with an embodiment of the present disclosure. At least one designated probe 34, e.g., a PM probe or a PV probe, of the probes Pl, P2,..., PN is configured to provide a user with the ability to mark sample volumes of interest Vsl, Date Recue/Date Received 2020-05-29 Vs2, VsM observed on an image of the sample 18 created by the PM or PV probe. A
sample 18 which is positioned on the sample holder 16 is imaged with the probe PV which is controlled by computer or processor 20. The image 38 of the sample 18 is shown on a display device 37, such as a computer display, where a user can mark a set of images 39 representing sample sections of interest Vsl', Vs2',..., VsM' which correspond to a set 32 of sample sections of interest Vsl, Vs2, , VsM
in physical space. The process of marking the set of images 39 on the display device 37can be done by using computer user interface techniques and user interface devices. An example of a user interface technique comprises a graphical user interface (GUI); and examples of user interfaces devices comprise a computer monitor, a touchscreen display, and a mobile device such as a phone or tablet.

[0055] Still referring to FIG. 3, the positions of Vsl, Vs2, VsM are recorded by the computer 20 and they can be specified in physical coordinates xi, yi, zi related to the designated PM or PV probe or equivalently in the coordinates of the corresponding data array 28. For the purpose of this disclosure, the process of marking and recording sample sections of interest Vsl, Vs2, VsM is called sampling volume definition. A few practical and non-limiting embodiments for such sampling volume definition are described here below.

[0056] Still referring to FIG. 3, during the process of sampling volume definition it is also beneficial to mark and record a tissue landmark 35 as a fiducial marker for establishing spatial correlations between imaging data acquired by the multi-modal optical imaging system and other previous or subsequent imaging and analysis modalities such as magnetic resonance imaging (MRI) or histological analysis. Alternatively, a fiducial marker 36 can be located on the sample holder 16 if the sample remains rigidly attached to the sample holder 16 for the above mentioned previous or subsequent alternative imaging procedures.

[0057] Still referring to FIG. 3, in a sample analysis process, sample 18 is attached to the sample holder 16 which in turn is attached to the motorized positioning assembly 14.
This allows the operator to position of sample 18 under various designated probes 34, e.g., optical probes P1, P2, PN, to perform optical imaging. In the event that the spatial orientation of sample 18 relative to the optical probes P1, P2, PN is fixed and only translations of sample 18 using motorized positioning assembly 14 are performed, the shape of sample 18 remains approximately the same during the sample Date Recue/Date Received 2020-05-29 movements. Since sample sections of interest Vsl, Vs2, VsM are defined within the coordinate system CSv; and since the coordinates of the coordinate system CSv are correlated to coordinates of all other coordinate systems CSi through the probe registration process, it is possible to completely or partially overlap the sample sections of interest Vsl, Vs2, VsM with volume Vi of each probe Pi and specify locations of these sections by using coordinates of the local coordinate system CSI. Thus, it is possible to spatially correlate imaging data obtained across the sections Vsl, Vs2, VsM by using probe Pi to imaging data acquired across these sections by using any other probe Pj. These data can be recorded, stored and possibly analyzed by computer or processor 20.

[0058] Still referring to FIG. 3, the spatial data correlation process described above is performed under the assumption that sample 18 does not change its orientation relative to the optical probes. However, in the event that of a large soft tissue sample and sample tilting during the positioning under probes P1, P2, PN, the sample shape and position may slightly change due to the force of gravity so consequently relative positions of two sample features within a sample section of interest Vsj may change when the sample section of interest Vsj is analyzed under a probe Pi.
If this relative change of feature position is larger than the required imaging resolution for the probe Pi, creating correction coordinate transformation equations that relate initial relative positions of these two features to the final ones is necessary in order to spatially correlate optical data for these two features acquired with the probe Pi to the data acquired by other probes P1, P2,..., PN. Creating such correlations of relative positions of tissue features when the tissue undergoes some kind of deformation is a technique useful with the embodiments of the present disclosure. An example can be found in the reference Suwelack, Stefan, et al. "Physics-based shape matching for intraoperative image guidance," Medical physics, 41.11 (2014): 111901.
Motorized Positioning Assembly

[0059] Still referring to FIG. 3, the motorized positioning assembly 14, e.g., having a mechanism 102 (FIG. 9A), comprises any suitable motorized positioning components. Such motorized positioning components comprise actuators that are based, for example, on DC motors, stepper motors, or piezoelectric effect. Typically, the motorized positioning assembly 14 has three translation stages for moving a sample 18 along three perpendicular axes of travel (X, Y, Z). The traveling ranges of these Date Recue/Date Received 2020-05-29 translation stages should be long enough to allow positioning sample sections of interest Vsl, Vs2, VsM within probe volumes V1, V2, VN. Besides the translation stages, additional positioning degrees of freedom may be useful such as rotations and tilts. Tilt stages are beneficial in the event that the optical probe response relies on the tilt sample orientation, e.g., in relation to polarization sensitive optical coherence tomography. For all motorized positioning components, keeping track of their positions is useful in order to perform optical probe registration processes and sampling volume definition as well as to track coordinates of sections of interest Vsl, Vs2, VsM of the sample being interrogated.

[0060] Referring to FIG. 4, this diagram illustrates, in a perspective view, a sample holder 16 and motorized positioning assembly 14 of a portable multi-modal tissue imaging system 10, implementable with a biopsy control system S, in accordance with an embodiment of the present disclosure. Tracking the positions (FIG. 3) is performable by using position encoders or sensors configured, and positioned, to detect typical stage positions (home and end positions) and to provide reference points for measuring position deviations. An example of a motorized positioning assembly 14 comprises an X translation stage 40, a Y translation stage 44, a Z
translation stage 46, a tilt stage 48, and, perpendicular thereto, a second tilt stage 49. A sample holder 16 is mounted on the top of the second tilt stage 49. The portable multi-modal tissue imaging system 10 is fixed to a base plate 42 for at least robustness and rigidity.
Optical Probe Registration

[0061] Referring to FIG. 5, this schematic diagram illustrates a probe registration module (not shown) in relation to the portable multi-modal tissue imaging system 10, implementable with a biopsy control system S, in accordance with an embodiment of the present disclosure. In practical applications, the optical probe registration is accomplished by using a registration object fixed in relation to the motorized positioning assembly 14. The registration object 50 contains a geometric feature 52 which is recognizable on images of all probes P1, P2, PN. The geometric feature 52 resembles a cross;
however, any geometric feature having characteristic size smaller than that required by optical probe registration precision and accuracy is usable for this purpose. By using the motorized positioning assembly 14, the geometric feature 52 is brought within various probe imaging volumes V1, V2, ..., Date Recue/Date Received 2020-05-29 VN and imaged. The relative physical positions of the geometric feature 52 for recorded images is easily measurable by recording positioning coordinates of the motorized positioning assembly 14 which are tracked by the computer or processor 20.

[0062] Still referring to FIG. 5, also, the position of the geometric feature 52 within a certain probe imaging volume Vi relative to the origin of the corresponding coordinate system CSi can be determined by the image of the geometric feature 52 that is acquired with probe Pi. In this manner, relative origin positions of all coordinate systems CSi are calculated. The type of coordinate systems CSi (Cartesian, cylindrical, spherical, etc.) and directions of their axes are made the same for all probes P1, P2, , PN and are coincident with degrees of freedom of motorized positioning assembly 14. As noted above, the motorized positioning assembly 14 typically contains translational motorized stages moving along the three perpendicular directions; however, in principle, the motorized positioning assembly 14 has motorized stages with a rotational stage replacing one of the translational stages. These directions are used to define axes of Cartesian coordinate systems CSi related to probes Pi so that the coordinate axis of the coordinate systems CSi are parallel to the perpendicular directions of the motorized translational stages.

[0063] Referring to FIG. 6A, this diagram illustrates, in a cutaway side view, a pinhole registration module 60 as an example of a probe registration module, implementable with a biopsy control system S, in accordance with an embodiment of the present disclosure. In the present disclosure, several non-limiting examples of probe registration modules are described in cases when all probes P1, P2.....
PN are either imaging probes that provide 2D (two dimensional) or 3D (three dimensional) images or all probes P1, P2, PN are laser-based probes, wherein a sample is probed with a focused laser beam. The pinhole registration module 60 comprises a housing 62, module cover

64 having a pinhole

65, and a photo-detector 66 placed below the pinhole 65. The photo-detector 66 is sensitive at all laser wavelengths of the laser-based optical probes.
[0064] Still referring to FIG. 6A, the pinhole 65 and the photo-detector 66 are disposed within the housing 62 such that the only light incident at the photo-detector 66 is the light that passes through the pinhole 65. The position of the focused laser beam of the laser-based optical probes can be located by scanning the pinhole 65 in the vicinity of such optical probes using the motorized positioning Date Recue/Date Received 2020-05-29 assembly 14. When the pinhole 65 is at the laser focus, the signal from the photo-detector 66 is maximal, whereby the signal is easily detected. For 3D imaging probes, e.g. 3D
scanners, OCT probes, confocal scanning microscopes, the position of the pinhole 65 is easily detected by making a 3D image of the pinhole 65, wherein pinhole geometry is easily recognized by way of its known shape and size.
Similarly, for the optical probes generating 2D images, detecting two coordinates of the pinhole 65 position in the plane defined by the 2D imaging is possible. However, for determining the third coordinate for such a 2D probe, an additional position sensing detector (not shown) is required.
[0065] Referring to FIG. 6B, this diagram illustrates, in a cutaway side view, a pinhole registration module localization performed with white light imaging probes, implementable with a biopsy control system S, in accordance with an embodiment of the present disclosure. In the foregoing example, two auxiliary laser beams 68 are used. Referring again to the example registration module (FIG. 5), two auxiliary laser beams 68 are aligned, wherein they intersect within the probe volume Vi corresponding to the 2D probe. Then the motorized positioning assembly 14 is used to register the pinhole 65 with the laser intersection point Li. That position, the laser intersection point Li, is detected either by observing the overlap of the laser spot reflections off the pinhole body or a pinhole surface 65a on an image created by probe Vi or by detecting the maximum laser beam transmission through the pinhole 65 by using the photo-detector 66. In all cases, the detected position of pinhole 65 is recorded using the X, Y, Z coordinates of the motorized positioning assembly 14 and is used as the origin of the local probe coordinate system.

[0066] Still referring to FIG. 6B, in a second embodiment of a probe registration module (not shown), the registration module contains a pattern that is photo-sensitive at the laser wavelengths of laser-based optical probes. When excited with such lasers, the pattern should emit a signal that can be detected with the corresponding optical probes, e.g., Raman or fluorescent signals, thus helping to localize a characteristic pattern point that provides the origin location of the local coordinate system.
Also, the pattern at the registration module should be recognizable when imaged with 2D and 3D
imaging probes in order to provide well defined origins of their local coordinate systems. Similar to the pinhole module, in the event that of 2D imaging probes, two auxiliary laser beams 68, such as two auxiliary intersecting laser beams, can be used to provide the third coordinate of the characteristic pattern point Li.

Date Recue/Date Received 2020-05-29

[0067] Still referring to FIG. 6B, in a third embodiment of a probe registration module (not shown), the registration module comprises a photo-sensitive material whose appearance, such as color and shade, is alterable upon exposure to the laser beams of the laser-based optical probes. In this manner, for laser-based probes, a pattern is written on the probe registration module at well-defined local coordinates providing simple registration. Such patterns are subsequently detected by 2D and 3D
imaging probes in the same manner as described for the second registration module, thereby allowing their registration as well.
Sampling Volume Definition

[0068] Still referring to FIG. 6B and referring back to FIG. 3, for the sampling volume definition process, a microscopy probe (PM) or a volume probe (PV) comprises a 2D probe.
For exemplary embodiments, we will consider two types of designated probes 34, e.g., 2D
probes and 3D probes.
The first type may be a 3D probe which provides a 3D image of a sample or a portion of the sample volume. A set 32 of sample sections of interest Vsl, Vs2, VsM, in physical space, of the sample 18 is imaged by the PM or the PV and is represented as set of images 39 on a display device 37 (FIG.
3). Examples of 3D-type probes include 3D scanners, optical coherence tomography probes, confocal microscopy probes, and non-linear optical probes. The 3D scanners are of any type, e.g., 3D scanners based on time-of-flight, triangulation, structured light, modulated light, stereoscopic systems, and photometric systems. The stereoscopic 3D scanners are usually implemented by using two video cameras, slightly apart, viewing a sample. In an example, the stereoscopic effect is also achievable by using a single camera that observes a sample 18 at two different positions, wherein the sample 18 is positioned by using the motorized positioning assembly 14. The 3D set of images 39 of a sample 18 provides coordinates of the sample surface profile relative to the coordinate system with respect to the 3D scanner probe. Once a 3D image 39 of a tissue volume is presented to a user, the user indicates sample sections of interest Vs 1', Vs2', VsM' on the set of images 39. The techniques for presenting 3D volumes on 2D and 3D computer displays as well as techniques for indicating sections of these displayed 3D images are utilizable in relation to embodiments of the present disclosure.

Date Recue/Date Received 2020-05-29

[0069] Still referring to FIG. 6B and referring back to FIG. 3, examples of such techniques include direct user input through a GUI, voice input, or text input. Also, selection, e.g., user selection, is facilitated by using a set of executable instructions, predetermined algorithms, and other computer inputs, such as machine learning and artificial intelligence (Al) instructions. In such embodiments of the present disclosure, at least one of the set of executable instructions, the predetermined algorithms, and the other computer inputs, e.g., the machine learning and the artificial intelligence (Al) instructions, inform the performance of a majority of the sampling volume definition process, wherein the user interface establishes a simple process comprising steps, such as inserting and removing a sample into the multi-modal imaging system and activating the imaging process.

[0070] Still referring to FIG. 6B and referring back to FIG. 3, the designated probe 34, e.g., a second type of PM or PV, is a 2D probe. An example of a 2D probe is a bright field microscope with a camera.
In this embodiment, the PM or the PV provides a 2D projection image of a 3D
surface of a sample 122. Since optical probes generally have limited penetration into tissue, the optical probe penetration depth can be used to define the 31d dimension and complete volume definition.
The set of images 39 represents a 2D image in this case and a user makes choices of Vs 1', Vs2', VsM' which are 2D
projections of physical sample volumes of interest V1, V2, VN. The 31d dimension added to the sample volumes of interest Vs1', Vs2', VsM' that defines V1, V2, VN is the longest penetration depth among the probes P1, P2, PN.

[0071] Referring to FIG. 7 and referring back to FIG. 3, this diagram illustrates, in a side elevation view, localization of sampling volumes of interest, implementable with a biopsy control system S, in accordance with an embodiment of the present disclosure. A sample volume of interest in this embodiment involves a PM or a PV, comprising a 2D probe. Elements 16, 20, 34, 37, 38, and 39 are also shown FIG. 3. A cross-sectional portion 70, e.g., of a sample 18, the image of which is rendered on a display device 37 as the image 38. A plane of the cross-sectional portion 70 is perpendicular to the imaging plane of the PM or the PV comprising the 2D probe. The cross-sectional portion 70 of the sample 18 being imaged is represented by a line 74 of the image 38. If the sample 18 is subsequently examined by a PM probe having an imaging penetration depth din the tissue, the sample volume of interest 72 is represented as a layer having a thickness approximately equal to, or equal to, Date Recue/Date Received 2020-05-29 the imaging penetration depth d and is represented by the set of images 39, e.g., a 2D image, rendered on the display device 37.

[0072] Still referring to FIG. 7 and referring ahead to FIGS 8A and 8B, the remaining parameter required to completely define the contour of the sample volume of interest 72 in the coordinate system CSv of the PM or the PV is the distance of sample volume of interest 72 from the PM or PV probe, that is a coordinate Z. A schematic of an exemplary embodiment is shown for determining the Z
coordinate of the sample volume of volume 72 (FIGS. 8A and 8B). Each laser of a pair of auxiliary lasers 80, 82 has a fixed position above the sample holder in a manner, wherein their respective laser beams 81, 83 intersect within the probe imaging volume Vv of the 2D probe in the case of an unoccupied volume Vv.

[0073] Referring to FIG. 8A, this diagram illustrates, in a side view, a general portable multi-modal tissue imaging system 10 for vertical coordinate determination in relation to sampling volume definition using the designated probe 34, such as a PM or a PV, e.g., a 2D
optical probe, and the pair of auxiliary lasers 80, 82, e.g., two guide lasers, with "crossed" respective laser beams 81, 83, implementable with a biopsy control system S, in accordance with an embodiment of the present disclosure. If a sample 18 is present within volume Vv, the laser intersection point Li will not generally coincide with the surface of the sample 18 where the sample 18 is represented by the cross-sectional portion 70. The reflections of the respective laser beams 81, 83 are visible as the respective two dots 84, 85 on the image 38 of sample 18 on a display device 37.

[0074] Referring to FIG. 8B, this diagram illustrated, in a side view, the general portable multi-modal tissue imaging system 10, as shown in FIG. 8A, implementable with a biopsy control system S, in the event that when alignment is achieved and the vertical coordinate determined, in accordance with an embodiment of the present disclosure. If the sample 18 is moved to a disposition that is perpendicular to the imaging 2D plane of the PV by using the motorized positioning assembly 14 as previously described, at a certain point, the surface of the sample 18 coincides with the intersection point between the auxiliary lasers 80, 82, e.g., the two guide lasers 80, 82. This position is recognizable on the image 38 when images of reflected laser beams, as represented by the respective two dots 84, 85, merge into Date Recue/Date Received 2020-05-29 a single dot 86. Since the position of the laser intersection point Li is fixed in coordinate system CSV, the sample position uniquely determines the position of the sample 18 within volume Vv.

[0075] Referring to FIG. 9A, this diagram illustrates, in a perspective view, a multi-modal optical imaging system 10 for tissue analysis, implementable with a biopsy control system S, in accordance with an embodiment of the present disclosure. Another technique for determining the vertical position of a sample 122 in coordinate system CSv is by using the PM or the PV, e.g., a 2D optical probe, with a small depth of field and a known focal plane position. By moving a sample section of interest along the vertical coordinate via the motorized positioning assembly 14 or the mechanism 102, bringing the image of the sample section of interest into sharp focus on the computer display is possible, thereby indicating the position of the sample section of interest at the focal plane of the PM or the PV, and thereby determining the Z coordinate of the sample section of interest within the coordinate system CSv.
Optical Probe

[0076] Still referring to FIG. 9A, after the position of sample 18 is registered and sample sections of interest Vsl, Vs2, VsN are chosen, data acquisition can begin. The data acquisition procedure is a function of the type of a corresponding optical probe being used. For the present optical biopsy system, any type of bio-imaging probe and any possible mode of operation of such a probe, including, but not limited to, optical probe systems described in any academic and patent literature, sold by a commercial vendor, or developed in-house, is utilizable with the embodiments of the present disclosure. Non-limiting examples of using probes with the embodiments of the present disclosure are based on the following techniques.
(a) Spontaneous Raman Scattering

[0077] Still referring to FIG. 9A, in this case, optical signals originate from inelastic Raman scattering of an excitation laser beam off a sample 122. The spectrum of the Raman signal depends on the type of chemical bonds within the sample. More details about the nature of the signal and Raman probes are described in the reference: Latka et al., "Fiber optic probes for linear and nonlinear Raman Date Recue/Date Received 2020-05-29 applications ¨ Current trends and future development," Laser Photonics Rev. 7, No. 5, 698-731 (2013).
(b) Stimulated Raman Scattering (SRS)

[0078] Still referring to FIG. 9A, SRS carries similar information as the spontaneous Raman scattering; however, the optical interaction is amplified through coherent amplification. More details about the nature of the signal and SRS probes are described in the reference:
Ji et al., 'Rapid, Label-Free Detection of Brain Tumors with Stimulated Raman Scattering Microscopy,' Sci Transl Med 5, 201ra1 19 (2013).
(c) Coherent Anti-Stokes Raman Scattering (CARS)

[0079] Still referring to FIG. 9A, CARS is another variant of coherent Raman scattering. More details about the nature of the signal and CARS probes are described in the reference:
Latka et al., 'Fiber optic probes for linear and nonlinear Raman applications ¨ Current trends and future development,' Laser Photonics Rev. 7, No. 5, 698-731(2013).
(e) Optical Coherence Tomography (OCT)

[0080] Still referring to FIG. 9A, OCT is technique analogue to ultrasound in which 3D image of the object can be generated from time-of-flight information. OCT uses light wave instead of sound wave as in ultrasound which provides images with a much higher resolution. More information on OCT are described in the reference: Jafri et al., "Optical coherence tomography guided neurosurgical procedures in small rodents," Journal of Neuroscience Methods 176 (2009) 85-95.
(f) Polarization Sensitive Optical Coherence Tomography (PS-OCT)

[0081] Still referring to FIG. 9A, PS-OCT is a functional variant of OCT in which the polarization of the sample can also be imaged. This enables contrast like tissue organization to be imaged. More information on PS-OCT are described in the reference: Ding et al., "Technology developments and Date Recue/Date Received 2020-05-29 biomedical applications of polarization-sensitive optical coherence tomography," Front.
Optoelectron. 2015, 8 (2): 119-121.
(g) Hyperspectral Imaging (HSI)

[0082] Still referring to FIG. 9A, HSI is a hybrid modality that combines imaging and spectroscopy.
By collecting spectral information at each pixel of a two-dimensional (2-D) detector array, HSI
generates a three-dimensional (3-D) dataset of spatial and spectral information. More details regarding HSI are described in the reference: Lu et al., "Medical hyperspectral imaging:
a review," Journal of Biomedical Optics 19(1), 010901 (2004).
(h) Fluorescence imaging

[0083] PM or PVStill referring to FIG. 9A, in vivo fluorescence imaging uses a sensitive camera to detect fluorescence emission from fluorophores in whole-body living small animals. More details regarding fluorescence imaging are described in the reference: Yao et al., "Fluorescence imaging in vivo: recent advances," Current Opinion in Biotechnology 2007, 18:17-25.
(i) Fluorescence Lifetime Imaging Microscopy (FLIM)

[0084] Still referring to FIG. 9A, FLIM is an imaging technique for producing an image based on the differences in the exponential decay rate of the fluorescence from a fluorescent sample. The lifetime of the fluorophore signal, rather than its intensity, is used to create the image in FLIM. This technique minimizes the effect of photon scattering in thick layers of sample. More details regarding FLIM are described in the reference: Becker, "Fluorescence lifetime imaging techniques and applications,"
Journal of Microscopy 2012, May 24.
(j) Second Harmonic Imaging Microscopy (SHIM)

[0085] Still referring to FIG. 9A, SHIM is based on a nonlinear optical effect known as second-harmonic generation (SHG). More details regarding the nature of the signal and probes for second Date Recue/Date Received 2020-05-29 harmonic imaging microscopy are described in the references: Campagnola, Paul J., and Leslie M.
Loew, "Second-harmonic imaging microscopy for visualizing biomolecular arrays in cells, tissues and organisms," Nature biotechnology 21.11 (2003): 1356-1360.
(k) Third Harmonic Imaging Microscopy

[0086] Still referring to FIG. 9A, third harmonic imaging microscopy is based on a nonlinear optical effect known as third-harmonic generation (THG). More details regarding the nature of the signal and probes for third harmonic imaging microscopy are described in the reference:
Kuzmin, N. V., et al.
"Third harmonic generation imaging for fast, label-free pathology of human brain tumors."
Biomedical Optics Express 7.5 (2016): 1889-1904.
Example(s)

[0087] Still referring to FIG. 9A and ahead to FIGS. 9B and 9C, a layered structure in the multi-modal optical imaging system 10 for tissue analysis is shown, in accordance with an embodiment of the present disclosure (FIGS. 9A through 9C). In FIG. 9A, the main opto-mechanical components are indicated. For fiber coupled optical probes described in the present disclosure, the term "distal" refers to the end of the optical fiber closest to a sample 122 while the term "proximal" refers to the opposite end of the optical fiber.

[0088] Still referring to FIG. 9A, ahead to FIGS. 9B and 9C, and back to FIGS.
1-5, 7, 8A, and 8B, a sample 122 is placed on a sample holder 120 which is attached to a motorized positioning assembly, e.g., comprising the motorized positioning assembly 14 (FIG. 4) having a mechanism 102. For structural integrity and robustness, the motorized positioning assembly 102 is fixed on the top of a sample system base-plate 100, comprising at least one of stainless steel and aluminum, and comprising a thickness in a range of approximately 10 mm to approximately 15 mm. The motorized positioning assembly 14 (FIG. 4) having a mechanism 102 is controlled through a motorized stage driver 104 that provides necessary electrical driving signals for the motorized stage actuators as well as collects electrical signals from the assembly sensors (such as encoders) that inform about the state of the assembly. Electrical power and control signals for motorized stage driver 104 are provided through a Date Recue/Date Received 2020-05-29 main control system 106 that includes electrical power supplies 108 and control computer 110 that has the same role as the computer or processor 20 (FIGS. 1-5, 7, 8A, and 8B).

[0089] Still referring to FIG. 9A and ahead to FIGS. 9B and 9C, a user interacts with the control computer 110 through a computer display 118, a keyboard 112, a mouse 116, and, potentially, by using any other computer-interacting peripheral device. Optical probes used for sample analysis are attached to a mechanical frame 152 that is fixed to the sample system base-plate 100. Brackets (not shown) are used to attach the optical probes to mechanical frame 152.

[0090] Still referring to FIG. 9A and ahead to FIGS. 9B and 9C, an OCT optical probe system can be any OCT system mentioned previously and in this exemplary embodiment includes an OCT control system 126, an optical scanner 124, and an optical scanner driver 128. The OCT
control system 126 comprises an OCT system components described in the previously disclosed references, such as a laser excitation source, an interferometer, a reference arm, optical detectors, electrical circuitry needed for the operation, as well as electrical and optical cables connecting individual components. An optical fiber, acting as an OCT sample arm, couples the OCT control system 126 with the optical scanner 124 that scans the OCT sample laser beam across the sample 122. The electrical power and control computer signals are provided through the main control system 106.

[0091] Still referring to FIG. 9A and ahead to FIGS. 9B and 9C, a coupled Raman probe 140 is used to excite the sample 122 by using a fiber-coupled narrow line-width laser source 142 and further collects and transfers the corresponding Raman signal to a spectrometer 144.
The electrical power and control computer signals for the fiber-coupled narrow line-width laser source 142 and the spectrometer 144 are provided through the main control system 106. In addition, a wide-field microscope 132 and a narrow-field microscope 130 are installed as convenient probes for quick sample examination as well as for sampling volume definition. Microscope signals are recorded by integrated cameras that are powered and controlled by the main control system 106.

[0092] Still referring to FIG. 9A, ahead to FIGS. 9B and 9C, and back to FIGS.
6A, 8A, and 8B, illumination sources 134, 136 provide illumination for respective wide-field microscope and narrow-field microscope 132, 130, wherein the illumination sources 134, 136 are controlled through an Date Recue/Date Received 2020-05-29 illumination controller 138, the illumination controller 138 powered and controlled with the main control system 106. Guide lasers 146, 148 are fixed in a geometry, wherein their respective laser beams (not shown) cross approximately at the center of fields of view of the narrow-field and wide field microscopes. The guide lasers 146, 148 are controlled through a guide laser driver 150 which is powered and controlled with the main control system 106 as well. The guide lasers 146, 148 (FIGS.
6A, 8A, and 8B) facilitate deployment of the portable multi-modal tissue imaging system 10 (FIG.
9A) at a location of interest, e.g., a surgical operating room, wherein the portable multi-modal tissue imaging system 10 is installable within a mobile unit (FIGS. 9B and 9C).

[0093] Referring to FIG. 9B, this diagram illustrates the portable multi-modal tissue imaging system 10, as shown in FIG. 9A, that is mounted on a mobile unit, implementable with a biopsy control system S, in accordance with an embodiment of the present disclosure. The electrical components and the optical elements at the distal sides of the fiber-coupled optical probes are enclosed in a cabinet 200 that is attached at the top of a base plate 208. The base plate 208 is mounted on casters 210, 212, 216, and a 4th caster (not shown). A break 218 facilitates locking the casters 210, 212, 216, and a 4t1i caster in place and fixes the portable multi-modal tissue imaging system 10 within a desired disposition for safety and for reducing mechanical disturbances during optical signal acquisitions.
Additional elements for improving mechanical stability are vibrational isolators 202, 204, 206 that fix the sample system base-plate 100 to the cabinet 200. More vibrational isolators could be present and not visible in the figure. For mounting simplicity, some smaller electrical components and optical elements on the distal fiber ends a disposed on the sample system base-plate 100 as well. For drawing simplicity, electrical and optical cables connecting various elements are not shown.

[0094] Referring to FIG. 9C, this diagram illustrates the portable multi-modal tissue imaging system 10, as shown in FIG. 9B, that includes an additional enclosure 300 for the portable multi-modal tissue imaging system 10, implementable with a biopsy control system S, in accordance with an embodiment of the present disclosure. The additional enclosure 300 is installed on the top of cabinet 200, enclosing the optical probe system mounted on the sample system base-plate 100. The additional enclosure 300 protects the internal optics from external disturbances, protects a user from exposure to optical probe laser beams, creates a controlled environment for sample data acquisition, including a stable thermal Date Recue/Date Received 2020-05-29 environment, and creates light-tight space within the additional enclosure 300 suitable for optical probe acquisitions of small signals that can be otherwise overwhelmed by external ambient light.

[0095] Still referring to FIG. 9C, the additional enclosure 300 has a door 314 which is used as an entrance point for inserting, and removing, the sample 122 in relation to the sample holder 120. A
monitor stand 310 provides a fixture for computer display 118. A front console 320 provides a mounting space for an emergency stop button 322, power button 324, as well as computer peripheral connections, such as a universal serial bus (USB) port and/or at least one video connection, such as at least one of a digital visual interface (DVI) connection, a high-definition multimedia interface (HDMI) connection, and a video graphics array (VGA) connection. In case of very sensitive optical probes or more dangerous optical probe excitation laser beams, an additional enclosure within the cabinet 200 is installed.

[0096] Referring to FIG. 10, this flow diagram illustrates a method M of using the portable multi-modal tissue imaging system 10, as shown in FIG. 9C, implementable with a biopsy control system S, comprising non-limiting process steps, in accordance with an embodiment of the present disclosure.
FIG. 10 also illustrates the basic work-flow for the portable multi-modal tissue imaging system 10, as shown and described in relation to FIG. 9C. Since optical probes are rigidly mounted on a common frame, optical probe registration is only occasionally required. During a daily procedure, the portable multi-modal tissue imaging system 10 is initialized and started typically by pressing a power button 324. The control computer 110 functions, described herein, are incorporable in a single control software program with a suitable user interface. After a user fixes a sample, e.g., the sample 122, onto the sample holder 120, the user enters the sample information within the control software, wherein the sample information becomes linked to acquired data. Subsequently, the motorized positioning assembly 14 (FIG. 4), having a mechanism 102, moves the sample 122 underneath the designated probes where sampling volume definition is performed. In this case, these probes are narrow-field and wide-field microscopes.

[0097] Still referring to FIG. 10, in the method M, after the user chooses the sampling regions of interest, the motorized positioning assembly 14 (FIG. 4), having a mechanism 102, moves the sample 122 underneath the OCT and/or, depending on the user choice, Raman probes, wherein data Date Recue/Date Received 2020-05-29 acquisition is performed. The user then reviews the data, and, based on the feedback, may decide to terminate the session by unloading the sample 122, to define and analyze new sampling regions of interest, or to load another sample 122. In the event of an emergency, the user has an option to terminate the session at any time by pressing the emergency stop button 322, wherein the current acquired data is saved, and wherein the sample 122 is ejected.

[0098] Still referring to FIG. 10, in the method M, the workflow initiates at the start with an initialize system 1000 step. Next a sample 122 is loaded at step 1002. Patient and sample information can also be entered into the system at step 1014. Next, the area of interest in the system is aligned with respect to the white light camera at step 1004. Once the sample 122 is aligned, the user can setup for a Raman scan (step 1006) and OCT scan (step 1016). Thereafter, the sample 122 is scanned at step 1008. After completion of the scan, the data can be reviewed by the user, and / or saved for export (step 1010).
Once the scan is completed (step 1010), the user may select to continue scanning where the workflow will revert back to one of the previous steps (i.e., steps 1002, 1004, 1006 or 1016). Alternatively, if all scanning is completed, the user may unload the sample (step 1018) and shut down the system (step 1026). During any operation steps of the system (i.e., steps 1000 to 1018, also illustrated by step 1026), an emergency stop action can take place to interrupt this process. If an emergency stop is required, the emergency stop button 322 is pressed (step 1020). Thereafter, the system is interrupted and all action is stopped (step 1022). The user is also presented with an option to save and / or export the data (step 1024). If the emergency stop is initiated, the system will also terminate with the system being shut down (step 1026).

[0099] Referring to FIG. 11A, this flow diagram illustrates detailed start and initialization steps, as indicated by block 1000, in the method M of using the portable multi-modal tissue imaging system 10, implementable with a biopsy control system S, as shown in FIG. 10, in accordance with an embodiment of the present disclosure. The process starts at step 1100. The computer or processor 20 (FIG. 1) or control computer 110 (FIG. 9B) is turned on (step 1102); and the service is initiated (step 1104). Thereafter, the service turns on the power distribution unit (1106) to power on the various system modules. The power distribution unit will power on the OCT module (step 1108), the Raman module (step 1110), the cooling sequence (step 1114) and turn on a light-emitting diode (LED) Date Recue/Date Received 2020-05-29 illumination (step 1114). Subsequently, the sample stage is moved to the home configuration orientation (step 1116).

[0100] Referring to FIG. 11B, this flow diagram illustrates detailed Raman setup steps, as indicated by block 1006, in the method M of using the portable multi-modal tissue imaging system 10, implementable with a biopsy control system S, as shown in FIG. 10, is in accordance with an embodiment of the present disclosure. The process starts at step 1120. The sample is placed underneath the white light camera (step 1112). Next, the user selects the points for the Raman scan based on the image presented on the white light camera at step 1124. After the sample is placed under the white light camera, the user selects a point at which to perform the Raman measurement and selects the scan parameters for the points selected in step 1116. Once either the step 1124 or the step 1126 is completed, the user is presented with a choice at step 1128 of either proceeding with an OCT scan setup at step 1130 for the same sample or continuing with sample acquisition at step 1132. Both of these steps 1130, 1132 are further described in relation to FIGS. 11C, 11D, and 11E.

[0101] Referring to FIG. 11C, this flow diagram illustrates the detailed OCT
scan setup and preview steps, as respectively indicated by blocks 1016 (FIG. 10) and 1130 (FIG. 11B), in the method M of using the multi-modal optical imaging system 10, implementable with a biopsy control system S, as shown in FIG. 10, in accordance with an embodiment of the present disclosure.
The process initiates at step 1140. Thereafter, a snapshot of the sample, e.g., the sample 18 or the sample 122, is captured by the white light camera and saved within the portable multi-modal tissue imaging system 10 in step 1142. Next, the sample is moved underneath the OCT scanner (step 1144), wherein the scan parameters and the area/line of interest is selected (step 1146). Next, the portable multi-modal tissue imaging system 10 starts a 2D continuous acquisition (step 1148). During the acquisition stage (step 1148), the acquired data is viewable in real-time and at least one option is selectable (step 1162). The at least one option comprises at least one of: saving or exporting the acquisition (step 1150), adjusting the scan parameters as well as moving the sample height and tilt (step 1152), and selecting another scan position (step 1154). Once the at least one option is selected and completed (step 1156), the workflow in the method M proceeds to either a 3D OCT setup (step 1158) (FIG.
11D) or to a Raman setup (step 1160) (FIG. 11B).

Date Recue/Date Received 2020-05-29

[0102] Referring to FIG. 11D, this flow diagram illustrates detailed 3D OCT
scan setup steps, as respectively indicated by blocks 1016 and 1158, in the method M of using the portable multi-modal tissue imaging system 10, implementable with a biopsy control system S, as shown in FIG. 10, in accordance with an embodiment of the present disclosure. The process initiates at step 1200.
Thereafter, a snapshot of the sample, e.g., the sample 18 or the sample 122, is captured by the white light camera and saved within the system 10 (step 1202). Next, the sample is moved underneath the OCT scanner (step 1204). Thereafter, the system 10 selects the 3D scan parameters (step 1208) and/or the 3D scan area on the white light image (step 1206). Once the parameters are selected (step 1210), the system 10 further proceeds to start a sample acquisition (step 1212) (FIG.
11E) and conduct either a 2D OCT setup (step 1214) (FIG. 11C) or conduct a Raman setup (step 1216) (FIG. 11B).

[0103] Referring to FIG. 11E, this flow diagram illustrates detailed data acquisition steps, as indicated by blocks 1008, 1010, 1132, and 1212, in the method M of using the portable multi-modal tissue imaging system 10, implementable with a biopsy control system S, as shown in FIGS. 11B, 11C, and 11D, in accordance with an embodiment of the present disclosure. The process initiates at step 1220.
The sample is moved underneath the OCT scanner in step 1226. An OCT image is subsequently acquired in step 1228. The image is then displayed on a "Review" page of the biopsy system user interface in step 1230. Next, the sample is moved with the selected points of interest underneath the Raman probe (step 1232). Thereafter, a Raman spectrum graph is acquired (step 1234). The Raman spectrum is displayed in the biopsy system software for review (step 1236).
Once one point has been scanned, the system 10 moves the sample to the next selected point for Raman scanning (step 1240).
This process repeats itself, i.e., steps 1232, 1234, 1236 and 1240, until all the selected points are scanned. The next step comprises saving and/or exporting the data (step 1242).
Alternatively, directly saving the image display on the OCT user interface (from step 1230) is performed (via step 1242).
Once the saving is completed, the acquisition is phase is completed (step 1244). In further embodiments, once the process is initiated (step 1220), the method M further comprises optionally removing the OCT background (step 1222), wherein artifacts are removable from the background of the OCT image. Once step 1222 is completed, the OCT background is captured and is subtracted from the acquired OCT image of the sample which will result in a cleaner image (step 1224). After the OCT background is captured and subtracted (step 1224), the process reverts back to the original placement of the OCT sample (step 1226).
Date Recue/Date Received 2020-05-29

[0104] Referring back to FIG. 1 through FIG. 11E, the portable multi-modal tissue imaging system is ideally contemplated for use in pathology labs; however, this system is applicable to other similar uses, in accordance with embodiments of the present disclosure. For example, beyond applications in pathology, the portable multi-modal tissue imaging system 10 is also useful in research and development activities for investigating response of various tissues to different types of optical probes and for correlating such data from various types of optical probes. In addition to combining OCT
modules and Raman modules in the multi-modal imaging system, other imaging modalities can be added into the portable multi-modal tissue imaging system 10, in accordance with embodiments of the present disclosure. For example, a 3D optical scanner or a probe is incorporable into the portable multi-modal tissue imaging system 10, whereby a surface contour scan of the tissue sample is providable. Surface contours provide a 3D image of the sample under white light conditions (an actual image) and provide the distance of the probe Pi to the sample which will assist in the alignment of the probe Pi during the alignment process.

[0105] Still referring back to FIG. 1 through FIG. 11E, the surface contour facilitates segmenting the tissue surface in the OCT image, as well as the sample area, within the camera image. Mapping a pixel location on a 2D display to the 3D sample surface requires knowledge of the height of the sample at the pixel location, so a 3D surface profile aids in providing accurate registration between user interface and sample coordinates. In addition, having a 3D scan of a sample allows for sample correlation between multiple scanning sessions performed on the same sample. While the descriptions herein are made in conjunction with various embodiments for illustrative purposes, these descriptions are not limited to such embodiments. On the contrary, the descriptions and illustrations contained herein encompass various alternatives, modifications, and equivalents, without departing from the embodiments, the general scope of which is defined in the appended claims.
Except to the extent necessary or inherent in the processes themselves, no particular order to the steps or to the stages of the methods or the processes described in the present disclosure is intended or implied. In many cases, the order of process steps may be varied without changing the purpose, effect, or import of the methods herein described.

Date Recue/Date Received 2020-05-29

[0106] Referring to FIG. 12, this schematic diagram illustrates a biopsy control system S for providing telepathology, in accordance with an embodiment of the present disclosure. The system S is capable of implementation with the portable multi-modal tissue imaging system 10. The biopsy control system S comprises: a biopsy apparatus 1250, the biopsy apparatus 1250 comprising: a positioning mechanism, e.g., as shown in FIGS. 1 through 11E; a removable sample holder, e.g., the sample holder 120 configured for removability, for accommodating a tissue sample of interest, e.g., the sample 18 or the sample 122 (FIGS. 1-11E), the removable sample holder disposed in relation to the positioning mechanism (FIGS. 1-11E); and a plurality of detectors disposed in relation to the removable sample holder (FIGS. 1-11E); and a processor (FIGS. 1-11E), operable with the biopsy apparatus 1250, the processor configured to: receive at least one measurement parameter associated with the tissue sample of interest, the at least one measurement parameter comprising a sample type;
retrieve, from a database, e.g., as stored in relation to a computer server 1251, by example only, past measurement data associated with the sample type; determine at least one optimal position of the removable sample holder in relation to the tissue sample of interest for sampling by the plurality of detectors based on the at least one measurement parameter and the past measurement data; and generate a set of instructions for moving the removable sample holder to at least one optimal position.

[0107] Still referring to FIG. 12, in accordance with an alternative embodiment, the biopsy control system S comprises: a biopsy apparatus 1250, the biopsy apparatus 1250 comprising: a positioning mechanism, e.g., as shown in FIGS. 1 through 11E; a removable sample holder for accommodating at least one tissue sample of interest, e.g., the sample 18 or the sample 122 (FIGS. 1-11E), the removable sample holder disposed in relation to the positioning mechanism (FIGS. 1-11E), the removable sample holder comprising a tissue sample storage extension (not shown) configured to incubate the at least one tissue sample of interest, the tissue sample storage extension configured to couple with the positioning mechanism (FIGS. 1-11E); and a plurality of detectors disposed in relation to the removable sample holder (FIGS. 1-11E); and a processor operable with the biopsy apparatus 1250, the processor configured to: receive at least one measurement parameter associated with the tissue sample of interest, e.g., the sample 18 or the sample 122 (FIGS. 1-11E), the at least one measurement parameter comprising a sample type; retrieve, from a database, past measurement data associated with the sample type; determine at least one optimal position of the removable sample holder in relation to the tissue sample of interest, e.g., the sample 18 or the sample 122 (FIGS. 1-11E), Date Recue/Date Received 2020-05-29 for sampling by the plurality of detectors based on the at least one measurement parameter and the past measurement data; and generate a set of instructions for moving the removable sample holder to at least one optimal position

[0108] Still referring to FIG. 12, in biopsy control system S, the processor (disposed in relation to at least one of the computer server 1251, the surgery center 1253, or the pathology center 1254) is configured to at least one of: transmit data relating to at least one of data relating to the at least one optimal position and sample information to the database, e.g., in relation to a computer server 1251, for storage thereof; receive user input relating to at least one modified position of the removable sample holder; and transmit data relating to the at least one modified position to the database for storage thereof. The system S further comprises a user interface (not shown) operable with the processor and the biopsy apparatus 1250, wherein the removable sample holder comprises a biopsy box 1252. The biopsy box 1252 is configured to receive and accommodate the tissue sample of interest, e.g., the sample 18 or the sample 122 (FIGS. 1-11E).

[0109] Still referring to FIG. 12, the user interface is configured to establish communication between a surgery center 1253 locatable anywhere in the world and a pathology center 1254 locatable anywhere in the world. The user interface facilitates transmitting at least one of surgical instruction and diagnostic information. The user interface facilitates recording at least one of surgical instruction and diagnostic information. The user interface is configured to establish communication in at least one format of a written format, a video format, and a pictorial format, whereby at least one of an expected biopsy analysis type, historical patient information, and historical surgical data is conveyable to the pathology center.

[0110] Still referring to FIG. 12, the database, e.g., as stored in relation to a computer server 1251, comprises an informatics database configured to store at least one of historical patient information and historical surgical data and to automatically collect real-time intraoperative surgical data relating to a current surgery, whereby understanding of the current surgery by a user at the pathology center is enhanceable. The informatics database is further configured to render anonymous at least one of historical patient information, historical surgical data, and real-time intraoperative surgical data and to transform at least one of the historical patient information, the historical surgical data, and the real-Date Recue/Date Received 2020-05-29 time intraoperative surgical data into a form that is compliant with at least one of a privacy policy and a privacy law.

[0111] Still referring to FIG. 12, the processor is optionally configured to grant complete control of the biopsy box 1252 to a user via the user interface (not shown) by entering at least one of a user identification, a password, an Internet Protocol (IP) address, and any other form of passkey to authenticate the user through the user interface. The processor is optionally configured to grant remote control of the biopsy box 1252 through the Reveal software, e.g., to load, select, capture, and store and/or export data. The positioning mechanism comprises an electromechanical stage for facilitating moving the biopsy box 1252. The processor is further operable with a web-connectable interface for facilitating complete control of the biopsy box 1252. The pathology center 1254 is remotely located in relation to the surgery center 1253, whereby complete remote control of the biopsy box 1252 via the electromechanical stage is enabled for a user at the pathology center 1254, and whereby positioning the tissue sample of interest under at least one detector of the plurality of detectors is optimizable.

[0112] Still referring to FIG. 12, the electromechanical stage facilitates positioning the tissue sample of interest under the plurality of detectors; and the plurality of detectors comprises at least one of at least one optical probe and at least one camera. The electromechanical stage facilitates at least one of:
prepositioning the tissue sample of interest under the plurality of optical probes by a user at the surgery center 1253; identifying areas of particular interest of the tissue sample prior to attendance thereof by a user at the pathology center 1254; positioning the tissue sample of interest under the plurality of detectors by one of a user at the surgery center 1253 and a user at the pathology center 1254; and repositioning the tissue sample of interest under the plurality of detectors by one of a user at the surgery center 1253 and a user at the pathology center 1254.

[0113] Still referring to FIG. 12, the user interface facilitates establishing communication via a contemporaneous communication feed in relation to both the surgery center 1253 and the pathology center 1254, whereby a user at the surgery center 1253 is able to monitor progress of an analysis by a user at the pathology center 1254, and whereby the user at the surgery center 1253 is able to transmit at least one of a suggestion and a clarification in relation to the areas of particular interest of the tissue Date Recue/Date Received 2020-05-29 sample. The electromechanical stage is movable in relation to five axes, the five axes comprising an X axis, a Y axis, a Z axis, a tilt-X axis, and a tilt-Y axis. Each detector of the plurality of detectors is independently movable. The electromechanical stage is actuable in at least one of the five axes for at least one of prepositioning, positioning, and repositioning the tissue sample of interest. An example of a motorized positioning assembly 14, having an electromechanically stage, comprises an X
translation stage 40, a Y translation stage 44, a Z translation stage 46, a tilt stage 48, and, perpendicular thereto, a second tilt stage 49. The at least one detector of the plurality of detectors is at least one of prepositionable, positionable, and repositionable for facilitating obtaining at least one parameter capable of indicating a pathology, an identification of the tissue of interest, and a classification of the tissue of interest.

[0114] Still referring to FIG. 12, the at least one detector of the plurality of detectors is at least one of prepositionable, positionable, and repositionable for facilitating obtaining the at least one parameter by implementing a plurality of characterization modalities, wherein the at least one detector of the plurality of detectors is at least one of prepositionable, positionable, and repositionable for facilitating implementing the plurality of characterization modalities comprises implementing at least one characterization modality of Raman spectral analysis, PS-OCT imaging, infrared imaging, white light microscopy, staining, fluorescence, and or any other suitable characterization modality, whereby multimodal characterization data is providable.

[0115] Still referring to FIG. 12, the user interface facilitates analyzing the multimodal characterization data by the user at the pathology center 1254, wherein the multimodal characterization data comprises data acquired from real-time analysis via at least one of the database, software, firmware, hardware, and the like, whereby pathology findings, comprising at least one of pathology information and pathology data, are providable, and whereby a summary of pathology findings is providable. The processor of the biopsy control system S is further configured to: transmit the summary of pathology findings from the pathology center 1254 to the surgery center 1253 via the contemporaneous communication feed; if further examination is required, recommence the biopsy session; and if further examination is not required, terminate the biopsy session.
Date Recue/Date Received 2020-05-29

[0116] Referring to FIG. 13, this flow diagram illustrates a method M1 of fabricating a biopsy control system S for providing telepathology, in accordance with an embodiment of the present disclosure.
The method M1 comprises: providing a biopsy apparatus, as indicated by block 1300, the biopsy apparatus providing, as indicated by block 1300, comprising: providing a positioning mechanism, as indicated by block 1301; providing a removable sample holder for accommodating a tissue sample of interest, the removable sample holder disposed in relation to the positioning mechanism, as indicated by block 1302; and providing a plurality of detectors disposed in relation to the removable sample holder, as indicated by block 1303; and providing a processor operable with the biopsy apparatus, as indicated by block 1304, providing the processor, as indicated by block 1304, comprising configuring the processor to: receive at least one measurement parameter associated with the tissue sample of interest, the at least one measurement parameter comprising a sample type, as indicated by block 1305;
retrieve, from a database, past measurement data associated with the sample type, as indicated by block 1306; determine at least one optimal position of the removable sample holder in relation to the tissue sample of interest for sampling by the plurality of detectors based on the at least one measurement parameter and the past measurement data, as indicated by block 1307; and generate a set of instructions for moving the removable sample holder to at least one optimal position, as indicated by block 1308.

[0117] Still referring to FIG. 13, in an alternative embodiment, the method M1 of fabricating a biopsy control system S for providing telepathology generally comprises: providing a biopsy apparatus, as indicated by block 1300, the biopsy apparatus providing comprising: providing a positioning mechanism, as indicated by block 1302; providing a removable sample holder for accommodating at least one tissue sample of interest, as indicated by block 1302, providing the removable sample holder comprising disposing the removable sample holder in relation to the positioning mechanism, providing the removable sample holder comprising providing a tissue sample storage extension configured to incubate the at least one tissue sample of interest, the tissue sample storage extension configured to couple with the positioning mechanism; and providing a plurality of detectors disposed in relation to the removable sample holder, as indicated by block 1303; and providing a processor operable with the biopsy apparatus, as indicated by block 1304, providing the processor comprising configuring the processor to: receive at least one measurement parameter associated with the tissue sample of interest, the at least one measurement parameter comprising a sample type, as indicated by Date Recue/Date Received 2020-05-29 block 1305; retrieve, from a database, past measurement data associated with the sample type, as indicated by block 1306; determine at least one optimal position of the removable sample holder in relation to the tissue sample of interest for sampling by the plurality of detectors based on the at least one measurement parameter and the past measurement data, as indicated by block 1307; and generate a set of instructions for moving the removable sample holder to at least one optimal position, as indicated by block 1308.

[0118] Still referring to FIG. 13, in the method Ml, providing a processor, as indicated by block 1304, further comprises configuring the processor to at least one of: transmit data relating to the at least one optimal position to the database for storage therein; receive user input relating to at least one modified position of the removable sample holder; transmit data relating to the at least one modified position to the database for storage therein. The method M1 further comprises providing a biopsy box user interface (not shown) operable with the processor and the biopsy apparatus, wherein providing the removable sample holder comprises providing a biopsy box 1252. The method M1 further comprises configuring the biopsy box 1252 to receive and accommodate the tissue sample of interest in the biopsy box 1252.

[0119] Still referring to FIG. 13, the method M1 further comprises:
configuring the biopsy box user interface to establish communication between a surgery center 1253 locatable anywhere in the world and pathology center 1254 locatable anywhere in the world, configuring the biopsy box user interface to transmit at least one of surgical instruction and diagnostic information, and configuring the biopsy box user interface to record at least one of surgical instruction and diagnostic information. Providing the biopsy box user interface comprises configuring the user interface to establish communication in at least one format of a written format, a video format, and a pictorial format, whereby at least one of an expected biopsy analysis type, historical patient information, and historical surgical data is conveyable to the pathology center 1254. Providing the biopsy box user interface comprises configuring the interface to interface with the database, the database comprising an informatics database configured to store at least one of the historical patient information and the historical surgical data and to automatically collect real-time intraoperative surgical data relating to a current surgery, whereby understanding of the current surgery performed at the surgery center 1253 by a user at the pathology center 1254 is enhanceable. Providing the biopsy box user interface comprises configuring Date Recue/Date Received 2020-05-29 the biopsy box user interface to interface with the database, the database comprising an informatics database configured to render anonymous at least one of the historical patient information, the historical surgical data, and the real-time intraoperative surgical data and to transform at least one of the historical patient information, the historical surgical data, and the real-time intraoperative surgical data into a form compliant with at least one of a privacy policy and a privacy law.

[0120] Still referring to FIG. 13, in the method Ml, providing the processor comprises configuring the processor to grant complete control of the biopsy box 1252 to a user via the biopsy box user interface (not shown) entering at least one of a user identification, a password, an IP address, and any other form of passkey to authenticate the user, wherein providing the positioning mechanism, as indicated by block 1301, comprises providing an electromechanical stage for facilitating moving the biopsy box 1252, wherein providing the processor, as indicated by block 1300, further comprises configuring the processor as operable with a web-connectable interface for facilitating complete control of the biopsy box 1252, and wherein the pathology center 1254 is remotely located in relation to the surgery center 1253, whereby complete remote control of the biopsy box 1252 via the electromechanical stage by a user located at the pathology center 1254 is enabled, and whereby positioning the tissue sample of interest under at least one optical probe of the plurality of optical probes is optimizable.

[0121] Still referring to FIG. 13, the method M1 further comprises configuring the electromechanical stage to position the tissue sample of interest under the plurality of detectors, wherein providing the plurality of detectors comprises providing at least one of at least one optical probe and at least one camera. The method M1 further comprises configuring the electromechanical stage to at least one of:
preposition the tissue sample of interest under the plurality of optical probes by way of the electromechanical stage by a user at the surgery center 1253; identify areas of particular interest of the tissue sample prior to attendance thereof by a user at the pathology center 1254; position the tissue sample of interest under the plurality of detectors by way of the electromechanical stage by one of a user at the surgery center 1253 and a user at the pathology center 1254;
reposition the tissue sample of interest under the plurality of detectors by way of the electromechanical stage by one of a user at the surgery center 1253 and a user at the pathology center 1254; and at least one of prepositioning, Date Recue/Date Received 2020-05-29 positioning, and repositioning at least one detector of the plurality of detectors in relation the tissue sample of interest.

[0122] Still referring to FIG. 13, in the method Ml, providing the biopsy box user interface comprises configuring the interface to establish communication by establishing a contemporaneous communication feed in relation to both the surgery center 1253 and the pathology center 1254, whereby a user at the surgery center 1253 can monitor progress of an analysis by a user at the pathology center 1254, and whereby the user at the surgery center 1253 can transmit at least one of a suggestion and a clarification in relation to the areas of particular interest of the tissue sample.
Providing the electromechanical stage comprises configuring the electromechanical stage to move in relation to five axes, the five axes comprising an X axis, a Y axis, a Z axis, a tilt-X axis, and a tilt-Y
axis. Providing the plurality of optical probes comprises configuring each detector of the plurality of detectors as being independently movable. At least one of prepositioning, positioning, and repositioning the tissue sample of interest comprises actuating the electromechanical stage in at least one of the five axes. At least one of prepositioning, positioning, and repositioning the at least one detector of the plurality of detectors facilitates obtaining at least one parameter capable of indicating at least one parameter of a pathology, an identification of the tissue of interest, and a classification of the tissue of interest.

[0123] Still referring to FIG. 13, the method M1 further comprises providing a tissue sample storage extension, e.g., a small incubator for maintaining the tissue sample in as fresh a condition as possible), wherein the tissue sample storage extension is configured to couple with the system S or a Synaptive Reveal system, and wherein all the ex-vivo tissue samples are disposable, and wherein the system S
or a Synaptive Reveal system is configured to load each tissue sample or a plurality of tissue samples into the biopsy box 1252 for each scan. The tissue sample storage extension facilitates automation of the scanning process. The user only need to dispose samples into the tissue sample storage extension; and the system S or a Synaptive Reveal system scans automatically scans at least one of the plurality of tissue samples. The tissue sample storage extension facilitates provision of the at least one tissue sample to the user for use in any other step of a biopsy procedure.

Date Recue/Date Received 2020-05-29

[0124] Referring to FIG. 14 and back to FIG. 13, this flow diagram illustrates a method M2 of providing telepathology, by way of a biopsy control system S, in accordance with an embodiment of the present disclosure. The method M2 comprises: providing the biopsy control system S, as indicated by block 1400, providing the system S comprising: providing a biopsy apparatus, as indicated by block 1300, the biopsy apparatus providing, as indicated by block 1300, comprising: providing a positioning mechanism, as indicated by block 1301; providing a removable sample holder for accommodating a tissue sample of interest, the removable sample holder disposed in relation to the positioning mechanism, as indicated by block 1302; and providing a plurality of detectors disposed in relation to the removable sample holder, as indicated by block 1303; and providing a processor operable with the biopsy apparatus, as indicated by block 1304, providing the processor comprising configuring the processor to: receive at least one measurement parameter associated with the tissue sample of interest, the at least one measurement parameter comprising a sample type, as indicated by block 1305; retrieve, from a database, past measurement data associated with the sample type, as indicated by block 1306; determine at least one optimal position of the removable sample holder in relation to the tissue sample of interest for sampling by the plurality of detectors based on the at least one measurement parameter and the past measurement data, as indicated by block 1307; and generate a set of instructions for moving the removable sample holder to at least one optimal position, as indicated by block 1308; commencing a biopsy session, as indicated by block 1401; receiving the at least one measurement parameter, as indicated by block 1402; retrieving, from the database, past measurement data, as indicated by block 1403; determining the at least one optimal position, as indicated by block 1404; and generating the set of instructions, as indicated by block 1405, thereby moving the removable sample holder to the at least one optimal position.

[0125] Still referring to FIG. 14 and back to FIG. 13, in an alternative embodiment, the method M2 comprises: providing the biopsy control system S, as indicated by block 1400, providing the system S comprising: providing a biopsy apparatus, as indicated by block 1300, the biopsy apparatus providing comprising: providing a positioning mechanism, as indicated by block 1301; providing a removable sample holder for accommodating at least one tissue sample of interest, the removable sample holder disposed in relation to the positioning mechanism, providing the removable sample holder comprising providing a tissue sample storage extension configured to incubate the at least one tissue sample of interest, the tissue sample storage extension configured to couple with the positioning Date Recue/Date Received 2020-05-29 mechanism, as indicated by block 1302; and providing a plurality of detectors disposed in relation to the removable sample holder, as indicated by block 1303; and providing a processor operable with the biopsy apparatus, as indicated by block 1304, providing the processor comprising configuring the processor to: receive at least one measurement parameter associated with the tissue sample of interest, the at least one measurement parameter comprising a sample type, as indicated by block 1305;
retrieve, from a database, past measurement data associated with the sample type, as indicated by block 1306; determine at least one optimal position of the removable sample holder in relation to the tissue sample of interest for sampling by the plurality of detectors based on the at least one measurement parameter and the past measurement data, as indicated by block 1307; and generate a set of instructions for moving the removable sample holder to at least one optimal position, as indicated by block 1308; commencing a biopsy session, as indicated by block 1401; receiving the at least one measurement parameter, as indicated by block 1402; retrieving, from the database, past measurement data, as indicated by block 1403; determining the at least one optimal position, as indicated by block 1404; and generating the set of instructions, as indicated by block 1405, thereby moving the removable sample holder to the at least one optimal position.

[0126] Still referring to FIG. 14 and back to FIG. 13, the method M2 further comprises at least one of: transmitting data relating to the at least one optimal position to the database; storing at least one of data relating to the at least one optimal position and sample information in the database; receiving user input relating to at least one modified position of the removable sample holder; transmitting data relating to the at least one modified position to the database; and storing data relating to the at least one modified position in the database. Providing the biopsy control system S
further comprises providing a biopsy box user interface operable with the processor and the biopsy apparatus, wherein providing the removable sample holder comprises providing a biopsy box 1252.

[0127] Still referring to FIG. 14 and back to FIG. 13, the method M2 further comprises disposing the tissue sample of interest in the biopsy box 1252. The method M2 further comprises establishing communication between a surgery center 1253 locatable anywhere in the world and pathology center 1254 locatable anywhere in the world by way of the biopsy box user interface, wherein the biopsy box user interface facilitates transmitting at least one of surgical instruction and diagnostic information, and wherein the user interface facilitates recording at least one of surgical instruction and Date Recue/Date Received 2020-05-29 diagnostic information. Establishing communication comprises establishing communication in at least one of a written format, a video format, and a pictorial format, thereby conveying an expected biopsy analysis type by the surgery center 1253, historical patient information, and historical surgical data to the pathology center 1254.

[0128] Still referring to FIG. 14 and back to FIG. 13, in the method M2, the database comprises an informatics database configured to store at least one of the historical patient information and the historical surgical data and to automatically collect real-time intraoperative surgical data relating to a current surgery, thereby enhancing understanding of the current surgery performed at the surgery center 1253 by a user at the pathology center 1254. The informatics database is further configured to render anonymous at least one of the historical patient information, the historical surgical data, and the real-time intraoperative surgical data and to transform at least one of the historical patient information, the historical surgical data, and the real-time intraoperative surgical data into a form compliant with at least one of a privacy policy and a privacy law.

[0129] Still referring to FIG. 14 and back to FIG. 13, in the method M2, providing the processor, as indicated by block 1304, comprises configuring the processor to grant complete control of the biopsy box 1252 to a user via the biopsy box user interface entering at least one of a user identification, a password, an IP address, and any other form of passkey to authenticate the user. Providing the positioning mechanism, as indicated by block 1301, comprises providing an electromechanical stage for facilitating moving the biopsy box 1252, wherein providing the processor, as indicated by block 1304, further comprises configuring the processor as operable with a web-connectable interface for facilitating complete control of the biopsy box 1252, and wherein the pathology center 1254 is remotely located in relation to the surgery center 1253, thereby enabling complete remote control of the biopsy box 1252 via the electromechanical stage by a user located at the pathology center 1254, and thereby optimizing positioning the tissue sample of interest under at least one detector of the plurality of detectors.

[0130] Still referring to FIG. 14 and back to FIG. 13, the method M2 further comprises positioning the tissue sample of interest under the plurality of detectors by way of the electromechanical stage, wherein providing the plurality of detectors comprises providing at least one of at least one optical Date Recue/Date Received 2020-05-29 probe and at least one camera. The method M2 further comprises at least one of: prepositioning the tissue sample of interest under the plurality of optical probes by way of the electromechanical stage by a user at the surgery center 1253; identifying areas of particular interest of the tissue sample prior to attendance thereof by a user at the pathology center 1254; positioning the tissue sample of interest under the plurality of detectors by way of the electromechanical stage by one of a user at the surgery center 1253 and a user at the pathology center 1254; repositioning the tissue sample of interest under the plurality of detectors by way of the electromechanical stage by one of a user at the surgery center 1253 and a user at the pathology center 1254; and at least one of prepositioning, positioning, and repositioning at least one detector of the plurality of detectors in relation the tissue sample of interest.

[0131] Still referring to FIG. 14 and back to FIG. 13, the method M2 further comprises establishing a contemporaneous communication feed in relation to both the surgery center 1253 and the pathology center 1254, thereby enabling a user at the surgery center 1253 to monitor progress of an analysis by a user at the pathology center 1254, and thereby enabling the user at the surgery center 1253 to transmit at least one of a suggestion and a clarification in relation to the areas of particular interest of the tissue sample, wherein providing the electromechanical stage comprises configuring the electromechanical stage to move in relation to five axes, the five axes comprising an X axis, a Y axis, a Z axis, a tilt-X
axis, and a tilt-Y axis, wherein providing the plurality of optical probes comprises configuring each detector of the plurality of detectors as independently movable, wherein at least one of prepositioning, positioning, and repositioning the tissue sample of interest comprises actuating the electromechanical stage in at least one of the five axes, and wherein at least one of prepositioning, positioning, and repositioning the at least one detector of the plurality of detectors facilitates obtaining at least one parameter capable of indicating at least one parameter of a pathology, an identification of the tissue of interest, and a classification of the tissue of interest. Obtaining the at least one parameter comprises implementing a plurality of characterization modalities, wherein implementing the plurality of characterization modalities comprises implementing at least one characterization modality of Raman spectral analysis, PS-OCT imaging, infrared imaging, white light microscopy, staining, fluorescence, and any other suitable characterization modality, thereby providing multimodal characterization data.

[0132] Still referring to FIG. 14 and back to FIG. 13, the method M2 further comprises analyzing the multimodal characterization data by the user at the pathology center 1254, wherein analyzing the Date Recue/Date Received 2020-05-29 multimodal characterization data comprises real-time analysis using at least one of the database, software, firmware, hardware, and the like, thereby providing pathology findings comprising at least one of pathology information and pathology data, and thereby providing a summary of pathology findings. Alternatively, analyzing the multimodal characterization data comprises: initially performing machine analysis, such as deep learning, principal component analysis, neural network, and the like, e.g., by way of the ImageDrive system, e.g., not necessarily in real time, initially performing machine analysis comprising: transmitting the multimodal characterization data to a processing unit, such as another server or the same server, for performing data analysis; and transmitting analyzed multimodal characterization data back to ImageDrive system for data storage.
The method M2 further comprises transmitting the summary of pathology findings from the pathology center 1254 to the surgery center 1253 via the contemporaneous communication feed; if further examination is required, recommencing the biopsy session; and if further examination is not required, terminating the biopsy session.

[0133] Referring to FIG. 15, this flow diagram illustrates a method M3 of performing telepathology, by way of a biopsy control system S, in accordance with an embodiment of the present disclosure.
The method M3 involves providing remote access to control the mechanisms of the stage, probes, and full functionality of the biopsy box 1252 to a fully-trained pathologist connected via a local network or a web application from within the same hospital or anywhere else in the world, e.g., at a pathology center 1254. The method M3 comprises, by example only: excising a tissue sample of interest, e.g., by a member of the surgical team within the operating room, e.g., at a surgery center 1253, and participating in the surgical procedure or a robotic system, as indicated by block 1550; and loading the tissue sample of interest into a biopsy box 1252, e.g., by a member of the surgical team within the operating room, e.g., at a surgery center 1253, and participating in the surgical procedure or a robotic system, as indicated by block 1552.

[0134] Still referring to FIG. 15, the method M3 further comprises establishing communication by a member of the surgical team, e.g., at a surgery center 1253, with a remote pathologist anywhere in the world, e.g., at a pathology center 1254, in the form of explicit or basic instructions, or a recorded conversation via a biopsy box user interface, as indicated by block 1554; and relaying implicit or explicit instructions from a surgery center 1253 to a pathology center 1254, as indicated by block Date Recue/Date Received 2020-05-29 1556. These communications is presented in the form of written, video, or pictorial format and conveys, to the remote pathologist, the type of analysis the surgeon expects to be performed along with any relevant patient or surgical related data. This communication may be tied to an informatics database that stores past historical data of the patient or surgery or that automatically collects ongoing intraoperative data tied to the current surgery to furnish the pathologist, e.g., at a pathology center 1254, with a more complete understanding of the current surgery, e.g., at a surgery center 1253.
Where necessary, anonymization of the patient information is performed in accordance with privacy policies and/or laws.

[0135] Still referring to FIG. 15, the method M3 further comprises: receiving a request for, and granting complete control of, the biopsy box 1252 to the pathology center 1254, e.g., to a pathologist at the pathology center 1254, via an unique identification number and password, IP address, and/or other form of passkey to authenticate the user, as indicated by block 1558;
gathering data relating to the tissue sample of interest, as indicated by block 1560; compiling and correlating the data relating of the tissue sample of interest, as indicated by block 1562; relaying pathology results based on the data relating to the tissue sample of interest from the pathology center 1254 to the surgery center 1253, as indicated by block 1564; terminating the session and releasing control of the biopsy box 1252 by the pathology center 1254 if no further requests are made by the surgery center 1253, as indicated by block 1566; and removing the tissue sample of interest from the biopsy box 1252 at the surgical center 1253, as indicted by block 1568.

[0136] Still referring to FIG. 15, in the method M3, pathologist may remotely control the complete functionality of the biopsy box 1252 with a web-connected interface for facilitating moving an electromechanical stage to position a loaded sample under a desired camera or probe within the device, e.g., the biopsy apparatus. If necessary, the surgical team may also pre-position a sample with the stage control or identify areas of interest before the pathologist at the pathology center 1254 acts upon the device, e.g., the biopsy apparatus. Additionally, the surgical team may observe the same video or picture feed that the pathologist sees, which could enable the surgical team to monitor the progress of the analysis, make suggestions or clarifications as to the area being targeted.
Date Recue/Date Received 2020-05-29

[0137] Still referring to FIG. 15, in the method M3, remote control of the biopsy box 1252 involves actuation of a 5-axis stage (X, Y, Z, tilt-X, and tilt-Y) to position the stage under the appropriate probes and/or cameras, and the control of those probes to obtain parameters that may indicate a disease pathology or lead to the identification or classification of the tissue of interest. These disease parameters may be obtained for example (but not limited) by a plurality of modalities including Raman Spectral data, PS-OCT imaging, IR, white light microscopy, staining, fluorescence, or any other technique. The pathologist may view these findings in real-time, using databases, programs, algorithms, software, or the like to analyze the data quickly and efficiently to produce a significant and meaningful result.

[0138] Still referring to FIG. 15, in the method M3, after the results have been collected and summarized, the pathologist at the pathology center 1254 would then relay their findings via the communication relay system contained within the biopsy box user interface, ending the session if no more sample examinations are requested. Execution of the method M3 provides a form of "telepathology" via the biopsy control system S. The method M3 further comprises automatically selecting at least one of an area of interest and a point of interest in relation to a tissue sample of interest for scanning by at least one technique of OCT and Raman spectroscopy (performable after loading the tissue sample of interest in the biopsy box 1252) by way of the Synaptive Reveal system, thereby providing at least one of OCT scan data and Raman spectroscopic data;
and automatically uploading at least one of the OCT scan data and the Raman spectroscopic data to at least one of a drive system and an informatics system, e.g., ImageDrive , wherein at least one of the OCT scan data and the Raman spectroscopic data is viewable by a user located anywhere, e.g., in the world, in space, or a space station, thereby eliminating manually selecting scan regions and waiting for completion of data capture. However, the user can still optionally remotely access the system S to take control of the data acquisition by way of the Synaptive Reveal system if needed or if certain other area of interest is preferred.

[0139] While the present disclosure describes various embodiments for illustrative purposes, such description is not intended to be limited to such embodiments. On the contrary, the applicant's teachings described and illustrated herein encompass various alternatives, modifications, and equivalents, without departing from the embodiments, the general scope of which is defined in the Date Recue/Date Received 2020-05-29 appended claims. Except to the extent necessary or inherent in the processes themselves, no particular order to steps or stages of methods or processes described in this disclosure is intended or implied. In many cases the order of process steps may be varied without changing the purpose, effect, or import of the methods described.

[0140] Information as herein shown and described in detail is fully capable of attaining the above-described object of the present disclosure, the presently preferred embodiment of the present disclosure, and is, thus, representative of the subject matter which is broadly contemplated by the present disclosure. The scope of the present disclosure fully encompasses other embodiments which may become obvious to those skilled in the art, and is to be limited, accordingly, by nothing other than the appended claims. All structural and functional equivalents to the elements of the above-described preferred embodiment and additional embodiments as regarded by those of ordinary skill in the art are intended to be encompassed by the present claims.

[0141] Moreover, no requirement exists for a system or method to address each and every problem sought to be resolved by the present disclosure, for such to be encompassed by the present claims.
Furthermore, no element, component, or method step in the present disclosure is intended to be dedicated to the public regardless of whether the element, component, or method step is explicitly recited in the claims. However, that various changes and modifications in form, material, work-piece, and fabrication material detail may be made, without departing from the spirit and scope of the present disclosure, as set forth in the appended claims, as may be apparent to those of ordinary skill in the art, are also encompassed by the present disclosure.
INDUSTRIAL APPLICABILITY

[0142] The present disclosure industrially applies to biopsy tissue analysis systems. More particularly, the present disclosure industrially applies to biopsy tissue analysis systems for use in operating rooms.
Even more particularly, the present disclosure industrially applies to biopsy tissue analysis systems for use in operating rooms that are remotely accessible.

Date Recue/Date Received 2020-05-29

Claims

What is claimed:

1. A biopsy control system for providing telepathology, comprising: a biopsy apparatus, the biopsy apparatus comprising:
a positioning mechanism;
a removable sample holder for accommodating at least one tissue sample of interest, the removable sample holder disposed in relation to the positioning mechanism, the removable sample holder cornprising a tissue sample storage extension configured to incubate the at least one tissue sample of interest, the tissue sample storage extension configured to couple with the positioning mechanism; and a plurality of detectors disposed in relation to the removable sample holder;
and a processor operable with the biopsy apparatus, the processor configured to:
receive at least one measurement parameter associated with the tissue sample of interest, the at least one measurement parameter comprising a sample type;
retrieve, from a database, past measurement data associated with the sample type;
determine at least one optimal position of the removable sample holder in relation to the tissue sample of interest for sampling by the plurality of detectors based on the at least one measurement parameter and the past measurement data; and generate a set of instructions for moving the removable sample holder to at least one optimal position.

2. The system of Claim 1, wherein the processor is configured to at least one of:
transmit data relating to at least one of data relating to the at least one optimal position and sample information to the database for storage thereof;
receive user input relating to at least one modified position of the removable sample holder; and transmit data relating to the at least one modified position to the database for storage thereof.

3. The system of Claim 1, further comprising a user interface operable with the processor Date Recue/Date Received 2020-11-29 and the biopsy apparatus, wherein the removable sample holder comprises a biopsy box.

4. The system of Claim 3, wherein the biopsy box is configured to receive and accommodate the tissue sample of interest.

5. The system of Claim 3, wherein the user interface is configured to establish communication between a surgery center locatable anywhere in the world and a pathology center locatable anywhere in the world, wherein the user interface facilitates transmitting at least one of surgical instruction and diagnostic information, and wherein the user interface facilitates recording at least one of surgical instruction and diagnostic information.

6. The system of Claim 5, wherein the user interface is configured to establish communication in at least one format of a written format, a video format, and a pictorial format, whereby at least one of an expected biopsy analysis type, historical patient information, and historical surgical data is conveyable to the pathology center.

7. The system of Claim 6, wherein the database comprises an informatics database configured to store at least one of the historical patient information and the historical surgical data and to automatically collect real-time intraoperative surgical data relating to a current surgery, whereby understanding of the current surgery by a user at the pathology center is enhanceable.

8. The system of Claim 7, wherein the informatics database is further configured to render anonymous at least one of the historical patient information, the historical surgical data, and the real-time intraoperative surgical data and to transform at least one of the historical patient information, the historical surgical data, and the real-time intraoperative surgical data into a form compliant with at least one of a privacy policy and a privacy law.

9. The system of Claim 3, wherein the processor is configured to grant complete control of the biopsy box to a user via the user interface by entering at least one of a user identification, a Date Recue/Date Received 2020-11-29 password, an IP address, and any other form of passkey to authenticate the user through the user interface.

10. The system of Claim 9, wherein the positioning mechanism comprises an electromechanical stage for facilitating moving the biopsy box, wherein the processor is further operable with a web-connectable interface for facilitating complete control of the biopsy box, and wherein a pathology center is remotely located in relation to a surgery center, whereby complete remote control of the biopsy box via the electromechanical stage is enabled for a user at the pathology center, and whereby positioning the tissue sample of interest under at least one detector of the plurality of detectors is optimizable.

11. The system of Claim 10, wherein the electromechanical stage facilitates positioning the tissue sample of interest under the plurality of detectors, and wherein the plurality of detectors comprises at least one of at least one optical probe and at least one camera.

12. The system of Claim 6, wherein the user interface facilitates establishing communication via a contemporaneous communication feed in relation to both the surgery center and the pathology center, whereby a user at the surgery center is able to monitor progress of an analysis by a user at the pathology center, and whereby the user at the surgery center is able to transmit at least one of a suggestion and a clarification in relation to the areas of particular interest of the tissue sample.

13. The system of Claim 12, wherein an electromechanical stage is movable in relation to five axes, the five axes comprising an X axis, a Y axis, a Z axis, a tilt-X axis, and a tilt-Y axis, wherein each detector of the plurality of detectors is independently movable, wherein the electromechanical stage is actuable in at least one of the five axes for at Date Recue/Date Received 2020-11-29 least one of prepositioning, positioning, and repositioning the tissue sample of interest, and wherein the at least one detector of the plurality of detectors is at least one of prepositionable, positionable, and repositionable for facilitating obtaining at least one parameter capable of indicating a pathology, an identification of the tissue of interest, and a classification of the tissue of interest.

14. The system of Claim 13, wherein the at least one detector of the plurality of detectors is at least one of prepositionable, positionable, and repositionable for facilitating obtaining the at least one parameter by implementing a plurality of characterization modalities, and wherein the at least one detector of the plurality of detectors is at least one of prepositionable, positionable, and repositionable for facilitating implementing the plurality of characterization modalities comprises implementing at least one characterization modality of Raman spectral analysis, PS-OCT imaging, infrared imaging, white light microscopy, staining, fluorescence, and or any other suitable characterizationmodality, whereby multimodal characterization data is providable.

15. The system of Claim 14, wherein the user interface facilitates analyzing the multimodal characterization data by the user at the pathology center, wherein the multimodal characterization data comprises data acquired from real-time analysis via at least one of the database, software, firmware, hardware, and the like, whereby pathology findings, comprising at least one of pathology information and pathology data, are providable, and whereby a summary of pathology findings is providable.

16. The system of Claim 15, wherein the processor is further configured to:
transmit the summary of pathology findings from the pathology center to the surgery center via the contemporaneous communication feed;
if further examination is required, recommence a biopsy session; and if further examination is not required, terminate a biopsy session.

Date Recue/Date Received 2020-11-29

17. A method of fabricating a biopsy control system for providing telepathology, comprising:
providing a biopsy apparatus, the biopsy apparatus providing comprising:
providing a positioning mechanism;
providing a removable sample holder for accommodating at least one tissue sample of interest, providing the removable sample holder comprising disposing the removable sample holder in relation to the positioning mechanism, providing the removable sample holder comprising providing a tissue sample storage extension configured to incubate the at least one tissue sample of interest, the tissue sample storage extension configured to couple with the positioning mechanism; and providing a plurality of detectors disposed in relation to the removable sample holder;
and providing a processor operable with the biopsy apparatus, providing the processor comprising configuring the processor to:
receive at least one measurement parameter associated with the tissue sample of interest, the at least one measurement parameter comprising a sample type;
retrieve, from a database, past measurement data associated with the sample type;
determine at least one optimal position of the removable sample holder in relation to the tissue sample of interest for sampling by the plurality of detectors based on the at least one measurement parameter and the past measurement data; and generate a set of instructions for moving the removable sample holder to the at least one optimal position.

18. The method of Claim 17, wherein providing a processor further comprises configuring the processor to at least one of:
transmit data relating to the at least one optimal position to the database for storage therein;
receive user input relating to at least one modified position of the removable sample holder;
transmit data relating to the at least one modified position to the database for storage therein.

19. The method of Claim 17, further comprising providing a biopsy box user interface Date Recue/Date Received 2020-11-29 operable with the processor and the biopsy apparatus, wherein providing the removable sample holder comprises providing a biopsy box.

20. The method of Claim 19, further comprising configuring the biopsy box to receive and accommodate the tissue sample of interest in the biopsy box.

21. The method of Claim 19, further comprising:
configuring the user interface to establish communication between a surgery center locatable anywhere in the world and pathology locatable anywhere in the world, configuring the user interface to transmit at least one of surgical instruction and diagnostic information, and configuring the biopsy box user interface to record at least one of surgical instruction and diagnostic information.

22. The method of Claim 21, wherein providing the user interface comprises configuring the user interface to establish communication in at least one format of a written format, a video format, and a pictorial format, whereby at least one of an expected biopsy analysis type, historical patient information, and historical surgical data is conveyable to the pathology center.

23. The method of Claim 18, wherein providing the user interface comprises configuring the interface to interface with the database, the database comprising an informatics database configured to store at least one historical patient information and historical surgical data and to automatically collect real-time intraoperative surgical data relating to a current surgery, whereby understanding of the current surgery by a user at a pathology center is enhanceable.

24. The method of Claim 23, wherein providing the user interface comprises configuring the user interface to interface with the database, the database comprising an informatics database configured to render anonymous at least one of historical patient information, historical surgical data, and real-time intraoperative surgical data and to transform at least one of the historical patient information, the historical surgical data, and the real-time intraoperative surgical data into a form compliant with at least one of a privacy policy and a privacy law.

Date Recue/Date Received 2020-11-29

25. The method of Claim 19, wherein providing the processor comprises configuring the processor to grant complete control of the biopsy box to a user via the biopsy box user interface entering at least one of a user identification, a password, an IP address, and any other form of passkey to authenticate the user.

26. The method of Claim 25, wherein providing the positioning mechanism comprises providing an electromechanical stage for facilitating moving the biopsy box, wherein providing the processor further comprises configuring the processor as operable with a web-connectable interface for facilitating complete control of the biopsy box, and wherein a pathology center is remotely located in relation to the surgery center, whereby complete remote control of the biopsy box via the electromechanical stage by a user located at the pathology center is enabled, and whereby positioning the tissue sample of interest under at least one optical probe is optimizable.

27. The method of Claim 26, further comprising configuring the electromechanical stage to position the tissue sample of interest under the plurality of detectors, wherein providing the plurality of detectors comprises providing at least one of at least one optical probe and at least one camera.

28. The method of Claim 26, further comprising configuring the electromechanical stage to at least one of:
preposition the tissue sample of interest under the at least one of optical probe by way of the electromechanical stage by a user at a surgery center;
identify areas of particular interest of the tissue sample prior to attendance thereof by a user at a pathology center;
position the tissue sample of interest under the plurality of detectors by way of the electromechanical stage by one of a user at the surgery center and a user at the pathology center;
reposition the tissue sample of interest under the plurality of detectors by way of the electromechanical stage by one of the user at the surgery center and the user at the pathology Date Recue/Date Received 2020-11-29 center; and at least one of prepositioning, positioning, and repositioning at least one detector of the plurality of detectors in relation the tissue sample of interest.

29. The method of Claim 22, wherein providing the user interface comprises configuring the interface to establish communication by establishing a continuous communication feed in relation to both a surgery center and the pathology center, whereby a user at the surgery center can monitor progress of an analysis by a user at the pathology center, and whereby the user at the surgery center can transmit at least one of a suggestion and a clarification in relation to the areas of particular interest of the tissue sample.

30. The method of Claim 29, wherein providing an electromechanical stage comprises configuring the electromechanical stage to move in relation to five axes, the five axes comprising an X axis, a Y axis, a Z axis, a tilt-X axis, and a tilt-Y axis, wherein providing the at least one optical probe comprises configuring each detector of the plurality of detectors as being independently movable, wherein at least one of prepositioning, positioning, and repositioning the tissue sample of interest comprises actuating the electromechanical stage in at least one of the five axes, and wherein at least one of prepositioning, positioning, and repositioning the at least one detector of the plurality of detectors facilitates obtaining at least one parameter capable of indicating at least one parameter of a pathology, an identification of the tissue of interest, and a classification of the tissue of interest.

31. A method of providing telepathology by way of biopsy control system, comprising:
providing the biopsy control system, providing the system comprising:
providing a biopsy apparatus, the biopsy apparatus providing comprising:
providing a positioning mechanism;
providing a removable sample holder for accommodating at least one tissue sample of interest, the removable sample holder disposed in relation to the positioning mechanism, Date Recue/Date Received 2020-11-29 providing the removable sample holder comprising providing a tissue sample storage extension configured to incubate the at least one tissue sample of interest, the tissue sample storage extension configured to couple with the positioning mechanism; and providing a plurality of detectors disposed in relation to the removable sample holder;
and providing a processor operable with the biopsy apparatus, providing the processor comprising configuring the processor to:
receive at least one measurement parameter associated with the tissue sample of interest, the at least one measurement parameter comprising a sample type;
retrieve, from a database, past measurement data associated with the sample type;
determine at least one optimal position of the removable sample holder in relation to the tissue sample of interest for sampling by the plurality of detectors based on the at least one measurement parameter and the past measurement data; and generate a set of instructions for moving the removable sample holder to the at least one optimal position;
commencing a biopsy session;
receiving the at least one measurement parameter; retrieving, from the database, past measurement data;
determining the at least one optimal position; and generating the set of instructions, thereby moving the removable sample holder to the at least one optimal position.

32. The method of Claim 31, further comprising at least one of:
transmitting data relating to the at least one optimal position to the database;
storing at least one of data relating to the at least one optimal position and sample information in the database;
receiving user input relating to at least one modified position of the removable sample holder;
transmitting data relating to the at least one modified position to the database; and storing data relating to the at least one modified position in the database.

33. The method of Claim 31, wherein providing the biopsy control system further comprises Date Recue/Date Received 2020-11-29 providing a user interface operable with the processor and the biopsy apparatus, wherein providing the removable sample holder comprises providing a biopsy box.

34. The method of Claim 33, further comprising disposing the tissue sample of interest in the biopsy box.

35. The method of Claim 33, further comprising establishing communication between a surgery center locatable anywhere in the world and pathology center locatable anywhere in the world by way of the user interface, wherein the user interface facilitates transmitting at least one of surgical instruction and diagnostic information, and wherein the user interface facilitates recording at least one of surgical instruction and diagnostic information.

36. The method of Claim 35, wherein establishing communication comprises establishing communication in at least one of a written format, a video format, and a pictorial format, thereby conveying an expected biopsy analysis type by the surgery center, historical patient information, and historical surgical data to the pathology center.

37. The method of Claim 32, further comprising providing the database, wherein providing the database the database comprises providing the database an informatics database configured to store at least one of historical patient information and historical surgical data and to automatically collect real-time intraoperative surgical data relating to a current surgery, thereby enhancing understanding of the current surgery by a pathology center.

38. The method of Claim 37, wherein providing the informatics database comprises further configuring the informatics database to render anonymous at least one of the historical patient information, the historical surgical data, and the real-time intraoperative surgical data and to transform at least one of the historical patient information, the historical surgical data, and the real-time intraoperative surgical data into a form compliant with at least one of a privacy policy and a privacy law.

Date Recue/Date Received 2020-11-29

39. The method of Claim 33, wherein providing the processor comprises configuring the processor to grant complete control of the biopsy box to a user via the user interface entering at least one of a user identification, a password, an IP address, and any other form of passkey to authenticate theuser.

40. The method of Claim 39, wherein providing the positioning mechanism comprises providing an electromechanical stage for facilitating moving the biopsy box, wherein providing the processor further comprises configuring the processor as operable with a web-connectable interface for facilitating complete control of the biopsy box, and wherein a pathology center is remotely located in relation to a surgery center, thereby enabling complete remote control of the biopsy box via the electromechanical stage by a user located at the pathology center, and thereby optimizing positioning the tissue sample of interest under at least one detector of the plurality of detectors.

41. The method of Claim 40, further comprising positioning the tissue sample of interest under the plurality of detectors by way of the electromechanical stage, wherein providing the plurality of detectors comprises providing at least one of at least one optical probe and at least one camera.

42. The method of Claim 36, wherein establishing communication further comprises establishing a contemporaneous communication feed in relation to both the surgery center and the pathology center, thereby enabling a user at the surgery center to monitor progress of an analysis by a user at the pathology center, and hereby enabling the user at the surgery center to transmit at least one of a suggestion and a clarification in relation to the areas of particular interest of the tissue sample.

43. The method of Claim 42, wherein providing the electromechanical stage comprises configuring a electromechanical stage to move in relation to five axes, the five axes comprising an X axis, a Date Recue/Date Received 2020-11-29 Y axis, a Z axis, a tilt-X axis, and a tilt-Y axis, wherein providing the at least one optical probe comprises configuring each detector of the plurality of detectors as independently movable, wherein at least one of prepositioning, positioning, and repositioning the tissue sample of interest comprises actuating the electromechanical stage in at least one of the five axes, and wherein at least one of prepositioning, positioning, and repositioning the at least one detector of the plurality of detectors facilitates obtaining at least one parameter capable of indicating at least one parameter of a pathology, an identification of the tissue of interest, and a classification of the tissue of interest.

44. The method of Claim 43, wherein obtaining the at least one parameter comprises implementing a plurality of characterization modalities, and wherein implementing the plurality of characterization modalities comprises implementing at least one characterization modality of Raman spectral analysis, PS-OCT
imaging, infrared imaging, white light microscopy, staining, multispectral, hyperspectral, fluorescence, 3D imaging, and any other suitable characterization modality, thereby providing multimodal characterization data.

45. The method of Claim 44, further comprising analyzing the multimodal characterization data by the user at the pathology center, wherein analyzing the multimodal characterization data comprises real-time analysis using at least one of the database, software, firmware, hardware, and the like, thereby providing pathology findings comprising at least one of pathology information and pathology data, and thereby providing a summary of pathology findings.

46. The method of Claim 45, further comprising:
transmitting the summary of pathology findings from the pathology center to the surgery center via the contemporaneous communication feed;
if further examination is required, recommencing the biopsy session; and if further examination is not required, terminating the biopsy session.

Date Recue/Date Received 2020-11-29