CROSS-REFERENCE TO RELATED APPLICATION(S) This document is a continuation application which claims the benefit of, and priority to: U.S. patent application Ser. No. 15/862,915, filed on Jan. 5, 2018, entitled “SYSTEMS, DEVICES AND METHODS FOR TISSUE REMOVAL AND ANALYSIS”; U.S. patent application Ser. No. 15/025,749, filed on Mar. 29, 2016, entitled “SYSTEMS, DEVICES AND METHODS FOR TISSUE REMOVAL AND ANALYSIS” (now issued as U.S. Pat. No. 9,883,854); and International Patent Application No. PCT/CA2015/050283, filed on Apr. 8, 2015, entitled “SYSTEMS, DEVICES AND METHODS FOR TISSUE REMOVAL AND ANALYSIS,” all of which are incorporated herein by reference in their entirety.
FIELD The present disclosure relates to optical tissue analysis devices. More particularly, the present disclosure relates to optical probes for intraoperative tissue analysis.
BACKGROUND In current state-of-the-art neurosurgery, the main challenge in brain tumor removal lies in identifying and removing the brain tumor margins, i.e., the boundary between tumor tissue and healthy tissue, while not the damaging healthy brain tissue. However, identifying tumor margins accurately during surgery is deemed challenging. Tumor removal often relies on the experience of the surgeon in identifying the tumor and its margins. However, in order to avoid damaging and removing any healthy brain tissue, surgeons will only try to remove most of the tumor instead of removing more tissue than the identified tumor.
Recently, Raman spectroscopy has been demonstrated that it can identify brain tumor margins through detecting the unique, “fingerprint” like, chemistry signature from the tumors. However, these high resolution, high power, and highly sensitive Raman spectrometer, or Raman system, are not stable and ergonomic enough to be used in an operation room environment. The design of these Raman systems also requires the tissue to be placed in close proximity (<1 cm) to the optical detection port to achieve a strong detected Raman signal from the tissue. This is difficult for open surgery if the tissue of interest is far away from the top of the opening. In non-open surgery, such as port-based surgeries, this design is not practical to be used in the operation room.
Some Raman systems, with lower resolution, lower power or lower sensitivity, can be used to identify tumor and tumor margin. These Raman systems require a long integration time (>1 min) to obtain a sufficiently strong Raman signal from the tissue to enables differentiation between healthy and tumor signatures. To differentiate between endogenous Raman signatures of healthy tissue and tumor tissue, statistic techniques may be used. Nevertheless, the accuracy of such approaches is constrained by difficulties in detecting a clear difference in the Raman spectra between healthy tissue and tumor tissue.
Therefore, a need exists for improved techniques for tissue removal and analysis.
SUMMARY Systems, devices, and methods are provided for performing tissue removal and analysis based on the in-situ optical analysis of tissue and liquid collected from the tissue region, in accordance with embodiments of the present disclosure. In one example embodiment, a tissue removal and analysis probe comprises an elongate tissue removal device, an optical fiber, and a fluid Tillable conduit, wherein distal ends of the optical fiber and the conduit are in communication with an external region that is adjacent to a distal functional portion of the tissue removal device. The optical analysis results of at least one of external tissue and collected fluid are employed to determine whether or not tissue removal is to be performed. Various devices are interfaced with the conduit for optical analysis of the collected fluid. In one example embodiment, the tissue removal device is movable relative to the optical fiber and conduit.
Accordingly, in a first aspect, a tissue removal and analysis system is provided, the system comprising: a tissue removal and analysis probe, the probe comprising: an elongate tissue removal device having a distal portion that is configured to sample or remove tissue; an optical fiber having a distal end in optical communication with an external region that is adjacent to the distal portion; and a fluid-Tillable conduit having a distal aperture in fluid communication with the external region for collecting a fluid sample from the external region; and an optical detection subsystem configured to be in optical communication with a proximal end of the optical fiber and with at least a portion of the fluid sample collected by the fluid-fillable conduit, wherein the optical detection subsystem is configured to direct first incident optical energy into the optical fiber and to detect first received optical energy that is responsively produced within the external region, and wherein the optical detection subsystem is further configured to direct second incident optical energy into the fluid sample collected by the fluid-Tillable conduit and to detect second received optical energy that is responsively produced within the fluid sample.
In another aspect, a tissue removal and optical detection probe is provided, the probe comprising: an elongate tissue removal device having a distal portion that is configured to sample or remove tissue; an optical fiber having a distal end in optical communication with an external region that is adjacent to the distal portion; and a fluid-Tillable conduit having a distal aperture in fluid communication with the external region for collecting a fluid sample from the external region, wherein the fluid-Tillable conduit is configured to be connectable to an optical detection subsystem, such that the fluid sample collected in the fluid-Tillable conduit is in optical communication with the optical detection subsystem when the fluid-Tillable conduit is connected to the optical detection subsystem.
In another aspect, a method of performing tissue removal, based on optical tissue analysis, is provided, the method comprising: positioning a distal portion of a tissue removal and analysis probe adjacent to a tissue region, whereby a the tissue removal and analysis probe is provided; collecting, within a conduit, fluid from the tissue region; directing first incident optical energy into the optical fiber and detecting first received optical energy that is responsively produced within the tissue region, thereby obtaining first received signals; and directing second incident optical energy into the fluid collected by the fluid-Tillable conduit and detecting second received optical energy that is responsively produced within the fluid sample, thereby obtaining second received signals; processing the first received signals and the second received signals to determine whether one more pre-selected criteria are met; and in the event that the one or more criteria are satisfied, employing the tissue removal device to perform tissue removal.
A further understanding of the functional and advantageous aspects of the present disclosure are realized by reference to the following detailed description and drawings.
BRIEF DESCRIPTION OF THE DRAWINGS Embodiments will now be described, by way of example only, with reference to the several figures of the drawings, in which:
FIG. 1 is a diagram illustrating a side view of an example tissue removal and analysis device;
FIG. 2 is a diagram illustrating an example system for performing tissue removal and optical analysis;
FIG. 3A is a diagram illustrating a cross-sectional side view of an example configuration for coupling optical energy into the fluid within a conduit;
FIG. 3B is a diagram illustrating a cross-sectional side view of an example configuration for coupling optical energy into the fluid within a conduit;
FIG. 3C is a diagram illustrating a cross-sectional side view of an example configuration for coupling optical energy into the fluid within a conduit;
FIG. 3D is a diagram illustrating a cross-sectional side view of an example configuration for coupling optical energy into the fluid within a conduit;
FIG. 3E is a diagram illustrating a perspective view of an example configuration for coupling optical energy into the fluid within a conduit;
FIG. 4 is a diagram illustrating another example system for performing tissue removal and optical analysis, wherein an external pump is employed to collected fluid within the conduit;
FIG. 5A is a diagram illustrating another example system for performing tissue removal and optical analysis, wherein the fluid conduit is interfaced with a fluid processing device;
FIG. 5B is a diagram illustrating a perspective view of an example microfluidic device interfaced with a conduit and an optical fiber;
FIG. 6A is a schematic diagram illustrating an example implementation of an optical detection subsystem;
FIG. 6B is a schematic diagram illustrating an example implementation of an optical detection subsystem;
FIG. 6C is a schematic diagram illustrating an example implementation of an optical detection subsystem that employs Raman detection;
FIG. 6D is a diagram illustrating an example of an optical detection subsystem that employs Raman detection, the optical detection subsystem having various example internal components;
FIG. 7 is a diagram illustrating a side view of an example tissue removal and analysis probe employing a dual-cannula tissue removal device;
FIG. 8A is a diagram illustrating a side view of an example tissue removal and analysis device, having a retractable optical fiber and conduit, in operation;
FIG. 8B is a diagram illustrating a side view of an example tissue removal and analysis device, having a retractable optical fiber and conduit, in operation;
FIG. 8C is a diagram illustrating a side view of an example tissue removal and analysis device, having a retractable optical fiber and conduit, in operation;
FIG. 9 is a flow diagram illustrating an example method of performing optical tissue and fluid analysis followed by optional tissue removal; and
FIG. 10 is a diagram illustrating a cross-sectional view of an example configuration of a distal portion of the optical sampling component of a tissue removal and analysis probe, wherein an additional fiber for optical coherence tomography detection is incorporated.
DETAILED DESCRIPTION Various embodiments and aspects of the present disclosure will be described with reference to details below discussed. 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 instances, well-known or conventional details are not described in order to provide a concise discussion of embodiments of the present disclosure.
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.
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.
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. Unless otherwise specified, the terms “about” and “approximately” mean plus or minus 25 percent or less.
Unless otherwise specified, any specified range or group is as a shorthand way of referring to each and every member of a range or group individually, as well as each and every possible sub-range or sub-group therein encompassed and similarly with respect to any sub-ranges or sub-groups therein encompassed. Unless otherwise specified, the present disclosure relates to, and explicitly incorporates, each and every specific member and combination of sub-ranges or sub-groups.
As used herein, the term “on the order of,” when used in conjunction with a quantity or parameter, refers to a range spanning approximately one tenth to ten times the stated quantity or parameter.
Unless defined otherwise, all technical and scientific terms herein used are intended to have the same meaning as commonly understood to one of ordinary skill in the art. Unless otherwise indicated, such as through context, as used herein, the following terms are intended to have the following meanings:
As used herein the phrase “intraoperative” refers to an action, process, method, event, or step that occurs, or is carried out, during at least a portion of a medical procedure. Intraoperative, as herein defined, is not limited to surgical procedures and may refer to other types of medical procedures, such as diagnostic and therapeutic procedures.
As herein used, the term “fluid” refers to liquid and/or gaseous substances.
In various example embodiments of the present disclosure, systems, devices, and methods are provided that enable the optical interrogation of both solid tissue and fluid samples within a region of interest, thereby allowing the optical interrogation of fluid that resides at, or near, tissue of interest.
The optical analysis of localized fluid, collected from a region of interest, in addition to the optical analysis of the tissue within the region of interest, may be beneficial in identifying tumor margins more accurately. For example, in tumor/tumor margin identification, using statistical analysis methods, e.g., principle component analysis, Raman spectra from both the tissue and its local extra-cellular, inter-cellular and intra-cellular fluid/matrix can be obtained together to potentially improve the accuracy in tumor identification. Accordingly, various embodiments of the present disclosure, and variations thereof, may be beneficial in improving the detection of endogenous contrast in tissue based on the additional optical data and analysis afforded by the collection of fluid samples from the region of interest.
Referring now FIG. 1, this diagram illustrates, in a side view, a tissue removal and analysis probe 100, the probe 100 adapted for the optical interrogation of a tissue 130 within a region of interest residing external to a distal region, e.g., an external region 135, of the device, wherein the probe 100 is also configured for the collection and optical interrogation of a fluid sample collected from the region of interest, in accordance with an embodiment of the present disclosure. An example tissue removal and analysis probe 100 comprises a body portion 110 that is configured to be manually or robotically supported, wherein the body portion 110 houses, or mechanically supports, a tissue removal device 120.
Still referring now FIG. 1, a distal tissue removal portion 125 of the tissue removal device 120 is configured to sample or remove tissue 130. Examples of suitable tissue removal devices 120 are below described. The probe 100 also comprises an optical fiber 140 having a distal end in optical communication with an external region 135 that is adjacent to the distal tissue removal portion 125 of the tissue removal device 120. The optical fiber 140 is coupled, other otherwise brought into optical communication, with an optical detection system, for optically interrogating tissue 130.
Still referring now FIG. 1, a fluid-Tillable conduit 150, having a lumen 152 with a distal aperture 154 in fluid communication with the external region 135, is provided for collecting a fluid sample from the external region 135. The fluid Tillable conduit 150 is configured to passively collect the fluid sample, e.g., via capillary action, or under the control of an active fluidic device, such as a pump 330 (FIG. 4). Various example configurations of interfacing fluidic devices with the fluid-Tillable conduit 150 are below described. The conduit 150 is directly interfaced with the optical detection system (for the optical interrogation of the fluid collected within lumen 152) or indirectly interfaced with the optical detection system via a fluid processing subsystem.
Still referring now FIG. 1, the optical fiber 140 and the fluid conduit 150 are provided within a common longitudinal housing. In some example implementations, the distal end of the optical fiber 140 and the distal aperture 154 of the conduit 150 are separated by a distance in ranges of less than 1 cm, less than 5 mm, less than 2.5 mm, less than 1 mm, or less than 500 microns. In some example implementations, the distal end of the optical fiber 140 and/or the distal aperture 154 of the conduit 150 are separated from the distal tissue removal portion 125 of the tissue sampling device 120 by a distance in ranges of less than 1 cm, less than 5 mm, less than 2.5 mm, less than 1 mm, or less than 500 microns.
Still referring now FIG. 1, although the optical fiber 140 and conduit 150 are shown as extending from the body portion 110 in a continuous, uninterrupted, manner for interfacing with external subsystems, the optical fiber 140 and/or the conduit 150 may couple with a respective optical fiber or conduit via a connector provided in a proximal region of probe 100, e.g., within the body portion 110. Tissue removal device 120 couples with an external controller (or suitable computing device) via cable 126, or alternatively, via a wireless connection.
Still referring now FIG. 1, an example tissue removal and optical analysis probe 100 comprises one or more fiducial markers 160 thereto attached. For example, fiducial markers 160, tracked via a tracking system, are employed in order to determine the real-time, e.g., intraoperative, location of the probe 100. For example, the tracked fiducial markers 160 are employed to track the location of one or more functional locations of the probe 100, e.g., the distal end of the optical fiber 140, the distal aperture 154 of conduit 150, and/or the distal tissue removal portion 125 of the tissue removal device 120. Such tracking is useful in correlating or registering the locations of optical measurements with measurements made using other imaging or detection modalities, e.g., including, but not limited to, magnetic resonance imaging, optical coherence tomography, ultrasound, near infrared imaging, hyperspectral imaging, through intra-surgical tracking and registration.
Referring to FIG. 2, this diagram illustrates an example system S1, whereby tissue removal and analysis probe 100 is interfaced with a plurality of subsystems, in accordance with an embodiment of the present disclosure. The example system S1 comprises a tissue removal and analysis probe 100, an optical detection subsystem 300, a tracking system 350, a tissue removal device controller 360, and a control and processing unit 200. The spatial position and orientation of the tissue removal and analysis probe 100 is monitored by the tracking system 350, as above noted. This example implementation of the control and processing unit 200, comprises: one or more processors 205 (for example, a CPU/microprocessor or a graphical processing unit, or a combination of a central processing unit or graphical processing unit), a bus 210, a memory 215, e.g., comprising random access memory (RAM) and/or read only memory (ROM), one or more internal storage devices 220, e.g., a hard disk drive, compact disk drive or internal flash memory, a power supply 225, one more communications interfaces 230, an optional external storage 235, an optional display 240, and one or more input/output devices and/or interfaces 245, e.g., a receiver, a transmitter, a speaker, a display, an imaging sensor, such as those used in a digital still camera or digital video camera, a clock, an output port, a user input device, such as a keyboard, a keypad, a mouse, a position tracked stylus, a foot switch, and/or a microphone for capturing speech commands.
Still referring to FIG. 2, the control and processing unit 200 is programmed with programs, subroutines, applications, or modules 250, which comprise executable instructions, which when executed by the processor 205, causes the system S1 to perform one or more methods described in the disclosure. Such instructions are stored, for example, in the memory 215 and/or the internal storage 220. In particular, in the example embodiment shown, tissue analysis module 252 comprises computer executable instructions for analyzing optical data obtained from optical detection system. For example, computer readable instructions are provided for processing optical data, obtained at different spatial locations, in order to determine the location of a tumor margin based on endogenous tissue contrast. The spatial location is correlated with the recorded optical data via the tracking of the position and orientation of the tissue removal and analysis probe 100. The example modules 250 also comprise a tracking and navigation module 254, comprising executable instructions for processing tracking data, and/or for rendering a navigation user interface on a display. The example processing modules are provided merely as non-limiting, illustrative examples.
Still referring to FIG. 2, although only one of each component is illustrated, any number of each component can be included in the control and processing unit 200. For example, a computer typically contains a number of different data storage media. Furthermore, although the bus 210 is depicted as a single connection between all of the components, the bus 210 may represent one or more circuits, devices, or communication channels which link two or more of the components. For example, in personal computers, the bus 210 often comprises a motherboard. The control and processing unit 200 may comprise many more or less components than those shown. One or more external subsystems, such as tissue removal device controller 126, may, instead, be integrated directly within the control and processing unit 200.
Still referring to FIG. 2, in one embodiment, the control and processing unit 200 comprises a general purpose computer or any other hardware equivalents. The control and processing unit 200 may also be implemented as one or more physical devices that are coupled with the processor 205 through one of more communications channels or interfaces. For example, the control and processing unit 200 is implemented by using application specific integrated circuits (ASICs). Alternatively, the control and processing unit 200 is implemented as a combination of hardware and software, wherein the software is loaded into the processor 205 from the memory 215 or over a network connection.
While some embodiments have been described in the context of fully functioning computers and computer systems, various embodiments are capable of being distributed as a program product in a variety of forms and are capable of being applied, regardless of the particular type of machine or computer readable media used to actually effect the distribution.
A computer readable medium can be used to store software and data which, when executed by a data processing system, causes the system to perform various methods. The executable software and data can be stored in various places including, for example, ROM, volatile RAM, non-volatile memory, and/or cache. Portions of this software and/or data can be stored in any one of these storage devices. In general, a machine readable medium comprises any mechanism that provides, e.g., stores and/or transmits, information in a form accessible by a machine, e.g., a computer, a network device, a personal digital assistant, a manufacturing tool, and any device with a set of one or more processors, etc.
Examples of computer-readable media comprise, but are not limited to, recordable and non-recordable type media, such as volatile devices, and non-volatile memory devices, read only memory (ROM), random access memory (RAM), flash memory devices, floppy disks, and other removable disks, magnetic disk storage media, optical storage media, e.g., compact discs (CDs), digital versatile disks (DVDs), etc., among others. The instructions can be embodied in digital and analog communication links for electrical, optical, acoustical, or other forms of propagated signals, such as carrier waves, infrared signals, digital signals, and the like. As herein used, the phrases “computer-readable material” and “computer readable storage medium” refer to all computer-readable media, except for a transitory propagating signal, per se.
Some aspects of the present disclosure are embodied, at least in part, in software. That is, the techniques can be carried out in a computer system or other data processing system in response to its processor, such as a microprocessor, executing sequences of instructions contained in a memory, such as ROM, volatile RAM, non-volatile memory, cache, magnetic disks, and optical disks, or a remote storage device. Further, the instructions can be downloaded into a computing device over a data network in a form of compiled and linked version. Alternatively, the logic to perform the processes as above discussed could be implemented in additional computer- and/or machine-readable media, e.g., discrete hardware components as large-scale integrated circuits (LSI's), application-specific integrated circuits (ASIC's), or firmware, such as electrically erasable programmable read-only memory (EEPROM's) and field-programmable gate arrays (FPGAs).
Referring back to FIG. 2, the optical fiber 140 is directly interfaced with an optical detection subsystem 300, such that optical excitation energy from optical detection subsystem 300 is coupled into optical fiber 140 for delivery and excitation of tissue external to the tissue removal and analysis probe 100, and such that optical energy that is responsively generated within the tissue and collected by the optical fiber 140 is delivered to, and detected by, the optical detection subsystem 300.
Still referring to FIG. 2, and referring ahead to FIGS. 3A-3E, an optical detection system, e.g., comprising an optical detection subsystem 300, is also configured to optically interrogate fluid that is collected by within the conduit 150. The optical coupling of optical detection system with the fluid collected by the conduit 150 is achieved according to many different embodiments. The configuration, as shown in FIG. 2, is but one example coupling configuration, in which a proximal end of the conduit 150 is interfaced with the optical detection subsystem 300, such that optical excitation energy is directly coupled with the fluid collected within the proximal portion of the conduit 150. In the example configuration, as shown in FIG. 2, the fluid fills the conduit under capillary action, e.g., a lumen 152 is sufficiently small to draw fluid from the external region adjacent to the tissue 130 to the optical detection subsystem 300. The optical detection subsystem 300 may alternatively comprises a mechanism for generating a negative pressure relative to the distal aperture 154, such that the fluid is actively drawn.
Still referring to FIG. 2, and referring ahead to FIGS. 3A-3E, in the example embodiment, as shown in FIG. 2, the optical detection subsystem 300 is configured to couple optical excitation energy into the fluid collected within the fluid conduit 150, and to detect optical energy that is responsively emitted from the fluid. Various non-limiting example configurations for coupling the optical energy into the fluid within the conduit 150, as respectively shown in FIGS. 3A-3E.
Referring to FIG. 3A, this diagram illustrates, in a cross-sectional side view, an example implementation of an external optical fiber 302, e.g., a fiber housed within the optical detection subsystem 300, that is brought into contact (butt coupling) with the fluid collected within conduit 150, in accordance with an embodiment of the present disclosure. As above noted, the fluid may be passively drawn into the conduit 150, e.g., via capillary forces, or actively drawn, such as via a pressure reduction mechanism, e.g., a fluid pump or a vacuum.
Referring to FIG. 3B, this diagram illustrates, in a cross-sectional side view, an example implementation in which the optical energy is coupled through free space into the fluid within the conduit 150 using a focusing element, e.g., a lens 304, in accordance with an embodiment of the present disclosure. Although a specific example embodiment involving the lens 304 is shown, any suitable optical element may be employed for coupling light, such as, but not limited to, a lens, mirror, and a diffractive element. The configuration shown is also schematically illustrated in FIG. 3E, wherein fluid flows into the distal end of conduit 150, and is optically interrogated at the proximal end thereof. In the configuration shown, the optical energy is shown as being directly coupled with the fluid.
Referring to FIG. 3C, this diagram illustrates, in a cross-sectional side view, an example implementation in which a proximal end of the conduit 150 is closed, in accordance with an embodiment of the present disclosure. In the example implementation shown, the proximal end is closed, e.g., enclosed or capped, by an optical window 306. A lateral port 308 enables filling of the fluid within the conduit, such that the fluid contacts window 306. Although the coupling of light into the fluid through free space via a focusing element is shown, the optical energy may be coupled through window 306 in a fiber-based, butt coupled configuration, as shown in FIG. 3A.
Referring to FIG. 3D, this diagram illustrates, in a cross-sectional side view, an example configuration for coupling optical energy into the fluid within the conduit 150, in accordance with an embodiment of the present disclosure. As above noted, the fluid may be passively drawn into the conduit 150, e.g., via capillary forces, or actively drawn, such as via a pressure reduction mechanism, e.g., a fluid pump or a vacuum. In the example implementation shown, a lateral conduit 310 connects, or is connectable, to an external pump of vacuum generating mechanism.
Referring to FIG. 3E, this diagram illustrates, in a perspective view, an example configuration for coupling optical energy into the fluid within the conduit 150, in accordance with an embodiment of the present disclosure. As above described, in the example system, as shown in FIG. 2, the fluid conduit 150 is interfaced with the optical detection subsystem 300. In an alternative example implementation, the fluid conduit 150 may be interfaced with an external optical fiber at an intermediate location external to the optical detection system 300.
Referring to FIG. 4, this diagram illustrates an example of such a configuration for s system S2, wherein an external optical fiber 320 extends from optical detection subsystem 300 to an intermediate location 325, where a distal end of external optical fiber 320 is brought into optical communication with fluid collected within the conduit 150, in accordance with an embodiment of the present disclosure. The example configuration of the system S2 shown may be implemented, for example, using an optical-fluid coupling arrangement similar to that shown in FIG. 3D (optionally by butt-coupling the distal end of external optical fiber 320 to window 306), and employing a pump 330 to draw fluid into the conduit 150 from the external region 135.
Referring to FIG. 5A, this diagram illustrates another example system S3, wherein a fluidic processing device 340 is employed to pre-process the collected fluid before the collected fluid is brought into optical communication with the optical detection subsystem 300, in accordance with an embodiment of the present disclosure. In one example embodiment, the fluidic processing device 340 comprises a microfluidic device, such as a device comprising one or more channels with a spatial dimension in a range of less than approximately 1 mm, or a device configured to process fluid volumes in a range of less than approximately 1 milliliter.
Referring to FIG. 5B, this diagram illustrates an example implementation, wherein an external optical fiber 320 is interfaced with a microfluidic device 400, such that the core of the optical fiber 320 is brought into optical communication with an internal flow channel 410 within the microfluidic device 400, in accordance with an embodiment of the present disclosure. The microfluidic device 400 comprises transparent materials having indices of refraction such that the internal flow channel 410 acts as an optical waveguide when filled with fluid, e.g., via total internal reflection or Bragg reflection. The microfluidic device 400 is interfaced with an external pump or vacuum generating device such that fluid is drawn into the conduit 150 and transported to the microfluidic device 400.
Still referring to FIG. 5B, the microfluidic device 400 comprises one or more functional regions configured to process the collected fluid before the collected fluid is optically interrogated with optical energy delivered by external optical fiber 320. For example, whole blood from the brain is collected by the conduit 150 and delivered to the microfluidic device 400, where a microfluidic extraction protocol is performed to separate one or more constituents of interest, such as cells or macromolecules, before an analytical interrogation step is performed. Such fluidic pre-processing of the collected fluid sample is advantageous in increasing the accuracy or sensitivity of the subsequent optical analysis.
Still referring to FIG. 5B, in one non-limiting example implementation, the microfluidic device 400 is configured to perform separation, whereby the microfluidic device 400 comprises a separation mechanism, such as, but not limited to, a filter, a filtration obstacle region, separation media, a magnetic separation chamber, a flow cytometric region, an electrophoretic separation region, and a dielectrophoresis separation region. The microfluidic device 400 may additionally or alternatively be configured to perform an assay, such as an assay involving an optical label, e.g., a fluorescent label, or a label-free assay. Other non-limiting examples of microfluidic components that may be included for the pre-processing of the collected fluid comprise lysis chambers, e.g., employing one or more of bead based mechanical lysis, electrical lysis, and ultrasonic lysis mechanisms.
Still referring to FIG. 5B, in some embodiments, the fluid conduit 150, or at least a portion thereof, may be configured to support the internal guidance of optical energy when the lumen 152 is filled with collected fluid. In other words, at least a portion of the conduit 150 may be configured as an optical waveguide, such that optical excitation energy that is coupled into a proximal end of the conduit 150 propagates within the lumen 152 of the conduit 150. The fluid conduit 150, or at least a portion of the fluid conduit 150, may, therefore, comprise a hollow-core optical fiber that provides lateral confinement and guiding of optical energy within the fluid-filled core.
Still referring to FIG. 5B, such an embodiment may be advantageous in facilitating a longer interaction length between the optical excitation energy and the fluid collected within the lumen 152, which may provide an enhancement in signal and detected endogenous contrast. Furthermore, in some embodiments, the lumen 152 of the conduit 150 may be configured to have a diameter that is sufficiently small to promote and/or enhance nonlinear optical interactions. For example, in some example embodiments, a portion of the fluid conduit 150 that is configured as an optical waveguide (when filled with the collected fluid) may have a diameter in ranges of less than 100 microns, less than 50 microns, less than 25 microns, less than 20 microns, less than 15 microns, less than 10 microns, or less than 5 microns.
Still referring to FIG. 5B, for example, the lateral confinement of the optical excitation energy may be employed to facilitate the production of an increased Raman signal. In this technique, fluid sample of interest is filled into the core of a hollow-core fiber from the distal end of the hollow-core fiber. In the opposite end, light is confined in the radial direction and propagating through the fluid core along the length of the fiber. The input light will then interact with the fluid in the core and induce Raman scattering over the propagation length of the optical excitation energy. In some embodiments, this propagation length may be only a portion of the total length of the hollow-core fiber, due to scattering and/or absorption. In other example embodiments in which the optical excitation energy is not substantially attenuated within the fluid core, the interaction may occur throughout the entire length of the hollow-core fiber. Due to the interaction of the optical excitation energy with the fluid, an induced Raman signal is produced via Raman scattering. This signal is also confined within the fiber core, and propagates towards the proximal end of the conduit, where is it optically delivered to the optical detection system for detection and subsequent processing and analysis. Using such a technique, the detected Raman signal may be increased by approximately two orders of magnitude relative to using a conventional technique that employs an objective for coupling the optical excitation energy without subsequent optical internal confinement and guidance within the conduit 150. Since Raman scattering signal is induced between the laser and the sample inside the hollow-core fiber, more Raman scattering signal may also be generated with a prolonged fiber length (depending on the relative attenuation of the optical excitation beam).
Still referring to FIG. 5B, the optical energy may be confined and guided according to several different mechanisms. In one example implementation, the walls of the fluid conduit 150 are selected to have a lower refractive index the fluid-filled core, such that the optical energy is guided via total internal reflection. Examples of such hollow-core optical fibers comprise hollow core polymer fibers, and Teflon capillary tubes. In other example embodiments, the optical energy may be guided via a mechanism other than total internal reflection. For example, the conduit 150, or at least a portion thereof, may be, or may comprise, a photonic crystal fiber, photonic bandgap fiber, whereby Bragg reflection or multiple interferences are employed to achieve confinement. As the air holes of such fibers are typically a few microns in diameter, the volume of fluid required to fill the core of the entire fiber length is only typically only nanoliters to microliters. Accordingly, only a very small sample of fluid is required from a local region to increase the endogenous Raman signal differences between tumor and healthy tissue.
Referring back to FIGS. 2, 4, and 5A, the optical detection subsystem 300 generally comprises at least one optical source, e.g., a laser, light emitting diode, or other optical source, and at least one optical detector. One source may be optically coupled with both the optical fiber 140 and the fluid collected within the conduit 150, e.g., using a beam-splitter, or alternatively, separate sources. Similarly, a detector may be shared for detection of optical energy collected from optical fiber 140 and from the fluid within the conduit 150, e.g., using a beam-splitter, with a removable beam block on one of both channels to select a single channel for detection, or separate detectors. The choice of a suitable detector will depend on a number of factors, including the type of optical modality that is employed for fluid and tissue analysis. Furthermore, in some embodiments, the collected optical energy that is received from one or both of optical fiber 140 and from the fluid within conduit 150 may be spectrally resolved using a spectrometer (or other spectrally selective optical element or optical device) prior to detection.
Still referring back to FIGS. 2, 4, and 5A, the optical detection system, e.g., comprising the optical detection subsystem 300, may be employ any one or more of a wide variety of optical modalities, including, but not limited to, Raman, fluorescence and reflectance modalities. In some example embodiments, the optical detection system may comprise one or more optical spectrometers. In some embodiments, a common optical modality may be employed for tissue detection (via the optical fiber 140) and for fluid optical analysis (via the conduit 150). For example, both tissue and fluid optical analysis may be performed via optical fluorescence detection or Raman detection. In one example implementation, the optical detection subsystem 300 is configured for excitation and detection of Raman signals in an external region via the optical fiber 140, and for excitation and detection of Raman signals from fluid that is collected within the conduit 150. Such an example embodiment may be employed to detect Raman signals from solid samples, such as tissue, as well as from localized fluidic samples, such as blood, protein, intercellular fluid, and intracellular fluid.
Referring to FIGS. 6A and 6B, together, these schematic diagrams respectively illustrate two different configurations of an optical detection subsystem 300, in accordance with embodiments of the present disclosure. In FIG. 6A, optical detection system, e.g., comprising an optical detection subsystem 300, is shown interfaced with the conduit 150, filled with fluid, as above described with reference to FIGS. 2 and 3A-E. Dedicated sources and detectors 362 and 364 are respectively, separately, interfaced with the fluid collected in the conduit 150 and with optical fiber 140 for optical fluid analysis and optical tissue analysis, respectively. As above noted, one or both of the sources and the detectors 362 and 364 comprise a spectrometer or one or more spectrally selective optical components. The controller 370, comprising one or more processors, memory elements, and/or other computing components, e.g., any of those illustrated in the control and processing unit 200, is employed to control one or more functions of the source/detectors 362 and 364, and is interfaced with the control and processing unit 200. The controller 370 may also, or alternatively, provide at least some processing of the received signals. In FIG. 6B, an alternative configuration is shown in which the optical detection system, e.g., comprising the optical detection subsystem 300, is indirectly interfaced with the conduit 150, filled with fluid, via the external optical fiber 320, as described with reference to FIG. 4.
Referring to FIG. 6C, this diagram illustrates an example implementation of an optical detection subsystem 300 for Raman detection, in accordance with an embodiment of the present disclosure. The implementation of the optical detection subsystem 300, similar to that shown in FIG. 6B, comprises two sources, two spectrometers, and a controller that controls the sources and spectrometers. The dedicated sources and the detectors 366 and 368 are respectively, separately, interfaced with the fluid filled conduit via the external optical fiber 320 and with the optical fiber 140, for optical fluid analysis and optical tissue analysis, respectively. For Raman detection, a narrowband source and spectrometer for narrower band dispersion are used for detecting the Raman scattering signals. Typically, a source for Raman detection has a 3 dB bandwidth of approximately 0.03 nm, center wavelength stable within 0.1 nm, and power stability of <5%. A typical Raman spectrometer covers a range of approximately 785 nm to 1200 nm for Stokes Raman detection with an excitation at 785 nm, and 633 nm to 790 nm for Stokes Raman detection with an excitation at 633 nm.
Referring to FIG. 6D, this diagram illustrates an example configuration of a Raman spectrometer 380 with an excitation source 381, in accordance with an embodiment of the present disclosure. This configuration utilizes a fiber bundle 382 that splits at least one optical fiber 383 to source 381. The source 381 excites the sample through the fiber bundle 382. The rest of the fibers in the bundle 382 collect the scattering signals from the sample and direct collect the scattering signals to a pin hole or a slit 384 for controlling the spatial resolution and light collection. The pass-through light is then collimated via collimation optics 386 and passes through an optical filter 388 to filter the excitation light and pass only the Raman scattering signal. The Raman scattering light is then spatially spread using a grating 390 to cover the spectral camera sensing chip 394 through another optional slit 392.
Still referring to FIG. 6D, in other embodiments, different optical modalities may be used for tissue detection (via the optical fiber 140) and for fluid detection (via the conduit 150). For example, fluorescence detection may be employed for tissue analysis; and Raman spectroscopy may be employed for fluid analysis, or vice versa. In other embodiments, optical detection system, e.g., comprising the optical detection subsystem 300, comprises a multimodal system that is reconfigurable such that one of a plurality of optical modalities is selectively employed for one of both of tissue analysis and fluid analysis.
Referring back to FIG. 1, the tissue removal device 120 comprises any device that is capable of the removal, sampling, or resection of tissue, such as, but not limited to, tissue resection devices, tissue ablation devices, and tissue biopsy devices. The configuration of the probe 100 depends on the specific tissue removal device that is employed. For example, although FIG. 1 shows an elongate tissue removal device, supported by a body portion 110, with an adjacent optical fiber 140, and a fluid conduit 150. This configuration is but one example configuration. For example, in another example implementation, one or more of the tissue removal device 120, the optical fiber 140, and the fluid conduit 150 may be housed within an elongate body (optionally with a removable sheath), provided that the distal portions thereof are accessible to the external region 135.
Referring to FIG. 7, this diagram illustrates an example implementation of a tissue removal and analysis probe 100 in which the tissue removal device 120 is a variable aspiration device, such as the Nico° Myriad® device, in accordance with an embodiment of the present disclosure. The example tissue removal device 120 comprises an inner cannula 600, a movable within outer cannula 610, wherein the device 120 has a sampling region 620 configured receive a tissue sample. The tissue sample is aspirated into the sampling region 620 under the application of suction (the inner cannula 600 is connectable to a suction mechanism for drawing tissue into the sampling region 620). The inner cannula 600 has a distal end 630 configured to cut tissue received within the sampling region 620.
Still referring to FIG. 7, a number of different types of tissue removal devices are currently employed. The simplest type is the use of scalpel or scissor. To enable cutting and dissection with simultaneous bipolar coagulation, electrosurgical bipolar scissors, were designed. Bipolar scissors can also be used for precise pinpoint or zone coagulation of blood-vessels and tissue. For tissue biopsy, a fine-needle might be used. During fine-needle aspiration, a long, thin needle is inserted into the suspicious area. A syringe is used to draw out fluid and cells for analysis. For a larger tissue sample, core needle biopsy might be performed. A larger needle with a cutting tip is used during core needle biopsy to draw a column of tissue out of a suspicious area. Vacuum-assisted biopsy is another type of biopsy, in which a suction device increases the amount of fluid and cells that is extracted through the needle. This can reduce the number of times the needle must be inserted to collect an adequate sample. More advanced tissue removal devices involve cutting through or vaporizing tissue using a laser, such as a CO2laser, a Nd:YAG laser, and an argon laser. The heat produced by the laser light and the penetration depth enables blood to clot quickly and minimize bleeding. The example embodiments described herein may be adapted to employ any one of these tissue removal devices and/or other types of tissue removal devices.
Referring to FIGS. 8A-8C, together, these diagrams respectively illustrate examples of a tissue removal and analysis device, e.g., the probe 100, in which the fluid conduit 150 and the optical fiber 140 are positionable relative to a tissue removal device 120, in accordance with embodiments of the present disclosure. As shown in FIG. 8A, a distal tissue removal portion 125 of tissue removal device 120 may be located at or adjacent to a region of interest. Tissue 130 may then by contacted with, or placed in front of, the optical fiber 140 and the conduit 150, as shown in FIG. 8B. This may be performed in the absence of suction, or, optionally, in the presence of suction. For example, suction may be controllably applied to draw the tissue 130 into contact with the opening of the tissue removal device 120, thus drawing the tissue 130 into a region that can be optically and fluidically interrogated with the optical fiber 140 and the fluid conduit 150, respectively, without drawing the tissue 130 into the tissue removal device 120. Optical analysis may then be performed on one or more of the tissue 130 (via light detected from the optical fiber 140) and on the fluid collected in the conduit 150. The results of the optical analysis may optionally be employed to determine whether or not to perform removal, e.g., resection of biopsy, of the tissue 130. For example, as shown in FIG. 8C, the optical fiber 140 and the conduit 150 are optionally retracted prior to performing tissue removal or sampling.
Still referring to FIGS. 8A-8C, together, in one example implementation, a mechanism, e.g. a switch, button, or other actuation mechanism, may be employed to trigger the acquisition of optical data from optical fiber 140 and from fluid collected within the fluid conduit 150. The actuation of this mechanism may also cause the optical fiber 140 and the conduit 150 to be moved relative to the tissue removal device 120, as shown in FIG. 8B. The actuation mechanism may also be configured to move the optical fiber 140 and the conduit 150 forward to perform the measurement and then back to its original position, e.g., farther from the tissue removal opening, when the acquisition of optical data is complete.
Still referring to FIGS. 8A-8C, together, in an alternative example implementation, the tissue removal and analysis device may be configured such that the tissue removal device 120 is movable relative to the optical fiber 140 and the conduit 150. For example, the tissue removal device 120 could be provided in an initially retracted state relative to the optical fiber 140 and the conduit 150, such that the distal tissue removal portion 125 is retracted relative to the distal ends of the optical fiber 140 and the conduit 150. This would allow distal tissue regions and fluids to be optically sampled (optionally scanning a region, for example, to produce one or more images). In the event that tissue of interest is identified for sampling or resection, the tissue removal device 120 can be extended such that the tissue removal portion 125 is adjacent to the tissue of interest, and the tissue 130 can be sampled or removed as above described.
Referring to FIG. 9, this flow chart illustrates an example method M of employing a tissue analysis and detection probe 100 for the optical interrogation, and optional subsequent removal or sampling of tissue, in accordance with an embodiment of the present disclosure. In step 700, the distal end of the probe 100 is placed in or adjacent to a region of interest. Fluid is then collected from the region of interest, e.g., actively, or passively, as above described, as shown at step 710. The optical detection system, e.g., comprising the optical detection subsystem 300, is then employed to optically interrogate the tissue 130 residing in the region of interest (via the solid core optical fiber) and the fluid collected within the conduit 150, as shown at step 720. The signals produced upon optical detection are processed, and the results of the optical analysis may then be employed to determine whether or not to perform subsequent tissue removal or sampling, and, if one or more criteria are met, the tissue 130 is removed or sampled, as shown at step 730.
Still referring to FIG. 9, although the preceding disclosure has described example embodiments involving a single solid core optical fiber for sampling tissue within a region of interest and a single conduit 150 for collecting fluid from the region of interest, one or more additional solid core optical fibers and/or one or more additional fluid conduits 150 may be employed. For example, in an example implementation, a fiber bundle may be employed in place of a single optical fiber. In embodiments in which a fiber bundle is employed, one or more optical fibers may be employed for optical excitation, and one or more other optical fibers may be employed for detection. A fiber bundle may also be employed to provide spatially-resolved signals.
Referring to FIG. 10, this diagram illustrates an example implementation in which an additional single mode optical fiber 145 is provided for detecting signals from the region of interest via optical coherence tomography (OCT), in accordance with an embodiment of the present disclosure. For example, an optical coherence detection/imaging fiber provides additional analysis, e.g., preliminary identification, of a tumor region via high resolution optical coherence tomography (OCT). For example, Sun et al. (“Review: Optical Scanning Probe for Optical Coherence Tomography,” Journal of Medical and Biological Engineering, 34(1): 95-100) describes some design of the scanning needle probes for OCT. The integrated probe, having the additional OCT modality, may provide improved accuracy of identifying tumor and tumor margins while avoiding damages to healthy tissue including fiber tracts.
Examples of the additional information one could obtain with Raman comprise information pertaining to cell lines, stem cells, extracellular matrix components, such as lipid, and cerebrospinal fluid. In addition, the ability to obtain Raman signals, and detect Raman signatures, from fluidic samples enables surgeons to obtain chemical information about tumors and cyst in non-solid from such as leukemia. Raman signatures obtained through cerebrospinal fluid and extracellular matrix around the tissue also provide chemical information that could help in a more accurate diagnostic of tumor tissue or tumor type around where the fluid and extracellular matrix is extracted. An example of identifying brain tumor type and grade through major and minor brain lipids can be found in reference from Krafft et al., “Near infrared Raman spectra of human brain lipids,” Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy Volume 61, Issue 7, May 2005, pp. 1529-1535.
Statistical analysis, such as principle component analysis, and discriminant analysis are commonly used to reduce the complicated Raman spectra into a few components with different variance and classifies the different Raman spectra into different categories through the similarity in the variances of the components. The accuracy of this technique typically relies on a set of controlled spectra. The more number of data, e.g., number of spectra from the different categories, and the closer the data is compared to the actual data for analysis, the higher the accuracy. For example, if this technique is used to determine between tumor and non-tumor samples, a large set of Raman spectra from tumor and non-tumor samples have to be obtained as a training set to create a classifier. In previously known devices, Raman spectra are typically only obtained from the solid tumor samples which limits most of the chemical information from the tissue itself. In stark contrast, the systems, devices and methods of the present disclosure allow Raman spectra to be obtained from both the tissue as well as from fluidics, e.g., extracellular matrix, around the tissue which enhances the chemical information obtained from the surgical area of interest. The enhanced chemical information further enables a more accurate classifier to be built, thus, increases the accurate of tumor or disease diagnostics through the use of Raman spectroscopy.
The specific embodiments described above have been shown by way of example; and understood is that these embodiments may be susceptible to various modifications and alternative forms. Further understood is that the claims are not intended to be limited to the particular forms disclosed, but rather to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure.
