The present application claims U.S. provisional application serial No. 62/810,510 filed on 26.2.2019; 62/823,252 filed on 3/25/2019; and 62/840,609, filed 2019, 4, 30, their entire contents are incorporated herein by reference.
Detailed Description
As discussed below, devices and methods are provided for stimulating fluorescence via illumination in one or more areas of interest in a human body, detecting areas of interest that are not or not readily visible subject to such stimulation, and effectively identifying those areas of interest. Tissue detection systems and methods of using tissue detection systems are used to facilitate such stimulation, detection, and identification. As discussed below, embodiments of the tissue detection system are used to stimulate fluorescence in relevant tissues and to quickly and conveniently detect fluorescence from those relevant tissues.
In some embodiments of the tissue detection system, the emitter and detector may be placed in direct or near contact with potentially fluorescing tissue material of one or more regions of interest, such that stimulation and detection occurs in a confined area. To illustrate, the emitter and detector may be separate from or part of the probe with or without the use of optical fibers, the probe may be positioned in contact with or in close proximity to one or more regions in which fluorescence may be stimulated with the emitter, and the detector may detect fluorescence in the one or more regions if such fluorescence exceeds a threshold. In some embodiments, the emission and detection are in the near Infrared (IR) spectral band, which may be selected to stimulate and detect fluorescence in, for example, parathyroid tissue.
Methods of using autofluorescence to distinguish parathyroid material from thyroid material or other tissue in the cervical disc are described in U.S. application serial No. 13/065,469, which is incorporated herein by reference in its entirety. U.S. application serial No. 13/065,469 discloses that thyroid and parathyroid glands autofluorescence in a wavelength range above 800nm (and sometimes centered at 822 nm) when exposed to radiation in a narrow wavelength range of about 785nm, which is well outside the visible range. Wavelength ranges above 800nm are also not visible, and the fluorescence intensity of parathyroid material is significantly higher than that of thyroid material.
This difference in the relative amounts of fluorescence can be used to differentiate different tissues (e.g., parathyroid material, thyroid material, and other tissues in the cervical disc) for surgery. To illustrate, even if the approximate location of the parathyroid material is known, it is difficult to visually distinguish the parathyroid material sufficiently accurately to perform the procedure, and this is a problem for any surgical procedure requiring identification of the parathyroid material.
Thetissue detection systems 10, 10', and 10 "and methods of using thetissue detection systems 10, 10', and 10" disclosed herein may be adapted for use in surgical procedures requiring identification of tissue. Thetissue detection systems 10, 10', and 10 "may be used to identify tissue, such as parathyroid material, thyroid material, and other tissue in the cervical region, to facilitate removal during surgery. In other words, identification of tissue by thetissue detection systems 10, 10', and 10 "allows identification of tissue material using positive or negative identification of tissue. Once identified (either positively or negatively identified), tissue material may be removed during surgery.
As depicted in fig. 1, thetissue detection system 10 includes aprobe 100, acontroller 140, and auser interface 150. Thecontroller 140 and theuser interface 150 may be combined with each other or separate from each other, and thecontroller 140 and/or theuser interface 150 may include a display (such as thedisplay 210 from fig. 5A and 5B) for displaying images (e.g., videos created using the tissue detection system 10).
As depicted in fig. 1,probe 100 may be positioned by operator O relative to patient P received on surgical table 160. Fig. 1 depictsprobe 100 positioned by operator O in contact with or in close proximity to a potentially fluorescing tissue material, such asparathyroid gland material 300 of patient P, during surgery. Accordingly, thetissue detection system 10 according to embodiments of the present disclosure may be used to detect (via positive or negative identification)parathyroid material 300 of an exposed internal cervical disc region of a patient P during surgery.
The identification ofparathyroid material 300 is an example of a procedure in which an operator O, such as a surgeon, nurse, surgical assistant, or other operating room personnel, may use thetissue detection system 10 to facilitate surgery on one or more regions of interest, which may not be visible to the eye. In the case of identifying parathyroid substance material, parathyroid substance material fluoresces in the near IR and is therefore not visible. The fluorescence intensity of the adjacent thyroid material and other materials is different from that of parathyroid material. Therefore, it is possible to identify a tissue material that is a parathyroid gland material (positive identification) and a tissue material that is not a parathyroid gland material (negative identification). Thus, the use ofprobe 100 in conjunction with controller/user interface 140/150 may be used for tactile identification of the relevant patch. Specific parameters suitable for parathyroid tissue, including stimulation and detection, are discussed below, but the basic concepts disclosed will be applicable to other applications in which fluorescence may be stimulated.
Fig. 2A depicts additional elements of thetissue detection system 10. In some embodiments, theprobe 100 may include one ormore probe bodies 130, which may be tubular or some other shape that is convenient to hold by hand, and may be made of a variety of possible materials, including metals, plastics, and/or composite materials, among others.
As depicted in fig. 2A, asingle probe body 130 is provided and thetissue detection system 10 further includes one ormore emitters 105 and one ormore detectors 110 coupled to the one ormore emitter fibers 115 and the one ormore detector fibers 120, respectively.Emitter 105 may be configured to emit radiation of a selected wavelength via rotation and/or device selection to stimulate fluorescence in the relevant area, andoptical element 125 may be provided to alter the emitted radiation fromemitter 105 lower or higher via filtering. Furthermore, thedetector 110 is configured to process radiation captured by theprobe 100. In the case of identifying parathyroid material, emitter 105 (with or without optical element 125) emits radiation at a wavelength of about 785nm to promote autofluorescence of parathyroid material, anddetector 110 is configured to process radiation captured byprobe 100, which is at a wavelength in the range 808-1000nm for parathyroid material undergoing autofluorescence.
Theemitter 105 and thedetector 110 may be separate from theprobe body 130 or be part of theprobe body 130. Also, theprobe body 130 includes a distal end 135 (fig. 2B), at least a portion of the one or more emitteroptical fibers 115 extends at least through theprobe body 130 and facilitates transmission of radiation from theemitter 105 to thedistal end 135 of theprobe body 130, and at least a portion of the one or more detectoroptical fibers 120 extends at least through theprobe body 130 and facilitates capture and transmission of radiation from thedistal end 135 of theprobe body 130 to thedetector 110. As depicted in fig. 2B, the one ormore emitter fibers 115 and the one ormore detector fibers 120 may terminate at adistal end 135 of theprobe body 130. However, other arrangements of the plurality of fibers, such as in a plurality of bundled probe bodies, may also be suitable. In any case, the emitting and detecting fibers may terminate or come together at thedistal end 135 of theprobe body 130.
Acontroller 140 may be used to control the transmission of radiation from theemitter 105 and control the detection of radiation at thedetector 110, and auser interface 150 may be used to interact with and control the operation of thecontroller 140. In use, emitter 105 (via control using controller/user interface 140/150) along with optical element(s) 125 (such as one or more optical lenses and/or filters, etc.) are configured to deliver radiation selected to be illuminated so as to stimulate fluorescence todistal end 135 ofprobe body 130 through one or more emitteroptical fibers 115. And in use, the detector 110 (via control using the controller/user interface 140/150) along with the optical element(s) 125 are configured to detect radiation collected at thedistal end 135 of theprobe body 130 by the one or more detectoroptical fibers 120. Theoptical element 125 is provided at the end of theprobe body 130 in fig. 2A, but other arrangements for filtering in the fiber optic coupling or the emitter and detector themselves are possible. Further, theuser interface 150 may include a switch (not shown) in the form of, for example, a manual or foot switch to initiate emission of illumination and detection of fluorescence from theemitter 105 anddetector 110, respectively. Furthermore, there may be an audio and/or visual indication that a suitable fluorescent signal has been detected.
During intra-operative use, thedistal end 135 of theprobe body 130 physically contacts or is in near contact (i.e., within at least 1-2 cm) with the underlying fluorescing tissue material of the relevant patch within the body, and the operator O directs thecontroller 140 to emit and detect through theuser interface 150 when thedistal end 135 of theprobe body 130 is in contact or near contact with the surface of the relevant patch. The detected fluorescence signal of the associated tissue is then compared to a threshold fluorescence signal of a reference tissue to determine whether the detected fluorescence signal is indicative of the presence of the reference tissue. Because the one ormore emitter fibers 115 and the one ormore detector fibers 120 terminate in a small area on the order of the size of the one or more fiber ends at thedistal end 135 of theprobe body 130, and because this small area is in contact or near contact with the surface, the area exposed to illumination/stimulation and detection is quite small, allowing for precise positioning of the tissue of interest.
In the case of identifying parathyroid material, theemitter 105 may be a narrow band source, such as a solid state laser, laser diode, or other suitable source, whose radiation output wavelength is in or near a narrow band near 785nm by tuning, device selection, and/or using a filtered combination of optical element(s) 125. Thedetector 110 may be an avalanche photodiode or other near-IR detector or a 2D array of IR detectors that may be used in conjunction with demodulation using, for example, a high-pass (or long-pass) filter (of the optical element(s) 125) such that radiation having a wavelength above the source wavelength (e.g., above 800nm and in the range 808 and 1000nm) is detected. The wavelength of radiation output by emitter 105 (via use of tuning, device selection, and/or filtering with optical element(s) 125) may be changed to be lower or higher than the wavelength of radiation used to identifyparathyroid material 300 to facilitate identification of other tissue materials.
One of the advantages of contacting the surface of the relevant patch with a small area at thedistal end 135 of theprobe body 130 where the emitter fiber(s) 115 and detector fiber(s) 120 terminate is that the optical signal is less affected by ambient light, which in the case of an operating room may have a significant near-IR component. Immunity to such ambient light can be further improved by modulating the emitter radiation and collecting the fluorescent signal using a phase-locking technique, such as lock-in detection or FFT (fast fourier transform) techniques.
As depicted in fig. 3A, thetissue detection system 10, or at least theprobe 100, may be integrated with anendoscopic probe 170. In this arrangement, theendoscopic probe 170 includes anendoscopic camera 175, anendoscopic probe body 180, and the one ormore emitter fibers 115 and the one ormore detector fibers 120 are brought into theendoscopic probe body 180 and integrated with theendoscopic optics 185 at least at a distal end 190 (fig. 3B) of theendoscopic probe body 180. Theendoscopic probe body 180 includes alumen 195 extending therethrough terminating at thedistal end 190, and theendoscopic camera 175 can visualize a region of interest adjacent thedistal end 190 via thelumen 195. This allows probing to be performed using theendoscopic camera 175 as a guide for placement of thedistal end 190 of theendoscopic probe body 180 and correspondingly supports the use of a much smaller area that needs to be surgically opened.
Detection using thetissue detection system 10 may be enhanced by using anexternal camera 200, whichexternal camera 200 may be used as a detector to capture radiation from the relevant fluorescing tissue, as depicted in fig. 4. In contrast to guiding the operation of thetissue detection system 10 by vision, the use of theexternal camera 200 with thetissue detection system 10 may provide increased illumination and clarity because theexternal camera 200 may be directed at potentially fluorescing tissue material over a larger field of view. Where only thetissue detection system 10 and probe 100 are used, potential candidates for potentially fluorescent tissue material will have to be identified by the eye, and use of theprobe 100 facilitates providing confirmation information via fluorescence of the potential candidates. By using theexternal camera 200 in combination with theprobe 100, the imaging region provided by theexternal camera 200 can be used to identify candidates of potentially fluorescent tissue materials within a larger field of view, and then theprobe 100 can be used to confirm via fluorescence information acquired from each of those candidates of potentially fluorescent tissue materials by placing the probe in contact or near contact with the surface of the potentially fluorescent tissue materials. Theexternal camera 200 provides a potentially helpful but not definitive level of image contrast, while theprobe 100 can be used to provide highly sensitive and quantitative measurements, since at each potentially fluorescing tissue material, thedistal end 135 of theprobe body 130 can be positioned in contact or near contact therewith, and a definitive indication of fluorescence can be obtained and measured. Thus, thetissue detection system 10 and the combined use of theprobe 100 and theexternal camera 200 may provide a powerful solution to identify one or more areas of highest fluorescence.
Fig. 5A schematically illustrates another arrangement of thetissue detection system 10 using a camera (including anendoscopic camera 175external camera 200 or otherwise) in which camera optics 205 (such as one or more optical lenses and/or filters, etc.) and a display 210 (such as a computer monitor/screen) are used with thetissue detection system 10 using theprobe 100 and a controller/user interface 140/150. Although not shown in fig. 5A, thetransmitter 105 may be interposed between the controller/user interface 140/150, and the controller/user interface 140/150 may be used to control the operation of theendoscope camera 175, theexternal camera 200, and thedisplay 210. Further, thedisplay 210 may be separate from or integrated with thecontroller 140 and/or theuser interface 150.
Fig. 5B schematically illustrates yet another arrangement of thetissue detection system 10 using analternative probe 220 andalternative camera 225 embodiment, where theprobe 220 provides only illumination and detection is by means of thecamera 225.Probe 220 is a hand-held flexible illumination probe that can be positioned by operator O in contact or near contact with the surface of the potentially fluorescing tissue material. Further,camera 225 may be an external near IR camera that functions as a detector to capture radiation from the relevant fluorescing tissue. Although not shown in fig. 5B, thetransmitter 105 may be interposed between the controller/user interface 140/150, and the controller/user interface 140/150 may be used to control the operation of thecamera 225 and thedisplay 210. Further, thedisplay 210 may be separate from or integrated with thecontroller 140 and/or theuser interface 150.
Theprobe 220 may be brought into contact or near contact with the potentially fluorescent tissue material, or at any desired angle relative to the tissue in which fluorescence is excited. The use of theprobe 220 enables illumination/stimulation of the relevant area that is not normally reached by illumination. However, fluorescence stimulated in the tissue of interest may be difficult to observe with one ormore detector fibers 120 incorporated in theprobe body 130. An example of this is a subsurface region where fluorescence is typically too weak to be detected with one ormore detector fibers 120. Other examples would be fluorescent tissue material at or just outside the boundaries of the field of view of the one ormore detector fibers 120. Theprobe 220 brings the light source close to the area of interest, which in turn increases the emitted fluorescence and enables thecamera 225 to view and capture it. And theexternal camera 225 may be directed at the potentially fluorescing tissue material over a larger field of view that includes the entire region of interest. Theprobe 220 may include only illumination fibers, and as few as one fiber is selected to maximize transmission of radiation therefrom. Such one or more illumination fibers may also have one or more lenses and/or filters or the like at one or more of its ends (ultimately oriented toward the tissue) that may eliminate any fluorescence emitted by the fiber material in response to the illumination.
Where illumination/stimulation is done with a hand-heldillumination probe 220, but detection is done by viewing an image of the entire relevant area using, for example, acamera 225, the problem of background light from, for example, operating room lights is different than if both illumination and detection were done at thedistal end 135 of theprobe 100. Since thecamera 225 essentially behaves as a plurality of parallel detectors and the fluorescence field can be anywhere within the imaging field, the demodulation techniques described above cannot be applied directly.
Fig. 6 illustrates an embodiment of a method of using thetissue detection system 10. First, at 20, aprobe 100 is provided and theprobe 100 includes one ormore emitter fibers 115 and one ormore detector fibers 120 extending therethrough to a distal end of aprobe body 135. At 22, the operator O receives an indication ((visual or otherwise) that thedistal end 135 of theprobe body 130 is in contact or near contact) with the surface of the potentially fluorescent tissue material at 24, the potentially fluorescent tissue material is illuminated with radiation from theemitter 105 via the optical element(s) 125 and the one ormore emitter fibers 115. at 26, the fluorescence (if any) is detected by thedetector 110 via the optical element(s) 125 and the one ormore detector fibers 120. at 28, thecontroller 140 and/or theuser interface 150 may provide an indication when the fluorescence detected by thedetector 110 exceeds a threshold value.Steps 24, 26, and 28 may also be performed with other embodiments disclosed herein.
FIG. 7 illustrates an embodiment of a method for calibrating thetissue detection system 10. First, at 30, thedistal end 135 of theprobe body 130 is positioned at various locations on the surface of the potentially fluorescent tissue material. At 32, transmission and detection using theemitter 105 anddetector 110, respectively, begins at each of the various locations. The detected fluorescent signal corresponding to the detected fluorescent light (if any) is acquired by thecontroller 140. At 34, thecontroller 140 discards any data corresponding to the detected fluorescent signal that is outside of the predetermined range. At 36, a threshold level is statistically derived from the remaining data of the corresponding detected fluorescent signal. Thus, using such calibration, threshold levels of potentially fluorescent tissue material and other tissue significantly different from the potentially fluorescent tissue material may be obtained. These threshold levels may be used to calculate a ratio, and when the ratio is below or above the threshold ratio, thecontroller 140 and/or theuser interface 150 may provide an indication.Steps 32, 34, and 36 may also be performed with other embodiments disclosed herein.
Referring to FIG. 8, an alternative embodiment of a tissue detection system, generally indicated by the numeral 10', is shown. The tissue detection system 10' includes an emitter 230 (which may be similar to the emitter 105) such as a solid state laser, laser diode, or other suitable source that may be configured to emit radiation at a selected wavelength and may be modulated by amodulator 235 to alter the emitted radiation lower or higher. Themodulator 235 may be of various types, such as a chopper, pockel cell, acousto-optic modulator, or other light modulation device. The modulated emitter signal is delivered fromemitter 230 to probe 240 (which may be similar to substitute probe 220) throughmodulator 235, and the modulated probe signal fromprobe 240 is applied to the relevant tile. Thereafter, anear IR camera 245, with or without camera optics 250 (e.g., one or more optical lenses and/or filters, etc.), views the relevant slice. NearIR camera 245 may be used as a detector to capture radiation from the fluorescing tissue of interest. The signal from thenear IR camera 245 may pass through thedemodulator 255, and thedemodulator 255 may also use the modulator frequency from themodulator 235 as an input before the demodulated signal from thedemodulator 255 is passed on to thedisplay 260. As with thedisplay 210, thedisplay 260 may be separate from or integrated with thecontroller 140 and/or theuser interface 150.
Demodulator 255 may be in the form of a fast digital processor such as a graphics or game processor or FPGA (field programmable gate array) capable of executing a large number of fast parallel processing algorithms. Successive image frames from thenear IR camera 245 undergo a pixel-by-pixel demodulation function, i.e., each pixel is demodulated by a demodulator by a fast parallel processor. The pixel-by-pixel demodulation function may include digital lock-in or fourier transform demodulation of the modulation frequency.
The rolling window of demodulated video frames can be continuously passed ontodisplay 260 for display fromdemodulator 255, which results in a slight start-up delay, and then a real-time demodulated video with very high gain to the emitted light stimulated by the modulated probe signal and high rejection of background illumination from, for example, an operating room light.
In one embodiment, thenear IR camera 245 may include an output that directly corresponds to the fluorescence detected by each detector in the camera imaging array of thenear IR camera 245. For this case, the brightness values of the detected fluorescence can be resolved in pixels, and the demodulation functions are performed in parallel in the fast digital processor ofdemodulator 255. In one embodiment. The Nvidia Tegra processor can be programmed to parse and perform digital lock operations for hundreds of pixels in parallel at the video rate.
In fig. 9, an alternative embodiment of a tissue detection system is shown, indicated by the numeral 10 ".Tissue detection system 10 "is similar to tissue detection system 10', buttissue detection system 10" instead employs a standard video camera 270 (which may employ camera optics 205) and a near IR camera 275 (which may employ camera optics 250), both of which image the same relevant slice. Near IR camera 275 may be used as a detector to capture radiation from the fluorescing tissue of interest. In this embodiment,demodulator 255 performs pixel locking on the output from near IR camera 275, and pixels meeting predetermined criteria are mixed with the output fromstandard video camera 270 bydemodulator 255 to produce a highlight of the video fromstandard video camera 270 for pixels showing fluorescence in the image ultimately displayed ondisplay 260.
Aspects of the embodiments may include any combination of processing elements and memory that may include computing devices executing software routines, including computers and personal electronic devices, as well as programmable electronic products, logic circuits, and other electronic implementations. Various combinations of optical elements may be employed including lasers, LEDs and other light sources, filters, lenses, mirrors, beam splitters, and the like. The details of the optical, electronic, and processing embodiments described herein are illustrative and not intended to be limiting, as alternative methods using other combinations of similar elements may be used to achieve the same results in substantially the same way.
It should be understood that the various aspects disclosed herein may be combined in different combinations than those specifically presented in the description and drawings. It will also be understood that, depending on the example, certain acts or events of any of the processes or methods described herein may be performed in a different sequence, may be added, merged, or omitted altogether (e.g., all described acts or events may not be necessary for performing these techniques), and further for clarity purposes, while certain aspects of the disclosure are described as being performed by a single module or unit, it should be understood that the techniques of this disclosure may be performed by a unit or combination of modules associated with, for example, a medical device.