Patent Grant
11653834
There are both clinical and non-clinical applications for imaging an object of interest. In a clinical example, a body part may be imaged in two or three dimensions in various ways, such as by using radiation (e.g., X-ray or CT imaging), magnetism (e.g., magnetic resonance imaging), sound (e.g., ultrasound imaging), or light (e.g., optical coherence tomography). Spectroscopic information is also useful, such as for determining the composition of an object of interest.
Overview
The present inventors have recognized, among other things, that laser scanning microscopy can presently only achieve penetration depths of less than 600 μm, because of light scattering effects. Laser scanning microscopy also often uses an exogenous fluorescent contrast agent that is introduced into the object to enhance the resulting image. If three-dimensional (3D) images are to be acquired, laser scanning microscopy serially adjusts the focal plane of the light to sample different depths within the object, however, this can be time-consuming.
The present inventors have also recognized that laminar optical tomography (LOT) allows depth-resolved, non-contact imaging of an object such as living tissue at high frame rates, and such as to depths of greater than 2 mm with up to 100 to 200 μm resolution. Unlike laser scanning microscopy, LOT concurrently obtains information about various depths in parallel, rather than serially. LOT can image absorption contrast (such as oxyhemoglobin, deoxyhemoglobin, or melanin concentration) as well as fluorescence. For example, LOT can be applied to in-vivo dermal imaging of skin cancer or in-vivo imaging of the function of a rat brain. The LOT techniques can be performed at orthogonal or oblique angles, such as described further below.
The present inventors have further recognized that a technique of using LOT to acquire images at multiple wavelengths (e.g., so as to be able to distinguish between multiple different light-absorptive substances) can use respective shutters to modulate light from corresponding individual lasers emitting light at different wavelengths. However, the present inventors have also recognized that this can dramatically slow down image acquisition speed and can limit the number of wavelengths, types of light sources, or types of data that can be acquired.
Accordingly, the present inventors have recognized and developed a technique that allows multi-spectral LOT data to be acquired in parallel, such that data at one wavelength can be acquired concurrently with data at another (different) wavelength. Among other things, this means that multiple lasers—or even a broadband light source such as an LED or a lamp—can be used to concurrently illuminate the tissue with different wavelengths of light. Moreover, by a clever arrangement of the detection configuration, each wavelength can be distinguished and recorded concurrently—in addition to allowing the concurrent depth-resolved LOT data. In such a parallel or concurrent mode, image acquisition can proceed as fast as scanning of an incident beam allows. This can be quite fast and may generally merely be limited by galvanometer mirror scanning speed, digital data acquisition rate, or the noise floor of the light detector. Furthermore, discrete wavelength laser sources can be very expensive, and will typically provide only as many different distinct wavelengths as the number of lasers. By contrast, the present systems or methods permit use of one or more broadband sources or multi-wavelength lasers to potentially allow concurrent imaging of detailed depth-resolved spectral optical response information. For fluorescence imaging, the present systems or methods allow the full spectrum of the fluorescent emission to be measured, if desired. One or more excitation wavelengths can be used concurrently, while one or more different fluorophores can be measured and distinguished concurrently. Multiple concurrent measurements of the fluorescence emission spectrum can be recorded, allowing for spectroscopic analysis as well as imaging using the present techniques.
Thus, the present inventors believe that the present techniques can provide dramatic improvements to the efficacy, speed, and potential applications of LOT. Examples of potential applications include, without limitation, fluorescence and absorption contrast imaging or spectroscopy of living tissues, such as the brain, retina, skin, or endothelial tissues, such as the oral mucosa, colon, or cervix. By concurrently acquiring multi-spectral absorption or fluorescence measurements, rapid functional imaging can be accomplished.
The present inventors have also recognized that the present techniques can be used concurrently with diffuse correlation spectroscopy (DCS)—which can benefit from the scanning and other aspects of the present techniques. The DCS information can be used to directly or indirectly provide additional useful information, such as blood flow, tissue oxygenation, oxygen metabolism, or the like. This is particularly useful where the region of interest includes brain tissue, for example, such as for ischemia or stroke characterization. For example, absorption contrast can provide oxygenation information, which, combined with DCS, can yield metabolism information. Certain examples in this document describe a combined LOT/DCS system that is capable of concurrently quantifying (1) absorption (and hence oxyhemoglobin and deoxyhemoglobin dynamics in living tissue), (2) fluorescence (such as that from a calcium sensitive or voltage sensitive dye, a targeted molecular probe, or an intrinsic fluorophore such as FAD, NADH, or collagen), and (3) blood flow, such as via DCS.
The present inventors have further recognized that the present techniques can benefit from using an at least partially flexible optical conduit to communicate with the target region. For a human or animal subject, this can permit convenient external or internal imaging of a target location. In certain examples, such as for internal imaging of a body lumen, 360-degree circumferential viewing can be accomplished, such as by using a rotatable angled mirror. The rotatable angled mirror can also be useful in laparoscopic or oral examination, such as for examining the oral mucosa, for example. A specified separation between a distal portion of the optical conduit and the target region of the body can be obtained using an inflatable balloon or other fixed or adjustable separation device.
The present inventors have further recognized that one approach would be to use a LOT system that is built on a rigid platform, with optical components steering the laser beam or other light down onto the object to be imaged. The platform can be raised and lowered, and the objective lens can be tilted, but its utility can be severely restricted if imaging is to occur in the clinic where the face and neck are not easily and comfortably accessible via a rigid platform. Accordingly, the present inventors have recognized that, by introducing an articulating arm, and solving the associated optical and configuration difficulties of sending and detecting LOT or DCS signals, one can be enabled to image any area near which one can position the articulating arm. This can help extend all of the benefits of LOT or DCS to situations in which the LOT or DCS information is to be acquired in a clinic.
In certain examples, the LOT or DCS system including the articulating arm can allow imaging of skin cancer lesions on the neck and face. The articulating arm can be used while still providing the LOT system with careful control over the off-axis returning light that allows depth-resolved LOT imaging (rather than just illumination). The articulating arm allows LOT or DCS to be extended to many more clinical applications than without the articulating arm, and can provide better signal-to-noise characteristics than an endoscopic embodiment. In certain examples, the LOT or DCS system including the articulating arm can be used in a non-medical imaging application, such as for example in industrial quality control in difficult to reach places (e.g., where depth-resolved imaging of turbid material is desirable). The articulating arm can also allow configurations that require delivered or detected light to retain one or more features that cannot be maintained during passage through an optical fiber. In certain examples, transmission of ultra-violet light, pulsed laser light, or polarized light can be significantly deteriorated by an endoscopic or other optical fiber conduit, as compared to an articulating arm including suitable reflectors, such as described further herein.
Example 1 can include subject matter that can comprise at least one light source providing at least one wavelength of light. In this example, the apparatus can comprise a scanner, configured to receive the light from the light source, and configured to scan a beam of the light across a target region. In this example, the apparatus can comprise a light detector, configured to receive from the target region a scanning response signal at a plurality of distances from a beam location upon the target region. In this example, the apparatus can comprise a wavelength separator, configured with respect to the light detector to direct a first wavelength of the scanning response signal to a different location of the light detector than a second wavelength of the scanning response signal, wherein the second wavelength is different from the first wavelength.
In Example 2, the subject matter of Example 1 can optionally comprise a signal processor, coupled to the light detector, the signal processor configured to concurrently process the scanning response signal of the first wavelength and the scanning response signal of the second wavelength. In this example, the lateral distances can define a linear first direction, and wherein the wavelength separator is configured to spatially separate wavelengths of the scanning response signal in a linear second direction that is orthogonal to the first direction.
In Example 3, the subject matter of any one of Examples 1 or 2 can optionally comprise the light detector including a two-dimensional array of light detector elements, and is configured to detect different wavelengths of the scanning response signal along a first dimension of the two-dimensional array, and to detect along a second dimension of the two-dimensional array optical responses from the different lateral distances from the beam location, and wherein the first and second dimensions of the two-dimensional array are orthogonal to each other, and comprising an imaging data memory including a two-dimensional array of memory locations for corresponding scanning locations of the target region, each two-dimensional array of memory locations storing data from the two-dimensional array of light detectors for a particular scanning location of the target region.
In Example 4, the subject matter of any one of Examples 1-3 can optionally comprise the light source comprising: a first laser, providing laser light at the first wavelength; and a second laser, providing laser light at the second wavelength that is different from the first wavelength, and wherein the first wavelength of the scanning response signal is in response to the first wavelength of laser light provided by the first laser, and wherein the second wavelength of the scanning response signal is in response to the second wavelength of laser light provided by the second laser.
In Example 5, the subject matter of any one of Examples 1˜4 can optionally be configured such that the first wavelength of the scanning response signal is in response to a first emission wavelength of a first fluorophore, and wherein the second wavelength of the scanning response signal is in response to a second emission wavelength of a second fluorophore of the same type as the first fluorophore or of a different type than the first fluorophore.
In Example 6, the subject matter of any one of Examples 1-5 can optionally comprise a beam splitter configured to communicate light with the scanner and the wavelength separator.
In Example 7, the subject matter of any one of Examples 1-6 can optionally comprise a housing that carries at least the scanner and an objective lens.
In Example 8, the subject matter of any one of Examples 1-7 can optionally comprise a tubular spacer, configured to fit about the objective lens and to maintain a specified distance between the objective lens and the target region.
In Example 9, the subject matter of any one of Examples 1-8 can optionally comprise an articulating arm, configured to communicate light along the articulating arm, between the housing and the target region, without requiring a fiber optic conduit.
In Example 10, the subject matter of any one of Examples 1-9 can optionally be configured such that the articulating arm comprises: first and second elongated segments, each segment defining a longitudinal direction; a pivot, coupling the first and second elongated segments, wherein at least one of the first and second elongated segments is configured to rotate about the longitudinal direction with respect to the pivot; and wherein the pivot comprises an angled mirror configured to redirect light from along a longitudinal direction of a first segment to be along a longitudinal direction of the second segment.
In Example 11, the subject matter of any one Examples 1-10 can optionally comprise at least two pivots and at least three segments.
In Example 12, the subject matter of any one of Examples 1-11 can optionally be configured such that the light source comprises a broadband light source.
In Example 13, the subject matter of any one of Examples 1-12 can optionally be configured such that the wavelength separator includes at least one of a prism, a diffraction grating, a dichroic filter, or multiple dichroic mirrors.
In Example 14, the subject matter of any one of Examples 1-13 can optionally be configured such that the wavelength separator receives light from a slit that defines a longitudinal direction such that the plurality of lateral distances from the beam location upon the target region correspond to different locations along the longitudinal direction of the slit.
In Example 15, the subject matter of any one of Examples 1-14 can optionally comprise: a correlator circuit, coupled to the light detector to receive and compute a temporal correlation of the scanning response signal from the target region; and a signal processor, configured to receive and use the temporal correlation to compute a first characteristic of the target region.
In Example 16, the subject matter of any one of Examples 1-15 can optionally comprise the signal processor configured to receive, in response to the same scanning, a fluorescence component of the scanning response signal, and to use the fluorescence component of the scanning response signal to compute a second characteristic of the target region.
In Example 17, the subject matter of any one of Examples 1-16 can optionally comprise the signal processor being configured to receive, in response to the same scanning, an absorption component of the scanning response signal, and to use the absorption component of the scanning response signal to compute a third characteristic of the target region.
In Example 18, the subject matter of any one of Examples 1-17 can optionally comprise the signal processor being configured to receive, in response to the same scanning, an absorption component of the scanning response signal, the absorption component comprising at least two different wavelengths of light, and to use the absorption component of the scanning response signal to compute the third characteristic of the target.
In Example 19, the subject matter of any one of Examples 1-18 can optionally comprise: an optical conduit, optically coupled to the scanner and the light detector, the optical conduit configured to communicate the beam of the first wavelength of light to the target region, and configured to communicate the scanning response signal from the target region; and a laparoscopic or endoscopic instrument carrying the optical conduit.
In Example 20, the subject matter of any one of Examples 1-19 can optionally be configured such that a distal portion of the conduit includes a longitudinal-to-side optical translator guide that comprises a mirror that is obliquely angled with respect to a longitudinal axis of the optical conduit.
In Example 21, the subject matter of any one of Examples 1-20 can optionally be configured such that the mirror is rotatable about the longitudinal axis of the optical conduit.
Example 22 can include, or can be combined with any one of Examples 1-21 to optionally include, subject matter including: sourcing light to form an incident beam; scanning a location of the incident beam across a target region; obtaining an optical response at different locations at different distances in a first direction from the beam location upon the target region; dispersing different wavelengths of the optical response; and detecting the dispersed wavelengths of the optical response from the different locations concurrently to provide information about the target region.
In Example 23, the subject matter of any one of Examples 1-22 can optionally be configured such that sourcing the light includes sourcing light at different wavelengths.
In Example 24, the subject matter of any one of Examples 1-23 can optionally be configured such that detecting the dispersed wavelengths of the optical response includes detecting a first and second wavelengths of fluorophore emission, wherein the first wavelength of fluorophore emission is different from the second wavelength of fluorophore emission.
In Example 25, the subject matter of any one of Examples 1-24 can optionally be configured such that detecting the dispersed wavelengths of the optical response includes detecting the first wavelength of fluorophore emission from a first type of fluorophore and detecting the second wavelength of fluorophore emission from a second type of fluorophore that is different from the first type of fluorophore.
In Example 26, the subject matter of any one of Examples 1-25 can optionally be configured such that dispersing different wavelengths of the optical response includes dispersing along a linear second direction that is orthogonal to the first direction at a light detector.
In Example 27, the subject matter of any one of Examples 1-26 can optionally comprise: storing a two-dimensional array of response information from the light detector for different beam locations of the target region; and using the stored two-dimensional array of response information from the light detector for different beam locations of the target region to construct at least one of: a three dimensional rendered image of the target region; an image representing chemical composition of the target region; and a plurality of images representing information about different depths of the target region.
In Example 28, the subject matter of any one of Examples 1-27 can optionally be configured such that dispersing different wavelengths comprises refracting different wavelengths by different amounts.
In Example 29, the subject matter of any one of Examples 1-28 can optionally be configured such that dispersing different wavelengths comprises diffracting the different wavelengths by different amounts.
In Example 30, the subject matter of any one of Examples 1-29 can optionally be configured such that dispersing different wavelengths includes filtering a first wavelength from a second wavelength.
In Example 31, the subject matter of any one of Examples 1-30 can optionally comprise: computing, for the multiple different lateral locations, a temporal correlation of the scanning optical response; and computing a first characteristic of the target region using the temporal correlation.
In Example 32, the subject matter of any one of Examples 1-31 can optionally comprise obtaining, in response to the same scanning, a fluorescence component of the scanning optical response signal; and using the fluorescence component of the scanning optical response signal to compute a second characteristic of the target region.
In Example 33, the subject matter of any one of Examples 1-32 can optionally comprise obtaining, in response to the same scanning, an absorption component of the scanning optical response signal; and using the absorption component of the scanning optical response signal to compute a third characteristic of the target region.
In Example 34, the subject matter of any one of Examples 1-33 can optionally comprise obtaining, in response to the same scanning, an absorption component of the scanning optical response signal, the absorption component comprising at least two different wavelengths of light; and using the absorption component of the scanning optical response signal to compute a third characteristic of the target region.
In Example 35, the subject matter of any one of Examples 1-34 can optionally comprise using an optical conduit to communicate light to and from the target region.
In Example 36, the subject matter of any one of Examples 1-35 can optionally comprise scanning an incident beam location and obtaining an optical response are carried out for a target location that is internal to a human or animal.
In Example 37, the subject matter of any one of Examples 1-36 can optionally be configured such that scanning an incident beam location and obtaining an optical response are carried out for a target location that is orthogonal to a longitudinal axis of the optical conduit.
In Example 38, the subject matter of any one of Examples 1-37 can optionally comprise: scanning the location of the incident beam across a target region comprising skin; and using the information about the target region to discriminate between first and second skin conditions.
In Example 39, the subject matter of any one of Examples 1-38 can optionally comprise using an oblique angle from the target region for at least one of the scanning or the obtaining the optical response.
These examples can be combined in any permutation or combination. This overview is intended to provide an overview of subject matter of the present patent application. It is not intended to provide an exclusive or exhaustive explanation of the invention. The detailed description is included to provide further information about the present patent application.
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
In the drawings, which are not necessarily drawn to scale, like numerals may describe similar components in different views. Like numerals having different letter suffixes may represent different instances of similar components. The drawings illustrate generally, by way of example, but not by way of limitation, various embodiments discussed in the present document.
Optical imaging or spectroscopy described can use laminar optical tomography (LOT), diffuse correlation spectroscopy (DCS), or the like. An incident beam is scanned across a target. In various examples, time-resolved (e.g., pulsed light) can be used, such as to obtain fluorescence lifetime or scattering information. Frequency modulated light can be used, in certain examples. Cross-polarized or other polarized light can be used, in certain examples. An optical response to the incident beam can be obtained, such as concurrently at different distances from the incident beam. Such different distances can be linearly displaced from the incident beam, circumferentially displaced from the incident beam, or displaced in orthogonal directions from the incident beam location, in various examples. The optical response from multiple incident wavelengths can be concurrently obtained by dispersing the response wavelengths in a direction orthogonal to the response distances from the incident beam. Temporal correlation can be measured, from which flow and other parameters can be computed. An optical conduit can enable endoscopic or laparoscopic imaging or spectroscopy of internal target locations. An articulating arm can communicate the light for performing the LOT, DCS, or the like. The imaging can be used for skin cancer diagnosis, such as distinguishing lentigo maligna (LM) from lentigo maligna melanoma (LMM).
In the example of
In the example of
In the example of
The second path 120 receives light from the beam-splitter 116. In this illustrative example, a refractive element, such as a lens 140, focuses the light onto an input of an element comprising a slit 142. An output of the slit 142 provides the light to a refractive element, in this example, such as the lens 144. However, at this point, the optical response light signal does not separate information according to wavelength. One approach to separate information by wavelength is to provide a shuttering mechanism to provide light of a particular wavelength, then analyze the response from that wavelength, and repeat in a time sequence for other wavelengths. However, shuttering is time-consuming such that it is possible that a biological change can occur before all wavelengths of light are provided and their responses observed. In the case of such an intervening biological change, the multiple wavelengths and their responses can fail to provide a unique spectroscopic solution, can involve using more sophisticated detection components, or can be slow.
The present inventors have recognized, among other things, that a wavelength separator such as a dispersive element 146 can be used in a clever arrangement to solve this problem. In this example, the lens 144 collimates and provides the light via a slit to the dispersive element 146, such as to a prism, diffraction grating, or one or more dichroic filters. The slit can be arranged in a first direction (e.g., ay-direction) such that distances along a length of the slit represent the various lateral distances, from the location of instance of the incident light, at which the optical response signal is observed. The present inventors have recognized, among other things, that the dispersive element 146 can be used to disperse the different wavelengths of the response signal in a second direction (e.g., an “x” direction) that is orthogonal to the first direction of the slit. The resulting x-y array of wavelength vs. lateral distance optical response information from the dispersive element 146 can be captured using a light detector, such as an x-y photomultiplier array 148, a charge-coupled device (CCD) light detector array, a photodiode array, or a square optical fiber bundle or collection of linear fiber or detector arrays.
In the example of
LOT using a single wavelength of incident light provides depth-resolved optical imaging information. By including the dispersive element 146 in the LOT system 100, such multiple different wavelengths can be used concurrently, and the resulting optical response information can be concurrently separated according to such different wavelengths. Such wavelength-separated information can then be processed, such as to generate a rendered volumetric image or to perform spectroscopic analysis of the composition of the object being examined. Concurrent use of different wavelengths allows faster imaging or spectroscopy. Information acquisition speed is particularly important for imaging or spectroscopy of biological targets, in which the target otherwise might undergo a change during the time between imaging or spectroscopy of first and second different wavelengths, which could potentially render a slower (e.g., serially-obtained) composite of such information useless. Moreover, the present inventors have recognized that concurrent use of different wavelengths allows use of different light sources. In certain examples, a cheaper broadband light source (e.g., a light-emitting diode (LED) or a lamp) can replace the laser light sources described above, since the resulting information can be spectrally separated such as described above. Thus, even though
The present approach can also be useful for observing an exogenous or endogenous fluorescence response, such as in tissue. In an exogenous approach, a contrast agent, which can include multiple fluorophores that emit a fluorescence response at different wavelengths, can be introduced into the tissue. In an endogenous approach, an intrinsic fluorophore emits the fluorescence response at a different wavelength than the excitation wavelength. In either an exogenous or endogenous approach, a single excitation wavelength (or even a broadband light source) can be used to obtain the fluorescent emission response. The optical response at the excitation wavelength can be notch-filtered or otherwise attenuated or removed from the optical response information, such as for emphasizing the fluorescent emission relative to the optical response at the excitation wavelength. The multiple fluorescence emission bands (e.g., from Nicotinamide adenine dinucleotide (NADH), flavin adenine dinucleotide (FAD), collagen, elastin, a calcium-sensitive or voltage sensitive dye, as an illustrative example) can be spectrally separated using the dispersive element 146, and detected using a 2 dimensional light detector array, or a series of stacked 1 dimensional linear light detector arrays, for example. In certain examples, information from the 2D light detector array 148 can be used to measure light scattering in two orthogonal directions (e.g., in an L-shape, rather than along a line). This may provide useful information about the tissue, such as information about the scattering anisotropy.
Thus, in certain examples, the above system 100 and method 300 can use a two-dimensional detector array, multiple linear detector arrays, or multiple linear detectors, along with a diffraction grating, prism, or other spectrally separating optical element to concurrently image multi-spectral on-axis or off-axis scattered light from a scanning spot to allow depth-resolved optical imaging or spectroscopy. For example, the two-dimensional detector array is useful for performing multi-spectral LOT imaging or spectroscopy. The linear array is useful for DCS. The above system 100 and method 300 are advantageous over a system and method that uses serial illumination of different wavelengths of laser light, and either multiple individual detectors or a linear array of detectors. Serial illumination of different wavelengths of light typically involves a complicated shuttering process. It will therefore result in slower imaging frame rates, and can result in a lack of simultaneity in measurements of living dynamic systems (e.g., movement artifacts or fast hemodynamic changes can inhibit quantitative spectroscopic analysis of results). Examples of some applications of the present systems and methods include, without limitation, fluorescence, absorption, or scattering contrast imaging or other spectroscopy of living tissues, such as the brain, retina, skin, or endothelial tissues such as the oral mucosa, colon, or cervix. By having concurrently acquired multi-spectral absorption or fluorescence measurements, rapid functional imaging can be accomplished. Multi-spectral detection allows separation of signals, such as from mixtures of fluorophores or chromophores, such as voltage or calcium sensitive dyes, molecular probes, collagen, NADH, flavoproteins, tryptophan, oxyhemoglobin, deoxyhemoglobin, melanin, lipid, water, cytochrome, etc. For example,
DCS generally involves using a laser source for providing incident light, such as at a wavelength that typically exhibits a desired coherence length over which the incident light maintains a desired degree of coherence. Light scattering by the tissue or other target object can be detected. Fluctuations in the detected scattered light can be ascertained, such as by using a correlator circuit or like module to compute one or more temporal correlation statistics of the detected scattered light. In tissue having blood flow, such as a region of interest of the brain, for example, less blood flow will result in a longer time-constant of temporal correlation of the detected scattered light. Conversely, more blood flow will result in a shorter time-constant of temporal correlation of the detected scattered light. Information about blood flow or changes in blood flow is useful by itself. Moreover, such information can also be used, for example, in determining tissue oxygenation, tissue oxygen extraction, or tissue oxygen metabolism. DCS information can also be used to generate 3D imaging information, such as described further below.
In this example, the different wavelengths of light from the corresponding different lasers 502, 504, 506, and 507 are combined and delivered to the lens 104, either directly or such as via an optional optical fiber conduit 108. In certain examples, such as for providing light for performing DCS, a single-mode low dispersion optical fiber conduit 108 is used. In this example, in which four different wavelengths of light are shown for illustrative purposes, the combining of the different wavelengths of light can be accomplished similarly to that described above with respect to
The light from the light sources 502, 504, 506, and 507 is delivered to the optical fiber or other optical conduit 108 and, similarly to the above description with respect to
k2=3μs′μa+6μs′2ko2Γτ (1)
where τ represents the autocorrelation time delay and ko represents the photon wavenumber in the medium. The parameter Γ=αDB characterizes blood flow; α represents the probability that a photon is scattered by a moving “cell” and is presumed proportional to cerebral blood volume. The blood flow speed can be parameterized by a Brownian diffusion constant, DB., such as described in Culver et al. and the references cited therein.
As described above, the DCS information can be used to obtain a rendered 3D image that includes information about any changes in the blood flow through the tissue. Moreover, blood flow information can also be used, for example, in determining and displaying a 3D representation of tissue oxygenation, tissue oxygen extraction, or tissue oxygen metabolism. The DCS-derived information is particularly useful in conjunction with the absorption or fluorescence spectroscopic information provided by the LOT concurrent to the DCS information generation.
Moreover, the present DCS configuration, which cleverly uses the x-y scanning from the LOT configuration of
For example, if only DCS information is desired, components 502, 504, 506, 110, 112, 532, 541, 539, 540, 140, 142, 144, 146, 152, and 148 can be omitted; such an example can still take advantage of the present scanning techniques in conjunction with DCS. If DCS and LOT fluorescence information is desired, components 532, 541, 539 can be added back in, along with at least one of components 502, 504, or 506 and a respective at least one of components 508, 110, or 112. If DCS and LOT absorption information is desired, components 540, 140, 142, 144, 146, 152, and 148 can be added back in, along with along with at least one of components 502, 504, or 506 and a respective at least one of components 508, 110, or 112. Multi-wavelength LOT absorption information can be obtained using the DCS laser 507 for providing at least one of the multiple wavelengths, if desired. In another example, if LOT absorption and fluorescence information is desired, but DCS information is not desired, the configuration of
Combining DCS with LOT presents certain technical challenges that the present approach has overcome, such as, for example, how to extract the distinct wavelengths useful for DCS from other wavelengths useful for LOT, and how to perform the different DCS and LOT processing concurrently—particularly where the LOT information can be both spatially-resolved and spectrally-resolved, such as described above with respect to
Among other things, the combined LOT/DCS system illustrated in
Although
For example, to use the 2D light detector array 148 to obtain the DCS information, the correlators 546A-H can be connected to elements in the light detector array 148 that detect the particular wavelength desired for DCS (e.g., 800 nm, in this example). As described above with respect to
In another example, the 2D light detector array 148 can be used to obtain the LOT fluorescence response, as well as the LOT absorption response. Since fluorescence response occurs at wavelengths that are different from the wavelength(s) of the incident light, the fluorescence response information can be obtained from the 2D light detector array 148 by ignoring information from those elements that are associated with incident wavelengths. For example, if the incident wavelengths used are 800 nm and 636 nm, which, as the result of the dispersive element 146 correspond to particular “rows” of the 2D light detector array 148, then the fluorescence response information can be obtained from other rows of the 2D light detector array 148. Similarly, if the incident wavelengths used are 800 nm and 636 nm, which, as the result of the dispersive element 146 correspond to particular “columns” of the 2D light detector array 148, then the fluorescence response information can be obtained from other columns of the 2D light detector array 148. In another example, if the incident wavelengths used are 800 nm, 636 nm, 532 nm, and 488 nm, which, as the result of the dispersive element 146 correspond to particular “rows” of the 2D light detector array 148, then the fluorescence response information can be obtained from other rows of the 2D light detector array 148. Similarly, if the incident wavelengths used are 800 nm, 636 nm, 532 nm, and 488 nm, which, as the result of the dispersive element 146 correspond to particular “columns” of the 2D light detector array 148, then the fluorescence response information can be obtained from other columns of the 2D light detector array 148. Using the 2D light detector array for obtaining LOT absorption and LOT fluorescence information would allow components 532, 541, and 539 to be omitted. Using the 2D light detector array for obtaining LOT absorption, LOT fluorescence, and DCS information would allow components 540, 542, 544, 532, 541, and 539 to be omitted.
Although certain examples have been discussed in terms of using a 2D light detector array, multiple 1D light detector arrays could be “stacked” or otherwise used, or a combination of 1D and 2D light detector arrays could be used. This will allow mixing or matching of different detector arrays having different properties, as desired.
The present inventors have also recognized that using an at least partially flexible optical conduit 130, such as shown in
In certain applications, it can be desirable to fixate the distance between the optical conduit or variable magnifier 132 and the site 704. In certain examples, this can be accomplished by using a transparent window 706 having the desired thickness to maintain the desired separation. In certain examples, this can be accomplished by using a toroidal or other balloon cuff 712 located circumferentially about the distal portion 700. The toroidal balloon cuff 712 can be remotely inflatable, such as via a fluid conduit 714 that extends toward a proximal external end of the endoscopic or laparoscopic apparatus. In certain examples, the desired separation can be maintained by a plurality of arms that can be remotely actuated to splay outward or retract inward. Other techniques can also be suitable for maintaining the desired separation.
In certain examples, the side-looking distal end of
In an example, the mirror 804 rotates together with the linear arrangement of fibers 808—this can be accomplished by rotating the endoscopic apparatus carrying these elements, or by providing rotation of these elements within the endoscopic apparatus carrying these elements. Such rotation permits 360-degree circumferential imaging or spectroscopy within the orifice 802. A back-and-forth rotation can also be used, e.g., a 360-degree rotation in one direction, followed by a 360-degree rotation in the opposite direction. The mirror 804 can also be inserted deeper into the orifice 802 or retracted outward from the orifice 802, together with or independent from the circumferential rotation. This can be accomplished by moving the endoscopic apparatus carrying these elements, or by providing telescopic extension or retraction of these elements within the endoscopic apparatus carrying these elements, or other desired element, such as, for example, a MEMs mirror array to steer the light.
Although the above description has emphasized examples in which light is incident substantially perpendicular to region of interest, the present inventors have also recognized that providing the incident light at a non-orthogonal angle to the region of interest can actually be desirable, and has the potential for providing higher sensitivity and better imaging or spectroscopic resolution. Without being bound by theory, this increased depth sensitivity is believed to be particularly effective at shallow depths, where there is a significant degree of directionality of the light within the tissue. An intersection point between incident light and detected light pathways will provide locations of highest sensitivity for imaging or spectroscopy. In some examples, detection can be performed at an oblique angle and illumination can be performed at a perpendicular angle.
The particular angle of incidence 910 can take on any desired value in the range of 0 degrees and 90 degrees. In an example, the angle 910 is between 10 degrees and 80 degrees. In another example, the angle 910 is between 20 degrees and 80 degrees. In another example, the angle 910 is between 10 degrees and 50 degrees.
In some examples, Monte Carlo simulation can be used to form a reconstruction model that can be used to create the plots of
Jn,m(r)=δMn,m/δμa(r). (2)
In Equation 2, above, for a given incident light location, n, and a given optical response detection location, m, the sensitivity function Jn,m(r) will be a function of the position r within the tissue. Mn,m represents a measurement at the tissue surface. μa(r) is the absorption at the position r within the tissue. δMn,m represents a change in the measurement Mn,m. δμa(r) represents a change in μa(r). Equation 2 uses the Born approximation, which assumes a linear model relating Mn,m and μa(r). The Born approximation assumes that δμa(r) is small, so that Jn,m(r) can be used to predict Mn,m. Alternatively, the Rytov approximation can be used, which replaces δμa(r) with exp(δμa(r)). However, the real relationship relating Mn,m and μa(r) is non-linear. Therefore, for larger absorption changes, δμa(r), or for other reasons, it may be desirable to use a non-linear reconstruction that updates estimates of Jn,m(r) based on the structure of the target object.
From Equation 2, if a modeled sensitivity function Jn,m(r) is known, then the absorption μa(r) at various positions within the tissue can be calculated from the measured δMn,m Monte Carlo simulation can be used to calculate the modeled sensitivity function Jn,m(r). At depths into the tissue that are shorter than the mean scattering length of light in the tissue, directionality of the incident light can be important. Therefore, at such distances into a tissue sample, information about the angles of propagation of the photons can be included in the model. At distances into the tissue that exceed the mean scattering length of the light in tissue, a diffusion approximation to the equation of radiative transport can optionally be used in the model. The radiative transport equation itself can be used in the model, if desired. Moreover, instead of Monte Carlo simulation, empirical measurements or other modeling (e.g., finite element modeling (FEM), finite difference modeling, Maxwell's equations, or the like) can be used to create the reconstruction model.
The reconstruction model can also incorporate any information known about the target object. For example, such known information can be incorporated into the model as one or more constraints upon the model, or as constraints upon 3D or other image reconstruction or spectroscopic information obtained using the model. In an example, if a particular type of target tissue is known, then the model can incorporate information about that particular target tissue type. For example, brain tissue exhibits less light scattering than skin tissue. Therefore, information about the lower scattering of brain tissue can be incorporated into the model. Darker skin exhibits more light absorption than lighter colored skin; this information about a known target can be incorporated into the model. Also, the model can also incorporate spectral information about the particular chromophores expected in that type of target tissue. Similarly, known information about target shape can be used to generate the model. Likewise, information about the particular wavelength of incident light can be incorporated into the model. In certain examples, it is not necessary to actually create a 3D image using the model. Instead, raw data can be processed or presented to a user without actually creating a 3D image. In an example, one can also use a non-linear model that need not require a linearization assumption like Born or Rytov. A look-up table approach could also be used, in an example. In an example, pixel-by-pixel analysis of optical properties and shape functions can be performed without performing a complete image reconstruction.
Although the above description has emphasized an example in which absorption due to light scattering is modeled, a target's fluorescence response can be similarly modeled. Fluorescence results from a photon being absorbed by a fluorophore and a different photon (of longer wavelength) being emitted. Therefore, the amount of fluorescence light emitted will depend on the absorption coefficient of the fluorophore, the quantum yield of the fluorophore (how many incident photons are generally required to trigger the fluorescent emission of a photon), and the concentration of the fluorophore in the target sample of interest. Therefore, fluorescence can be modeled by replacing μa(r) in Equation 2 with a μaf(r) term denoting fluorescence absorption. Other less simplified models can also be used. For example, because in fluorescence the absorbed photon is of shorter wavelength than the emitted photon, the incoming and emitted photons experience different absorption and scattering, and such differences can be included in the model. The directionality of the incident light is important in modeling scattering events until a fluorophore is encountered, however, since fluorescence emission is generally random in direction, this can also be incorporated into the model. In another example, a combined model of both fluorescence and absorption can also be used, such as to account for interaction between the fluorescence response and the absorption response of a target region of interest. In an example, Raman scattering or other optical contrast can be examined.
Articulating Arm Example
As described above, LOT can allow non-contact depth-resolved optical imaging, such as for example of living tissues to depths even greater than 2 millimeters with on the order of about 100 to 200 micrometer resolution, and with sensitivity to both absorption and fluorescence contrast. In certain examples, LOT can use a beam of light that is scanned over the surface of the tissue, such as by using galvanometer mirrors, such as described above. In response to the scanning beam, light can be detected, such as from areas adjacent to the location of scanning beam upon the target. The further away from the incident beam location that the light has traveled, the deeper that it has traveled into the tissue, and this can thereby be used to provide depth sensitive measurements. Using a model-based reconstruction algorithm, this data can be reconstructed into depth-resolved images of optical contrast, in certain examples, such as described above.
The present inventors have recognized, among other things, that LOT or DCS data can be more conveniently acquired (such as in a clinical setting) using an articulating arm, such as for communicating light to or from the target location, such as the surface of a person's body or any other desired target location. Such an articulating arm can provide three pivots (e.g., correspondingly providing three axes of rotation), which can advantageously be used to allow LOT or DCS techniques to be performed at any desired location on the external surface of the body, for example. Moreover, one or more additional pivots can be further added, such as to further increase the degrees of freedom (e.g., by correspondingly providing further axes of rotation, if desired). In certain examples, the articulating arm setup can be used to allow LOT or DCS techniques to be performed during surgery, such as to help distinguish diseased tissue from normal tissue, for example. In certain examples, the articulating arm setup can be combined with the endoscopic arrangement, such as described above.
The sensitivity of LOT to oxygenation contrast and to both intrinsic (e.g., collagen, NADH, flavoproteins, tryptophan and oxy- and deoxy-hemoglobin, melanin, lipid, water, cytochrome etc.) and exogenous contrast (e.g. voltage, calcium or pH sensitive dyes, molecular probes), as well as the above-described LOT example providing parallelized multi-spectral detection (sometimes referred to by the present inventors as “SpectraLOT”) can produce a highly versatile and relatively inexpensive medical imaging modality with particular suitability to clinical imaging applications, particularly when used with the articulating arm, endoscopic apparatus, or both.
A LOT or DCS system using the articulating arm can be configured in various ways. For example,
Example of Simultaneous Multi-Wavelength LOT Imaging of Skin Cancer
Lentigo maligna (LM) is a lesion in the skin's epidermis. LM mostly occurs in older individuals, such as on sun-damaged skin of the head and neck. The lesions typically appear as a dark brown to tan discoloration on the skin. The lesion boundaries and depth of invasion are difficult to determine. Such information can be very important for proper treatment. Upon extension of the invasion from the epidermis into the dermis, LM is referred to as lentigo maligna melanoma (LMM). The prognosis for LMM is worse than for LM because the dermis contains both vascular and lymphatic networks, thereby providing a metastatic potential. A treatment for LM and LMM is surgical excision of the tumor-containing tissue. Since the lesions typically occur on the face and neck, the surgery has an additional complexity to fully remove the tumor-containing tissue while preserving facial features. At the present time, it is uncertain whether LM will provide good contrast, because (without being bound by theory) the edges are believed not usually high in melanin. However, it is believed that other dermatology applications can also benefit from the present systems and methods.
Melanocytes, the pigment (melanin) producing cells in the epidermis, are the cells that become cancerous in malignant melanomas. At present, the discoloration associated with an increased concentration of melanin is generally the surgeon's primary way of determining surgical margins of LM. However, in some cases, the true margins of LM extend beyond the area of pigmentation visible from the surface. This can lead to re-excisions or recurrence of the disease.
Dermal vascularity is expected to significantly increase beneath in situ LMM, such as compared with normal skin or when LM is present without dermal invasion, in which cases the vascularity is believed less likely to significantly differ from surrounding skin. Therefore, LOT's ability to measure the amount, and oxygenation state of blood beneath a lesion can be useful for surgical staging or further treatment planning.
While LOT can be used for studying hemodynamics, such as in the exposed rodent brain, it can also be configured for clinical use. By way of example, but not by way of limitation, it can be used to acquire simultaneous three-wavelength measurements of skin. Among the benefits of making multi-wavelength spectroscopic measurements simultaneously are that doing so allows very rapid acquisition, and precise spectroscopy of skin chromophores. If images of three wavelengths were acquired sequentially, there would be significant risk of the patient moving, which would prevent accurate pixel-by-pixel analysis of the resulting data. LOT can provide the surgeon with a tool to help pre-surgical planning. LOT can be used to measure the depth of invasion and to provide measurements that allow the surgeon to better delineate the tumor boundaries. By simultaneously scanning and measuring 3 wavelengths of light, LOT could provide accurate measurements of subsurface melanin, oxy-hemoglobin (HbO) concentration, or deoxy-hemoglobin (HbR) concentration. Such measurements could help enable more precise excisions around the tumor-containing tissue, thereby minimizing the amount of tissue removed, such as near important facial features.
While the multi-wavelength incident beam is scanned over the region of interest, scattered light emerging from the tissue travels back through the objective lens 134, through the scan lens 128 and onto the galvanometer mirrors 124, 126. The mirrors 124, 126 de-scan the remitted light, directing it back towards the dichroic 1602 and the polarizing beam splitter 116 cube. Fluorescent response light (at wavelengths different from that of the incident light) can be redirected by the dichroic 1602 to a fluorescence light detector, such as the 1×16 photomultiplier tube (PMT) array 1606, via the lens 1608 and filter 1610.
Of the remaining response light, which continues through the dichroic 1602 to the polarizing beam splitter 116, specular reflections will have maintained their P polarization, and will not be reflected by the polarizing beam splitter 116. However, the scattered response light should be randomly polarized. Therefore, approximately half of the scattered response light will be reflected by the polarizing beam splitter 116 toward the “absorption” detector portion of the system 1600. This light then passes through a magnification lens 140 on its way to a slit 1612. The light passing through the slit 1612 emerges as a line of multi-wavelength light. The center of this line of multi-wavelength light corresponds to on-axis light, while light further from the center of this line corresponds to the light emerging from the tissue 1604 at successive distances from the location of the incident light beam spot sourced onto the tissue 1604. This line of light emerging from the slit 1612 can pass through a dispersion element 146, such as a prism (e.g., PS853, Thorlabs), which can separate the light into three lines of distinct wavelengths. The three distinct lines of light can be redirected by a mirror or lens 1614 and passed through a second polarizing beam splitter 116 cube, such as to remove any residual P-polarized light, before being projected onto a detector 148, such as an 8×8 two-dimensional PMT light detector array (e.g., H7546B, Hamamatsu). The combined use of a prism 146 (or other dispersive element) and a two-dimensional light detector array 148 permits simultaneous detection of light with multiple wavelengths and different depth-sensitivities, such as described above. The system magnification can be configured such that the distance between channels on the PMT 2-D array 148, when projected onto the object plane at the tissue 1604, can be reduced to the desired source-detector separation distance (e.g., 1.2 mm distance, at the array 148, can correspond to 200 μm distance at the tissue 1604). A 24-channel transimpedance amplifier can be coupled to the outputs of the channels of the PMT array 148, such as to convert the current output of each PMT channel into a voltage signal. In an illustrative example, the system 1600 can use four 8-channel simultaneous sampling data acquisition boards (e.g., NI PCI-6133, National Instruments, 3 MHz sample rate per channel) to sample the signal from each of the 24 channels (3 lines) on the 2D array PMT, and 7 channels on the linear fluorescence PMT. Acquisition speed can be limited by the galvanometric scanners (average maximum speed, about 4500 lines per second). Therefore, 100×100 source-position data can be acquired at 45 frames per second (fps), and 40×40 source-position data can be acquired at over 100 fps. The 8th channel on the fluorescence data acquisition card can be used to monitor the position of the x-galvanometer mirror.
Synchronization and control of the LOT system 1600 can be achieved using a Matlab Graphical User Interface, in an example. The control software allows the user to change one or more parameters such as the field of view, pixels per frame, frame rate, or number of lasers used. Following a scan, the measured data can be processed in hardware or software, such as by a signal processor or other circuit 160, into an image (or any of the plurality (e.g., 32) of simultaneously acquired images) and displayed on a screen, such as a display provided by a user interface 162, such as described above with respect to
In
In
The above detailed description includes references to the accompanying drawings, which form a part of the detailed description. The drawings show, by way of illustration, specific embodiments in which the invention can be practiced. These embodiments are also referred to herein as “examples.” All publications, patents, and patent documents referred to in this document are incorporated by reference herein in their entirety, as though individually incorporated by reference. In the event of inconsistent usages between this document and those documents so incorporated by reference, the usage in the incorporated reference(s) should be considered supplementary to that of this document; for irreconcilable inconsistencies, the usage in this document controls.
In this document, the terms “a” or “an” are used, as is common in patent documents, to include one or more than one, independent of any other instances or usages of “at least one” or “one or more.” In this document, the term “or” is used to refer to a nonexclusive or, such that “A or B” includes “A but not B,” “B but not A,” and “A and B,” unless otherwise indicated. In the appended claims, the terms “including” and “in which” are used as the plain-English equivalents of the respective terms “comprising” and “wherein.” Also, in the following claims, the terms “including” and “comprising” are open-ended, that is, a system, device, article, or process that includes elements in addition to those listed after such a term in a claim are still deemed to fall within the scope of that claim. Moreover, in the following claims, the terms “first,” “second,” and “third,” etc. are used merely as labels, and are not intended to impose numerical requirements on their objects.
Method examples described herein can be machine-implemented or computer-implemented at least in part. Some examples can include a tangible computer-readable medium or machine-readable medium encoded with instructions operable to configure an electronic device to perform methods as described in the above examples. An implementation of such methods can include code, such as microcode, assembly language code, a higher-level language code, or the like. Such code can include computer readable instructions for performing various methods. The code may form portions of computer program products. Further, the code may be tangibly stored on one or more volatile or non-volatile computer-readable media during execution or at other times. These computer-readable media may include, but are not limited to, hard disks, removable magnetic disks, removable optical disks (e.g., compact disks and digital video disks), magnetic cassettes, memory cards or sticks, random access memories (RAMs), read only memories (ROMs), and the like.
The above description is intended to be illustrative, and not restrictive. For example, the above-described examples (or one or more aspects thereof) may be used in combination with each other. Other embodiments can be used, such as by one of ordinary skill in the art upon reviewing the above description. The Abstract is provided to comply with 37 C.F.R. § 1.72(b), to allow the reader to quickly ascertain the nature of the technical disclosure. It is submitted with the understanding that it will not be used to interpret or limit the scope or meaning of the claims. Also, in the above Detailed Description, various features may be grouped together to streamline the disclosure. This should not be interpreted as intending that an unclaimed disclosed feature is essential to any claim. Rather, inventive subject matter may lie in less than all features of a particular disclosed embodiment. Thus, the following claims are hereby incorporated into the Detailed Description, with each claim standing on its own as a separate embodiment. The scope of the invention should be determined with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled.
This application is a divisional of U.S. patent application Ser. No. 15/915,180, filed Mar. 8, 2018, which is a continuation of U.S. patent application Ser. No. 15/087,979, filed Mar. 31, 2016 (now abandoned), which is a continuation of U.S. patent application Ser. No. 12/655,325, filed Dec. 29, 2009 (now U.S. Pat. No. 9,655,523), which is a continuation under 35 U.S.C. 111(a) of PCT Patent Application PCT/US2008/008081, filed Jun. 27, 2008 (now expired), which claims the benefit of the following three U.S. provisional patent applications: Application 60/937,724, filed Jun. 29, 2007; Application 61/000,792, filed Oct. 29, 2007; and Application 61/130,904, filed Jun. 4, 2008. Each of the above-identified applications is incorporated herein by reference in its entirety.
This invention was made with government support under grant number NS053684 awarded by the National Institutes of Health (NIH). The Government has certain rights in this invention. Additional support was received from the Wallace H. Coulter Foundation.
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